Analysis

Geneyx Tests

  

 Geneyx Tests Offer your patients new encompassing 1000+ health categories and conditions, medication effects, and health traits.
Unmatched by any other report, they will gain knowledge allowing them to take a proactive approach to live a longer and healthier life.

Newmarket opportunities can be immediately addressed using our numerous off-the-shelf CLIA/CAP-clinically ready tests and reports with a click of a button, that is fully white-labeled for your organization. Maximize your existing genetic data by providing valuable, actionable findings to your customers with previously sequenced samples. Geneyx makes it easy to identify new opportunities for genetic tests, which allows you to generate more revenues with higher margins

Select from our comprehensive portfolio, including:

DNA UNLOCKED® Comprehensive Screening

Test Information Sheet

Whole Exome Sequencing (WES) and Microarray or

Whole Genome Sequencing (WGS)

 

Description:

With today’s technology we are entering an age of genomics, big data, and precision medicine. By sequencing vital regions of the genome or the entire genome of a person, preventive strategies or targeted treatment and management strategies can be applied to improve the health state of the test subject with implications for the family as well. The DNA UNLOCKED® Comprehensive Screening test is indicated for all individuals who would like to gain insights about their carrier status, predisposition status or affected status for a large number of conditions with a genetic basis, wellness insights, medication response and other health risks recommended for screening by the ACMG. With this knowledge the test subject and his or her healthcare providers and counselors could personalize their health and medical management plan by implementing lifestyle modifications or treatments to prevent or better manage these disorders and improve the test subject’s current health state.

 

Whole exome sequencing (WES) can be used to analyze most of the genes in an individual at one time to identify the mutation(s) that are causing a genetic disorder. This test is most appropriate for patients with undiagnosed conditions for which a genetic etiology is suspected and who have had a clinical genetics evaluation with negative test results for chromosome microarray and/or other targeted sequencing tests. WES targets the protein-coding regions of the genome, which represents approximately 20,000 genes and about 2% of the genome.  Individual exons of each gene are initially captured or separated from the rest of the genome and analyzed using massively parallel sequencing. The patient’s sequence is then compared to the reference genome sequence to identify variants that are different and are therefore, potentially causative in the patient’s condition. Ideally, this test is performed by sequencing the patient and both parents (trios) together to identify de novo variants, assign phase to inherited variants for autosomal recessive inheritance or to determine autosomal dominant or X-linked inheritance. However, depending upon the availability of the parents, other family members may also be utilized to maximize the chance of identifying causative variants in the patient.

 

Microarray allows for the genotyping of specific variations or polymorphisms associated with various conditions or traits in the genome of an individual. It is different from WES in that specific variants are targeted either within the protein-coding regions or in the non-coding regions of the genome.

 

Whole genome sequencing (WGS) allows for sequencing of the entire genome of an individual. It is different from WES in that there is not a targeting step included before the sequencing enabling more uniform sequence coverage throughout the genome and in

difficult to sequence regions of the genome. WGS analyzes the protein-coding regions of

the genome but may include regulatory regions or deep intronic regions and microRNAs and may detect cryptic chromosome rearrangements such as translocations and inversions. WGS is most appropriate for patients who have received a negative WES result when a genetic disease etiology is strongly suspected.

 

Test Method:

WES or WGS will be performed on the patient and their family members to target the exonic regions of their genomes. These regions will be sequenced using the Illumina NovaSeq 6000 with 100-150 bp paired-end reads. The DNA sequence will then be mapped to, and analyzed in comparison with, the published human genome build (UCSC hg19 reference sequence). The targeted coding exons and splice junctions of the known protein-coding RefSeq genes will be assessed for the average depth of coverage (minimum average coverage of 80X for WES and 15X-30X for WGS) and data quality threshold values. Sequence changes in the patient will be compared to the other provided family members. All reportable sequence variants will be confirmed by Sanger sequence analysis using a separate DNA preparation. Average quality thresholds may range from >90-95% of the targeted region, indicating a small portion of the target region may not be covered with sufficient depth or quality to confidently call variant positions. In addition to Next Generation Sequencing (NGS) for capturing the whole exome, microarray method using Illumina iScan technology, will be used to capture regions of the genome that are within and outside of the protein coding genes (i.e. intergenic). SNPs (Single Nucleotide Polymorphisms) or variants from the microarray may also be used in the analysis to generate parts of this report or for research purposes and for improving the report in the future. The sequencing, genotyping, alignment, and variant calling of the data will be performed at the Gene by Gene, Ltd. laboratory located in 1445 North Loop West, Suite 760 Houston, TX 77008. Analysis, interpretation and report will be performed by TOVANA HEALTH located at 945 McKinney St. Suite# 11977 Houston, TX 77002.

 

 

Limitations:

Absence of a causative variant(s) related to the reported phenotype by WES and microarray methods or WGS does not exclude a genetic basis of the patient’s condition. Some types of genetic abnormalities, such as copy number changes, trinucleotide repeat expansions, small insertion/deletions and X-linked recessive mutations which manifest in females due to skewed X-inactivation may not be detectable with the technologies utilized for this testing. This test does not analyze mitochondrial DNA sequence or epigenetic changes of the genome. It is possible that the genomic region where a disease-causing mutation exists in the proband was not captured or accurately mapped to the reference sequence using the current technologies and therefore was not detected. Additionally, it is possible that a particular genetic abnormality may not be recognized as the underlying cause of the genetic disorder due to incomplete scientific knowledge about the function of all genes in the human genome and the impact of variations in those genes. Variants in genes associated with the medical condition or thought to potentially be clinically relevant for the patient’s medical condition or family history will be reported. In addition, based on the consent process, the patient or their parents may have opted to receive clinically relevant incidental findings not related to the primary clinical phenotype in the patient, which would also be reported back to you (Table 2). This report has been evaluated and accredited by the College of American Pathologists (CAP) for the clinical whole exome, whole genome and clinical microarray sections of the report.

 

 

 

 

 

 

 

 

Indications:

 

Indications for this test and analysis service is broad and depends on the needs of the patient. Generally, this test is considered a screening test, but can be used as a diagnostic aid to support or rule out a diagnosis if there is involvement of a healthcare provider and clinical judgement or confirmatory testing is performed. Some of the indications for using this test include:

 

  • General health screening (i.e. Proactive patient directed/self-exploratory screening for informational or preventive reasons)
  • Pre-conception carrier screening (for reproductive planning prior to pregnancy)
  • Cancer predispositions/risks (especially if strong family history of cancer)
  • Screening based on signs/symptoms and medical history or to help confirm a diagnosis
  • Screening based on family history of a certain disease/condition
  • Carrier or affected status for diseases recommended for screening by ACMGG (American College of Medical Genetics and Genomics)
  • Carrier or affected status for other rare or severe disease (both early-onset or late-onset)
  • Predisposition/risk for certain chronic diseases

 

 

 

 

 

 

Table 1 – List of categories included in the test (>3000 total genes screened/analyzed)

 

Categories Included

Cancer Predispositions

Cardiovascular Conditions

Dental Conditions

Dermatological (Skin) Conditions

Developmental Malformations

Endocrinological Conditions

Gastrointestinal Conditions

Hematological (Blood Cell) Conditions

Immunological Conditions & Infectious Disease Predisposition

Hepatological (Liver) Conditions

Metabolic & Newborn Screening Conditions

Mitochondrial (Nuclear) Conditions

Musculoskeletal Conditions

Neurological Conditions

Ophthalmological (Eye) Conditions

Otological (Ear) Conditions

Pulmonary (Lung) Conditions

Renal (Kidney) Conditions

Reproductive (Fertility) Conditions

Preconception Carrier Screening

American College of Medical Genetics (ACMG) Recommended Conditions

Conditions Based on Reported Medical & Family Health History

Pharmacogenomics (Drug Metabolism & Reactions)

Fitness Traits

Nutrition Traits

Additional Traits

Ancestry (optional)

 

 

Table 2 – List of 59 conditions recommended for testing by the American College of Medical Genetics and Genomics (ACMGG)

 

Disease name and MIM Number Gene and MIM Number

Adenomatous polyposis coli (MIM 175100) APC (MIM 611731)

Aortic aneurysm, familial thoracic 4 (MIM 132900) MYH11 (MIM 160745)

Aortic aneurysm, familial thoracic 6 (MIM 611788) ACTA2 (MIM 102620)

Arrhythmogenic right ventricular cardiomyopathy, type 5 (MIM 604400) TMEM43 (MIM 612048)

Arrhythmogenic right ventricular cardiomyopathy, type 8 (MIM 607450) DSP (MIM 125647)

Arrhythmogenic right ventricular cardiomyopathy, type 9 (MIM 609040) PKP2 (MIM 602861)

Arrhythmogenic right ventricular cardiomyopathy, type 10 (MIM 610193) DSG2 (MIM 125671)

Arrhythmogenic right ventricular cardiomyopathy, type 11 (MIM 610476) DSC2 (MIM 125645)

Breast-ovarian cancer, familial 1 (MIM 604370) BRCA1 (MIM 113705)

Breast-ovarian cancer, familial 2 (MIM 612555) BRCA2 (MIM 600185)

Brugada syndrome 1 (MIM 601144) SCN5A (MIM 600163)

Catecholaminergic polymorphic ventricular tachycardia (MIM 604772) RYR2 (MIM 180902)

Dilated cardiomyopathy 1A (MIM 115200) LMNA (MIM 150330)

MYBPC3 (MIM 600958)

Ehlers-Danlos syndrome, type 4 (MIM 130050) COL3A1 (MIM 120180)

Fabry’s disease (MIM 301500) GLA (MIM 300644)

Familial hypercholesterolemia (MIM 143890) APOB (MIM 107730)

LDLR (MIM 606945)

Familial hypertrophic cardiomyopathy 1 (MIM 192600) MYH7 (MIM 160760)

Familial hypertrophic cardiomyopathy 3 (MIM 115196) TPM1 (MIM 191010)

Familial hypertrophic cardiomyopathy 4 (MIM 115197) MYBPC3 (MIM 600958)

Familial hypertrophic cardiomyopathy 6 (MIM 600858) PRKAG2 (MIM 602743)

Familial hypertrophic cardiomyopathy 7 (MIM 613690) TNNI3 (MIM 191044)

Familial hypertrophic cardiomyopathy 8 (MIM 608751) MYL3 (MIM 160790)

Familial hypertrophic cardiomyopathy 10 (MIM 608758) MYL2 (MIM 160781)

Familial hypertrophic cardiomyopathy 11 (MIM 612098) ACTC1 (MIM 102540)

Familial medullary thyroid carcinoma (MIM 155240) RET (MIM 164761)

Hypercholesterolemia, autosomal dominant, 3 (MIM 603776) PCSK9 (MIM 607786)

Juvenile polyposis (MIM 174900) BMPR1A (MIM 601299)

SMAD4 (MIM 600993)

Left ventricular noncompaction 6 (MIM 601494) TNNT2 (MIM 191045)

Li-Fraumeni syndrome 1 (MIM 151623) TP53 (MIM 191170)

Loeys-Dietz syndrome type 1A (MIM 609192) TGFBR1 (MIM 190181)

Loeys-Dietz syndrome type 1B (MIM 610168) TGFBR2 (MIM 190182)

Loeys-Dietz syndrome type 2A (MIM 608967) TGFBR1 (MIM 190181)

Loeys-Dietz syndrome type 2B (MIM 610380) TGFBR2 (MIM 190182)

Loeys-Dietz syndrome type 3 (MIM 613795) SMAD3 (MIM 603109)

Long QT syndrome 1 (MIM 192500) KCNQ1 (MIM 607542)

Long QT syndrome 2 (MIM 613688) KCNH2 (MIM 152427)

Long QT syndrome 3 (MIM 603830) SCN5A (MIM 600163)

Lynch syndrome (MIM 120435) MLH1 (MIM 120436)

MSH2 (MIM 609309)

MSH6 (MIM 600678)

PMS2 (MIM 600259)

Malignant hyperthermia (MIM 145600) RYR1 (MIM 180901)

CACNA1S (MIM 114208)

Marfan syndrome (MIM 154700) FBN1 (MIM 134797)

TGFBR1 (MIM 190181)

Multiple endocrine neoplasia, type 1 (MIM 131100) MEN1 (MIM 613733)

Multiple endocrine neoplasia, type 2a (MIM 171400) RET (MIM 164761)

Multiple endocrine neoplasia, type 2b (MIM 162300) RET (MIM 164761)

MYH-associated polyposis (MIM 608456) MUTYH (MIM 604933)

Neurofibromatosis, type 2 (MIM 101000) NF2 (MIM 607379)

Ornithine transcarbamylase deficiency (MIM 311250) OTC (MIM 300461)

Paragangliomas 1 (MIM 168000) SDHD (MIM 602690)

Paragangliomas 2 (MIM 601650) SDHAF2 (MIM 613019)

Paragangliomas 3 (MIM 605373) SDHC (MIM 602413)

Paragangliomas 4 (MIM 115310) SDHB (MIM 185470)

Peutz-Jeghers syndrome (MIM 175200) STK11 (MIM 602216)

Pilomatrixoma (MIM 132600) MUTYH (MIM 604933)

PTEN hamartoma tumor syndrome (MIM 153480) PTEN (MIM 601728)

Retinoblastoma (MIM 180200) RB1 (MIM 614041)

Tuberous sclerosis 1 (MIM 191100) TSC1 (MIM 605284)

Tuberous sclerosis 2 (MIM 613254) TSC2 (MIM 191092)

Von Hippel-Lindau syndrome (MIM 193300) VHL (MIM 608537)

Wilms tumor (MIM 194070) WT1 (MIM 607102)

Wilson disease (MIM 277900) ATP7B (MIM 606882)

 

 

Ordering:

CATALOG NUMBER: 1100101, 1197201, 1100001

TURNAROUND TIME: 4-8 weeks

PREFERRED SPECIMEN: Buccal swab

ALTERNATIVE SPECIMEN:  

Extracted DNA: 20ul of 50ng/ul, OD260/OD280 ~ 1.8, include details of extraction method with samples

 

Blood: 3-5cc drawn in EDTA (purple-top) tube

———————————————————————-

Carrier Screening

Test Information Sheet

Whole Exome Sequencing (WES), MLPA, PCR Amplification

 

Description:

Pre-conception carrier screening has been a widely adopted method over the years to determine a couple’s risk of having an affected child of certain autosomal recessive and X-linked disorders. Improvements in technology and scientific knowledge has allowed for more expanded carrier screening with greater detection rates of mutations for various populations. The Carrier Screening test analyzes and interprets 356 genes to give the test subject insights about their carrier status for diseases that are severe and/or debilitating (Table 1). With this knowledge he or she and the healthcare providers involved in their care could personalize their reproductive management plan to better prepare for and potentially prevent diseases in their future children.

 

Whole exome sequencing (WES) can be used to analyze most of the genes in an individual at one time to identify the mutation(s) that are causing a genetic disorder or for health screening purposes. This test is most appropriate for individuals who wish to have children to determine their carrier status of disease and determine their pregnancy risk of having an affected child. WES targets the protein-coding regions of the genome, which represents approximately 20,000 genes and about 2% of the genome. Individual exons of each gene are initially captured or separated from the rest of the genome and analyzed using massively parallel sequencing. The patient’s sequence is then compared to the reference genome sequence to identify variants that are different to determine their carrier status of potentially pathogenic, or likely pathogenic variants. Ideally, this test is performed by sequencing the patient and his or her partner together to accurately identify the  inherited variants for diseases of autosomal recessive inheritance or X-linked inheritance in females and thus their pregnancy risk of having an affected child.

 

*Fragile X CGG Repeat Analysis of the FMR1 gene is performed by PCR amplification using Asuragen, Inc. AmplideX® FMR1 PCR reagents followed by capillary electrophoresis for allele sizing is performed. Analysis of FMR1 is performed in association with sequencing of the coding regions.

 

*Spinal Muscular Atrophy (SMA) testing analyzes the copy numbers of the SMN1 and SMN2 genes using the Multiplex Ligation-Dependent Probe Amplification (MLPA) method. The individual dosage of exons 7 and 8 as well as the combined dosage of exons 1, 4, 6 and 8 of SMN1 and SMN2 are assessed. Copy number gains and losses can be detected with this assay. Depending on ethnicity, 6 – 29 % of carriers will not be identified by dosage sensitive methods as this testing cannot detect individuals with two copies (duplication) of the SMN1 gene on one chromosome and loss of SMN1 (deletion) on the other chromosome (silent 2+0 carrier) or individuals that carry an intragenic mutation in SMN1. Please also note that 2% of  individuals with SMA have an SMN1 mutation that occurred de novo. Typically, in these cases, only one parent is an SMA carrier. Analysis of SMN1 is performed in association with sequencing of the coding regions.

 

*Duchenne Muscular Dystrophy (DMD) testing is done by Multiplex Ligation-Dependent Probe Amplification (MLPA) to analyze the copy numbers of all DMD exons. Potentially pathogenic single exon deletions and duplications are confirmed by a second method. Analysis of DMD is performed in association with sequencing of the coding regions.

 

*Please note: these test methods are optional and can be included as part of the Carrier Screening as an add-on at an additional cost.

 

Test Method:

WES will be performed on the patient and their family members to target the exonic regions of their genomes. These regions will be sequenced using the Illumina NovaSeq 6000 with 100-150 bp paired-end reads. The DNA sequence will then be mapped to, and analyzed in comparison with, the published human genome build (UCSC hg19 reference sequence). The targeted coding exons and splice junctions of the known protein-coding RefSeq genes will be assessed for the average depth of coverage (minimum average coverage of 80X for WES and 15X-30X for WGS) and data quality threshold values. Sequence changes in the patient will be compared to the other provided family members. All reportable sequence variants will be confirmed by Sanger sequence analysis using a separate DNA preparation. Average quality thresholds may range from >90-95% of the targeted region, indicating a small portion of the target region may not be covered with sufficient depth or quality to confidently call variant positions. In addition to Next Generation Sequencing (NGS) for capturing the whole exome, Multiplex ligation-dependent probe amplification (MLPA) is done using MLPA® probe sets and reagents from MRC-Holland, Netherlands to examine SMA (kit #P460) and DMD (kit# P034-100 and P035-10). Analytical sensitivity and specificity of the MLPA method are both 99%. To examine carrier status of Fragile X syndrome, CGG repeat size was assessed using AmplideX FMR1 (kit#49402 Asuragen, Austin, TX) according to manufacturer instructions. All results are reported in reference to Human Genome 19, Human Build 37. The sequencing, alignment, and variant calling of the NGS data, as well as the Fragile X, SMA and DMD analysis, will be performed at the Gene by Gene, Ltd. laboratory located in 1445 North Loop West, Suite 760 Houston, TX 77008. Analysis, interpretation, and report will be performed by TOVANA HEALTH located at 945 McKinney St. Suite# 11977 Houston, TX 77002.

 

Limitations:

Variants in genes associated with severe or debilitating conditions that merit to be screened for in pre-conception testing are included in this report (Table 1). Absence of a causative variant(s) by WES does not exclude a genetic basis of the individual’s condition. Some types of genetic abnormalities, such as copy number changes, trinucleotide repeat expansions, small insertion/deletions and X-linked recessive mutations which manifest in females due to skewed X-inactivation may not be detectable with the technologies utilized for this testing. This test does not analyze mitochondrial DNA sequence or epigenetic changes of the genome. It is possible that the genomic region where a disease-causing mutation exists in the proband was not captured or accurately mapped to the reference sequence using the current technologies and therefore was not detected. Additionally, it is possible that a particular genetic abnormality may not be recognized a cause of a genetic disorder screened for due to incomplete scientific knowledge about the function of all genes in the human genome and the impact of variations in those genes. For diseases assessed using the MLPA testing method, false positive or negative results may occur due to rare sequence variants in target regions detected by MLPA probes. This report has been evaluated and accredited by the College of American Pathologists (CAP).

 

 

 

 

 

 

 

 

Table 1 – List of 356 genes screened/analyzed and associated conditions

 

List of Genes

OPA3, PHGDH, MTTP, CNGA3, ACADS, EOGT, CYP11B1, TBX19, ABCD1, SAMHD1, TYR, COL4A5, ASL, SLC35A3, WISP3, ASNS, AGA, ATM, AIRE, BBS1, BBS10, TRIM32, BBS2, BEST1, ARL6, BBS4, CLCNKB, BSND, HBB, BTD, BLM, ZNF469, ASPA, CPS1, SDHA, SLC25A20, CPT1A, CPT2, SNAP29, CYP27A1, VPS13A, CYBA, NCF1, CYBB, ERCC8, CFH, PLAA, CYP11A1, MPL, NGLY1, PMM2, DOLK, FRMD4A, CFTR, CTNS, CDH23, STRC, GJB2, GJB6, OTOA, MYO15A, PJVK, TMC1, SYNE4, LOXHD1, TMPRSS3, DHCR24, AQP2, BMPER, DLD, DMD, ELP1, CDAN1, SEC23B, TERT, RTEL1, ADAMTS2, NR2E3, LAMA3, LAMB3, LAMC2, ITGB4, PRICKLE1, LMAN1, F7, F11, LDLR, MEFV, FANCA, FANCC, SLC2A2, RDH5, GALT, GBA, ITGA2B, ITGB3, CYP1B1, ETFDH, GCDH, AMT, GLDC, G6PC, SLC37A4, GAA, AGL, GBE1, PYGM, PFKM, NBEAL2, GH1, GHRHR, FTO, CTSC, HBA2, CD59, TECPR2, HPS3, HPS6, HMGCL, MTHFR, ABCC8, AGXT, HOGA1, SARS2, CYP11B2, TRPM6, TBCE, ALPL, SLC34A3, TSHR, GNE, PLA2G6, SCN9A, NTRK1, IVD, TMEM216, ROGDI, GALC, GHR, GUCY2D, RPE65, AIPL1, LCA5, SURF1, ERBB3, PIP5K1C, MYBPC1, AIMP1, HSPD1, TRMU, LMNA, BCKDHA, BCKDHB, DBT, GUCY2C, ACADM, MLC1, AMN, CC2D1A, ARSA, CEP152, MED17, RYR1, NDUFA11, NDUFAF5, NDUFS4, NDUFS6, UQCRQ, TK2, DGUOK, SUCLA2, PUS1, MOCS1, GNPTG, MCOLN1, SGSH, IDUA, PIGN, SUMF1, DYSF, SGCG, FKTN, FKRP, RAPSN, TYMP, NEB, INVS, NPHS1, NPHS2, IGHMBP2, G6PC3, SMPD1, NPC1, RAG2, TCIRG1, SNX10, COL11A2, SLC26A4, PEX1, PEX6, PEX2, PAH, PKHD1, ADGRG1, VRK1, SEPSECS, VPS53, RSPH9, DNAL1, DNAH5, DNAI1, DNAI2, PEPD, PCCA, MYH2, BCHE, CTSK, PNPO, TULP1, EYS, CERKL, FAM161A, PRCD, PDE6G, DHDDS, C8orf37, CRB1, VDR, HEXB, ADA, RAG1, POC1A, SLC17A5, DHCR7, VPS37A, DDR2, ABCA4, NUP62, LIFR, ABCA3, HEXA, SLC19A2, GALNT3, SAMD9, FAH, HPD, MYO7A, USH1C, PCDH15, USH2A, CLRN1, CASQ2, ACADVL, ATP7B, WAS, LIPA, DCAF17, XPC, ERCC5, POLH, FMR1, SMN1, GDF5, NBN, B3GALT6, WNT7A, EZH2, SLC26A3, CYP21A2, TRIM36, INPP5E, LYST, ASS1, NKX2-5, NKX2-6, GATA6, GDF1, TBX1, FCGR2A, TGFB1, SLC3A1, PLOD1, FBP1, GLB1, CBS, CCDC88C, HPSE2, GCSH, ALDH4A1, TTC7A, MGP, STAT5B, PNPLA6, CLDN16, SIL1, MKS1, MMP13, TUBGCP6, OCLN, BUB1B, CA2, LRP5, AMHR2, AMH, UROS, CYP27B1, CHRNG, LPIN1, ROR2, CDSN, GM2A, SPART, TAT, XDH, BTK, GCM2, PQBP1, MRSD, AR, STAR, ECM1, BBS5, STAT5B, PCNT, ALS2, B4GALNT1, FECH, PDHB, PPT1, CTH, SLC7A9, FUCA1, ETFA, ETFB, PCCB, ANTXR2, AASS, PRODH, MAN2B1, GNPTAB, ARSB, NEU1, MMADHC, IDS, FMO3, ETHE1, MLYCD, HADHA, CCDC28B, MCPH1, ATP6V0A2, ATP6V1B1, RARS2, OAT, VSX2, TOR1A

 

 

Conditions Include

17-beta-hydroxysteroid dehydrogenase deficiency, type III

3-beta-hydroxysteroid dehydrogenase deficiency, type II

3-hydroxy-3-methylglutaryl-CoA lyase deficiency

3-Methylcrotonyl-CoA carboxylase 1 deficiency

3-Methylcrotonyl-CoA carboxylase 2 deficiency

3-phosphoglycerate dehydrogenase deficiency

6-pyruvoyl-tetrahydropterin synthase (PTPS) deficiency

Abetalipoproteinemia

Achalasia-addisonianism-alacrima syndrome

Achromatopsia

Achromatopsia, CNGA3-related

Achromatopsia, CNGB3-related

Acrodermatitis enteropathica

Acute infantile liver failure

Acyl-CoA dehydrogenase 9 deficiency

Acyl-CoA oxidase 1 deficiency

Adrenoleukodystrophy

Adrenoleukodystrophy, X-linked

Aicardi-Goutières syndrome

Aicardi-Goutières syndrome, RNASEH2C-related

Aicardi-Goutières syndrome, SAMHD1-related

Aicardi-Goutières syndrome, TREX1-related

Alkaptonuria

Alpha-1 antitrypsin deficiency (AAT deficiency)

Alpha-Mannosidosis

Alpha-thalassemia

Alport syndrome, COL4A4-related

Alport syndrome, autosomal recessive

Alport syndrome, X-linked

Alstrom syndrome

Amish infantile epilepsy syndrome

Andermann syndrome/Hereditary motor and sensory neuropathy with agenesis of the corpus callosum

Argininosuccinic Aciduria, also known as Argininosuccinic acid lyase deficiency

Aromatase deficiency

Arthrogryposis, mental retardation and seizures

Arts syndrome

Asparagine synthetase deficiency

Aspartylglycosaminuria

Ataxia neuropathy spectrum

Ataxia with vitamin E deficiency

Ataxia-Telangiectasia

Ataxia-telangiectasia-like disorder

Autism spectrum, disorder, epilepsy and arthrogryposis

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED)

Autoimmune polyglandular syndrome, type 1

Bardet-Biedl syndrome

Bardet-Biedl syndrome, BBS1-related

Bardet-Biedl syndrome, BBS12-related

Bare lymphocyte syndrome, type II

Bartter syndrome, type 4

Bartter syndrome, type 4A

Becker muscular dystrophy (single nucleotide variants and small deletions/duplications)

Bernard-Soulier syndrome (BSS), type A1

Bernard-Soulier syndrome (BSS), type C

Beta hemoglobinopathy, beta thalassemia

Beta hemoglobinopathy, sickle cell disease

Beta-ketothiolase deficiency

Bilateral frontoparietal polymicrogyria

Biotinidase deficiency

Bloom syndrome

Canavan disease

Carbamoyl phosphate synthetase I deficiency

Carnitine deficiency

Carnitine palmitoyltransferase I deficiency

Carnitine palmitoyltransferase IA deficiency

Carnitine palmitoyltransferase II deficiency

Carpenter syndrome

Cartilage-hair hypoplasia

Cerebrotendinous xanthomatosis

Charcot-Marie-Tooth disease, GJB1-related

Charcot-Marie-Tooth disease, PRPS1-related

Charcot-Marie-Tooth disease, type 4D

Chediak-Higashi syndrome

Cholesteryl ester storage disease

Choreoacanthocytosis

Choroideremia

Chronic granulomatous disease, cytochrome b-negative

Chronic granulomatous disease, X-Linked

Ciliary dyskinesia, primary, with or without situs inversus

Citrin deficiency

Citrullinemia, type 1

Cobalamin C disease (Methylmalonic aciduria and homocystinuria, type cblC)

Cohen syndrome

Combined malonic and methylmalonic aciduria

Combined oxidative phosphorylation deficiency 3 (COXPD3)

Combined oxidative phosphorylation deficiency 4

Complex I mitochondrial respiratory chain deficiency

Congenital adrenal hyperplasia

Congenital adrenal hyperplasia, 17-a-hydroxylase deficiency

Congenital adrenal hyperplasia, 21-hydroxylase deficiency

Congenital amegakaryocytic thrombocytopenia

Congenital disorder of glycosylation, type 1A

Congenital disorder of glycosylation, type 1A, PMM2-related

Congenital disorder of glycosylation, type 1B

Congenital disorder of glycosylation, type 1C

Congenital Finnish nephrosis (Nephrotic syndrome, NPHS1-related)

Congenital insensitivity to pain with anhidrosis (CIPA)

Congenital lipoid adrenal hyperplasia

Congenital myasthenic syndrome, CHRNE-associated

Congenital myasthenic syndrome, RAPSN-associated

Congenital neutropenia, autosomal recessive

Corneal dystrophy and perceptive deafness syndrome

Corticosterone methyloxidase deficiency

Costeff disease optic atrophy (3-Methyl glutaconic aciduria, type 3)

CRB1-associated retinal dystrophies

Creatine transporter defect, SLC6A8-related

Creatine transporter defect (Cerebral creatine deficiency syndrome 1)

Crigler-Najjar syndrome

Cystic fibrosis

Cystinosis

D-Bifunctional protein deficiency

Deafness, autosomal recessive 77

Desbuquois dysplasia, type 1

Diabetes, type 1, juvenile

Dihydrolipoamide dehydrogenase deficiency (Maple syrup urine disease, type III)

Du Pan syndrome

Duchenne muscular dystrophy (single nucleotide variants and small deletions/duplications)

Dyskeratosis congenita, autosomal recessive

Dyskeratosis congenita, X-linked

Dystrophic epidermolysis bullosa, autosomal recessive

Early onset myopathy with fatal cardiomyopathy

Ehlers-Danlos syndrome dermatosparaxis type (formerly VIIC)

Ellis-van Creveld syndrome

Emery-Dreifuss muscular dystrophy

Emery-Dreifuss myopathy, X-Linked

Enhanced S-Cone syndrome (Goldmann-Favre syndrome)

Ethylmalonic encephalopathy

Fabry disease

Factor IX deficiency

Factor V Leiden thrombophilia

Factor XI deficiency

Familial dysautonomia

Familial hypercholesterolemia, LDLR-associated

Familial hypercholesterolemia, LDLRAP1-associated

Familial hyperinsulinism, ABCC8-related

Familial hyperinsulinism, KCNJ11-related

Familial Mediterranean Fever (FMF)

Familial neurohypophyseal diabetes insipidus (FNDI), autosomal recessive

Fanconi anemia, type A

Fanconi anemia, type C

Fanconi anemia, type G

Fetal akinesia deformation sequence, DOK7-related

Fragile X syndrome (single nucleotide variants and small deletions/duplications)

Fumarase deficiency

Galactokinase deficiency/Galactosemia, type II

Galactosemia

Galactosemia, GALT-related

Gaucher disease

Gaucher disease, atypical due to Saposin C deficiency

Geroderma osteodysplastica

Gitelman syndrome

Glucose-6-phosphate dehydrogenase deficiency (G6PD)

Glutaric acidemia, type I (Glutaryl-CoA dehydrogenase deficiency)

Glutaric acidemia, type IIa

Glutaric acidemia, type IIb

Glutaric acidemia, type IIc

Glutathione synthetase deficiency

Glycine encephalopathy

Glycine encephalopathy, AMT-related

Glycine encephalopathy, GLDC-related

Glycogen storage disease, type Ia

Glycogen storage disease, type Ib

Glycogen storage disease, type II (Pompe disease)

Glycogen storage disease, type III or Cori disease (includes type IIIa and type IIIb)

Glycogen storage disease, type V (McArdle’s disease)

Glycogen storage disease, type IV

Glycogen storage disease, type VII

GM1 gangliosidosis

GRACILE Syndrome

Guanidinoacetate methyltransferase deficiency

Hb beta chain-related hemoglobinopathy

Hemochromatosis, type 2A, HFE2-related

Hemoglobinopathy, Hb C

Hemoglobinopathy, Hb D

Hemoglobinopathy, Hb E

Hemoglobinopathy, Hb O

Hemophilia A

Hemophilia B

Hepatocerebral mitochondrial DNA depletion syndrome, MPV17-related

Hereditary fructose intolerance

Hereditary spastic paraparesis, type 49 (SPG49)

Herlitz junctional epidermolysis bullosa, Herlitz type, non-Herlitz type

Herlitz junctional epidermolysis bullosa, LAMB3-related

Herlitz junctional epidermolysis bullosa, LAMC2-related

Hermansky-Pudlak syndrome

Hermansky-Pudlak syndrome, HPS3-related

Hermansky-Pudlak syndrome, type III

HFE-associated hereditary hemochromatosis

Holocarboxylase synthetase deficiency

Homocystinuria

Homocystinuria caused by cystathionine beta-synthase deficiency

Homocystinuria, CBS-related

Homocystinuria due to deficiency of N (5,10)-methylenetetrahydrofolate reductase activity

Hydrolethalus syndrome

Hyperinsulinemic hypoglycemia

Hyperoxaluria, type 2 (Primary hyperoxaluria, type 2)

Hyperphosphatemic familial tumoral calcinosis

Hypogonadotropic hypogonadism

Hypohidrotic ectodermal dysplasia

Hypohidrotic ectodermal dysplasia, X-Linked

Hypophosphatasia, autosomal recessive

Inclusion body myopathy 2 (GNE-Myopathy)

Infantile cerebral and cerebellar atrophy

Infantile Refsum disease

Isovaleric acidemia

Joubert syndrome 2

Juvenile retinoschisis, X-linked

Krabbe disease

Krabbe disease, atypical due to Saposin A deficiency

Lamellar ichthyosis, type 1

Leber congenital amaurosis (LCA)

Leber congenital amaurosis, LCA5-related

Leber congenital amaurosis, RDH12-related

Leber congenital amaurosis 2

Leber congenital amaurosis 10, CEP290-related

Leigh Syndrome, French-Canadian type

Lethal arthrogryposis with anterior horn cell disease

Lethal congenital contracture syndrome 1 (Multiple contracture syndrome, Finnish type)

Leukoencephalopathy with vanishing white matter

Limb-girdle muscular dystrophy, type 2A

Limb-girdle muscular dystrophy, type 2B

Limb-girdle muscular dystrophy, type 2C

Limb-girdle muscular dystrophy, type 2D

Limb-girdle muscular dystrophy, type 2E

Limb-girdle muscular dystrophy, type 2I

Lipoid adrenal hyperplasia

Lipoprotein lipase deficiency

Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency

Luteinizing hormone resistance

Lysinuric protein intolerance

Maple syrup urine disease, type 1A

Maple syrup urine disease, type 1B

Meckel-Gruber syndrome

Medium-chain acyl-CoA dehydrogenase deficiency (MCAD)

MEDNIK syndrome

Megalencephalic leukoencephalopathy with subcortical cysts

Menkes syndrome

Metachromatic leukodystrophy

Metachromatic leukodystrophy due to Saposin B deficiency

Methylmalonic acidemia, MMAA-related

Methylmalonic acidemia, MMAB-related

Methylmalonic aciduria

Methylmalonic aciduria and homocystinuria, cblD type

Methylmalonic aciduria, cblA type

Methylmalonic aciduria, cblB type

Methylmalonic aciduria, mut (0) type

Methylmalonic aciduria, MUT-related

Microphthalmia/anophthalmia

Mitochondrial complex I deficiency

Mitochondrial complex III deficiency

Mitochondrial complex IV deficiency

Mitochondrial myopathy and sideroblastic anemia (MLAS1)

Mitochondrial neurogastrointestinal encephalopathy (MNGIE)

Motor neuropathy, distal hereditary

MTHFR deficiency

Mucolipidosis II alpha/beta

Mucolipidosis III alpha/beta

Mucolipidosis III gamma

Mucolipidosis IV

Mucopolysaccharidosis, type I (Hurler syndrome)

Mucopolysaccharidosis, type II (Hunter syndrome)

Mucopolysaccharidosis, type IIIA (Sanfilippo A)

Mucopolysaccharidosis, type IIIB (Sanfilippo B)

Mucopolysaccharidosis, type IIIC (Sanfilippo C)

Mucopolysaccharidosis, type IIID

Mucopolysaccharidosis, type IVB (Morquio)

Mucopolysaccharidosis, type VI (Maroteaux-Lamy)

Mucopolysaccharidosis, type IX

Mulibrey nanism

Multiple sulfatase deficiency

Muscle-eye-brain disease

Muscle-Eye-Brain Disease, POMGNT1-related/Muscular dystrophy-dystroglycanopathy (limb- girdle), type C3

Myotubular myopathy, MTM1-related

Myotubular myopathy, X-Linked

N-acetylglutamate synthase deficiency

Navajo neurohepatopathy (NNH)

Nemaline myopathy

Nemaline myopathy II

Nemaline myopathy, NEB-related

Nephrotic syndrome, type I

Neuronal ceroid lipofuscinosis, CLN5-related (including Finnish variant)

Neuronal ceroid lipofuscinosis, PPT1-related

Neuronal ceroid lipofuscinosis, TPP1-related

Neuronal ceroid-lipofuscinosis, CLN6-related

Neuronal ceroid-lipofuscinosis, CLN8-related (Northern epilepsy variant)

Neuronal ceroid-lipofuscinosis, MFSD8-related

Neuronal ceroid-lipofuscinosis, CLN3-related (Batten disease)

Niemann-Pick disease, type A

Niemann-Pick disease, type B

Niemann-Pick disease, type C

Niemann-Pick disease, type C, NPC1-related

Niemann-Pick disease, type C, NPC2-related

Niemann-Pick disease, type C1/type D

Niemann-Pick disease, type C2

Niemann-Pick disease, SMPD1-associated

Nijmegen Breakage syndrome

Non-syndromic deafness

Nonsyndromic hearing loss, GJB2-related

Occipital horn syndrome

Odonto-onycho-dermal dysplasia

Omenn syndrome (Reticuloendotheliosis with eosinophilia)

Ornithine aminotransferase deficiency (Gyrate atrophy of choroid and retina with or without ornithinemia)

Ornithine transcarbamylase deficiency

Ornithine translocase deficiency (Hyperornithinemia-hyperammonemia-homocitrullinemia syndrome or HHH syndrome)

Osteopetrosis, infantile malignant/Osteopetrosis, autosomal recessive

Osteoporosis and hyperlipidaemia

Pendred syndrome

Peroxisome biogenesis disorders

Phenylalanine hydroxylase deficiency, includes phenylketonuria

Phenylketonuria

Pituitary hormone deficiency

Polycystic kidney disease, autosomal recessive

Pontocerebellar hypoplasia

Pontocerebellar hypoplasia, type 1A

Primary ciliary dyskinesia, DNAH5-associated

Primary ciliary dyskinesia, DNAI1-associated

Primary congenital glaucoma

Primary hyperoxaluria, type 1

Primary hyperoxaluria, type 3

Progressive cerebello-cerebral atrophy

Progressive familial intrahepatic cholestasis, type 2

Prolidase deficiency

PROP1-related combined pituitary hormone deficiency

PROP1-related combined pituitary hormone deficiency, 3

Propionic acidemia, alpha subunit

Propionic acidemia, beta subunit

Propionic acidemia, PCCA-related

Propionic acidemia, PCCB-related

Prothrombin thrombophilia

PRPS1-related Charcot-Marie-Tooth disease with deafness, X-Linked

Pseudocholinesterase deficiency

Pseudoxanthoma elasticum

Pycnodysostosis

Pyruvate dehydrogenase deficiency, autosomal recessive

Pyruvate dehydrogenase deficiency, X-Linked

Renal tubular acidosis and deafness

Retinal degeneration in ciliopathies, association with Joubert syndrome

Retinitis pigmentosa 20

Retinitis pigmentosa 25

Retinitis pigmentosa 26

Retinitis pigmentosa 28

Retinitis pigmentosa 59

Retinitis pigmentosa, modifier of

Rhizomelic chondrodysplasia punctata

Rhizomelic chondrodysplasia punctata, type 3 Alkyl-DHAP synthase deficiency

Riboflavin-responsive complex I deficiency

Roberts syndrome

Salla disease

Sandhoff disease

Schimke immuno osseous dysplasia

Schopf-Schulz-Passarge syndrome

Segawa syndrome

Severe combined immunodeficiency (SCID), autosomal recessive due to adenosine deaminase deficiency

Severe combined immunodeficiency, Athabaskan-type (SCIDA)

Severe combined immunodeficiency, RAG1-related

Severe combined immunodeficiency, X-linked

Short stature, combined pituitary hormone deficiency and suprasellar mass

Short-chain acyl-CoA dehydrogenase deficiency (SCAD)

Shwachman-Diamond syndrome

Sjögren-Larsson syndrome

Smith-Lemli-Opitz syndrome

Spastic ataxia of Charlevoix-Saguenay, autosomal recessive

Spinal muscular atrophy (single nucleotide variants and small deletions/duplications)

Spondylothoracic dysostosis (STD)

Steal syndrome

Steroid-resistant nephrotic syndrome

Stuve-Wiedemann syndrome

Sulfate transporter-related osteochondrodysplasia (includes Achondrogenesis type 1B, Atelosteogenesis type 2, Diastrophic dysplasia, and Recessive multiple epiphyseal dysplasia)

Tay-Sachs disease (hexosaminidase A deficiency)

Tumoral calcinosis, normophosphatemic

Tyrosinemia, type I

Usher syndrome, type 1B

Usher syndrome, type 1C

Usher syndrome, type 1D

Usher syndrome type 1F

Usher syndrome, type 2A

Usher syndrome, type 3

Very-long chain acyl-CoA dehydrogenase deficiency (VLCAD)

Vitamin D-dependent rickets, type I

Walker-Warburg syndrome

Walker-Warburg syndrome, FKTN-related

Weyers acrofacial dysostosis

Wilson Disease

Wolman disease

Zellweger syndrome spectrum, PEX1-related

Zellweger syndrome spectrum, PEX6-related

Zellweger spectrum disorders, PEX10-related

 

 

Ordering:

CATALOG NUMBER:

1100104, 1197204, 1100004

TURNAROUND TIME:

2-5 weeks

PREFERRED SPECIMEN:

Buccal swab

ALTERNATIVE SPECIMEN:

 

Extracted DNA: 20ul of 50ng/ul, OD260/OD280 ~ 1.8, include details of extraction method with samples

 

Blood: 3-5cc drawn in EDTA (purple-top) tube

Cancer Predisposition Screening

Test Information Sheet

Whole Exome Sequencing (WES) and Microarray

 

Description:

Cancer is a disease in which abnormal cells divide uncontrollably driven by mutations in the cell’s DNA and destroy body tissue. Cancer can be an isolated tumor or can be metastatic and spread from the originating tissue affecting multiple organs. If not diagnosed early cancer can be at a later progressive stage and can be difficult to treat. It is now known that about 5-10% of all cancers (depending on the cancer type or origin) are inherited (i.e. an individual who is a carrier of a cancer-causing mutation/variant can be predisposed to cancer in his or her lifetime). The Cancer Predisposition Screening test is indicated for all individuals who would like to gain insights about their carrier status or predisposition status for cancer-related conditions (i.e. disease-causing or disease-associated variants that may increase the risk of cancer), and other health risks recommended for screening by the ACMG. With this knowledge the test subject and his or her healthcare providers and counselors could personalize their health and medical management plan by implementing monitoring program, lifestyle modifications or treatments to prevent or better manage these inherited cancer disorders.

 

Whole exome sequencing (WES) can be used to analyze most of the genes in an individual at one time to identify the mutation(s) that are causing a genetic disorder or for health screening purposes. This test is most appropriate for individuals with a medical history or those with a family history of certain cancer related conditions who would like to be screened for their cancer predisposition or risk (Table 1) and for the ACMG recommended actionable conditions for diagnostic and/or prevention purposes (Table 2). WES targets the protein-coding regions of the genome, which represents approximately 20,000 genes and about 2% of the genome. Individual exons of each gene are initially captured or separated from the rest of the genome and analyzed using massively parallel sequencing. The patient’s sequence is then compared to the reference genome sequence to identify variants that are different and are therefore, potentially causative in the patient’s condition. Ideally, this test is performed by sequencing the patient and both parents (trios) together to identify de novo variants, assign phase to inherited variants for autosomal recessive inheritance or to determine autosomal dominant or X-linked inheritance. However, depending upon the availability of the parents, other family members may also be utilized to maximize the chance of identifying causative variants in the patient.

 

Microarray allows for the genotyping of specific variations or polymorphisms associated with cancer predisposition conditions in the genome of an individual. It is different from WES in that specific variants are targeted either within the protein-coding regions or in the non-coding regions of the genome.

 

Test Method:

WES will be performed on the patient and their family members to target the exonic regions of their genomes. These regions will be sequenced using the Illumina NovaSeq 6000 with 100-150 bp paired-end reads. The DNA sequence will then be mapped to, and analyzed in comparison with, the published human genome build (UCSC hg19 reference sequence). The targeted coding exons and splice junctions of the known protein-coding RefSeq genes will be assessed for the average depth of coverage (minimum average coverage of 80X for WES and 15X-30X for WGS) and data quality threshold values. Sequence changes in the patient will be compared to the other provided family members. All reportable sequence variants will be confirmed by Sanger sequence analysis using a separate DNA preparation. Average quality thresholds may range from >90-95% of the targeted region, indicating a small portion of the target region may not be covered with sufficient depth or quality to confidently call variant positions. In addition to Next Generation Sequencing (NGS) for capturing the whole exome, microarray method using Illumina iScan technology, will be used to capture regions of the genome that are within and outside of the protein coding genes (i.e. intergenic). SNPs (Single Nucleotide Polymorphisms) or variants from the microarray may also be used in the analysis to generate parts of this report or for research purposes and for improving the report in the future. The sequencing, genotyping, alignment, and variant calling of the data will be performed at the Gene by Gene, Ltd. laboratory located in 1445 North Loop West, Suite 760 Houston, TX 77008. Analysis, interpretation and report will be performed by TOVANA HEALTH located at 945 McKinney St. Suite# 11977 Houston, TX 77002.

 

Limitations:

Absence of a causative variant(s) related to the reported phenotype by the WES and microarray methods does not exclude a genetic basis of the individual’s condition. Some types of genetic abnormalities, such as copy number changes, trinucleotide repeat expansions, small insertion/deletions and X-linked recessive mutations which manifest in females due to skewed X-inactivation may not be detectable with the technologies utilized for this testing. This test does not analyze mitochondrial DNA sequence or epigenetic changes of the genome. It is possible that the genomic region where a disease-causing mutation exists in the proband was not captured or accurately mapped to the reference sequence using the current technologies and therefore was not detected. Additionally, it is possible that a particular genetic abnormality may not be recognized as the underlying cause of the genetic disorder due to incomplete scientific knowledge about the function of all genes in the human genome and the impact of variations in those genes. Variants in genes associated with cancer predisposition conditions are included in this report (Table 1). In addition, based on the consent process, this individual may have opted to receive clinically relevant incidental findings that are actionable or preventive health conditions, not related to the cancer disease phenotype in this individual, and may have also been included in this report (Table 2). This report has been evaluated and accredited by the College of American Pathologists (CAP) for the clinical whole exome and clinical microarray sections of the report.

 

Table 1 – List of cancer predisposition categories and conditions genetically screened (125 total genes screened/analysed)

 

Cancer Predisposition Disease Categories and Conditions Included (but not limited to)

Ataxia-Telangiectasia

BAP1 hereditary cancer predisposition syndrome

Basal cell nevus syndrome

Birt-Hogg-Dubé syndrome

Bloom syndrome

Breast and gynecological cancers

Carney complex

CASR-related conditions

CDC73-related conditions

Chronic pancreatitis related cancers

Colorectal cancer

Constitutional mismatch repair-deficiency

Costello syndrome

DICER1 syndrome

Endocrine cancers (thyroid and parathyroid cancer)

Familial acute myeloid leukemia with mutated CEBPA

Familial adenomatous polyposis

Familial gastrointestinal stromal tumor syndrome

Familial neuroblastoma

Familial platelet disorder with propensity to myeloid malignancy

Fanconi anemia

Gastric cancer

GATA2 deficiency

Hematological cancers (Myelodysplastic syndrome/Leukemia)

Hereditary breast and ovarian cancer syndrome (HBOC)

Hereditary diffuse gastric cancer syndrome

Hereditary leiomyomatosis and renal cell cancer

Hereditary papillary renal cell carcinoma

Juvenile polyposis syndrome

Li-Fraumeni syndrome

Lynch syndrome

Melanoma-Pancreatic cancer syndrome

Multiple endocrine neoplasia, type 1 (MEN1)

Multiple endocrine neoplasia, type 2 (MEN2)

MUTYH-associated polyposis syndrome

Neurofogical/Nervousibromatosis, type 1

Neurofibromatosis, type 2

Neurol system and brain cancers

Nijmegen breakage syndrome

Oligodontia-colorectal cancer syndrome

Pancreatic cancer

Pediatric hematologic malignancies

Pediatric nervous system/brain tumors

Pediatric solid tumors

Perlman syndrome

Peutz-Jeghers syndrome

Prostate cancer

PTEN-related disorders

RECQL4-related disorders

Renal and urinary tract cancer

Retinoblastoma

Rhabdoid tumor predisposition syndrome

Schwannomatosis

Simpson-Golabi-Behmel syndrome

Skin cancer (including melanoma)

Small cell carcinoma of the ovary hypercalcemic type

Soft tissue and bone cancer (sarcomas)

Tuberous sclerosis complex

von Hippel-Lindau syndrome

Weaver syndrome

Werner syndrome

Wilms tumor

WT1-related disorders

Xeroderma pigmentosum

 

Table 2 – List of 59 conditions recommended for testing by the American College of Medical Genetics and Genomics (ACMGG)

 

Disease name and MIM Number

Gene and MIM Number

Adenomatous polyposis coli (MIM 175100)

APC (MIM 611731)

Aortic aneurysm, familial thoracic 4 (MIM 132900)

MYH11 (MIM 160745)

Aortic aneurysm, familial thoracic 6 (MIM 611788)

ACTA2 (MIM 102620)

Arrhythmogenic right ventricular cardiomyopathy, type 5 (MIM 604400)

TMEM43 (MIM 612048)

Arrhythmogenic right ventricular cardiomyopathy, type 8 (MIM 607450)

DSP (MIM 125647)

Arrhythmogenic right ventricular cardiomyopathy, type 9 (MIM 609040)

PKP2 (MIM 602861)

Arrhythmogenic right ventricular cardiomyopathy, type 10 (MIM 610193)

DSG2 (MIM 125671)

Arrhythmogenic right ventricular cardiomyopathy, type 11 (MIM 610476)

DSC2 (MIM 125645)

Breast-ovarian cancer, familial 1 (MIM 604370)

BRCA1 (MIM 113705)

Breast-ovarian cancer, familial 2 (MIM 612555)

BRCA2 (MIM 600185)

Brugada syndrome 1 (MIM 601144)

SCN5A (MIM 600163)

Catecholaminergic polymorphic ventricular tachycardia (MIM 604772)

RYR2 (MIM 180902)

Dilated cardiomyopathy 1A (MIM 115200)

LMNA (MIM 150330)

MYBPC3 (MIM 600958)

Ehlers-Danlos syndrome, type 4 (MIM 130050)

COL3A1 (MIM 120180)

Fabry’s disease (MIM 301500)

GLA (MIM 300644)

Familial hypercholesterolemia (MIM 143890)

APOB (MIM 107730)

LDLR (MIM 606945)

Familial hypertrophic cardiomyopathy 1 (MIM 192600)

MYH7 (MIM 160760)

Familial hypertrophic cardiomyopathy 3 (MIM 115196)

TPM1 (MIM 191010)

Familial hypertrophic cardiomyopathy 4 (MIM 115197)

MYBPC3 (MIM 600958)

Familial hypertrophic cardiomyopathy 6 (MIM 600858)

PRKAG2 (MIM 602743)

Familial hypertrophic cardiomyopathy 7 (MIM 613690)

TNNI3 (MIM 191044)

Familial hypertrophic cardiomyopathy 8 (MIM 608751)

MYL3 (MIM 160790)

Familial hypertrophic cardiomyopathy 10 (MIM 608758)

MYL2 (MIM 160781)

Familial hypertrophic cardiomyopathy 11 (MIM 612098)

ACTC1 (MIM 102540)

Familial medullary thyroid carcinoma (MIM 155240)

RET (MIM 164761)

Hypercholesterolemia, autosomal dominant, 3 (MIM 603776)

PCSK9 (MIM 607786)

Juvenile polyposis (MIM 174900)

BMPR1A (MIM 601299)

SMAD4 (MIM 600993)

Left ventricular noncompaction 6 (MIM 601494)

TNNT2 (MIM 191045)

Li-Fraumeni syndrome 1 (MIM 151623)

TP53 (MIM 191170)

Loeys-Dietz syndrome type 1A (MIM 609192)

TGFBR1 (MIM 190181)

Loeys-Dietz syndrome type 1B (MIM 610168)

TGFBR2 (MIM 190182)

Loeys-Dietz syndrome type 2A (MIM 608967)

TGFBR1 (MIM 190181)

Loeys-Dietz syndrome type 2B (MIM 610380)

TGFBR2 (MIM 190182)

Loeys-Dietz syndrome type 3 (MIM 613795)

SMAD3 (MIM 603109)

Long QT syndrome 1 (MIM 192500)

KCNQ1 (MIM 607542)

Long QT syndrome 2 (MIM 613688)

KCNH2 (MIM 152427)

Long QT syndrome 3 (MIM 603830)

SCN5A (MIM 600163)

Lynch syndrome (MIM 120435)

MLH1 (MIM 120436)

MSH2 (MIM 609309)

MSH6 (MIM 600678)

PMS2 (MIM 600259)

Malignant hyperthermia (MIM 145600)

RYR1 (MIM 180901)

CACNA1S (MIM 114208)

Marfan syndrome (MIM 154700)

FBN1 (MIM 134797)

TGFBR1 (MIM 190181)

Multiple endocrine neoplasia, type 1 (MIM 131100)

MEN1 (MIM 613733)

Multiple endocrine neoplasia, type 2a (MIM 171400)

RET (MIM 164761)

Multiple endocrine neoplasia, type 2b (MIM 162300)

RET (MIM 164761)

MYH-associated polyposis (MIM 608456)

MUTYH (MIM 604933)

Neurofibromatosis, type 2 (MIM 101000)

NF2 (MIM 607379)

Ornithine transcarbamylase deficiency (MIM 311250)

OTC (MIM 300461)

Paragangliomas 1 (MIM 168000)

SDHD (MIM 602690)

Paragangliomas 2 (MIM 601650)

SDHAF2 (MIM 613019)

Paragangliomas 3 (MIM 605373)

SDHC (MIM 602413)

Paragangliomas 4 (MIM 115310)

SDHB (MIM 185470)

Peutz-Jeghers syndrome (MIM 175200)

STK11 (MIM 602216)

Pilomatrixoma (MIM 132600)

MUTYH (MIM 604933)

PTEN hamartoma tumor syndrome (MIM 153480)

PTEN (MIM 601728)

Retinoblastoma (MIM 180200)

RB1 (MIM 614041)

Tuberous sclerosis 1 (MIM 191100)

TSC1 (MIM 605284)

Tuberous sclerosis 2 (MIM 613254)

TSC2 (MIM 191092)

Von Hippel-Lindau syndrome (MIM 193300)

VHL (MIM 608537)

Wilms tumor (MIM 194070)

WT1 (MIM 607102)

Wilson disease (MIM 277900)

ATP7B (MIM 606882)

 

Ordering:

CATALOG NUMBER:

1100110, 1197210, 1100010

TURNAROUND TIME:

3-5 weeks

PREFERRED SPECIMEN:

Buccal swab

ALTERNATIVE SPECIMEN:

 

Extracted DNA: 20ul of 50ng/ul, OD260/OD280 ~ 1.8, include details of extraction method with samples

 

Blood: 3-5cc drawn in EDTA (purple-top) tube

Personalized Nutrition & Fitness

Test Information Sheet

Microarray

 

Description:

Today we are learning more and more about the interaction of our diet, exercise, and other lifestyle habits with our genetics and how it may affect our health and wellness. With the Personalized Nutrition & Fitness Genome test, we analyzed and interpret vital parts of an individual’s genome to give insights about their nutrition and fitness traits, as well as some additional traits and ancestry. With this knowledge the test subject and his or her healthcare providers, dieticians/nutritionists or fitness trainers could personalize their diet or fitness routine.

 

Microarray allows for the genotyping of specific variations or polymorphisms associated with cardiovascular conditions in the genome of an individual. It is different from WES in that specific variants are targeted either within the protein-coding regions or in the non-coding regions of the genome.

 

Test Method:

Genotyping method of DNA is done using Illumina iScan technology to capture regions of the genome that are within (i.e. exonic) and outside of the protein coding genes (i.e. intergenic). SNPs (Single Nucleotide Polymorphisms) or variants from the microarray data are used in the analysis to generate parts of this report. The genotyping of the data is performed at the Gene by Gene, Ltd. laboratory located in 1445 North Loop West, Suite 760 Houston, TX 77008. Analysis, interpretation and report is performed by TOVANA HEALTH located at 945 McKinney St. Suite# 11977 Houston, TX 77002.

 

Limitations:

Absence of a causative variant(s) or SNPs (Single Nucleotide Polymorphisms) related to a trait by data obtained from microarray method does not exclude a genetic basis of the individual’s condition/trait. Some types of genetic abnormalities may not be detectable with the technologies utilized for this testing. This test does not analyze mitochondrial DNA sequence or epigenetic changes of the genome. It is possible that the genomic region where a variant contributing to the trait/condition exists in the individual tested was not captured or accurately mapped to the reference sequence using the current technologies and therefore was not detected. Additionally, it is possible that a particular genetic change may not be recognized as the underlying cause of the trait due to incomplete scientific knowledge about the function of all genes in the human genome and the impact of variations in those genes. Variants in genes associated with the trait or thought to potentially relevant for the individual’s analysis are included in this report. It should be noted that the heritability (i.e. the proportion that genetic variation contributes to the variance of a phenotypic trait) is only partial (< 100%) for the traits being analyzed. Lifestyle and other environmental factors contribute the variance of the trait as well and should be accounted for when interpreting these results. Variants or SNPs in genes associated with various traits related to nutrition, fitness, and additional traits are included in this report (Table 1).

 

Table 1 – List of traits Included in the test

 

Category/Section

Traits

Nutrition

 

Cardiometabolic Health

·        Caffeine Metabolism

·        Type 2 Diabetes Risk / Whole Grains & Fiber Benefits

·        Omega-3 and Omega-6 Levels

 

Food Reactions & Taste Perception

·        Lactose Intolerance

·        Bitter Taste Perception

 

Nutritional Needs & Nutrition Metabolism

·        Vitamin B2 (Riboflavin)

·        Vitamin B12 (Cobalamin)

·        Vitamin C (Ascorbic Acid)

 

Fitness

 

·        Exercise Behavior

·        Power and Strength

·        Endurance / Endurance Training

·        Pain Sensitivity

·        Achilles Tendon Injury / Tendinopathy

·        Muscle Fatigue & Cramping

·        Aerobic Capacity (VO2max)

·        Blood Pressure Response to Exercise

·        Weight – BMI Response to Exercise

Additional Traits

 

·        Wet vs. Dry Earwax, Sweating and Body Odor

·        Hair Loss and Baldness (Androgenic Alopecia)

·        Dental Caries

·        Sleep Depth (Deep Sleep)

Ancestry Genetics (optional)

 

Family ancestry

·        Discover the percentage breakdown of your origins

·        Connect with your autosomal DNA relatives within the last 5 generations

·        Learn if you have a connection with ancient European groups

·        Compare matching segments of DNA (blocks) with your genetic matches

 

 

Ordering:

CATALOG NUMBER:

1100113, 1197213, 1100013

TURNAROUND TIME:

2-4 weeks

PREFERRED SPECIMEN:

Buccal swab

ALTERNATIVE SPECIMEN:

 

Extracted DNA: 20ul of 50ng/ul, OD260/OD280 ~ 1.8, include details of extraction method with samples

 

Blood: 3-5cc drawn in EDTA (purple-top) tube

 

Substance Use Disorders (SUD)

& Preventive Health Screening

Test Information Sheet

Whole Exome Sequencing (WES), Microarray and

Specialized SUD (Substance Use Disorders) Assay

 

Description:

According to the DSM-5, a “substance use disorder describes a problematic pattern of using alcohol or another substance that results in impairment in daily life or noticeable distress.” The Substance Use Disorders & Preventive Health Screening test is indicated for all individuals who would like to gain insights about their carrier status or predisposition status for substance use disorders, and other health risks recommended for screening by the ACMG. With this knowledge the test subject and his or her healthcare providers and counselors could personalize their health and substance use rehabilitation management plan by implementing lifestyle modifications or treatments to prevent these disorders or improve the test subject’s current health state.

 

Whole exome sequencing (WES) can be used to analyze most of the genes in an individual at one time to identify the mutation(s) that are causing a genetic disorder or for health screening purposes. This test is most appropriate for generally healthy individuals or those with a family history of certain medical conditions who would like to be screened for the ACMG recommended actionable conditions for prevention purposes. WES targets the protein-coding regions of the genome, which represents approximately 20,000 genes and about 2% of the genome. Individual exons of each gene are initially captured or separated from the rest of the genome and analyzed using massively parallel sequencing. The patient’s sequence is then compared to the reference genome sequence to identify variants that are different and are therefore, potentially causative in the patient’s condition. Ideally, this test is performed by sequencing the patient and both parents (trios) together to identify de novo variants, assign phase to inherited variants for autosomal recessive inheritance or to determine autosomal dominant or X-linked inheritance. However, depending upon the availability of the parents, other family members may also be utilized to maximize the chance of identifying causative variants in the patient.

 

Microarray and Specialized Substance Use Disorders Assay allows for the genotyping of specific variations or polymorphisms associated with substance use or addiction disorders in the genome of an individual (Table 1). It is different from WES in that specific variants are targeted either within the protein-coding regions or in the non-coding regions of the genome.

 

Test Method:

WES will be performed on the patient and their family members to target the exonic regions of their genomes. These regions will be sequenced using the Illumina NovaSeq 6000 with 100-150 bp paired-end reads. The DNA sequence will then be mapped to, and analyzed in comparison with, the published human genome build (UCSC hg19 reference sequence). The targeted coding exons and splice junctions of the known protein-coding RefSeq genes will be assessed for the average depth of coverage (minimum average coverage of 80X for WES and 15X-30X for WGS) and data quality threshold values. Sequence changes in the patient will be compared to the other provided family members. All reportable sequence variants will be confirmed by Sanger sequence analysis using a separate DNA preparation. Average quality thresholds may range from >90-95% of the targeted region, indicating a small portion of the target region may not be covered with sufficient depth or quality to confidently call variant positions. In addition to Next Generation Sequencing (NGS) for capturing the whole exome, microarray method using Illumina iScan technology, as well as a custom designed assay will be used to capture regions of the genome that are within and outside of the protein coding genes (i.e. intergenic). SNPs (Single Nucleotide Polymorphisms) or variants from the microarray and custom assay data will also be used in the analysis to generate parts of this report. The sequencing, genotyping, alignment and variant calling of the data will be performed at the Gene by Gene, Ltd. laboratory located in 1445 North Loop West, Suite 760 Houston, TX 77008. Analysis, interpretation and report will be performed by TOVANA HEALTH located at 945 McKinney St. Suite# 11977 Houston, TX 77002.

 

Limitations:

Absence of a causative variant(s) related to the reported phenotype by the WES and microarray methods does not exclude a genetic basis of the individual’s condition. Some types of genetic abnormalities, such as copy number changes, trinucleotide repeat expansions, small insertion/deletions and X-linked recessive mutations which manifest in females due to skewed X-inactivation may not be detectable with the technologies utilized for this testing. This test does not analyze mitochondrial DNA sequence or epigenetic changes of the genome. It is possible that the genomic region where a disease-causing mutation exists in the proband was not captured or accurately mapped to the reference sequence using the current technologies and therefore was not detected. Additionally, it is possible that a particular genetic abnormality may not be recognized as the underlying cause of the genetic disorder due to incomplete scientific knowledge about the function of all genes in the human genome and the impact of variations in those genes. Variants in genes associated with substance use disorders are included in this report (Table 1). In addition, based on the consent process, this individual may have opted to receive clinically relevant incidental findings that are actionable or preventive health conditions, not related to the substance use disorder phenotype in this individual, and may have also been included in this report (Table 2). This report has been evaluated and accredited by the College of American Pathologists (CAP) for the clinical whole exome and clinical microarray sections of the report, but not the non-clinical sections (i.e. Substance Use Disorder Traits section).

 

Table 1 – List of Substance Use Disorder (SUD) categories and traits genetically screened

 

SUD Category

SUD Trait

Smoking Behavior

Nicotine Dependence

Smoking Behavior

Smoking Cessation (former smoking status)

Smoking Behavior

Cigarettes Per Day (CPD)

Smoking Behavior

Nicotine metabolite ratio (NMR)

Alcohol Use Disorder

Alcohol Consumption (drinks/week)

Alcohol Use Disorder

MaxDrinks (Maximum drinks in a 24-hour period)

Alcohol Use Disorder

Alcohol Dependence (AD)

Alcohol Use Disorder

Flushing response to alcohol

Alcohol Use Disorder

Drinker Behavior (likely to report consuming alcohol)

Cannabis Use Disorder

Cannabis Dependence (CAD)

Stimulant Use Disorder

Cocaine Dependence (CD)

Opioid Use Disorder

Opioid Dependence/Addiction

Polysubstance Use Disorder

Polysubstance Dependence/Addiction

Polysubstance Use Disorder

Polysubstance Drug Abuse

 

 

Table 2 – List of 59 conditions recommended for testing by the American College of Medical Genetics and Genomics (ACMG)

 

Disease name and MIM Number

Gene and MIM Number

Adenomatous polyposis coli (MIM 175100)

APC (MIM 611731)

Aortic aneurysm, familial thoracic 4 (MIM 132900)

MYH11 (MIM 160745)

Aortic aneurysm, familial thoracic 6 (MIM 611788)

ACTA2 (MIM 102620)

Arrhythmogenic right ventricular cardiomyopathy, type 5 (MIM 604400)

TMEM43 (MIM 612048)

Arrhythmogenic right ventricular cardiomyopathy, type 8 (MIM 607450)

DSP (MIM 125647)

Arrhythmogenic right ventricular cardiomyopathy, type 9 (MIM 609040)

PKP2 (MIM 602861)

Arrhythmogenic right ventricular cardiomyopathy, type 10 (MIM 610193)

DSG2 (MIM 125671)

Arrhythmogenic right ventricular cardiomyopathy, type 11 (MIM 610476)

DSC2 (MIM 125645)

Breast-ovarian cancer, familial 1 (MIM 604370)

BRCA1 (MIM 113705)

Breast-ovarian cancer, familial 2 (MIM 612555)

BRCA2 (MIM 600185)

Brugada syndrome 1 (MIM 601144)

SCN5A (MIM 600163)

Catecholaminergic polymorphic ventricular tachycardia (MIM 604772)

RYR2 (MIM 180902)

Dilated cardiomyopathy 1A (MIM 115200)

LMNA (MIM 150330)

MYBPC3 (MIM 600958)

Ehlers-Danlos syndrome, type 4 (MIM 130050)

COL3A1 (MIM 120180)

Fabry’s disease (MIM 301500)

GLA (MIM 300644)

Familial hypercholesterolemia (MIM 143890)

APOB (MIM 107730)

LDLR (MIM 606945)

Familial hypertrophic cardiomyopathy 1 (MIM 192600)

MYH7 (MIM 160760)

Familial hypertrophic cardiomyopathy 3 (MIM 115196)

TPM1 (MIM 191010)

Familial hypertrophic cardiomyopathy 4 (MIM 115197)

MYBPC3 (MIM 600958)

Familial hypertrophic cardiomyopathy 6 (MIM 600858)

PRKAG2 (MIM 602743)

Familial hypertrophic cardiomyopathy 7 (MIM 613690)

TNNI3 (MIM 191044)

Familial hypertrophic cardiomyopathy 8 (MIM 608751)

MYL3 (MIM 160790)

Familial hypertrophic cardiomyopathy 10 (MIM 608758)

MYL2 (MIM 160781)

Familial hypertrophic cardiomyopathy 11 (MIM 612098)

ACTC1 (MIM 102540)

Familial medullary thyroid carcinoma (MIM 155240)

RET (MIM 164761)

Hypercholesterolemia, autosomal dominant, 3 (MIM 603776)

PCSK9 (MIM 607786)

Juvenile polyposis (MIM 174900)

BMPR1A (MIM 601299)

SMAD4 (MIM 600993)

Left ventricular noncompaction 6 (MIM 601494)

TNNT2 (MIM 191045)

Li-Fraumeni syndrome 1 (MIM 151623)

TP53 (MIM 191170)

Loeys-Dietz syndrome type 1A (MIM 609192)

TGFBR1 (MIM 190181)

Loeys-Dietz syndrome type 1B (MIM 610168)

TGFBR2 (MIM 190182)

Loeys-Dietz syndrome type 2A (MIM 608967)

TGFBR1 (MIM 190181)

Loeys-Dietz syndrome type 2B (MIM 610380)

TGFBR2 (MIM 190182)

Loeys-Dietz syndrome type 3 (MIM 613795)

SMAD3 (MIM 603109)

Long QT syndrome 1 (MIM 192500)

KCNQ1 (MIM 607542)

Long QT syndrome 2 (MIM 613688)

KCNH2 (MIM 152427)

Long QT syndrome 3 (MIM 603830)

SCN5A (MIM 600163)

Lynch syndrome (MIM 120435)

MLH1 (MIM 120436)

MSH2 (MIM 609309)

MSH6 (MIM 600678)

PMS2 (MIM 600259)

Malignant hyperthermia (MIM 145600)

RYR1 (MIM 180901)

CACNA1S (MIM 114208)

Marfan syndrome (MIM 154700)

FBN1 (MIM 134797)

TGFBR1 (MIM 190181)

Multiple endocrine neoplasia, type 1 (MIM 131100)

MEN1 (MIM 613733)

Multiple endocrine neoplasia, type 2a (MIM 171400)

RET (MIM 164761)

Multiple endocrine neoplasia, type 2b (MIM 162300)

RET (MIM 164761)

MYH-associated polyposis (MIM 608456)

MUTYH (MIM 604933)

Neurofibromatosis, type 2 (MIM 101000)

NF2 (MIM 607379)

Ornithine transcarbamylase deficiency (MIM 311250)

OTC (MIM 300461)

Paragangliomas 1 (MIM 168000)

SDHD (MIM 602690)

Paragangliomas 2 (MIM 601650)

SDHAF2 (MIM 613019)

Paragangliomas 3 (MIM 605373)

SDHC (MIM 602413)

Paragangliomas 4 (MIM 115310)

SDHB (MIM 185470)

Peutz-Jeghers syndrome (MIM 175200)

STK11 (MIM 602216)

Pilomatrixoma (MIM 132600)

MUTYH (MIM 604933)

PTEN hamartoma tumor syndrome (MIM 153480)

PTEN (MIM 601728)

Retinoblastoma (MIM 180200)

RB1 (MIM 614041)

Tuberous sclerosis 1 (MIM 191100)

TSC1 (MIM 605284)

Tuberous sclerosis 2 (MIM 613254)

TSC2 (MIM 191092)

Von Hippel-Lindau syndrome (MIM 193300)

VHL (MIM 608537)

Wilms tumor (MIM 194070)

WT1 (MIM 607102)

Wilson disease (MIM 277900)

ATP7B (MIM 606882)

 

 

 

Ordering:

CATALOG NUMBER:

1100116, 1100016

TURNAROUND TIME:

2-4 weeks

PREFERRED SPECIMEN:

Buccal swab

ALTERNATIVE SPECIMEN:

 

Extracted DNA: 20ul of 50ng/ul, OD260/OD280 ~ 1.8, include details of extraction method with samples

 

Blood: 3-5cc drawn in EDTA (purple-top) tube

Cardiovascular Disease (CVD) Screening

Test Information Sheet

Whole Exome Sequencing (WES) and Microarray

 

Description:

Cardiovascular disease (CVD) is a leading health problem and encompasses a broad range of disorders including diseases of the vasculature, the myocardium, the heart’s electrical circuit, and congenital heart disease. For nearly all of these disorders, inherited DNA sequence variants play a role in conferring risk for disease. The Cardiovascular Disease Screening test is indicated for all individuals who would like to gain insights about their carrier status or predisposition status for cardiovascular conditions with a genetic basis, and other health risks recommended for screening by the ACMG. With this knowledge the test subject and his or her healthcare providers and counselors could personalize their health and medical management plan by implementing lifestyle modifications or treatments to prevent or better manage these disorders and improve the test subject’s current health state.

 

Whole exome sequencing (WES) can be used to analyze most of the genes in an individual at one time to identify the mutation(s) that are causing a genetic disorder or for health screening purposes. This test is most appropriate for individuals with a medical history or those with a family history of certain cardiovascular conditions who would like to be screened for cardiovascular conditions (Table 1) and for the ACMG recommended actionable conditions for diagnostic and/or prevention purposes (Table 2). WES targets the protein-coding regions of the genome, which represents approximately 20,000 genes and about 2% of the genome. Individual exons of each gene are initially captured or separated from the rest of the genome and analyzed using massively parallel sequencing. The patient’s sequence is then compared to the reference genome sequence to identify variants that are different and are therefore, potentially causative in the patient’s condition. Ideally, this test is performed by sequencing the patient and both parents (trios) together to identify de novo variants, assign phase to inherited variants for autosomal recessive inheritance or to determine autosomal dominant or X-linked inheritance. However, depending upon the availability of the parents, other family members may also be utilized to maximize the chance of identifying causative variants in the patient.

 

Microarray allows for the genotyping of specific variations or polymorphisms associated with cardiovascular conditions in the genome of an individual. It is different from WES in that specific variants are targeted either within the protein-coding regions or in the non-coding regions of the genome.

 

Test Method:

WES will be performed on the patient and their family members to target the exonic regions of their genomes. These regions will be sequenced using the Illumina NovaSeq 6000 with 100-150 bp paired-end reads. The DNA sequence will then be mapped to, and analyzed in comparison with, the published human genome build (UCSC hg19 reference sequence). The targeted coding exons and splice junctions of the known protein-coding RefSeq genes will be assessed for the average depth of coverage (minimum average coverage of 80X for WES and 15X-30X for WGS) and data quality threshold values. Sequence changes in the patient will be compared to the other provided family members. All reportable sequence variants will be confirmed by Sanger sequence analysis using a separate DNA preparation. Average quality thresholds may range from >90-95% of the targeted region, indicating a small portion of the target region may not be covered with sufficient depth or quality to confidently call variant positions. In addition to Next Generation Sequencing (NGS) for capturing the whole exome, microarray method using Illumina iScan technology, will be used to capture regions of the genome that are within and outside of the protein coding genes (i.e. intergenic). SNPs (Single Nucleotide Polymorphisms) or variants from the microarray may also be used in the analysis to generate parts of this report or for research purposes and for improving the report in the future. The sequencing, genotyping, alignment, and variant calling of the data will be performed at the Gene by Gene, Ltd. laboratory located in 1445 North Loop West, Suite 760 Houston, TX 77008. Analysis, interpretation and report will be performed by TOVANA HEALTH located at 945 McKinney St. Suite# 11977 Houston, TX 77002.

 

Limitations:

Absence of a causative variant(s) related to the reported phenotype by the WES and microarray methods does not exclude a genetic basis of the individual’s condition. Some types of genetic abnormalities, such as copy number changes, trinucleotide repeat expansions, small insertion/deletions and X-linked recessive mutations which manifest in females due to skewed X-inactivation may not be detectable with the technologies utilized for this testing. This test does not analyze mitochondrial DNA sequence or epigenetic changes of the genome. It is possible that the genomic region where a disease-causing mutation exists in the proband was not captured or accurately mapped to the reference sequence using the current technologies and therefore was not detected. Additionally, it is possible that a particular genetic abnormality may not be recognized as the underlying cause of the genetic disorder due to incomplete scientific knowledge about the function of all genes in the human genome and the impact of variations in those genes. Variants in genes associated with cardiovascular conditions are included in this report (Table 1). In addition, based on the consent process, this individual may have opted to receive clinically relevant incidental findings that are actionable or preventive health conditions, not related to the cardiovascular disease phenotype in this individual, and may have also been included in this report (Table 2). This report has been evaluated and accredited by the College of American Pathologists (CAP) for the clinical whole exome and clinical microarray sections of the report.

 

Table 1 – List of cardiovascular disease categories and conditions genetically screened (374 total genes screened/analyzed)

Cardiovascular Disease Category

Conditions Included (but not limited to)

Congenital heart disease

CHARGE syndrome, Holt-Oram syndrome, RASopathies, Sotos syndrome, Heterotaxy and Situs Inversus

Pulmonary hypertension

Pulmonary arterial hypertension, Hereditary Hemorrhagic Telangiectasia

Familial Hypercholesterolemia

 

Aortopathy and connective tissue disorders

Marfan syndrome, Loeys-Dietz syndrome, Ehlers-Danlos syndrome, dolichoectasia, vascular malformations, Alport syndrome

Cardiomyopathy and skeletal muscle disease

Metabolic disorders, mitochondrial disorders, arrhythmogenic cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, RASopathies, left ventricular noncompaction, transthyretin amyloidosis, hereditary hemochromatosis, Cardio-Facio-Cutaneous syndrome

Conduction disorders and related conditions

Arrhythmias, sudden unexpected death in epilepsy (SUDEP), Brugada syndrome, Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT), Long QT Syndrome (LQTS), Short QT Syndrome (SQTS), Atrial Fibrillation, Sudden Cardiac Arrest Arrhythmia

Hemiplegia/Stroke

 

 

Table 2 – List of 59 conditions recommended for testing by the American College of Medical Genetics and Genomics (ACMGG)

 

Disease name and MIM Number

Gene and MIM Number

Adenomatous polyposis coli (MIM 175100)

APC (MIM 611731)

Aortic aneurysm, familial thoracic 4 (MIM 132900)

MYH11 (MIM 160745)

Aortic aneurysm, familial thoracic 6 (MIM 611788)

ACTA2 (MIM 102620)

Arrhythmogenic right ventricular cardiomyopathy, type 5 (MIM 604400)

TMEM43 (MIM 612048)

Arrhythmogenic right ventricular cardiomyopathy, type 8 (MIM 607450)

DSP (MIM 125647)

Arrhythmogenic right ventricular cardiomyopathy, type 9 (MIM 609040)

PKP2 (MIM 602861)

Arrhythmogenic right ventricular cardiomyopathy, type 10 (MIM 610193)

DSG2 (MIM 125671)

Arrhythmogenic right ventricular cardiomyopathy, type 11 (MIM 610476)

DSC2 (MIM 125645)

Breast-ovarian cancer, familial 1 (MIM 604370)

BRCA1 (MIM 113705)

Breast-ovarian cancer, familial 2 (MIM 612555)

BRCA2 (MIM 600185)

Brugada syndrome 1 (MIM 601144)

SCN5A (MIM 600163)

Catecholaminergic polymorphic ventricular tachycardia (MIM 604772)

RYR2 (MIM 180902)

Dilated cardiomyopathy 1A (MIM 115200)

LMNA (MIM 150330)

MYBPC3 (MIM 600958)

Ehlers-Danlos syndrome, type 4 (MIM 130050)

COL3A1 (MIM 120180)

Fabry’s disease (MIM 301500)

GLA (MIM 300644)

Familial hypercholesterolemia (MIM 143890)

APOB (MIM 107730)

LDLR (MIM 606945)

Familial hypertrophic cardiomyopathy 1 (MIM 192600)

MYH7 (MIM 160760)

Familial hypertrophic cardiomyopathy 3 (MIM 115196)

TPM1 (MIM 191010)

Familial hypertrophic cardiomyopathy 4 (MIM 115197)

MYBPC3 (MIM 600958)

Familial hypertrophic cardiomyopathy 6 (MIM 600858)

PRKAG2 (MIM 602743)

Familial hypertrophic cardiomyopathy 7 (MIM 613690)

TNNI3 (MIM 191044)

Familial hypertrophic cardiomyopathy 8 (MIM 608751)

MYL3 (MIM 160790)

Familial hypertrophic cardiomyopathy 10 (MIM 608758)

MYL2 (MIM 160781)

Familial hypertrophic cardiomyopathy 11 (MIM 612098)

ACTC1 (MIM 102540)

Familial medullary thyroid carcinoma (MIM 155240)

RET (MIM 164761)

Hypercholesterolemia, autosomal dominant, 3 (MIM 603776)

PCSK9 (MIM 607786)

Juvenile polyposis (MIM 174900)

BMPR1A (MIM 601299)

SMAD4 (MIM 600993)

Left ventricular noncompaction 6 (MIM 601494)

TNNT2 (MIM 191045)

Li-Fraumeni syndrome 1 (MIM 151623)

TP53 (MIM 191170)

Loeys-Dietz syndrome type 1A (MIM 609192)

TGFBR1 (MIM 190181)

Loeys-Dietz syndrome type 1B (MIM 610168)

TGFBR2 (MIM 190182)

Loeys-Dietz syndrome type 2A (MIM 608967)

TGFBR1 (MIM 190181)

Loeys-Dietz syndrome type 2B (MIM 610380)

TGFBR2 (MIM 190182)

Loeys-Dietz syndrome type 3 (MIM 613795)

SMAD3 (MIM 603109)

Long QT syndrome 1 (MIM 192500)

KCNQ1 (MIM 607542)

Long QT syndrome 2 (MIM 613688)

KCNH2 (MIM 152427)

Long QT syndrome 3 (MIM 603830)

SCN5A (MIM 600163)

Lynch syndrome (MIM 120435)

MLH1 (MIM 120436)

MSH2 (MIM 609309)

MSH6 (MIM 600678)

PMS2 (MIM 600259)

Malignant hyperthermia (MIM 145600)

RYR1 (MIM 180901)

CACNA1S (MIM 114208)

Marfan syndrome (MIM 154700)

FBN1 (MIM 134797)

TGFBR1 (MIM 190181)

Multiple endocrine neoplasia, type 1 (MIM 131100)

MEN1 (MIM 613733)

Multiple endocrine neoplasia, type 2a (MIM 171400)

RET (MIM 164761)

Multiple endocrine neoplasia, type 2b (MIM 162300)

RET (MIM 164761)

MYH-associated polyposis (MIM 608456)

MUTYH (MIM 604933)

Neurofibromatosis, type 2 (MIM 101000)

NF2 (MIM 607379)

Ornithine transcarbamylase deficiency (MIM 311250)

OTC (MIM 300461)

Paragangliomas 1 (MIM 168000)

SDHD (MIM 602690)

Paragangliomas 2 (MIM 601650)

SDHAF2 (MIM 613019)

Paragangliomas 3 (MIM 605373)

SDHC (MIM 602413)

Paragangliomas 4 (MIM 115310)

SDHB (MIM 185470)

Peutz-Jeghers syndrome (MIM 175200)

STK11 (MIM 602216)

Pilomatrixoma (MIM 132600)

MUTYH (MIM 604933)

PTEN hamartoma tumor syndrome (MIM 153480)

PTEN (MIM 601728)

Retinoblastoma (MIM 180200)

RB1 (MIM 614041)

Tuberous sclerosis 1 (MIM 191100)

TSC1 (MIM 605284)

Tuberous sclerosis 2 (MIM 613254)

TSC2 (MIM 191092)

Von Hippel-Lindau syndrome (MIM 193300)

VHL (MIM 608537)

Wilms tumor (MIM 194070)

WT1 (MIM 607102)

Wilson disease (MIM 277900)

ATP7B (MIM 606882)

Ordering:

CATALOG NUMBER:

1100120, 1197220, 1100020

TURNAROUND TIME:

3-5 weeks

PREFERRED SPECIMEN:

Buccal swab

ALTERNATIVE SPECIMEN:

 

Extracted DNA: 20ul of 50ng/ul, OD260/OD280 ~ 1.8, include details of extraction method with samples

 

Blood: 3-5cc drawn in EDTA (purple-top) tube

——————————————————————————– Neurological Genetics Screening

Test Information Sheet

Whole Exome Sequencing (WES) and Microarray

 

Description:

A neurological disorder is any medical problem that affects the nervous system that includes your brain, spinal cord, and other nerves. Problems with the structure or function of any part of the nervous system can lead to a neurological disorder. One of the causes of neurological disorders include changes in our genes which can be de novo or inherited. The Neurological Genetics Screening test is indicated for all individuals who would like to gain insights about their carrier status, predisposition status or affected status for neurological conditions with a genetic basis, and other health risks recommended for screening by the ACMG. With this knowledge the test subject and his or her healthcare providers and counselors could personalize their health and medical management plan by implementing lifestyle modifications or treatments to prevent or better manage these disorders and improve the test subject’s current health state.

 

Whole exome sequencing (WES) can be used to analyze most of the genes in an individual at one time to identify the mutation(s) that are causing a genetic disorder or for health screening purposes. This test is most appropriate for individuals with a medical history or those with a family history of certain neurological conditions who would like to be screened for neurological conditions (Table 1) and for the ACMG recommended actionable conditions for diagnostic and/or prevention purposes (Table 2). WES targets the protein-coding regions of the genome, which represents approximately 20,000 genes and about 2% of the genome. Individual exons of each gene are initially captured or separated from the rest of the genome and analyzed using massively parallel sequencing. The patient’s sequence is then compared to the reference genome sequence to identify variants that are different and are therefore, potentially causative in the patient’s condition. Ideally, this test is performed by sequencing the patient and both parents (trios) together to identify de novo variants, assign phase to inherited variants for autosomal recessive inheritance or to determine autosomal dominant or X-linked inheritance. However, depending upon the availability of the parents, other family members may also be utilized to maximize the chance of identifying causative variants in the patient.

 

Microarray allows for the genotyping of specific variations or polymorphisms associated with neurological conditions in the genome of an individual. It is different from WES in that specific variants are targeted either within the protein-coding regions or in the non-coding regions of the genome.

 

Test Method: 

WES will be performed on the patient and their family members to target the exonic regions of their genomes. These regions will be sequenced using the Illumina NovaSeq 6000 with 100-150 bp paired-end reads. The DNA sequence will then be mapped to, and analyzed in comparison with, the published human genome build (UCSC hg19 reference sequence). The targeted coding exons and splice junctions of the known protein-coding RefSeq genes will be assessed for the average depth of coverage (minimum average coverage of 80X for WES and 15X-30X for WGS) and data quality threshold values. Sequence changes in the patient will be compared to the other provided family members. All reportable sequence variants will be confirmed by Sanger sequence analysis using a separate DNA preparation. Average quality thresholds may range from >90-95% of the targeted region, indicating a small portion of the target region may not be covered with sufficient depth or quality to confidently call variant positions. In addition to Next Generation Sequencing (NGS) for capturing the whole exome, microarray method using Illumina iScan technology, will be used to capture regions of the genome that are within and outside of the protein coding genes (i.e. intergenic). SNPs (Single Nucleotide Polymorphisms) or variants from the microarray may also be used in the analysis to generate parts of this report or for research purposes and for improving the report in the future. The sequencing, genotyping, alignment, and variant calling of the data will be performed at the Gene by Gene, Ltd. laboratory located in 1445 North Loop West, Suite 760 Houston, TX 77008. Analysis, interpretation and report will be performed by TOVANA HEALTH located at 945 McKinney St. Suite# 11977 Houston, TX 77002.

 

Limitations: 

Absence of a causative variant(s) related to the reported phenotype by the WES and microarray methods does not exclude a genetic basis of the individual’s condition. Some types of genetic abnormalities, such as copy number changes, trinucleotide repeat expansions, small insertion/deletions and X-linked recessive mutations which manifest in females due to skewed X-inactivation may not be detectable with the technologies utilized for this testing. This test does not analyze mitochondrial DNA sequence or epigenetic changes of the genome. It is possible that the genomic region where a disease-causing mutation exists in the proband was not captured or accurately mapped to the reference sequence using the current technologies and therefore was not detected. Additionally, it is possible that a particular genetic abnormality may not be recognized as the underlying cause of the genetic disorder due to incomplete scientific knowledge about the function of all genes in the human genome and the impact of variations in those genes. Variants in genes associated with neurological conditions are included in this report (Table 1). In addition, based on the consent process, this individual may have opted to receive clinically relevant incidental findings that are actionable or preventive health conditions, not related to the cardiovascular disease phenotype in this individual, and may have also been included in this report (Table 2). This report has been evaluated and accredited by the College of American Pathologists (CAP) for the clinical whole exome and clinical microarray sections of the report.

 

Table 1 – List of neurological conditions genetically screened (1370 total genes screened/analysed)

 

Conditions Included (but not limited to)

Aicardi-Goutières syndrome

Alzheimer disease and dementia

Amyotrophic lateral sclerosis (ALS) and phenocopies

Arthrogryposis multiplex congenita (AMC)

Autophagic vacuolar myopathy

Baraitser-Winter cerebrofrontofacial syndrome

Brain malformations

Cardiomyopathy and skeletal muscle disease

Cerebellar ataxia

Cerebellar hypoplasia

Cerebral cavernous malformations (CCM)

Cerebral cortical malformations

Charcot-Marie-Tooth disease

CHARGE syndrome

Cobblestone Lissencephaly

Coffin-Siris and Nicolaides-Baraitser syndrome (CSS, NCBRS)

Cohesinopathies (Cornelia de Lange syndrome)

Congenital disorders of glycosylation

Congenital fiber-type disproportion

Congenital hypotonia

Congenital muscular dystrophy

Congenital myasthenic syndrome

Congenital myopathy

Dejerine-Sottas syndrome

Disorders causing optic atrophy

Distal hereditary motor neuropathy

Distal myopathy

Dystonia

Dystroglycanopathy

Dystrophinopathies

Early infantile epileptic encephalopathy

Emery-Dreifuss muscular dystrophy

Facial dysostosis

Familial dysautonomia

Familial hemiplegic migraine

Fetal akinesia deformation sequence (FADS)

Hereditary motor neuropathies

Hereditary neuropathies

Hereditary optic atrophy

Hereditary Parkinson’s disease

Hereditary sensory and autonomic neuropathy

Hereditary spastic paraplegia

Holoprosencephaly

Hyperekplexia

Hyperkalemic periodic paralysis

Hypokalemic periodic paralysis

Inclusion body myopathy

Intellectual disability and developmental delay

Leukodystrophy and peroxisome biogenesis disorders

Leukoencephalopathy

Macrocephaly

Malignant hyperthermia susceptibility (MHS)

Megalencephaly

Microcephaly

Microcephaly and pontocerebellar hypoplasia

Multiminicore disease

Muscular dystrophies

Myoclonic epilepsy panel

Myofibrillar myopathy

Myopathies

Myotonia

Nemaline myopathy

Neurodegeneration with brain iron accumulation

Neuromuscular disorders comprehensive

Neuronal ceroid lipofuscinoses

Neuronal migration disorders

Neuropathy

Non-dystrophic myotonia

Oculomotor

Ophthalmoplegia

Pantothenate kinase-associated neurodegeneration

Periodic palsy

Polymicrogyria

Pontocerebellar hypoplasia

Progressive external ophthalmoplegia (PEO)

Proximal motor neuropathy

RASopathies

Rett and Angelman syndromes and related disorders

Riboflavin transporter deficiency neuronopathy

Seckel syndrome

Small fiber neuropathy

Spinal muscular atrophy (SMA),

Spinocerebellar ataxia (SCA)

Trichothiodystrophy

Tuberous sclerosis complex

Type VI collagenopathies

Warburg micro syndrome (WARBM)

 

Table 2 – List of 59 conditions recommended for testing by the American College of Medical Genetics and Genomics (ACMGG)

 

Disease name and MIM Number

Gene and MIM Number

Adenomatous polyposis coli (MIM 175100)

APC (MIM 611731)

Aortic aneurysm, familial thoracic 4 (MIM 132900)

MYH11 (MIM 160745)

Aortic aneurysm, familial thoracic 6 (MIM 611788)

ACTA2 (MIM 102620)

Arrhythmogenic right ventricular cardiomyopathy, type 5 (MIM 604400)

TMEM43 (MIM 612048)

Arrhythmogenic right ventricular cardiomyopathy, type 8 (MIM 607450)

DSP (MIM 125647)

Arrhythmogenic right ventricular cardiomyopathy, type 9 (MIM 609040)

PKP2 (MIM 602861)

Arrhythmogenic right ventricular cardiomyopathy, type 10 (MIM 610193)

DSG2 (MIM 125671)

Arrhythmogenic right ventricular cardiomyopathy, type 11 (MIM 610476)

DSC2 (MIM 125645)

Breast-ovarian cancer, familial 1 (MIM 604370)

BRCA1 (MIM 113705)

Breast-ovarian cancer, familial 2 (MIM 612555)

BRCA2 (MIM 600185)

Brugada syndrome 1 (MIM 601144)

SCN5A (MIM 600163)

Catecholaminergic polymorphic ventricular tachycardia (MIM 604772)

RYR2 (MIM 180902)

Dilated cardiomyopathy 1A (MIM 115200)

LMNA (MIM 150330)

MYBPC3 (MIM 600958)

Ehlers-Danlos syndrome, type 4 (MIM 130050)

COL3A1 (MIM 120180)

Fabry’s disease (MIM 301500)

GLA (MIM 300644)

Familial hypercholesterolemia (MIM 143890)

APOB (MIM 107730)

LDLR (MIM 606945)

Familial hypertrophic cardiomyopathy 1 (MIM 192600)

MYH7 (MIM 160760)

Familial hypertrophic cardiomyopathy 3 (MIM 115196)

TPM1 (MIM 191010)

Familial hypertrophic cardiomyopathy 4 (MIM 115197)

MYBPC3 (MIM 600958)

Familial hypertrophic cardiomyopathy 6 (MIM 600858)

PRKAG2 (MIM 602743)

Familial hypertrophic cardiomyopathy 7 (MIM 613690)

TNNI3 (MIM 191044)

Familial hypertrophic cardiomyopathy 8 (MIM 608751)

MYL3 (MIM 160790)

Familial hypertrophic cardiomyopathy 10 (MIM 608758)

MYL2 (MIM 160781)

Familial hypertrophic cardiomyopathy 11 (MIM 612098)

ACTC1 (MIM 102540)

Familial medullary thyroid carcinoma (MIM 155240)

RET (MIM 164761)

Hypercholesterolemia, autosomal dominant, 3 (MIM 603776)

PCSK9 (MIM 607786)

Juvenile polyposis (MIM 174900)

BMPR1A (MIM 601299)

SMAD4 (MIM 600993)

Left ventricular noncompaction 6 (MIM 601494)

TNNT2 (MIM 191045)

Li-Fraumeni syndrome 1 (MIM 151623)

TP53 (MIM 191170)

Loeys-Dietz syndrome type 1A (MIM 609192)

TGFBR1 (MIM 190181)

Loeys-Dietz syndrome type 1B (MIM 610168)

TGFBR2 (MIM 190182)

Loeys-Dietz syndrome type 2A (MIM 608967)

TGFBR1 (MIM 190181)

Loeys-Dietz syndrome type 2B (MIM 610380)

TGFBR2 (MIM 190182)

Loeys-Dietz syndrome type 3 (MIM 613795)

SMAD3 (MIM 603109)

Long QT syndrome 1 (MIM 192500)

KCNQ1 (MIM 607542)

Long QT syndrome 2 (MIM 613688)

KCNH2 (MIM 152427)

Long QT syndrome 3 (MIM 603830)

SCN5A (MIM 600163)

Lynch syndrome (MIM 120435)

MLH1 (MIM 120436)

MSH2 (MIM 609309)

MSH6 (MIM 600678)

PMS2 (MIM 600259)

Malignant hyperthermia (MIM 145600)

RYR1 (MIM 180901)

CACNA1S (MIM 114208)

Marfan syndrome (MIM 154700)

FBN1 (MIM 134797)

TGFBR1 (MIM 190181)

Multiple endocrine neoplasia, type 1 (MIM 131100)

MEN1 (MIM 613733)

Multiple endocrine neoplasia, type 2a (MIM 171400)

RET (MIM 164761)

Multiple endocrine neoplasia, type 2b (MIM 162300)

RET (MIM 164761)

MYH-associated polyposis (MIM 608456)

MUTYH (MIM 604933)

Neurofibromatosis, type 2 (MIM 101000)

NF2 (MIM 607379)

Ornithine transcarbamylase deficiency (MIM 311250)

OTC (MIM 300461)

Paragangliomas 1 (MIM 168000)

SDHD (MIM 602690)

Paragangliomas 2 (MIM 601650)

SDHAF2 (MIM 613019)

Paragangliomas 3 (MIM 605373)

SDHC (MIM 602413)

Paragangliomas 4 (MIM 115310)

SDHB (MIM 185470)

Peutz-Jeghers syndrome (MIM 175200)

STK11 (MIM 602216)

Pilomatrixoma (MIM 132600)

MUTYH (MIM 604933)

PTEN hamartoma tumor syndrome (MIM 153480)

PTEN (MIM 601728)

Retinoblastoma (MIM 180200)

RB1 (MIM 614041)

Tuberous sclerosis 1 (MIM 191100)

TSC1 (MIM 605284)

Tuberous sclerosis 2 (MIM 613254)

TSC2 (MIM 191092)

Von Hippel-Lindau syndrome (MIM 193300)

VHL (MIM 608537)

Wilms tumor (MIM 194070)

WT1 (MIM 607102)

Wilson disease (MIM 277900)

ATP7B (MIM 606882)

 

 

Ordering:

CATALOG NUMBER:

1100123, 1197223, 1100023

TURNAROUND TIME:

3-5 weeks

PREFERRED SPECIMEN:

Buccal swab

ALTERNATIVE SPECIMEN:

 

Extracted DNA: 20ul of 50ng/ul, OD260/OD280 ~ 1.8, include details of extraction method with samples

 

Blood: 3-5cc drawn in EDTA (purple-top) tube

Ophthalmological Genetics Screening 

Test Information Sheet

Whole Exome Sequencing (WES) and Microarray

 

Description:

Genetic testing for ophthalmological or eye disorders is becoming an increasingly useful diagnostic tool, especially considering the promising developments in gene therapy in this field. Many genes are involved in the complex process of normal eye development and function. When pathogenic variants or mutations occur in these genes, a serious eye disease can result. The Ophthalmological Genetics Screening test is indicated for all individuals who would like to gain insights about their carrier status, predisposition status or affected status for ophthalmological conditions with a genetic basis, and other health risks recommended for screening by the ACMG. With this knowledge the test subject and his or her healthcare providers and counselors could personalize their health and medical management plan by implementing lifestyle modifications or treatments to prevent or better manage these disorders and improve the test subject’s current health state.

 

Whole exome sequencing (WES) can be used to analyze most of the genes in an individual at one time to identify the mutation(s) that are causing a genetic disorder or for health screening purposes. This test is most appropriate for individuals with a medical history or those with a family history of certain ophthalmological conditions who would like to be screened for ophthalmological conditions (Table 1) and for the ACMG recommended actionable conditions for diagnostic and/or prevention purposes (Table 2). WES targets the protein-coding regions of the genome, which represents approximately 20,000 genes and about 2% of the genome. Individual exons of each gene are initially captured or separated from the rest of the genome and analyzed using massively parallel sequencing. The patient’s sequence is then compared to the reference genome sequence to identify variants that are different and are therefore, potentially causative in the patient’s condition. Ideally, this test is performed by sequencing the patient and both parents (trios) together to identify de novo variants, assign phase to inherited variants for autosomal recessive inheritance or to determine autosomal dominant or X-linked inheritance. However, depending upon the availability of the parents, other family members may also be utilized to maximize the chance of identifying causative variants in the patient.

 

Microarray allows for the genotyping of specific variations or polymorphisms associated with ophthalmological conditions in the genome of an individual. It is different from WES in that specific variants are targeted either within the protein-coding regions or in the non-coding regions of the genome.

 

Test Method: 

WES will be performed on the patient and their family members to target the exonic regions of their genomes. These regions will be sequenced using the Illumina NovaSeq 6000 with 100-150 bp paired-end reads. The DNA sequence will then be mapped to, and analyzed in comparison with, the published human genome build (UCSC hg19 reference sequence). The targeted coding exons and splice junctions of the known protein-coding RefSeq genes will be assessed for the average depth of coverage (minimum average coverage of 80X for WES and 15X-30X for WGS) and data quality threshold values. Sequence changes in the patient will be compared to the other provided family members. All reportable sequence variants will be confirmed by Sanger sequence analysis using a separate DNA preparation. Average quality thresholds may range from >90-95% of the targeted region, indicating a small portion of the target region may not be covered with sufficient depth or quality to confidently call variant positions. In addition to Next Generation Sequencing (NGS) for capturing the whole exome, microarray method using Illumina iScan technology, will be used to capture regions of the genome that are within and outside of the protein coding genes (i.e. intergenic). SNPs (Single Nucleotide Polymorphisms) or variants from the microarray may also be used in the analysis to generate parts of this report or for research purposes and for improving the report in the future. The sequencing, genotyping, alignment, and variant calling of the data will be performed at the Gene by Gene, Ltd. laboratory located in 1445 North Loop West, Suite 760 Houston, TX 77008. Analysis, interpretation and report will be performed by TOVANA HEALTH located at 945 McKinney St. Suite# 11977 Houston, TX 77002.

 

Limitations: 

Absence of a causative variant(s) related to the reported phenotype by the WES and microarray methods does not exclude a genetic basis of the individual’s condition. Some types of genetic abnormalities, such as copy number changes, trinucleotide repeat expansions, small insertion/deletions and X-linked recessive mutations which manifest in females due to skewed X-inactivation may not be detectable with the technologies utilized for this testing. This test does not analyze mitochondrial DNA sequence or epigenetic changes of the genome. It is possible that the genomic region where a disease-causing mutation exists in the proband was not captured or accurately mapped to the reference sequence using the current technologies and therefore was not detected. Additionally, it is possible that a particular genetic abnormality may not be recognized as the underlying cause of the genetic disorder due to incomplete scientific knowledge about the function of all genes in the human genome and the impact of variations in those genes. Variants in genes associated with ophthalmological conditions are included in this report (Table 1). In addition, based on the consent process, this individual may have opted to receive clinically relevant incidental findings that are actionable or preventive health conditions, not related to the cardiovascular disease phenotype in this individual, and may have also been included in this report (Table 2). This report has been evaluated and accredited by the College of American Pathologists (CAP) for the clinical whole exome and clinical microarray sections of the report.

 

Table 1 – List of ophthalmological conditions genetically screened (416 total genes screened/analysed)

 

Conditions Included (but not limited to)

Albinism

Aniridia

Anterior segment dysgenesis syndrome

Autosomal dominant and X-linked retinitis pigmentosa

Autosomal recessive and X-linked retinitis pigmentosa

Axenfeld-Rieger syndrome

Bardet-Biedl syndrome

CHARGE syndrome

Choroideremia

Cone-rod dystrophy

Congenital cataracts

Congenital stationary night blindness (CSNB)

Corneal dystrophy

Duane-Radial ray syndrome

Ectopia lentis

Flecked retina disorders

Glaucoma

Hereditary optic atrophy

Leber congenital amaurosis

Leber hereditary optic atrophy

Macular degeneration (based on single genes or monogenic)

Microphthalmia-Anophthalmia-Coloboma (MAC)

Oculo-Facio-Cardio-Dental syndrome

Oculomotor

Ophthalmoplegia

Retinoblastoma

Senior-Loken syndrome

Stargardt disease and macular dystrophy

Stickler syndrome and high myopia

Usher syndrome

Vitreoretinopathy and Wagner syndrome

 

 

Table 2 – List of 59 conditions recommended for testing by the American College of Medical Genetics and Genomics (ACMGG)

 

Disease name and MIM Number

Gene and MIM Number

Adenomatous polyposis coli (MIM 175100)

APC (MIM 611731)

Aortic aneurysm, familial thoracic 4 (MIM 132900)

MYH11 (MIM 160745)

Aortic aneurysm, familial thoracic 6 (MIM 611788)

ACTA2 (MIM 102620)

Arrhythmogenic right ventricular cardiomyopathy, type 5 (MIM 604400)

TMEM43 (MIM 612048)

Arrhythmogenic right ventricular cardiomyopathy, type 8 (MIM 607450)

DSP (MIM 125647)

Arrhythmogenic right ventricular cardiomyopathy, type 9 (MIM 609040)

PKP2 (MIM 602861)

Arrhythmogenic right ventricular cardiomyopathy, type 10 (MIM 610193)

DSG2 (MIM 125671)

Arrhythmogenic right ventricular cardiomyopathy, type 11 (MIM 610476)

DSC2 (MIM 125645)

Breast-ovarian cancer, familial 1 (MIM 604370)

BRCA1 (MIM 113705)

Breast-ovarian cancer, familial 2 (MIM 612555)

BRCA2 (MIM 600185)

Brugada syndrome 1 (MIM 601144)

SCN5A (MIM 600163)

Catecholaminergic polymorphic ventricular tachycardia (MIM 604772)

RYR2 (MIM 180902)

Dilated cardiomyopathy 1A (MIM 115200)

LMNA (MIM 150330)

MYBPC3 (MIM 600958)

Ehlers-Danlos syndrome, type 4 (MIM 130050)

COL3A1 (MIM 120180)

Fabry’s disease (MIM 301500)

GLA (MIM 300644)

Familial hypercholesterolemia (MIM 143890)

APOB (MIM 107730)

LDLR (MIM 606945)

Familial hypertrophic cardiomyopathy 1 (MIM 192600)

MYH7 (MIM 160760)

Familial hypertrophic cardiomyopathy 3 (MIM 115196)

TPM1 (MIM 191010)

Familial hypertrophic cardiomyopathy 4 (MIM 115197)

MYBPC3 (MIM 600958)

Familial hypertrophic cardiomyopathy 6 (MIM 600858)

PRKAG2 (MIM 602743)

Familial hypertrophic cardiomyopathy 7 (MIM 613690)

TNNI3 (MIM 191044)

Familial hypertrophic cardiomyopathy 8 (MIM 608751)

MYL3 (MIM 160790)

Familial hypertrophic cardiomyopathy 10 (MIM 608758)

MYL2 (MIM 160781)

Familial hypertrophic cardiomyopathy 11 (MIM 612098)

ACTC1 (MIM 102540)

Familial medullary thyroid carcinoma (MIM 155240)

RET (MIM 164761)

Hypercholesterolemia, autosomal dominant, 3 (MIM 603776)

PCSK9 (MIM 607786)

Juvenile polyposis (MIM 174900)

BMPR1A (MIM 601299)

SMAD4 (MIM 600993)

Left ventricular noncompaction 6 (MIM 601494)

TNNT2 (MIM 191045)

Li-Fraumeni syndrome 1 (MIM 151623)

TP53 (MIM 191170)

Loeys-Dietz syndrome type 1A (MIM 609192)

TGFBR1 (MIM 190181)

Loeys-Dietz syndrome type 1B (MIM 610168)

TGFBR2 (MIM 190182)

Loeys-Dietz syndrome type 2A (MIM 608967)

TGFBR1 (MIM 190181)

Loeys-Dietz syndrome type 2B (MIM 610380)

TGFBR2 (MIM 190182)

Loeys-Dietz syndrome type 3 (MIM 613795)

SMAD3 (MIM 603109)

Long QT syndrome 1 (MIM 192500)

KCNQ1 (MIM 607542)

Long QT syndrome 2 (MIM 613688)

KCNH2 (MIM 152427)

Long QT syndrome 3 (MIM 603830)

SCN5A (MIM 600163)

Lynch syndrome (MIM 120435)

MLH1 (MIM 120436)

MSH2 (MIM 609309)

MSH6 (MIM 600678)

PMS2 (MIM 600259)

Malignant hyperthermia (MIM 145600)

RYR1 (MIM 180901)

CACNA1S (MIM 114208)

Marfan syndrome (MIM 154700)

FBN1 (MIM 134797)

TGFBR1 (MIM 190181)

Multiple endocrine neoplasia, type 1 (MIM 131100)

MEN1 (MIM 613733)

Multiple endocrine neoplasia, type 2a (MIM 171400)

RET (MIM 164761)

Multiple endocrine neoplasia, type 2b (MIM 162300)

RET (MIM 164761)

MYH-associated polyposis (MIM 608456)

MUTYH (MIM 604933)

Neurofibromatosis, type 2 (MIM 101000)

NF2 (MIM 607379)

Ornithine transcarbamylase deficiency (MIM 311250)

OTC (MIM 300461)

Paragangliomas 1 (MIM 168000)

SDHD (MIM 602690)

Paragangliomas 2 (MIM 601650)

SDHAF2 (MIM 613019)

Paragangliomas 3 (MIM 605373)

SDHC (MIM 602413)

Paragangliomas 4 (MIM 115310)

SDHB (MIM 185470)

Peutz-Jeghers syndrome (MIM 175200)

STK11 (MIM 602216)

Pilomatrixoma (MIM 132600)

MUTYH (MIM 604933)

PTEN hamartoma tumor syndrome (MIM 153480)

PTEN (MIM 601728)

Retinoblastoma (MIM 180200)

RB1 (MIM 614041)

Tuberous sclerosis 1 (MIM 191100)

TSC1 (MIM 605284)

Tuberous sclerosis 2 (MIM 613254)

TSC2 (MIM 191092)

Von Hippel-Lindau syndrome (MIM 193300)

VHL (MIM 608537)

Wilms tumor (MIM 194070)

WT1 (MIM 607102)

Wilson disease (MIM 277900)

ATP7B (MIM 606882)

 

 

Ordering:

CATALOG NUMBER:

1100126, 1197226, 1100026

TURNAROUND TIME:

3-5 weeks

PREFERRED SPECIMEN:

Buccal swab

ALTERNATIVE SPECIMEN:

 

Extracted DNA: 20ul of 50ng/ul, OD260/OD280 ~ 1.8, include details of extraction method with samples

 

Blood: 3-5cc drawn in EDTA (purple-top) tube

Dermatological Genetics Screening 

Test Information Sheet

Whole Exome Sequencing (WES) and Microarray

 

Description:

Some genetic diseases impact the dermis or skin. Dermatological problems may range from minor to extremely complex and can be inherited. The Dermatological Genetics Screening test is indicated for all individuals who would like to gain insights about their carrier status, predisposition status or affected status for dermatological conditions with a genetic basis, and other health risks recommended for screening by the ACMG. With this knowledge the test subject and his or her healthcare providers and counselors could personalize their health and medical management plan by implementing lifestyle modifications or treatments to prevent or better manage these disorders and improve the test subject’s current health state.

 

Whole exome sequencing (WES) can be used to analyze most of the genes in an individual at one time to identify the mutation(s) that are causing a genetic disorder or for health screening purposes. This test is most appropriate for individuals with a medical history or those with a family history of certain dermatological conditions who would like to be screened for dermatological conditions (Table 1) and for the ACMG recommended actionable conditions for diagnostic and/or prevention purposes (Table 2). WES targets the protein-coding regions of the genome, which represents approximately 20,000 genes and about 2% of the genome. Individual exons of each gene are initially captured or separated from the rest of the genome and analyzed using massively parallel sequencing. The patient’s sequence is then compared to the reference genome sequence to identify variants that are different and are therefore, potentially causative in the patient’s condition. Ideally, this test is performed by sequencing the patient and both parents (trios) together to identify de novo variants, assign phase to inherited variants for autosomal recessive inheritance or to determine autosomal dominant or X-linked inheritance. However, depending upon the availability of the parents, other family members may also be utilized to maximize the chance of identifying causative variants in the patient.

 

Microarray allows for the genotyping of specific variations or polymorphisms associated with dermatological conditions in the genome of an individual. It is different from WES in that specific variants are targeted either within the protein-coding regions or in the non-coding regions of the genome.

 

Test Method: 

WES will be performed on the patient and their family members to target the exonic regions of their genomes. These regions will be sequenced using the Illumina NovaSeq 6000 with 100-150 bp paired-end reads. The DNA sequence will then be mapped to, and analyzed in comparison with, the published human genome build (UCSC hg19 reference sequence). The targeted coding exons and splice junctions of the known protein-coding RefSeq genes will be assessed for the average depth of coverage (minimum average coverage of 80X for WES and 15X-30X for WGS) and data quality threshold values. Sequence changes in the patient will be compared to the other provided family members. All reportable sequence variants will be confirmed by Sanger sequence analysis using a separate DNA preparation. Average quality thresholds may range from >90-95% of the targeted region, indicating a small portion of the target region may not be covered with sufficient depth or quality to confidently call variant positions. In addition to Next Generation Sequencing (NGS) for capturing the whole exome, microarray method using Illumina iScan technology, will be used to capture regions of the genome that are within and outside of the protein coding genes (i.e. intergenic). SNPs (Single Nucleotide Polymorphisms) or variants from the microarray may also be used in the analysis to generate parts of this report or for research purposes and for improving the report in the future. The sequencing, genotyping, alignment, and variant calling of the data will be performed at the Gene by Gene, Ltd. laboratory located in 1445 North Loop West, Suite 760 Houston, TX 77008. Analysis, interpretation and report will be performed by TOVANA HEALTH located at 945 McKinney St. Suite# 11977 Houston, TX 77002.

 

Limitations: 

Absence of a causative variant(s) related to the reported phenotype by the WES and microarray methods does not exclude a genetic basis of the individual’s condition. Some types of genetic abnormalities, such as copy number changes, trinucleotide repeat expansions, small insertion/deletions and X-linked recessive mutations which manifest in females due to skewed X-inactivation may not be detectable with the technologies utilized for this testing. This test does not analyze mitochondrial DNA sequence or epigenetic changes of the genome. It is possible that the genomic region where a disease-causing mutation exists in the proband was not captured or accurately mapped to the reference sequence using the current technologies and therefore was not detected. Additionally, it is possible that a particular genetic abnormality may not be recognized as the underlying cause of the genetic disorder due to incomplete scientific knowledge about the function of all genes in the human genome and the impact of variations in those genes. Variants in genes associated with dermatological conditions are included in this report (Table 1). In addition, based on the consent process, this individual may have opted to receive clinically relevant incidental findings that are actionable or preventive health conditions, not related to the cardiovascular disease phenotype in this individual, and may have also been included in this report (Table 2). This report has been evaluated and accredited by the College of American Pathologists (CAP) for the clinical whole exome and clinical microarray sections of the report.

 

Table 1 – List of dermatological conditions genetically screened (148 total genes screened/analyzed)

 

Conditions Included (but not limited to)

Aicardi-Goutieres syndrome (AGS)

Basal cell nevus syndrome

Birt-Hogg-Dubé syndrome

Cardio-Facio-Cutaneous syndrome

Cutis laxa

Dyskeratosis congenita

Ectodermal Dysplasia with or without Tooth Agenesis

Epidermolysis bullosa

Epidermolysis bullosa junctional

Epidermolysis bullosa simplex

Ichthyosis (congenital and extended)

Legius syndrome

Lynch syndrome

Melanoma

Melanoma-pancreatic cancer syndrome

Neurofibromatosis, type 2

Noonan syndrome with Multiple Lentigines

PTEN-related disorders

Schwannomatosis

TP63-related disorders

Tuberous sclerosis complex

Van der Woude syndrome

Waardenburg syndrome

 

 

Table 2 – List of 59 conditions recommended for testing by the American College of Medical Genetics and Genomics (ACMGG)

 

Disease name and MIM Number

Gene and MIM Number

Adenomatous polyposis coli (MIM 175100)

APC (MIM 611731)

Aortic aneurysm, familial thoracic 4 (MIM 132900)

MYH11 (MIM 160745)

Aortic aneurysm, familial thoracic 6 (MIM 611788)

ACTA2 (MIM 102620)

Arrhythmogenic right ventricular cardiomyopathy, type 5 (MIM 604400)

TMEM43 (MIM 612048)

Arrhythmogenic right ventricular cardiomyopathy, type 8 (MIM 607450)

DSP (MIM 125647)

Arrhythmogenic right ventricular cardiomyopathy, type 9 (MIM 609040)

PKP2 (MIM 602861)

Arrhythmogenic right ventricular cardiomyopathy, type 10 (MIM 610193)

DSG2 (MIM 125671)

Arrhythmogenic right ventricular cardiomyopathy, type 11 (MIM 610476)

DSC2 (MIM 125645)

Breast-ovarian cancer, familial 1 (MIM 604370)

BRCA1 (MIM 113705)

Breast-ovarian cancer, familial 2 (MIM 612555)

BRCA2 (MIM 600185)

Brugada syndrome 1 (MIM 601144)

SCN5A (MIM 600163)

Catecholaminergic polymorphic ventricular tachycardia (MIM 604772)

RYR2 (MIM 180902)

Dilated cardiomyopathy 1A (MIM 115200)

LMNA (MIM 150330)

MYBPC3 (MIM 600958)

Ehlers-Danlos syndrome, type 4 (MIM 130050)

COL3A1 (MIM 120180)

Fabry’s disease (MIM 301500)

GLA (MIM 300644)

Familial hypercholesterolemia (MIM 143890)

APOB (MIM 107730)

LDLR (MIM 606945)

Familial hypertrophic cardiomyopathy 1 (MIM 192600)

MYH7 (MIM 160760)

Familial hypertrophic cardiomyopathy 3 (MIM 115196)

TPM1 (MIM 191010)

Familial hypertrophic cardiomyopathy 4 (MIM 115197)

MYBPC3 (MIM 600958)

Familial hypertrophic cardiomyopathy 6 (MIM 600858)

PRKAG2 (MIM 602743)

Familial hypertrophic cardiomyopathy 7 (MIM 613690)

TNNI3 (MIM 191044)

Familial hypertrophic cardiomyopathy 8 (MIM 608751)

MYL3 (MIM 160790)

Familial hypertrophic cardiomyopathy 10 (MIM 608758)

MYL2 (MIM 160781)

Familial hypertrophic cardiomyopathy 11 (MIM 612098)

ACTC1 (MIM 102540)

Familial medullary thyroid carcinoma (MIM 155240)

RET (MIM 164761)

Hypercholesterolemia, autosomal dominant, 3 (MIM 603776)

PCSK9 (MIM 607786)

Juvenile polyposis (MIM 174900)

BMPR1A (MIM 601299)

SMAD4 (MIM 600993)

Left ventricular noncompaction 6 (MIM 601494)

TNNT2 (MIM 191045)

Li-Fraumeni syndrome 1 (MIM 151623)

TP53 (MIM 191170)

Loeys-Dietz syndrome type 1A (MIM 609192)

TGFBR1 (MIM 190181)

Loeys-Dietz syndrome type 1B (MIM 610168)

TGFBR2 (MIM 190182)

Loeys-Dietz syndrome type 2A (MIM 608967)

TGFBR1 (MIM 190181)

Loeys-Dietz syndrome type 2B (MIM 610380)

TGFBR2 (MIM 190182)

Loeys-Dietz syndrome type 3 (MIM 613795)

SMAD3 (MIM 603109)

Long QT syndrome 1 (MIM 192500)

KCNQ1 (MIM 607542)

Long QT syndrome 2 (MIM 613688)

KCNH2 (MIM 152427)

Long QT syndrome 3 (MIM 603830)

SCN5A (MIM 600163)

Lynch syndrome (MIM 120435)

MLH1 (MIM 120436)

MSH2 (MIM 609309)

MSH6 (MIM 600678)

PMS2 (MIM 600259)

Malignant hyperthermia (MIM 145600)

RYR1 (MIM 180901)

CACNA1S (MIM 114208)

Marfan syndrome (MIM 154700)

FBN1 (MIM 134797)

TGFBR1 (MIM 190181)

Multiple endocrine neoplasia, type 1 (MIM 131100)

MEN1 (MIM 613733)

Multiple endocrine neoplasia, type 2a (MIM 171400)

RET (MIM 164761)

Multiple endocrine neoplasia, type 2b (MIM 162300)

RET (MIM 164761)

MYH-associated polyposis (MIM 608456)

MUTYH (MIM 604933)

Neurofibromatosis, type 2 (MIM 101000)

NF2 (MIM 607379)

Ornithine transcarbamylase deficiency (MIM 311250)

OTC (MIM 300461)

Paragangliomas 1 (MIM 168000)

SDHD (MIM 602690)

Paragangliomas 2 (MIM 601650)

SDHAF2 (MIM 613019)

Paragangliomas 3 (MIM 605373)

SDHC (MIM 602413)

Paragangliomas 4 (MIM 115310)

SDHB (MIM 185470)

Peutz-Jeghers syndrome (MIM 175200)

STK11 (MIM 602216)

Pilomatrixoma (MIM 132600)

MUTYH (MIM 604933)

PTEN hamartoma tumor syndrome (MIM 153480)

PTEN (MIM 601728)

Retinoblastoma (MIM 180200)

RB1 (MIM 614041)

Tuberous sclerosis 1 (MIM 191100)

TSC1 (MIM 605284)

Tuberous sclerosis 2 (MIM 613254)

TSC2 (MIM 191092)

Von Hippel-Lindau syndrome (MIM 193300)

VHL (MIM 608537)

Wilms tumor (MIM 194070)

WT1 (MIM 607102)

Wilson disease (MIM 277900)

ATP7B (MIM 606882)

Ordering:

CATALOG NUMBER:

1100129, 1197229, 1100029

TURNAROUND TIME:

3-5 weeks

PREFERRED SPECIMEN:

Buccal swab

ALTERNATIVE SPECIMEN:

 

Extracted DNA: 20ul of 50ng/ul, OD260/OD280 ~ 1.8, include details of extraction method with samples

 

Blood: 3-5cc drawn in EDTA (purple-top) tube

Renal & Genitourinary Genetics Screening

Test Information Sheet

Whole Exome Sequencing (WES) and Microarray

 

Description:

Inherited or genetic renal or kidney disease affects around 10% of adults with end-stage kidney disease and up to 70% of children with early onset kidney disease. The urinary tract comprises the renal pelvis, the ureter, the urinary bladder, and the urethra. Congenital diseases of these structures with a genetic basis can lead to a range of diseases sometimes associated with fetal losses or kidney failure in childhood and later in life. A definitive diagnosis through genomic testing may negate the need for prolonged diagnostic investigations and surveillance, facilitate reproductive planning and provide accurate counselling for at-risk relatives. The Renal & Genitourinary Genetics Screening test is indicated for all individuals who would like to gain insights about their carrier status, predisposition status or affected status for renal & genitourinary conditions with a genetic basis, and other health risks recommended for screening by the ACMG. With this knowledge the test subject and his or her healthcare providers and counselors could personalize their health and medical management plan by implementing lifestyle modifications or treatments to prevent or better manage these disorders and improve the test subject’s current health state.

 

Whole exome sequencing (WES) can be used to analyze most of the genes in an individual at one time to identify the mutation(s) that are causing a genetic disorder or for health screening purposes. This test is most appropriate for individuals with a medical history or those with a family history of certain renal & genitourinary  conditions who would like to be screened for renal & genitourinary  conditions (Table 1) and for the ACMG recommended actionable conditions for diagnostic and/or prevention purposes (Table 2). WES targets the protein-coding regions of the genome, which represents approximately 20,000 genes and about 2% of the genome. Individual exons of each gene are initially captured or separated from the rest of the genome and analyzed using massively parallel sequencing. The patient’s sequence is then compared to the reference genome sequence to identify variants that are different and are therefore, potentially causative in the patient’s condition. Ideally, this test is performed by sequencing the patient and both parents (trios) together to identify de novo variants, assign phase to inherited variants for autosomal recessive inheritance or to determine autosomal dominant or X-linked inheritance. However, depending upon the availability of the parents, other family members may also be utilized to maximize the chance of identifying causative variants in the patient.

 

Microarray allows for the genotyping of specific variations or polymorphisms associated with renal & genitourinary conditions in the genome of an individual. It is different from WES in that specific variants are targeted either within the protein-coding regions or in the non-coding regions of the genome.

 

Test Method: 

WES will be performed on the patient and their family members to target the exonic regions of their genomes. These regions will be sequenced using the Illumina NovaSeq 6000 with 100-150 bp paired-end reads. The DNA sequence will then be mapped to, and analyzed in comparison with, the published human genome build (UCSC hg19 reference sequence). The targeted coding exons and splice junctions of the known protein-coding RefSeq genes will be assessed for the average depth of coverage (minimum average coverage of 80X for WES and 15X-30X for WGS) and data quality threshold values. Sequence changes in the patient will be compared to the other provided family members. All reportable sequence variants will be confirmed by Sanger sequence analysis using a separate DNA preparation. Average quality thresholds may range from >90-95% of the targeted region, indicating a small portion of the target region may not be covered with sufficient depth or quality to confidently call variant positions. In addition to Next Generation Sequencing (NGS) for capturing the whole exome, microarray method using Illumina iScan technology, will be used to capture regions of the genome that are within and outside of the protein coding genes (i.e. intergenic). SNPs (Single Nucleotide Polymorphisms) or variants from the microarray may also be used in the analysis to generate parts of this report or for research purposes and for improving the report in the future. The sequencing, genotyping, alignment, and variant calling of the data will be performed at the Gene by Gene, Ltd. laboratory located in 1445 North Loop West, Suite 760 Houston, TX 77008. Analysis, interpretation and report will be performed by TOVANA HEALTH located at 945 McKinney St. Suite# 11977 Houston, TX 77002.

 

Limitations: 

Absence of a causative variant(s) related to the reported phenotype by the WES and microarray methods does not exclude a genetic basis of the individual’s condition. Some types of genetic abnormalities, such as copy number changes, trinucleotide repeat expansions, small insertion/deletions and X-linked recessive mutations which manifest in females due to skewed X-inactivation may not be detectable with the technologies utilized for this testing. This test does not analyze mitochondrial DNA sequence or epigenetic changes of the genome. It is possible that the genomic region where a disease-causing mutation exists in the proband was not captured or accurately mapped to the reference sequence using the current technologies and therefore was not detected. Additionally, it is possible that a particular genetic abnormality may not be recognized as the underlying cause of the genetic disorder due to incomplete scientific knowledge about the function of all genes in the human genome and the impact of variations in those genes. Variants in genes associated with renal & genitourinary conditions are included in this report (Table 1). In addition, based on the consent process, this individual may have opted to receive clinically relevant incidental findings that are actionable or preventive health conditions, not related to the cardiovascular disease phenotype in this individual, and may have also been included in this report (Table 2). This report has been evaluated and accredited by the College of American Pathologists (CAP) for the clinical whole exome and clinical microarray sections of the report.

 

Table 1 – List of renal & genitourinary conditions genetically screened (125 total genes screened/analyzed)

 

Conditions Included (but not limited to)

17-alpha-hydroxylase/17,20-lyase deficiency

17-beta hydroxysteroid dehydrogenase 3 deficiency

3-beta-hydroxysteroid dehydrogenase deficiency

3-methylglutaconic aciduria, type V

46XY sex reversal 1

5-alpha reductase deficiency

Action myoclonus–renal failure syndrome

Alpha thalassemia X-linked intellectual disability syndrome

Alport syndrome

Alveolar capillary dysplasia with misalignment of pulmonary veins

Ankyloblepharon-ectodermal defects-cleft lip/palate syndrome

Atypical hemolytic uremic (aHUS)

Axenfeld-Rieger syndrome

Bardet-Biedl syndrome

Bartter syndrome

Bowen-Conradi syndrome

C3 glomerulopathy

Cardiac-urogenital syndrome

CHARGE syndrome

Congenital anomalies of kidney and urinary tract (CAKUT)

Congenital anomalies of kidney and urinary tract syndrome with or without hearing loss, abnormal ears, or developmental delay (CAKUTHED)

Dilated cardiomyopathy with ataxia syndrome

Duane-Radial Ray syndrome (DRRS)

Dyskeratosis congenita

Ehlers-Danlos syndrome, classic-like, 1

Epidermolysis bullosa simplex with muscular dystrophy

Floating-Harbor syndrome

Focal glomerulonephrosis

Hand-foot-genital syndrome

Hypospadias 1, X-linked

Hypospadias 2, X-linked

Intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita, and genital anomalies (IMAGe)

Joubert syndrome

Leydig cell hypoplasia

Lower urinary tract obstruction, congenital

Macrocephaly, alopecia, cutis laxa, and scoliosis

Meckel syndrome

Megacystis-microcolon-intestinal hypoperistalsis syndrome

Meier-Gorlin syndrome 7

Methemoglobinemia and ambiguous genitalia

Nephronophthisis

Nephrotic syndrome

Noonan syndrome with multiple lentigines (formerly called LEOPARD syndrome)

Opitz G/BBB syndrome

Opitz GBBB syndrome, type II

Otopalatodigital syndrome type 2

Perlman syndrome

Pigmentary disorder, reticulate, with systemic manifestations, X-linked

Polycystic kidney disease

Prune belly syndrome

Pseudohypoaldosteronism

Renal coloboma syndrome

Renal hypodysplasia/aplasia 1

Renal tubular acidosis with deafness

Robinow syndrome, autosomal dominant 1

Schinzel-Giedion syndrome

Simpson-Golabi-Behmel syndrome

Tetra-amelia syndrome 1

Thrombotic thrombocytopenic purpura, hereditary

Urofacial syndrome 1

VACTERL association, X-linked Hereditary motor neuropathies

Beckwith-Wiedemann syndrome

Birt-Hogg-Dube syndrome

Cowden syndrome 1

DICER1 syndrome

Fanconi anemia complementation group N

Leiomyomatosis and renal cell cancer

Lhermitte-Duclos syndrome

Li-Fraumeni syndrome

Lynch syndrome

Mismatch repair cancer syndrome

Mosaic variegated aneuploidy syndrome 1

Mosaic variegated aneuploidy syndrome 2

Mosaic variegated aneuploidy syndrome 3

Paragangliomas 1, with or without deafness

Paragangliomas 3

Paragangliomas 4

Paragangliomas 5

Parathyroid carcinoma (Hyperparathyroidism-jaw tumor syndrome)

Perlman syndrome

Pheochromocytoma

Renal cell carcinoma, papillary, 1, familial and somatic

Rhabdoid tumor predisposition syndrome 1

Rhabdoid tumor predisposition syndrome 2

Simpson-Golabi-Behmel syndrome, type 1

Tuberous sclerosis-1

Tuberous sclerosis-2

Tumor predisposition syndrome

von Hippel-Lindau syndrome

Wilms tumor (Wilms tumor, type 1, Nephroblastoma)

 

Table 2 – List of 59 conditions recommended for testing by the American College of Medical Genetics and Genomics (ACMGG)

 

Disease name and MIM Number

Gene and MIM Number

Adenomatous polyposis coli (MIM 175100)

APC (MIM 611731)

Aortic aneurysm, familial thoracic 4 (MIM 132900)

MYH11 (MIM 160745)

Aortic aneurysm, familial thoracic 6 (MIM 611788)

ACTA2 (MIM 102620)

Arrhythmogenic right ventricular cardiomyopathy, type 5 (MIM 604400)

TMEM43 (MIM 612048)

Arrhythmogenic right ventricular cardiomyopathy, type 8 (MIM 607450)

DSP (MIM 125647)

Arrhythmogenic right ventricular cardiomyopathy, type 9 (MIM 609040)

PKP2 (MIM 602861)

Arrhythmogenic right ventricular cardiomyopathy, type 10 (MIM 610193)

DSG2 (MIM 125671)

Arrhythmogenic right ventricular cardiomyopathy, type 11 (MIM 610476)

DSC2 (MIM 125645)

Breast-ovarian cancer, familial 1 (MIM 604370)

BRCA1 (MIM 113705)

Breast-ovarian cancer, familial 2 (MIM 612555)

BRCA2 (MIM 600185)

Brugada syndrome 1 (MIM 601144)

SCN5A (MIM 600163)

Catecholaminergic polymorphic ventricular tachycardia (MIM 604772)

RYR2 (MIM 180902)

Dilated cardiomyopathy 1A (MIM 115200)

LMNA (MIM 150330)

MYBPC3 (MIM 600958)

Ehlers-Danlos syndrome, type 4 (MIM 130050)

COL3A1 (MIM 120180)

Fabry’s disease (MIM 301500)

GLA (MIM 300644)

Familial hypercholesterolemia (MIM 143890)

APOB (MIM 107730)

LDLR (MIM 606945)

Familial hypertrophic cardiomyopathy 1 (MIM 192600)

MYH7 (MIM 160760)

Familial hypertrophic cardiomyopathy 3 (MIM 115196)

TPM1 (MIM 191010)

Familial hypertrophic cardiomyopathy 4 (MIM 115197)

MYBPC3 (MIM 600958)

Familial hypertrophic cardiomyopathy 6 (MIM 600858)

PRKAG2 (MIM 602743)

Familial hypertrophic cardiomyopathy 7 (MIM 613690)

TNNI3 (MIM 191044)

Familial hypertrophic cardiomyopathy 8 (MIM 608751)

MYL3 (MIM 160790)

Familial hypertrophic cardiomyopathy 10 (MIM 608758)

MYL2 (MIM 160781)

Familial hypertrophic cardiomyopathy 11 (MIM 612098)

ACTC1 (MIM 102540)

Familial medullary thyroid carcinoma (MIM 155240)

RET (MIM 164761)

Hypercholesterolemia, autosomal dominant, 3 (MIM 603776)

PCSK9 (MIM 607786)

Juvenile polyposis (MIM 174900)

BMPR1A (MIM 601299)

SMAD4 (MIM 600993)

Left ventricular noncompaction 6 (MIM 601494)

TNNT2 (MIM 191045)

Li-Fraumeni syndrome 1 (MIM 151623)

TP53 (MIM 191170)

Loeys-Dietz syndrome type 1A (MIM 609192)

TGFBR1 (MIM 190181)

Loeys-Dietz syndrome type 1B (MIM 610168)

TGFBR2 (MIM 190182)

Loeys-Dietz syndrome type 2A (MIM 608967)

TGFBR1 (MIM 190181)

Loeys-Dietz syndrome type 2B (MIM 610380)

TGFBR2 (MIM 190182)

Loeys-Dietz syndrome type 3 (MIM 613795)

SMAD3 (MIM 603109)

Long QT syndrome 1 (MIM 192500)

KCNQ1 (MIM 607542)

Long QT syndrome 2 (MIM 613688)

KCNH2 (MIM 152427)

Long QT syndrome 3 (MIM 603830)

SCN5A (MIM 600163)

Lynch syndrome (MIM 120435)

MLH1 (MIM 120436)

MSH2 (MIM 609309)

MSH6 (MIM 600678)

PMS2 (MIM 600259)

Malignant hyperthermia (MIM 145600)

RYR1 (MIM 180901)

CACNA1S (MIM 114208)

Marfan syndrome (MIM 154700)

FBN1 (MIM 134797)

TGFBR1 (MIM 190181)

Multiple endocrine neoplasia, type 1 (MIM 131100)

MEN1 (MIM 613733)

Multiple endocrine neoplasia, type 2a (MIM 171400)

RET (MIM 164761)

Multiple endocrine neoplasia, type 2b (MIM 162300)

RET (MIM 164761)

MYH-associated polyposis (MIM 608456)

MUTYH (MIM 604933)

Neurofibromatosis, type 2 (MIM 101000)

NF2 (MIM 607379)

Ornithine transcarbamylase deficiency (MIM 311250)

OTC (MIM 300461)

Paragangliomas 1 (MIM 168000)

SDHD (MIM 602690)

Paragangliomas 2 (MIM 601650)

SDHAF2 (MIM 613019)

Paragangliomas 3 (MIM 605373)

SDHC (MIM 602413)

Paragangliomas 4 (MIM 115310)

SDHB (MIM 185470)

Peutz-Jeghers syndrome (MIM 175200)

STK11 (MIM 602216)

Pilomatrixoma (MIM 132600)

MUTYH (MIM 604933)

PTEN hamartoma tumor syndrome (MIM 153480)

PTEN (MIM 601728)

Retinoblastoma (MIM 180200)

RB1 (MIM 614041)

Tuberous sclerosis 1 (MIM 191100)

TSC1 (MIM 605284)

Tuberous sclerosis 2 (MIM 613254)

TSC2 (MIM 191092)

Von Hippel-Lindau syndrome (MIM 193300)

VHL (MIM 608537)

Wilms tumor (MIM 194070)

WT1 (MIM 607102)

Wilson disease (MIM 277900)

ATP7B (MIM 606882)

 

 

Ordering:

CATALOG NUMBER:

1100132, 1197232, 1100032

TURNAROUND TIME:

3-5 weeks

PREFERRED SPECIMEN:

Buccal swab

ALTERNATIVE SPECIMEN:

 

Extracted DNA: 20ul of 50ng/ul, OD260/OD280 ~ 1.8, include details of extraction method with samples

 

Blood: 3-5cc drawn in EDTA (purple-top) tube

And More

  1. Bamshad et al. (2011) Exome sequencing as a tool for Mendelian disease gene discovery. Nature Reviews Genetics. 12:745-755.
  2. Clark MM et al. (2018) Meta-analysis of the diagnostic and clinical utility of genome and exome sequencing and chromosomal microarray in children with suspected genetic diseases. NPJ Genom Med. 2018 Jul 9;3:16.
  3. Green RC, Berg JS, Grody WW, et al. ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genet Med, 2013; 15(7):565-574.
  4. ACMG policy statement: updated recommendations regarding analysis and reporting of secondary findings in clinical genome-scale sequencing. Genet Med, 2014; Epub.
  5. Hindorff LA, MacArthur J (European Bioinformatics Institute), Morales J (European Bioinformatics Institute), Junkins HA, Hall PN, Klemm AK, and Manolio TA. A Catalog of Published Genome-Wide Association Studies.
  6. Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), 2018. World Wide Web URL: https://omim.org/.
  7. National Library of Medicine (US). Genetics Home Reference [Internet]. Bethesda (MD): The Library; 2013 Sep 16 [cited 2018 Mar 13]. Available from: https://ghr.nlm