Success Story

Confirming Achromatopsia Diagnosis with Geneyx Analysis

December 8, 2022

Human vision relies on two types of photoreceptor cells: rods and cones. Rods are responsible for vision under low-light conditions, and cones are responsible for day-light vision and color perception. Cones can be further distinguished into three classes, and any alteration in a cone class can lead to color blindness (1). However, if all three cones are non-functional it leads to achromatopsia, which is an inability to see clearly in bright light, poor visual acuity, and color blindness (2).

Achromatopsia is an autosomal recessive and rare condition, with a frequency of 1 in 30,000 live births worldwide. There are a few genetic causes of achromatopsia, and one involves cyclic nucleotide-gated ion channels (CNGB3). Few mutations in CNGB3 have been characterized for achromatopsia, and the majority of these mutations are loss of function resulting in a truncated protein. Achromatopsia is typically diagnosed around six months of age due to intolerance to the perception of light (photophobia) and involuntary eye movement (nystagmus)(2).

A clinical geneticist team at the Hadassah Medical Center, Jerusalem, has been analyzing thousands of rare genetic disorders during the last decade and strives to provide accurate diagnoses to patients and their families. With their current platform, they achieve a diagnostic yield of approximately 50%, and for the remaining undiagnosed cases, they choose to implement Geneyx Analysis. One complex case they encountered was a female of Ethiopian descent that was diagnosed with achromatopsia. To confirm the clinical diagnosis, next-generation sequencing was performed. The fastq files were processed using the secondary pipeline integrated with Geneyx, and the VCF files were then annotated and analyzed using Geneyx Analysis.

Achromatopsia was entered in the phenotyper and resulted in a highly prioritized variant in the CNGB3 gene (Figure 1). Using the FastTrack filter logic, the variant displayed as the first candidate among 62,000 variants. The zygosity for this variant was homozygous in the autosomal recessive CNGB3 gene, and the ACMG classification showed a likely pathogenic finding. Of interest, this variant was a splice site donor near exon 9 of the CNGB3 gene but showed a low coverage profile upon BAM visualization. Further investigation was made to understand if this mutation was the result of a compound heterozygous mutation due to an overlapping CNV.

Figure 1: CNGB3 displayed as the candidate variant with achromatopsia used for phenotypic prioritization.

CNV analysis in Geneyx resulted in identifying a heterozygous deletion event that overlapped two exons of the CNGB3 gene. According to ClinVar, this event has been classified as pathogenic and was rare in control databases. This event was characterized by a high-quality score indicating that the significant reduction in coverage over this region was due to a deletion event. Furthermore, this confirmed an overlap with the splice site mutation in the CNGB3 gene, resulting in a compound heterozygous mutation (Figure 2).

Figure 2: Coverage profile for exon 9 of the CNGB3 gene shows deletion event overlapping with the splice site intronic variant, resulting in a compound heterozygous mutation.

In this case study, Geneyx Analysis was able to identify a rare compound heterozygous mutation associated with achromatopsia. Using phenotypic prioritization, the candidate variant was quickly identified and allowed the investigator to pursue a deeper understanding of the genetic profile. CNV analysis discovered an overlapping heterozygous deletion, which then characterized the causal finding as a compound heterozygous mutation of the CNGB3.  In summary, Geneyx Analysis is a leading variant analysis and interpretation platform that can handle complex cases, including compound mutations of CNVs and SNVs. For this reason, the Hadassah Medical Center in Jerusalem, and other hospitals worldwide, are able to continue to identify rare mutations using Geneyx Analysis and improve diagnostic yields and improve patient care.

Works Cited:

  1. Purves D, Augustine GJ, Fitzpatrick D, et al., editors. Neuroscience. 2nd edition. Sunderland (MA): Sinauer Associates; 2001. Cones and Color Vision. Available from:
  2. Kohl S, Jägle H, Wissinger B, Zobor D. Achromatopsia. 2004 Jun 24 [updated 2018 Sep 20]. In: Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2022. PMID: 20301591.


More success Stories

See Geneyx In Action

Detecting Uniparental disomy (UPD) with Geneyx Analysis

UPD occurs at a frequency of 1 in 2000 individuals worldwide (1). The most well-known conditions of UPD include Prader-Willi syndrome, characterized by binge-eating and obesity, and Angelman syndrome, which causes intellectual disability and impaired speech

Applying Geneyx for high-throughput diagnostic settings

Implementation of Geneyx Analysis allowed customized gene panels with automatic reporting capabilities to easily accommodate for their large sample workflows. Coupled with this workflow automation, was the requirement to have customized reports. The Geneyx team was able to provide their customization requests to render reports using dynamic and static information
Woman Scientist

Identifying multi-nucleotide variants associated with congenital hypotonia and global developmental delay

WGS identified a likely pathogenic, de novo variant in POLR2A, which has a strong association with the phenotype displayed by the individual. The variant was adjacent to a polymorphism variant that was inherited from one of the parents, and this caused their in-house pipeline to mis-identify it as an inherited MNV in the exome sequencing analysis. The WGS findings led to a positive finding that could be presented to the patient.
Congenital Hypotonia

Identifying a unique novel genetic event for juvenile Parkinson

With their current platform, they achieve a diagnostic yield of approximately 50%, and for the remaining undiagnosed cases, they choose to implement Geneyx Analysis. One complex case they encountered was a large family presenting with early onset Parkinson’s disease (Juvenile Parkinson), which affected several siblings born to closely related parents. The team had sent 10 samples for exome sequencing, which was the standard and most comprehensive genetic test available for clinical diagnostics. However, the results from exome sequencing were inconclusive, so they implemented whole genome sequencing on a subset of the family and analyzed the data with Geneyx.
Genetic Event for Juvenile Parkinson

Identifying novel  mutations responsible for colon  cancer predisposition

Prof Revital Kariv, M.D., and her team diagnose and treat patients with colon cancer. In many cases, they identify families with a clear predisposition to develop polyposis and thereafter colon cancer quite early in their lives, implying a strong inherited genetic background for the trait.
Colon Cancer

Increasing the accuracy and decreasing the time required for  clinical genetic analysis

In 2017, The genetic team at the largest pediatric hospital in Europe, Prof Antonio Novelli and his team of geneticists used to analyze dozens of rare genetic disorder cases per month.
L'ospedale Bambino Gesù (Foto Omniroma)

Selected Videos

Geneyx Analysis Version 5.12 Release