Identifying novel mutations responsible for colon cancer predisposition

Tel Aviv Sourasky Medical Center

Identifying novel mutations responsible for colon cancer predisposition

March 3, 2018

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. At the time, using their available genetic tests (typically small gene panels), only 30% of these families were genetically diagnosed. They thought it is not enough to be acceptable. What about the other 70%? Top clinicians at the department, who are experts in the genetics of familial colon cancer, designed and launched a small pilot program, with 5 families presenting early hamartomatous polyposis. These families would be the whole genome sequenced and deeply analyzed utilizing the Geneyx Analysis platform. All genetic variants across a patient’s 3 billion bases of DNA would be used to try to identify the genetic cause of their early predisposition to the disease.

Geneyx solution:

Geneyx Analysis automatically downloaded the raw Whole Genome Sequencing (WGS) genetic data, ran the rapid DRAGEN primary and secondary pipelines with quality control processes, called millions of genetic variants including structural and copy number variations, and prepared fully annotated cases for analysis and interpretation by the GI clinical team. All that remained was to enter the phenotypes of the patients.

The findings:

Remarkably, the genetic culprit was detected in all 5 cases, presenting the subsequently validated causal events at the highest ranks, out of tens of thousands of candidate variants. This included a loss-of-function SNV in BMPR1A (for this proband the suspected gene was SMAD4 for which Sanger sequencing produced no clinically significant finding) and three SV events – two distinct cases of inversions, one affecting BMPR1A and the other affecting STK11, and deletion in BMPR1A identified in two unrelated probands of a common ethnic origin, a possible founder mutation.

Prospective scalability:

Identifying the specific mutation responsible for cancer predisposition is crucial to each of these families, both for clinical surveillance and preventive treatments for the carriers of the mutation. It is also crucial for family planning, especially in severe cases of very early and lethal disease.

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

Confirming Achromatopsia Diagnosis with 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.

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

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.

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.

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.

Better Data for Better Health

Tel Aviv Sourasky Medical Center