Whole Exome Sequencing (WES)

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Next generation sequencing (NGS) technologies using gene panels screen for mutations in a limited number of pre-selected genes. NGS using WES enables a more comprehensive analysis that covers the protein coding regions (exons containing more than 80% of disease-causing mutations) and exon-intron boundaries of all human genes.

Coverage may not be uniform in all the genes tested and large rearrangements cannot be reliably detected by these NGS methods. Therefore additional testing may be required in mutation-negative patients to exclude this possibility.

WES usually takes 3-6 weeks before a report is provided since the medical scientists who perform the test as part of a multi-disciplinary team also evaluate previous pathology reports, and other information relevant to the genes prioritised for WES. All causative gene variants identified are furthermore confirmed with a second method called Sanger sequencing, to ensure accuracy of positive genetic results.

WES is evaluated in a clinical context to distinguish between monogenic and polygenic familial breast cancer, or multifactorial disease caused by gene-environment interaction. This is necessary to identify patients with different treatment requirements. Our pathology-supported genetic testing approach enables the generation of a comprehensive report, which highlights both genetic and modifiable lifestyle risk factors relevant to the clinical profile of the tested individual.

Management of patients can be extended beyond familial risk using WES, to also assess the role of genetics in (treatment-related) co-morbidities and medication side effects, if clinically indicated. The report will be customised according to the information provided in the questionnaire at referral, integrated with the genetic findings.

In some patients, due to their unique genetic blueprint, variants of uncertain clinical significance are identified. This is why the WES service is linked to the generation of a research database. The WES data is stored with approval of the patient and may be re-analysed on request if new information becomes available of relevance to the patient or to address a new health concern or family condition that may present in future.

Tools developed for WES (to select genes for variant calling and to facilitate interpretation):

Step 1: Genecare pre-screen report

· BRCA1/2 checklist (available on the CANSA website), and/or

· Questionnaire-based lifestyle assessment (Genecare pre-screen report)

Step 2: Pathway panel screen

· BRCA1/2 family-specific, population-specific founder mutation, or full gene screen, and/or

· Chronic disease screen (Wellness GeneScreen / GenePro performed by MDS lab in Durban)

Step 3: Gknowmix knowledge database

· Data integration for translation into adaptable reports: from pre-screen assessment to panel-based testing to WES in genetically uncharacterised cases.