ArticleGenetics in medicine : official journal of the American College of Medical Genetics2021
Evaluating the molecular diagnostic yield of joint genotyping-based approach for detecting rare germline pathogenic and putative loss-of-function variants.
Article in Genetics in medicine : official journal of the American College of Medical Genetics, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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Who cites it
3 citing papers in PubMed, 8 citations in OpenAlex.
- Integrative Analysis of Germline Rare Variants in Clear and Non-clear Cell Renal Cell Carcinoma.European urology open science · 2024Article
- Interplay of Mendelian and polygenic risk factors in Arab breast cancer patients.Genome medicine · 2023Article
- Germline predisposition to pediatric Ewing sarcoma is characterized by inherited pathogenic variants in DNA damage repair genes.American journal of human genetics · 2022Article
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Authors and funding
10 authors at 3 institutions in 2 countries.
Funding
Abstract
purposeCohort-based germline variant characterization is the standard approach for pathogenic variant discovery in clinical and research samples. However, the impact of cohort size on the molecular diagnostic yield of joint genotyping is largely unknown.
methodsHead-to-head comparison of the molecular diagnostic yield of joint genotyping in two cohorts of 239 cancer patients in the absence and then in the presence of 100 additional germline exomes.
resultsIn 239 testicular cancer patients, 4 (7.4%, 95% confidence interval [CI]: 2.1-17.9) of 54 pathogenic variants in the cancer predisposition and American College of Medical Genetics and Genomics (ACMG) genes were missed by one or both computational runs of joint genotyping. Similarly, 8 (12.1%, 95% CI: 5.4-22.5) of 66 pathogenic variants in these genes were undetected by joint genotyping in another independent cohort of 239 breast cancer patients. An exome-wide analysis of putative loss-of-function (pLOF) variants in the testicular cancer cohort showed that 162 (8.2%, 95% CI: 7.1-9.6) pLOF variants were only detected in one analysis run but not the other, while 433 (22.0%, 95% CI: 20.2-23.9%) pLOF variants were filtered out by both analyses despite having sufficient sequencing coverage.
conclusionOur analysis of the standard germline variant detection method highlighted a substantial impact of concurrently analyzing additional genomic data sets on the ability to detect clinically relevant germline pathogenic variants.
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