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Diagnostic implications of pitfalls in causal variant identification based on 4577 molecularly characterized families.

ABSTRACT: Despite large sequencing and data sharing efforts, previously characterized pathogenic variants only account for a fraction of Mendelian disease patients, which highlights the need for accurate identification and interpretation of novel variants. In a large Mendelian cohort of 4577 molecularly characterized families, numerous scenarios in which variant identification and interpretation can be challenging are encountered. We describe categories of challenges that cover the phenotype (e.g. novel allelic disorders), pedigree structure (e.g. imprinting disorders masquerading as autosomal recessive phenotypes), positional mapping (e.g. double recombination events abrogating candidate autozygous intervals), gene (e.g. novel gene-disease assertion) and variant (e.g. complex compound inheritance). Overall, we estimate a probability of 34.3% for encountering at least one of these challenges. Importantly, our data show that by only addressing non-sequencing-based challenges, around 71% increase in the diagnostic yield can be expected. Indeed, by applying these lessons to a cohort of 314 cases with negative clinical exome or genome reports, we could identify the likely causal variant in 54.5%. Our work highlights the need to have a thorough approach to undiagnosed diseases by considering a wide range of challenges rather than a narrow focus on sequencing technologies. It is hoped that by sharing this experience, the yield of undiagnosed disease programs globally can be improved.

SUBMITTER: AlAbdi L

PROVIDER: S-EPMC10465531 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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Diagnostic implications of pitfalls in causal variant identification based on 4577 molecularly characterized families.

AlAbdi Lama L Maddirevula Sateesh S Shamseldin Hanan E HE Khouj Ebtissal E Helaby Rana R Hamid Halima H Almulhim Aisha A Hashem Mais O MO Abdulwahab Firdous F Abouyousef Omar O Alqahtani Mashael M Altuwaijri Norah N Jaafar Amal A Alshidi Tarfa T Alzahrani Fatema F Alkuraya Fowzan S FS

Nature communications 20230829 1

Despite large sequencing and data sharing efforts, previously characterized pathogenic variants only account for a fraction of Mendelian disease patients, which highlights the need for accurate identification and interpretation of novel variants. In a large Mendelian cohort of 4577 molecularly characterized families, numerous scenarios in which variant identification and interpretation can be challenging are encountered. We describe categories of challenges that cover the phenotype (e.g. novel a ...[more]

PMID: 37644014

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Diagnostic implications of pitfalls in causal variant identification based on 4577 molecularly characterized families.

Publications

Diagnostic implications of pitfalls in causal variant identification based on 4577 molecularly characterized families.

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