Curating the Clinical Genome 2024 ePoster Gallery-Challenges of Classifying Variants Associated with Disorders of Somatic Mosaicism and Classification Framework Creation

Challenges of Classifying Variants Associated with Disorders of Somatic Mosaicism and Classification Framework Creation

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The document discusses the challenges in classifying variants associated with disorders of somatic mosaicism and the creation of a classification framework. It notes that disorders of somatic mosaicism are rare conditions caused by post-zygotic events leading to segmental distribution of disease. The authors aim to establish a broadly-applicable framework for the classification of somatic variants associated with these disorders. The study identified 129 genes linked to disorders of somatic mosaicism and proposed a targeted hybrid capture-based test with a minimum coverage depth of 4000x. The framework includes multiple criteria modifications from ACMG/AMP guidelines, such as PS3, PS4, PM1, PM2, PM5, PM6, PP2, BA1, BS1, and BS2, and introduces a new criterion, PS_ Regulation. The framework's application includes the use of REVEL for predictive analysis of DoSM genes and ensuring concordance with ClinVar. The study recommends continued evaluation of the framework to enhance diagnostic accuracy and improve outcomes for individuals affected by disorders of somatic mosaicism. Overall, the document emphasizes the need for standardized guidelines specific to disorders of somatic mosaicism due to the unique nature of these conditions compared to germline or cancer variants.

Keywords

variants classification

somatic mosaicism disorders

classification framework

post-zygotic events

segmental distribution

hybrid capture-based test

minimum coverage depth

ACMG/AMP guidelines

REVEL predictive analysis

standardized guidelines

Alexa Dickson (dalexa@wustl.edu)