43. Challenges of classifying variants associated with disorders of somatic mosaicism and guideline creation

Abstract

Disorders of somatic mosaicism (DoSM) constitute rare genetic disorders characterized by post-zygotic events leading to segmental distribution of disease. The early presentation of associated phenotypes often mimics germline diseases, complicating molecular diagnosis. Additionally, current guidelines from the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) focus specifically on germline and cancer variants, complicating the interpretation of DoSM-associated somatic variation. The ClinGen Brain Malformation Expert Panel guidelines have created valuable updates to account for brain-specific disorders of somatic mosaicism, but their applicability to the diverse DoSM presentations is limited. At Washington University School of Medicine, we have identified shortcomings in applying ACMG/AMP germline guidelines to DoSM variants, prompting the development of DoSM-specific variant interpretation guidelines. Leveraging our laboratory's extensive experience in somatic variation interpretation, we have developed DoSM guidelines that are applicable across genes and clinical contexts pertinent to non-cancerous somatic testing. These guidelines address the critical need for accurate somatic variant interpretation in DoSM, where treatment advances hinge on understanding the overlap between somatic variants in DoSM and tumors. This comprehensive framework addresses the gap in existing guidelines, offering an iinvaluable resource for clinical laboratories engaged in non-cancerous somatic testing and advancing precision medicine for patients with DoSM. We will present the developed guidelines, discuss challenges specific to DoSM and criteria development, and interesting cases studies where DoSM-specific guidelines were critical to accurate diagnosis.