体細胞モザイク疾患における複雑な遺伝学：非悪性病変における複数の「ヒット」の発生率の評価

Vascular anomalies encompass a heterogeneous group of vascular tumors and malformations and are most often caused by singular somatic variants that arise in utero. The presence of multiple variants, including those in at least two different genes (multigenic variants), is rare in these mosaic disorders, and their contribution to histology and phenotype has not been well characterized. We present our molecular and histologic experience with multiple variants in a large cohort of individuals with vascular anomalies and other suspected somatic mosaic disorders. We performed a retrospective review of 1,299 individuals with suspected somatic mosaic disorders who were sequenced at our institution and identified 92 individuals (7%) with at least two clinically reportable variants. Our cohort includes eighteen individuals with multigenic variants with unknown phenotypic implications and thirteen individuals with well described multigenic variants with clear phenotypic significance. For many individuals, the multiple variants had clear clinical implications, including variants that may respond to targeted therapy (n=73) or germline variants (n=33) with surveillance implications for that individual and their immediate relatives. Provided clinical information and available H&E-stained slides (n=37) were reviewed, and lesions were classified according to established guidelines whenever possible. The majority of lesions had histologic features concordant with the observed genetic variants. However, four out of eighteen lesions with multigenic variants with unknown phenotypic implications had unique or unusual histologic features that did not fit into a specific diagnostic category. Our results demonstrate that broad sequencing of vascular anomalies, even in patients with known pathogenic variants, can be useful to identify additional clinically relevant variants which may refine diagnosis, respond to targeted therapy, or reveal a germline disorder that contributes to phenotype and may require increased surveillance.