Current Status of Genetic Testing and Mosaic Variant Assessment in Somatic Overgrowth and Vascular Anomalies: Insights from the Cancer Genomics Consortium Working Group.

Abstract

Somatic overgrowth and vascular anomalies are often present at birth but may only be clinically recognized later in life. Affected tissues commonly include veins and arteries, skin, adipose tissue, bone, and brain, resulting in a broad phenotypic spectrum encompassing vascular malformations, lipomatous and melanocytic nevus syndromes, skeletal abnormalities, and brain malformations. These conditions are typically caused by postzygotic variants present in a subset of cells due to mosaicism. The developmental timing and cell lineages involved determine the extent and distribution of affected tissues. While germline variants and their clinical consequences are well characterized, the impact of somatic mosaic variants remains less well understood. Because these variants are often absent or present at very low levels in blood, sensitive assays and analysis of affected tissues are required for detection. Advances in high-depth next-generation sequencing have enabled reliable identification of low-level mosaic variants and are central to the genetic diagnosis of these disorders. Numerous causative genes have been described, most notably activating variants in the PI3K-MTOR and RAS-MAPK pathways. Genetic testing provides diagnostic confirmation, informs prognosis and recurrence risk, and in some cases enables targeted therapy, such as alpelisib for PIK3CA-related overgrowth spectrum. However, testing strategies vary across laboratories in gene panel content, sequencing depth, and tissue requirements, leading to inconsistent diagnostic approaches. This review summarizes known causative genes, current testing methodologies, variant interpretation and reporting practices, major genomic alteration classes and recurrent hotspot variants, and highlights key knowledge gaps from clinical and laboratory perspectives.