Profiling PIK3CA variants in disorders of somatic mosaicism

Purpose: Variants in PIK3CA (encoding p110α; the catalytic subunit of PI3K) characterize some disorders of somatic mosaicism (DoSM) conditions with clinical features, including sporadic overgrowth and vascular malformations. Here, we profile PIK3CA variants in DoSM. Methods: We applied a next-generation, sequencing-based, laboratory-developed test, using an average coverage of approximately 2000× for up to 37 genes associated with DoSM, on a cohort of 1197 patients with DoSM referred for clinical genomics services between 2013 and 2022. Results: We identified clinically reportable variants in 747 (62.4%) individuals in this cohort. Notably, 371 clinically reportable variants in PIK3CA were identified in 368 patients, constituting approximately 49.2% of all patients with reportable findings. Variants in the C2 domain of p110α are enriched in DoSM (this cohort) compared with those of cancer (Catalogue of Somatic Mutations in Cancer [COSMIC] database), highlighting the role of the C2 domain in driving uncontrolled cell proliferation in DoSM. Furthermore, we report 17 novel variants in PIK3CA that are not previously reported in DoSM and describe clinical presentation correlation for 4 novel variants. Conclusion: Our findings from the largest single-center cohort of patients with DoSM expand the spectrum of variants in PIK3CA and shed light on the less-studied role of the C2 domain in the pathogenesis of DoSM.