Co-existence of 2 clinically significant variants causing disorders of somatic mosaicism

Disorders of somatic mosaicism (DoSM) are a heterogeneous group of conditions caused by postzygotic variants in genes within the PI3K/AKT/mTOR and RAS/MAPK signaling pathway. The co-existence of 2 activating variants in this disease group is extremely rare.

A deep sequencing next-generation sequencing assay for the molecular diagnosis of DoSM was run on 936 individuals with DoSM.

A single pathogenic or likely pathogenic (P/LP) variant was identified in 584 of 617 (94.8%) positive cases; 33 of 617 (5.2%) cases carried 2 P/LP variants. Of these 33 cases, 22 carried 2 P/LP variants in the same gene, including 8 associated with a loss-of-function disease mechanism and 14 associated with a gain-of-function disease mechanism. Eleven cases had P/LP variants in 2 different genes, including PIKC3A variants in 7 cases and 4 cases with 2 P/LP variants in non-PIK3CA genes.

To our knowledge, this is the largest cohort with the co-existence of 2 P/LP somatic variants causing DoSM. The study of the co-existence of 2 clinically significant variants in DoSM requires unique considerations regarding variant allelic fractions, the combination of variants, affected tissue types, and the severity of the disease. Investigations into this unique cohort may further our understanding of the disease mechanism and potential therapeutic options.