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

Abstract

Purpose: 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.

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

Results: 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.

Conclusion: 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.

Keywords: Disorders of somatic mosaicism; NGS; PI3K/AKT/mTOR; RAS/MAPK.

Figure 1

Genetic results summary of all the 936 cases with DoSM. In the cohort of 936 individuals with DoSM, 617 (65.9%) were reported with at least 1 clinically significant variant in the submitted specimen. A single clinically significant variant was identified in 584 of 617 (94.8%) cases, whereas 33 of 617 (5.2%) cases carried 2 clinically significant variants in the submitted specimens. Of the 33 cases with 2 clinically significant variants, 22 cases were identified with 2 clinically significant variants in the same gene, including 8 cases associated with LOF disease mechanism and 14 cases associated with GOF disease mechanism. The remaining 11 cases with 2 clinically significant variants in 2 different genes, including PIKC3A variants observed in 7 cases, and the remaining 4 cases with 2 clinically significant variants in non-PIK3CA genes only. DoSM, disorders of somatic mosaicism; GOF, gain of function; LOF, loss of function.

Figure 2

TEK protein structure and variant distribution in the 11 cases with TEK 2 clinically significant variants. TEK protein functional domains include EGF, FN3, TM, and TK. A total of 11 cases (case IDs from 2-a to 2-k) were listed with variant distribution in 2 major patterns. Variant distribution pattern #1 was observed in 5 cases with one p.Arg849Trp variant along with another variant either at the 3′ end (case IDs: 2-d, 2-e, and 2-g) or in the middle TK functional domain (case IDs: 2-b and 2-f). Pattern #2 was observed in 5 cases with the co-existence of the p.Tyr897Cys variant and another variant in cis at either p.Arg918His (case IDs: 2-a, 2-h, 2-I, and 2-k) or p.Arg915Cys (case ID: 2-c). EGF, epidermal growth factor-like domain; FN3, fibronectin type-III domain; TK, tyrosine kinase domain; TM, transmembrane domain.

Figure 3

PIK3CA protein structure and variant distribution in the 7 cases with clinically significant variants in PIK3CA and another gene. PIK3CA protein functional domains include ABD, C2, Helical, Kinase, and RBD. A total of 7 cases (case IDs from 3-a to 3-g) were listed with 5 partner genes (BRAF, GNAQ, KRAS, TEK, and RASA1). Each of the 7 cases has a unique PIK3CA variant: 3 harboring the PI3K helical domain, and 4 harboring the PI3/4-kinase domain. ABD, adapter binding domain; C2, calcium-dependent phospholipid-binding domain; Helical, PI3K helical domain; Kinase, PI3/4-kinase domain; RBD, Ras binding domain.