23. Paired exome analysis in Mosaic Disease yields expanded Genotype-Phenotype Associations

Introduction Somatic mosaicism is increasingly detectable through the use of highly sensitive molecular methodologies. Knowledge of the genetic underpinnings of mosaic disease can aid in diagnosis, inform management and surveillance, and guide therapeutic decision making. Herein, we examine the impact of comprehensive genomic analysis of paired tissue sources in individuals with clinical features of mosaic disease. Methods Comprehensive genomic profiling was performed across a cohort of 43 individuals with vascular, lymphatic, or capillary malformations, somatic overgrowth, hamartomatous lesions, or vascular tumors. High-depth paired exome sequencing of a comparator sample and disease-involved tissue was performed, along with whole transcriptome analysis of disease-involved tissue. Results The diagnostic yield within this cohort was 67% (29/43). Pathogenic variation included germline findings in 5 individuals, somatic findings in 22 individuals, and both germline and somatic variant contribution in 2 individuals. Variants occurred primarily within the PI3K-AKT and RAS-MAPK pathways. Oncogenic hotspot SNVs comprised 56% (19/34) of detected variants. Small indel events comprised 29% (10/34) of detected variation. Larger structural variation was detected in the form of an internal tandem duplication, as well as chromosome-arm level loss of heterozygosity. Expanded genotype-phenotype associations were gleaned from 5 individuals. Use of paired exome analysis extended the breadth of medically meaningful findings outside of somatic hotspots by 44%. Conclusion Paired exome sequencing is a sensitive method to detect germline and somatic variation within known and emerging gene targets enabling expanded genotype-phenotype associations to be learned.