Exome Sequencing of Premature Adult Deaths in the Population-Based Polish WOBASZ Study: High Yield of Reportable Findings

Premature adult death (PAD) may conceal clinically relevant monogenic disease. We performed exome sequencing in 127 deceased participants of the population-based Polish WOBASZ study (91 males, 36 females; mean age at death 47 years, range 26–55). Reportable variants were identified in 52 individuals (40.9%); after excluding low-penetrance risk factors and speculative findings, 39 (30.7%) remained. Genetic findings were considered highly likely to have contributed to cause of death in 9 (7.1%) and moderately likely in 16 (12.6%). Thirteen participants (10.2%) carried reportable variants in genes on the ACMG secondary findings list. Cancer-predisposition variants were enriched relative to 1,000 reference adults [3.9% vs 1.5%; Odds ratio (OR) 2.7, p=0.065], and genotype–cause-of-death concordance was greater for cancer than non-cancer ACMG findings (3/5 vs 0/8; OR 23.8, p=0.035). Broadly defined genetic cancer predisposition was present in 8 (28.6%) cancer deaths, involving BRCA1, BRCA2, MSH6, EPCAM, RAD51D, CHEK2 and JAK2. Additional findings included dominant neurodevelopmental variants, variants in genes associated with cardiomyopathy and vascular disease, two 22q11.2 deletions, and candidate novel associations implicating DROSHA, KCNQ1 and LZTS1 in germline cancer predisposition and EOLA2 and ARID4A in metabolic or neurodevelopmental disease. These results support broad exome/genome-based molecular autopsy in PAD.