Premium
Pathogenic ASXL1 somatic variants in reference databases complicate germline variant interpretation for Bohring–Opitz Syndrome
Author(s) -
Carlston Colleen M.,
O'DonnellLuria Anne H.,
Underhill Hunter R.,
Cummings Beryl B.,
Weisburd Ben,
Minikel Eric V.,
Birnbaum Daniel P.,
Tvrdik Tatiana,
MacArthur Daniel G.,
Mao Rong
Publication year - 2017
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.23203
Subject(s) - biology , exome sequencing , genetics , penetrance , exome , database , germline , phenotype , germline mutation , population , failure to thrive , gene , mutation , medicine , environmental health , computer science
Abstract The clinical interpretation of genetic variants has come to rely heavily on reference population databases such as the Exome Aggregation Consortium (ExAC) database. Pathogenic variants in genes associated with severe, pediatric‐onset, highly penetrant, autosomal dominant conditions are assumed to be absent or rare in these databases. Exome sequencing of a 6‐year‐old female patient with seizures, developmental delay, dysmorphic features, and failure to thrive identified an ASXL1 variant previously reported as causative of Bohring–Opitz syndrome (BOS). Surprisingly, the variant was observed seven times in the ExAC database, presumably in individuals without BOS. Although the BOS phenotype fit, the presence of the variant in reference population databases introduced ambiguity in result interpretation. Review of the literature revealed that acquired somatic mosaicism of ASXL1 variants (including pathogenic variants) during hematopoietic clonal expansion can occur with aging in healthy individuals. We examined all ASXL1 truncating variants in the ExAC database and determined most are likely somatic. Failure to consider somatic mosaicism may lead to the inaccurate assumption that conditions like BOS have reduced penetrance, or the misclassification of potentially pathogenic variants.