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Hum Mutat. 2017 May;38(5):517-523. doi: 10.1002/humu.23203. Epub 2017 Mar 21.

Pathogenic ASXL1 somatic variants in reference databases complicate germline variant interpretation for Bohring-Opitz Syndrome.

Author information

Department of Pathology, University of Utah, Salt Lake City, Utah.
ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, Utah.
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts.
Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts.
Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts.
Department of Pediatrics, Division of Medical Genetics, University of Utah, Salt Lake City, Utah.
Department of Radiology, University of Utah, Salt Lake City, Utah.
Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, Massachusetts.


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.


ASXL1; Bohring-Opitz syndrome; DNMT3A; Exome Aggregation Consortium; Tatton-Brown-Rahman syndrome; clonal hematopoiesis of indeterminate potential; somatic mosaicism; variant interpretation

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