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Pathogenic ASXL1 somatic variants in reference databases complicate germline variant interpretation for Bohring-Opitz
Colleen M Carlston1,2, Anne H O'Donnell-Luria3,4,5, Hunter R Underhill6,7
1Department of Pathology, University of Utah, Salt Lake City, Utah.
Human Mutation
|February 24, 2017
Summary
Genetic variant interpretation is complicated by somatic mosaicism. ASXL1 variants found in reference databases may be acquired, not inherited, impacting diagnoses like Bohring-Opitz syndrome.
Area of Science:
- Genetics
- Clinical Diagnostics
- Bioinformatics
Background:
- Reference population databases like ExAC are crucial for clinical variant interpretation.
- Pathogenic variants in highly penetrant, autosomal dominant pediatric conditions are expected to be rare in these databases.
Observation:
- A patient with Bohring-Opitz syndrome (BOS) presented with an ASXL1 variant previously linked to the condition.
- This ASXL1 variant was surprisingly found multiple times in the ExAC database, challenging initial interpretation.
Findings:
- ASXL1 variants, including pathogenic ones, can arise from acquired somatic mosaicism during aging.
- Analysis of ASXL1 truncating variants in ExAC suggests most are likely somatic, not germline.
Implications:
- Failure to account for somatic mosaicism can lead to misinterpreting variant pathogenicity.
- This may result in inaccurate assumptions about disease penetrance or misclassification of genetic variants.
Keywords:
ASXL1Bohring-Opitz syndromeDNMT3AExome Aggregation ConsortiumTatton-Brown-Rahman syndromeclonal hematopoiesis of indeterminate potentialsomatic mosaicismvariant interpretationMore Related Videos
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