Interpreting variants in genes affected by clonal hematopoiesis in population data

Abstract

Reference population databases like the Genome Aggregation Database (gnomAD) have improved our ability to interpret the human genome. Variant frequencies and frequency-derived tools (such as depletion scores) have become fundamental to variant interpretation and the assessment of variant-gene-disease relationships. Clonal hematopoiesis (CH) obstructs variant interpretation as somatic variants that provide proliferative advantage will affect variant frequencies, depletion scores, and downstream filtering. Further, default filtering of variants or genes associated with CH risks filtering bona fide germline variants as variants associated with CH can also cause Mendelian conditions. Here, we provide our insights on interpreting population variant data in genes affected by clonal hematopoiesis, as well as recommendations for careful review of 36 established CH genes associated with neurodevelopmental conditions.