KCNK3 (also known as TASK1) was first reported as a risk factor for autosomal dominant pulmonary arterial hypertension in 2013 by Ma et al. (PMID: 23883380). Using variant filtering of whole-exome sequence data from three members of a multi-generational family, a novel heterozygous missense variant was identified that co-segregated with the disease, but with some evidence of reduced penetrance. Independent validation by sequence analysis detected additional missense variants in 2/92 familial and 3/230 sporadic cases. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Summary of genetic evidence: 7 points. Variants in this gene have since been reported in at least 22 probands in 11 publications. All variants are rare, likely deleterious missense variants. Ma et al. and Cunningham et al. (PMIDs: 23883380; 30365877) have demonstrated a functional impact for 8 variants. Summary of experimental evidence: 5 points. The gene-disease association is supported by expression studies, functional alteration and an animal model of disease (PMIDs: 16574908; 26912814; 31347976). The evidence supporting this gene-disease relationship has been replicated over 8 years. In summary, KCNK3 is definitively associated with autosomal dominant pulmonary arterial hypertension. This classification was approved by the ClinGen PH Working Group on Feb 10, 2021.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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