KCNH2 encodes the alpha subunit of the rapidly activating delayed rectifier cardiac potassium channel (Ikr). Brugada et al. (PMID 14676148) were the first to identify 2 rare KCNH2 missense variants leading to the same amino-acid change (p.Asn588Lys, ClinVar Variation ID# 14436 & 14437) in 2 small families with Short QT Syndrome (SQTS) using a candidate-gene approach. This genetic evidence was subsequently supported by multiple other publications identifying rare missense KCNH2 variants in SQTS patients. Experimental evidence derived from non-patient cells, human-induced pluripotent stem cell-derived cells and a rabbit animal model (PMID 30496390) all support this gene’s relationship with SQTS. These experimental studies demonstrate that genetic variants identified in SQTS patients lead to potassium current perturbations concordant with SQTS phenotype and shortening of the QT interval. It is noteworthy that of the 18 probands with SQTS in whom KCNH2 variants were identified, 13 had one of 2 variants; 7 with p.Thr618Ile variant (ClinVar Variation ID# 67297) and 6 with p.Asn588Lys.
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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