Syndromic disorders caused by gain-of-function variants in KCNH1, KCNK4, and KCNN3—a subgroup of K+ channelopathies

Abstract

<jats:title>Abstract</jats:title><jats:p>Decreased or increased activity of potassium channels caused by loss-of-function and gain-of-function (GOF) variants in the corresponding genes, respectively, underlies a broad spectrum of human disorders affecting the central nervous system, heart, kidney, and other organs. While the association of epilepsy and intellectual disability (ID) with variants affecting function in genes encoding potassium channels is well known, GOF missense variants in K<jats:sup>+</jats:sup> channel encoding genes in individuals with syndromic developmental disorders have only recently been recognized. These syndromic phenotypes include Zimmermann–Laband and Temple–Baraitser syndromes, caused by dominant variants in <jats:italic>KCNH1</jats:italic>, FHEIG syndrome due to dominant variants in <jats:italic>KCNK4</jats:italic>, and the clinical picture associated with dominant variants in <jats:italic>KCNN3</jats:italic>. Here we review the presentation of these individuals, including five newly reported with variants in <jats:italic>KCNH1</jats:italic> and three additional individuals with <jats:italic>KCNN3</jats:italic> variants, all variants likely affecting function. There is notable overlap in the phenotypic findings of these syndromes associated with dominant <jats:italic>KCNN3</jats:italic>, <jats:italic>KCNH1</jats:italic>, and <jats:italic>KCNK4</jats:italic> variants, sharing developmental delay and/or ID, coarse facial features, gingival enlargement, distal digital hypoplasia, and hypertrichosis. We suggest to combine the phenotypes and define a new subgroup of potassium channelopathies caused by increased K<jats:sup>+</jats:sup> conductance, referred to as syndromic neurodevelopmental K<jats:sup>+</jats:sup> channelopathies due to dominant variants in <jats:italic>KCNH1</jats:italic>, <jats:italic>KCNK4</jats:italic>, or <jats:italic>KCNN3</jats:italic>.</jats:p>