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

Abstract

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+ 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 KCNH1, FHEIG syndrome due to dominant variants in KCNK4, and the clinical picture associated with dominant variants in KCNN3. Here we review the presentation of these individuals, including five newly reported with variants in KCNH1 and three additional individuals with KCNN3 variants, all variants likely affecting function. There is notable overlap in the phenotypic findings of these syndromes associated with dominant KCNN3, KCNH1, and KCNK4 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+ conductance, referred to as syndromic neurodevelopmental K+ channelopathies due to dominant variants in KCNH1, KCNK4, or KCNN3.

• Authors: Karen W Gripp, Sarah F Smithson, Ingrid J Scurr, Julia Baptista, Anirban Majumdar, Germaine Pierre, Maggie Williams, Lindsay B Henderson, Ingrid M Wentzensen, Heather McLaughlin, Lisette Leeuwen, Marleen E H Simon, Ellen van Binsbergen, Mary Beth P Dinulos, Julie D Kaplan, Anne McRae, Andrea Superti-Furga, Jean-Marc Good, Kerstin Kutsche
• Journal: European journal of human genetics : EJHG (Eur J Hum Genet) Vol. 29 Issue 9 Pg. 1384-1395 (09 2021) ISSN: 1476-5438 [Electronic] England
• PMID: 33594261 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s).

Chemical References

• Ether-A-Go-Go Potassium Channels
• KCNH1 protein, human
• KCNK4 protein, human
• KCNN3 protein, human
• Potassium Channels
• Small-Conductance Calcium-Activated Potassium Channels

Topics

• Abnormalities, Multiple (genetics, pathology)
• Adolescent
• Adult
• Channelopathies (genetics, pathology)
• Child
• Craniofacial Abnormalities (genetics, pathology)
• Ether-A-Go-Go Potassium Channels (genetics)
• Female
• Fibromatosis, Gingival (genetics, pathology)
• Gain of Function Mutation
• Hallux (abnormalities, pathology)
• Hand Deformities, Congenital (genetics, pathology)
• Humans
• Intellectual Disability (genetics, pathology)
• Male
• Nails, Malformed (genetics, pathology)
• Phenotype
• Potassium Channels (genetics)
• Small-Conductance Calcium-Activated Potassium Channels (genetics)
• Thumb (abnormalities, pathology)