RESUMEN
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.
Asunto(s)
Anomalías Múltiples/genética , Canalopatías/genética , Anomalías Craneofaciales/genética , Canales de Potasio Éter-A-Go-Go/genética , Fibromatosis Gingival/genética , Mutación con Ganancia de Función , Hallux/anomalías , Deformidades Congénitas de la Mano/genética , Discapacidad Intelectual/genética , Uñas Malformadas/genética , Canales de Potasio/genética , Canales de Potasio de Pequeña Conductancia Activados por el Calcio/genética , Pulgar/anomalías , Anomalías Múltiples/patología , Adolescente , Adulto , Canalopatías/patología , Niño , Anomalías Craneofaciales/patología , Femenino , Fibromatosis Gingival/patología , Hallux/patología , Deformidades Congénitas de la Mano/patología , Humanos , Discapacidad Intelectual/patología , Masculino , Uñas Malformadas/patología , Fenotipo , Pulgar/patologíaRESUMEN
We describe six individuals with microdeletions and microduplications in the distal 22q11.2 region detected by microarray. Five of the abnormalities have breakpoints in the low-copy repeats (LCR) in this region and one patient has an atypical rearrangement. Two of the six patients with abnormalities in the region between LCR22 D-E have hearing loss, which has previously been reported only once in association with these abnormalities. We especially note the behavioral/neuropsychiatric problems, including the severity and early onset, in patients with distal 22q11.2 rearrangements. Our patients add to the genotype-phenotype correlations which are still being generated for these chromosomal anomalies.