Submission Details

KCNH1 (also referred to as hEAG/EAG1/Kv10.1) encodes a voltage gated potassium channel with high expression levels in CNS. Heterozygous de novo rare missense variants in KCNH1 are reported in individuals with a clinical diagnosis of Temple-Baraitser syndrome whose features include ID, epilepsy, hypoplasia/aplasia of the nails of the thumb and great toe (PMID: 25420144), Zimmermann-Laband syndrome which is characterized by ID, hypoplasia of nails and terminal phalanges, facial dysmorphism, gingival enlargement, hypertrichosis (PMID: 25915598), and in individuals with non-syndromic ID with or without epilepsy (PMID: 33811134). Due to phenotypic overlap of these clinical entities, shared missense variants observed in these conditions and a common molecular mechanism of the identified missense changes (gain of function), these entities represent a phenotypic continuum and have been curated under the encompassing term of “KCNH1-associated disorders” (PMIDs: 26264464, 27282200, 25420144, 25915598, 33811134, 33594261, 33494179, 26818738, 32956079).

Evidence supporting this gene-disease relationship includes case-level data and functional studies on the missense variants. Notably, experimental data using patient cells and knock-in animal models with disease causing variants are lacking for KCNH1.

There are roughly 30 affected individuals with KCNH1 variants reported in the literature to date (PMIDs: 33594261, 33494179, 33811134). Nearly all of the cases had de novo missense variants; however, there are at least 2 reports of inheritance of this disorder from mothers who showed low level somatic mosaicism for the KCNH1 variant (PMID: 25420144). Two independent studies assessed a handful of KCNH1 missense variants seen in affected individuals by in vitro patch-clamp studies and were shown to cause gain of function effects (PMIDs: 25420144, 25915598). The postulated disease mechanism for KCNH1 missense variants is through gain of function, though in a single case, an inherited nonsense variant (exon 8 of 11) was reported in an individual with seizures and in other asymptomatic family members suggesting non-penetrance (PMID: 33494179). This case was not scored.

For experimental evidence and animal models for KCNH1, there are only loss of function-based mouse and Zebrafish models reported (PMIDs: 22927438, 22927438). Since this is not consistent with the postulated molecular mechanism of the missense KCNH1 variants seen in the affected individuals, these studies were not scored.

KCNH1 is definitively associated with KCNH1-associated disorders. This classification has been approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on April 5, 2022 (SOP Version 8).