Abstract
Here, we describe four patients suffering from a rather broad spectrum of epilepsy-related disorders, ranging from developmental and epileptic encephalopathy with intellectual disability (DEE) to genetic generalized epilepsy (GGE), which all harbor novel KCNH1 mutations. In one family, we found a weak association of a novel nonsense mutation with epilepsy, suggesting reduced penetrance, and which shows, in agreement with previous findings, that gain-of-function effects rather than haploinsufficiency are important for the pathogenicity of mutations. De novo missense variants in the pore region of the channel result in severe phenotypes presenting usually with DEE with various malformations. The potential pathogenicity of a novel KCNH1 germline mutation located outside of the critical pore domain observed in a GGE patient with a milder phenotype is supported by the fact that the very same amino acid exchange was detected as a somatic mutation in the resected brain tissue of a patient suffering from a focal cortical dysplasia type IIb. Thus, our case series broadens the phenotypic spectrum of KCNH1-associated diseases.
Highlights
Pathogenic KCNH1 mutations have been identified in uncharacterized patients with intellectual disability, epilepsy and variable skeletal abnormalities, which could be ascribed neither to a Zimmermann–Laband syndrome (ZLS) nor to a Temple–Baraitser syndrome (TMBTS) phenotype [3]
We present patients harboring novel missense mutations in the KCNH1 gene suffering from epilepsy, but otherwise presenting distinct clinical features, broadening the phenotypic spectrum of KCNH1 mutations
The proof of its potential pathogenicity is related to the fact that the very same mutation was detected in the epileptogenic focal cortical dysplasia type IIb (FCD IIb) lesion from case 4 as a somatic mutation (Figure 2a), appearing under these circumstances de novo
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Pathogenic KCNH1 mutations have been identified in uncharacterized patients with intellectual disability, epilepsy and variable skeletal abnormalities, which could be ascribed neither to a ZLS nor to a TMBTS phenotype [3]. A KCNH1 mutation originally described in a ZLS patient was found in a patient with a TMBTS phenotype [4]. This phenotypic variability and the great overlap between both syndromes suggest that ZLS and TMBTS are a continuum of the same disease. We present patients harboring novel missense mutations in the KCNH1 gene suffering from epilepsy, but otherwise presenting distinct clinical features, broadening the phenotypic spectrum of KCNH1 mutations. The missing strong association of a novel nonsense mutation with epilepsy in one family indicates that gain-of-function effects, rather than haploinsufficiency, are important for pathogenicity
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