BACKGROUND AND OBJECTIVES: KCNH5 encodes the voltage-gated potassium channel EAG2/Kv10.2. We aimed to delineate the neurodevelopmental and epilepsy phenotypic spectrum associated with de novo KCNH5 variants. METHODS: We screened 893 individuals with developmental and epileptic encephalopathies for KCNH5 variants using targeted or exome sequencing. Additional individuals with KCNH5 variants were identified through an international collaboration. Clinical history, EEG, and imaging data were analyzed; seizure types and epilepsy syndromes were classified. We included 3 previously published individuals including additional phenotypic details. RESULTS: We report a cohort of 17 patients, including 9 with a recurrent de novo missense variant p.Arg327His, 4 with a recurrent missense variant p.Arg333His, and 4 additional novel missense variants. All variants were located in or near the functionally critical voltage-sensing or pore domains, absent in the general population, and classified as pathogenic or likely pathogenic using the American College of Medical Genetics and Genomics criteria. All individuals presented with epilepsy with a median seizure onset at 6 months. They had a wide range of seizure types, including focal and generalized seizures. Cognitive outcomes ranged from normal intellect to profound impairment. Individuals with the recurrent p.Arg333His variant had a self-limited drug-responsive focal or generalized epilepsy and normal intellect, whereas the recurrent p.Arg327His variant was associated with infantile-onset DEE. Two individuals with variants in the pore domain were more severely affected, with a neonatal-onset movement disorder, early-infantile DEE, profound disability, and childhood death. DISCUSSION: We describe a cohort of 17 individuals with pathogenic or likely pathogenic missense variants in the voltage-sensing and pore domains of Kv10.2, including 14 previously unreported individuals. We present evidence for a putative emerging genotype-phenotype correlation with a spectrum of epilepsy and cognitive outcomes. Overall, we expand the role of EAG proteins in human disease and establish KCNH5 as implicated in a spectrum of neurodevelopmental disorders and epilepsy.

• MeSH
• dítě MeSH
• draslíkové kanály ether-a-go-go * genetika   MeSH
• epilepsie generalizovaná * genetika   MeSH
• epilepsie * genetika   MeSH
• fenotyp MeSH
• lidé MeSH
• mutace MeSH
• novorozenec MeSH
• záchvaty genetika   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• novorozenec MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

BACKGROUND: Classic symptoms of long QT syndrome (LQTS) include prolongation of QT interval on electrocardiograph, syncope, and cardiac arrest due to a distinctive form of polymorphic ventricular tachycardia, known as Torsade de Pointes. We assessed occurrence of LQTS signs in individuals from 30 Czech families with mutations in KCNQ1 and KCNH2 genes. METHODS AND RESULTS: One hundred five individuals from 30 Czech families with LQTS were genotyped for KCNQ1 and KCNH2. The occurrence of typical LQTS signs (pathologic prolongation of QT interval; syncope; cardiac arrest; Torsade de Pointes) was clinically assessed by exercise test with QT interval analysis. Family history of sudden cardiac death was taken. Statistical analysis was performed to determine correlation of clinical results and mutation status. KCNQ1 gene mutations were found in 23 families, and KCNH2 gene mutations in eight families. Only 46 (70%) of the 66 mutation carriers had at least two of the typical LQTS signs. The others were minimally or asymptomatic. From 39 noncarrier individuals, only 1 fulfilled the clinical criteria of LQTS diagnosis, another 4 had an intermediate probability of diagnosis. The exercise test had 92% sensitivity and 93% specificity for LQTS diagnosis. CONCLUSIONS: Incidence of classical signs of LQTS was not high in Czech carriers of KCNQ1 and KCNH2 mutations. Therefore, proper diagnosis relies on detection of symptoms at presentation. The exercise test may be beneficial owing to its high sensitivity and specificity for LQTS diagnosis.

• MeSH
• dospělí MeSH
• draslíkové kanály ether-a-go-go genetika   MeSH
• elektrokardiografie statistika a číselné údaje   MeSH
• genetická predispozice k nemoci epidemiologie   genetika   MeSH
• hodnocení rizik MeSH
• jednonukleotidový polymorfismus genetika   MeSH
• lidé MeSH
• mutace genetika   MeSH
• prevalence MeSH
• reprodukovatelnost výsledků MeSH
• RNA dlouhá nekódující genetika   MeSH
• senzitivita a specificita MeSH
• syndrom dlouhého QT diagnóza   epidemiologie   genetika   MeSH
• zátěžový test statistika a číselné údaje   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH