HGNC Approved Gene Symbol: KCNH5
Cytogenetic location: 14q23.2 Genomic coordinates (GRCh38): 14:62,699,464-63,045,458 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 14q23.2 | Developmental and epileptic encephalopathy 112 | 620537 | Autosomal dominant | 3 |
The KCNH5 gene encodes a voltage-gated potassium channel that is expressed in the nervous system (summary by Yang et al., 2013).
By EST database searching, Occhiodoro et al. (1998) identified an EST isolated from an adult brain cDNA library that showed significant homology to the rat ether-a-go-go (eag) voltage-gated potassium channel (see KCNH1; 603305) and to a human cDNA clone mapping to chromosome 14 (WI-6411). Sequencing of the clone indicated that the deduced protein, designated KCNH5, shares 58% sequence identity with KCNH1 over a total overlap of 457 amino acids. RT-PCR showed that KCNH5 is not expressed in differentiating myoblasts. Northern blot analysis detected expression of an approximately 11-kb transcript in adult brain tissue only.
In a 13-year-old boy with developmental and epileptic encephalopathy-112 (DEE112; 620537), Veeramah et al. (2013) identified a de novo heterozygous missense mutation in the KCNH5 gene (R327H; 605716.0001). The mutation was identified by whole-exome sequencing.
In a patient with DEE112, Minardi et al. (2020) identified a heterozygous missense mutation in the KCNH5 gene (R327H; 605716.0001). The mutation was identified by whole-exome sequencing.
In an infant (patient 532) with DEE112, Imafidon et al. (2021) identified a de novo heterozygous missense mutation in the KCNH5 gene (I463T; 605716.0002). The mutation was identified by whole-exome sequencing. The patient had hyperekplexia and dysmorphic features.
In 3 unrelated Chinese patients with DEE112, Hu et al. (2022) identified de novo heterozygous mutations in the KCNH5 gene: the previously identified R327H mutation, S321N, and an intronic mutation c.2020-4A-G (605716.0003). The mutations were identified by whole-exome sequencing.
Happ et al. (2023) identified heterozygous mutations in the KCNH5 gene in 17 unrelated patients with DEE12, 3 of whom were previously reported: 9 patients (including 2 previously reported) had the recurrent R327H mutation, 4 patients had an R333H mutation (605716.0004), and 1 patient each had different missense mutations, K324E, I463T (605716.0002; previously reported patient), T468P (605716.0005), and F471S (605716.0006). The mutations were identified by whole-exome sequencing and/or sequencing of the KCNH5 gene. The mutation occurred de novo in 14 patients and was inherited from an affected mother in 1 patient (patient 14); in 2 patients, parental testing was not performed.
Happ et al. (2023) identified genotype-phenotype correlations in a cohort of 17 patients with DEE112. The 9 patients with a R327H mutation (605716.0001) generally had severe epilepsy, which was drug resistant in some patients, as well as learning difficulties or mild to severe intellectual disability. The 4 patients with an R333H mutation (605716.0004) in the second recurrent voltage-sensing domain of KCNH5 tended to have a comparatively milder disease process with drug-responsive seizures, mild developmental delays, and normal cognitive development. Patients with the missense mutations I463T (605716.0002) or T468P (605716.0005) in or at the S6 transmembrane pore-forming domain had severe disease with drug-resistant seizures and limited developmental progression.
In a 13-year-old boy with developmental and epileptic encephalopathy-12 (DEE12; 620537), Veeramah et al. (2013) identified a de novo heterozygous c.980G-A transition in the KCNH5 gene, resulting in an arg327-to-his (R327H) substitution at a conserved residue in the S4 helix of the voltage-sensing domain. The mutation, which was found by whole-exome sequencing, was not present in the 1000 Genomes Project or Exome Sequencing Project databases. The patient was 1 of 10 probands with a similar phenotype who underwent whole-exome sequencing.
In a patient (patient 25) with DEE12, Minardi et al. (2020) identified a heterozygous c.980G-A transition (c.980G-A, NM_139318) in the KCNH5 gene, resulting in the R326H mutation. The mutation was identified by whole-exome sequencing. The inheritance pattern was unknown because the parents could not be tested.
In a patient (patient 1) with DEE12, Hu et al. (2022) identified a de novo heterozygous R327H mutation in the KCNH5 gene. The mutation was identified by whole-exome sequencing.
In 7 unrelated, newly identified patients with DEE12, Happ et al. (2023) identified heterozygosity for the R327H mutation in the voltage sensing domain of the KCNH5 gene. The mutation was identified by whole-exome sequencing and/or sequencing of the KCHN5 gene and occurred de novo in all 7.
Variant Function
By structural modeling, Yang et al. (2013) found evidence that the R327H mutation would destabilize the resting and early activation states of the KCNH5 channel by weakening ionic interactions between residue 327 and other negatively charged residues, thus favoring channel opening. Voltage-clamp recordings showed that the mutation caused a hyperpolarizing shift in the voltage dependence of activation and an acceleration of activation. The findings were consistent with a gain of function.
In a patient (patient 532) with developmental and epileptic encephalopathy-112 (DEE112; 620537), Imafidon et al. (2021) identified a de novo heterozygous c.1388T-C transition in the KCNH5 gene, resulting in an ile463-to-thr (I463T) substitution. The mutation was identified by whole-exome sequencing.
In a patient (patient 2) with developmental and epileptic encephalopathy-12 (DEE12; 620537), Hu et al. (2022) identified a de novo heterozygous c.2020-4A-G transition in intron 10 of the KCNH5 gene, predicted to result in a splicing abnormality. The mutation was found by whole-exome sequencing.
In 4 unrelated patients with developmental and epileptic encephalopathy-12 (DEE12; 620537), Happ et al. (2023) identified a heterozygous arg333-to-his (R333H) mutation in the second recurrent voltage-sensing domain of the KCNH5 gene. The mutation was identified by whole-exome sequencing and/or sequencing of the KCHN5 gene. The mutation occurred de novo in 3 patients and was inherited from an affected mother in 1 patient.
In a patient (patient 16) with developmental and epileptic encephalopathy-12 (DEE12; 620537), Happ et al. (2023) identified a de novo heterozygous thr468-to-pro (T468P) mutation in the KCNH5 gene. The mutation was found by whole-exome sequencing and/or sequencing of the KCHN5 gene.
In a patient (patient 17) with developmental and epileptic encephalopathy-12 (DEE12; 620537), Happ et al. (2023) identified a de novo heterozygous phe471-to-ser (F471S) mutation in the KCNH5 gene. The mutation was found by whole-exome sequencing and/or sequencing of the KCHN5 gene.
Happ, H. C., Sadleir, L. G., Zemel, M., de Valles-Ibanez, G., Hildebrand, M. S., McConkie-Rosell, A., McDonald, M., May, H., Sands, T., Aggarwal, V., Elder, C., Feyma, T., and 43 others. Neurodevelopmental and epilepsy phenotypes in individuals with missense variants in the voltage-sensing and pore domains of KCNH5. Neurology 100: e603-e615, 2023. [PubMed: 36307226] [Full Text: https://doi.org/10.1212/WNL.0000000000201492]
Hu, X., Yang, J., Zhang, M., Fang, T., Gao, Q., Liu, X. Clinical feature, treatment, and KCNH5 mutations in epilepsy. Front. Pediat. 10: 858008, 2022. [PubMed: 35874597] [Full Text: https://doi.org/10.3389/fped.2022.858008]
Imafidon, M. E., Sikkema-Raddatz, B., Abbott, K. M., Meems-Veldhuis, M. T., Swertz, M. A., van der Velde, K. J., Beunders, G., Bos, D. K., Knoers, N. V. A. M., Kerstjens-Frederikse, W. S., van Diemen, C. C. Strategies in rapid genetic diagnostics of critically ill children: experiences from a Dutch university hospital. Front. Pediat. 9: 600556, 2021. [PubMed: 34136434] [Full Text: https://doi.org/10.3389/fped.2021.600556]
Minardi, R., Licchetta, L., Baroni, M. C., Pippucci, T., Stipa, C., Mostacci, B., Severi, G., Toni, F., Bergonzini, L., Carelli, V., Seri, M., Tinuper, P., Bisulli, F. Whole-exome sequencing in adult patients with developmental and epileptic encephalopathy: it is never too late. Clin. Genet. 98: 477-485, 2020. [PubMed: 32725632] [Full Text: https://doi.org/10.1111/cge.13823]
Occhiodoro, T., Bernheim, L., Liu, J.-H., Bijlenga, P., Sinnreich, M., Bader, C. R., Fischer-Lougheed, J. Cloning of a human ether-a-go-go potassium channel expressed in myoblasts at the onset of fusion. FEBS Lett. 434: 177-182, 1998. [PubMed: 9738473] [Full Text: https://doi.org/10.1016/s0014-5793(98)00973-9]
Veeramah, K. R., Johnstone, L., Karafet, T. M., Wolf, D., Sprissler, R., Salogiannis, J., Barth-Maron, A., Greenberg, M. E., Stuhlmann, T., Weinert, S., Jentsch, T. J., Pazzi, M., Restifo, L. L., Talwar, D., Erickson, R. P., Hammer, M. F. Exome sequencing reveals new causal mutations in children with epileptic encephalopathies. Epilepsia 54: 1270-1281, 2013. [PubMed: 23647072] [Full Text: https://doi.org/10.1111/epi.12201]
Yang, Y., Vasylyev, D. V., Dib-Hajj, F., Veeramah, K. R., Hammer, M. F., Dib-Hajj, S. D., Waxman, S. G. Multistate structural modeling and voltage-clamp analysis of epilepsy/autism mutation Kv10.2-R327H demonstrate the role of this residue in stabilizing the channel closed state. J. Neurosci. 33: 16586-16593, 2013. [PubMed: 24133262] [Full Text: https://doi.org/10.1523/JNEUROSCI.2307-13.2013]