ClinVar

In a patient with Temple-Baraitser syndrome (TMBTS; 611816), Simons et al. (2015) identified a heterozygous c.1465C-T transition in exon 8 of the KCNH1 gene, resulting in a leu489-to-phe (L489F) substitution at a highly conserved residue in the S6 transmembrane helix, which is a central component of the channel pore. The mutation, which was found by whole-exome sequencing, was not present in the dbSNP (build 141), 1000 Genomes Project, or Exome Sequencing Project databases, or in an in-house control exome dataset of 100 family trios of children with neurologic disorders. In vitro functional expression studies in Xenopus oocytes showed that the mutation caused a decreased threshold of activation and delayed deactivation compared to wildtype, consistent with a gain of function. The patient's mother, who had epilepsy without other features of the disorder, was found to carry the mutation in the mosaic state (13.6% of reads from peripheral blood DNA). These findings suggested that a low level of this mutational load contributed to the epilepsy phenotype in the mother.