ClinVar

In 3 unrelated patients with Temple-Baraitser syndrome (TMBTS; 611816), Simons et al. (2015) identified a de novo heterozygous c.1480A-G transition in exon 8 of the KCNH1 gene, resulting in an ile494-to-val (I494V) substitution at a highly conserved residue in the S6 transmembrane helix, which is a central component of the channel pore. The mutations, which were found by whole-exome sequencing, were 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. One of the patients was a Chinese girl previously reported by Jacquinet et al. (2010), another was a Turkish boy previously reported by Yesil et al. (2014), and the third was a Hispanic girl.