KCNH1 and Temple-Baraitser Syndrome

KCNH1 (HGNC:6250) has been robustly associated with Temple-Baraitser syndrome (MONDO_0012735) through multiple independent case studies and patient series. Several unrelated probands, including a Lebanese child with a de novo mutation, have been reported with missense variants in KCNH1 that lead to a gain‑of‑function effect. In one representative study, whole genome sequencing identified the variant c.1042G>A (p.Gly348Arg) in a TBS patient, with predictions and subsequent Sanger confirmation providing strong evidence of pathogenicity (PMID:27282200).

Genetic evidence supporting the association comes from recurrent identification of de novo missense variants across independent families. Additional patient series, including those reporting 6 and 7 probands respectively, consistently demonstrate that pathogenic KCNH1 variants result in overlapping neurodevelopmental features such as intellectual disability and seizure (PMID:25420144). Moreover, while family segregation data are minimal due to the de novo nature of these variants, the convergence of mutational findings across studies supports the genetic etiology of Temple‑Baraitser syndrome.

Functional studies further substantiate the role of KCNH1 in the disease mechanism. In vivo experiments in Drosophila and patch‑clamp analyses in heterologous cells have shown that KCNH1 gain‑of‑function mutations lead to altered channel gating and conductance changes, findings that are concordant with the neurological phenotypes observed in patients (PMID:16452147, PMID:25915598).

The integration of genetic and experimental evidence suggests that KCNH1 mutations are a strong contributor to the clinical presentation of Temple‑Baraitser syndrome. Although additional evidence exists from broader cohorts and functional assays, the current data are sufficient to support diagnostic decision‑making and justify clinical testing for KCNH1 in patients with TBS phenotypes.

Key take‑home: KCNH1 variants, most notably de novo missense mutations, are strongly associated with Temple‑Baraitser syndrome, making them clinically actionable for diagnosis and management.

References

• BMC medical genetics • 2016 • Temple-Baraitser Syndrome and Zimmermann-Laband Syndrome: one clinical entity? PMID:27282200
• Nature genetics • 2015 • Mutations in the voltage‑gated potassium channel gene KCNH1 cause Temple‑Baraitser syndrome and epilepsy PMID:25420144
• Genetics • 2006 • In vivo analysis of a gain‑of‑function mutation in the Drosophila eag‑encoded K+ channel PMID:16452147
• Nature genetics • 2015 • Mutations in KCNH1 and ATP6V1B2 cause Zimmermann‑Laband syndrome PMID:25915598

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