Patients with KCNH1-related intellectual disability without distinctive features of Zimmermann-Laband/Temple-Baraitser syndrome

We report a series of seven patients with ID and de novo pathogenic KCNH1 variants identified by whole-exome sequencing or an epilepsy gene panel in whom the diagnosis of TBS/ZLS had not been first considered. Four of these variants, p.(Thr294Met), p.(Ala492Asp), p.(Thr493Asn) and p.(Gly496Arg), were located in the transmembrane domains S3 and S6 of Kv10.1 and one, p.(Arg693Gln), in its C-terminal cyclic nucleotide-binding homology domain (CNBHD). Clinical reappraisal by the referring clinical geneticists confirmed the absence of the distinctive gingival and nail features of TBS/ZLS.
Our study expands the phenotypical spectrum of KCNH1-related encephalopathies to individuals with an attenuated extraneurological phenotype preventing a clinical diagnosis of TBS or ZLS. This subtype may be related to recurrent substitutions of the Gly496, suggesting a genotype–phenotype correlation and, possibly, to variants in the CNBHD domain.

Source: Journal of Medical Genetics - April 22, 2022 Category: Genetics & Stem Cells Authors: Aubert Mucca, M., Patat, O., Whalen, S., Arnaud, L., Barcia, G., Buratti, J., Cogne, B., Doummar, D., Karsenty, C., Kenis, S., Leguern, E., Lesca, G., Nava, C., Nizon, M., Piton, A., Valence, S., Villard, L., Weckhuysen, S., Keren, B., Mignot, C. Tags: Phenotypes Source Type: research