Patients with KCNH1 -related intellectual disability without distinctive features of Zimmermann-Laband/Temple-Baraitser syndrome - Archive ouverte HAL Access content directly
Journal Articles Journal of Medical Genetics Year : 2021

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

Marion Aubert Mucca
  • Function : Author
Olivier Patat
Sandra Whalen
Lionel Arnaud
  • Function : Author
Julien Buratti
Benjamin Cogné
Diane Doummar
  • Function : Author
Caroline Karsenty
  • Function : Author
Sandra Kenis
  • Function : Author
Eric Leguern
  • Function : Author
Gaetan Lesca
Caroline Nava
Mathilde Nizon
Amelie Piton
  • Function : Author
Stéphanie Valence
  • Function : Author
Sarah Weckhuysen
  • Function : Author
Boris Keren
Cyril Mignot
  • Function : Author

Abstract

De novo missense variants in KCNH1 encoding Kv10.1 are responsible for two clinically recognisable phenotypes: Temple-Baraitser syndrome (TBS) and Zimmermann-Laband syndrome (ZLS). The clinical overlap between these two syndromes suggests that they belong to a spectrum of KCNH1 -related encephalopathies. Affected patients have severe intellectual disability (ID) with or without epilepsy, hypertrichosis and distinctive features such as gingival hyperplasia and nail hypoplasia/aplasia (present in 20/23 reported cases). 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.

Dates and versions

hal-03244899 , version 1 (01-06-2021)

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Marion Aubert Mucca, Olivier Patat, Sandra Whalen, Lionel Arnaud, Giulia Barcia, et al.. Patients with KCNH1 -related intellectual disability without distinctive features of Zimmermann-Laband/Temple-Baraitser syndrome. Journal of Medical Genetics, 2021, pp.jmedgenet-2020-107511. ⟨10.1136/jmedgenet-2020-107511⟩. ⟨hal-03244899⟩
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