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Patients with KCNH1-related intellectual disability without distinctive features of Zimmermann-Laband/Temple-Baraitser syndrome
  1. Marion Aubert Mucca1,
  2. Olivier Patat1,
  3. Sandra Whalen2,
  4. Lionel Arnaud3,
  5. Giulia Barcia4,
  6. Julien Buratti3,
  7. Benjamin Cogné5,
  8. Diane Doummar6,
  9. Caroline Karsenty7,
  10. Sandra Kenis8,
  11. Eric Leguern3,
  12. Gaetan Lesca9,10,
  13. Caroline Nava3,
  14. Mathilde Nizon5,
  15. Amelie Piton11,
  16. Stéphanie Valence6,
  17. Laurent Villard12,
  18. Sarah Weckhuysen13,14,
  19. Boris Keren3,
  20. Cyril Mignot3,15,16
  1. 1 Service de Génétique Médicale, CHU Toulouse Purpan, Toulouse, France
  2. 2 Unité Fonctionnelle de Génétique Clinique, Centre de Référence Anomalies du développement et syndromes malformatifs, APHP.Sorbonne Université, Hôpital Armand Trousseau, Paris, Île-de-France, France
  3. 3 APHP.Sorbonne Université, Département de Génétique, Groupe Hospitalier Pitié Salpêtrière et Hôpital Trousseau, Paris, Île-de-France, France
  4. 4 APHP, Service de Génétique Médicale, Hôpital Necker-Enfants Malades, Imagine Institute, Paris Descartes University, Paris, France
  5. 5 Service de Génétique Médicale, L'institut du thorax, INSERM, CNRS, UNIV Nantes, Centre Hospitalier Universitaire de Nantes, Nantes, France
  6. 6 Service de Neuropédiatrie - Unité de neuropédiatrie et pathologie du développement, CHU Paris Est - Hôpital d'Enfants Armand-Trousseau, Paris, France
  7. 7 Service de Neuropédiatrie, CHU Toulouse, Hôpital des Enfants, Toulouse, France
  8. 8 Child Neurology Department, University of Antwerp, University Hospital Antwerp, Edegem, Antwerp, Belgium
  9. 9 EuroEPINOMICS, EuroEPINOMICS, Strasbourg, France
  10. 10 Service de Génétique, LBMMS, Groupement Hospitalier Est, CHU de Lyon, Lyon, France
  11. 11 Laboratory of Genetic Diagnosis, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
  12. 12 Laboratoire de génétique moléculaire, Département de Génétique Médicale, CHU de Marseille - Hôpital La Timone, Marseille, France
  13. 13 Applied&Translational Genomics group, VIB-Center for Molecular Neurology, University of Antwerp, Antwerp, Belgium
  14. 14 Neurology Department, University Hospital Antwerp, Antwerp, Belgium
  15. 15 INSERM, U1127, CNRS UMR 7225, Sorbonne Université, UPMC Univ Paris 06 UMR S1127, Institut du Cerveau et la Moelle épinière ICM, Paris, France
  16. 16 Centre de Référence Déficiences Intellectuelles de Causes Rares, GH Pitié Salpêtrière, Paris, France
  1. Correspondence to Dr Olivier Patat, Department of Medical Genetics, University Hospital Centre Toulouse, Toulouse 31300, Midi-Pyrénées, France; patat.o{at}


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.

  • genetics
  • mutation
  • phenotype

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  • Contributors MAM and OP: data collection, data analysis, and manuscript writing and editing; SWh and SWe: data collection and manuscript writing and editing; LA, DD, CK, SK, EL, GL, CN, SV, LV, BK, BC and MN: data collection and manuscript editing; GB, JB and AP: data collection; CM: study conception, data collection, data analysis, and manuscript writing and editing.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.