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Eight further individuals with intellectual disability and epilepsy carrying bi-allelic CNTNAP2 aberrations allow delineation of the mutational and phenotypic spectrum
  1. Mateja Smogavec1,
  2. Alison Cleall2,
  3. Juliane Hoyer3,
  4. Damien Lederer4,
  5. Marie-Cécile Nassogne5,
  6. Elizabeth E Palmer6,7,
  7. Marie Deprez4,
  8. Valérie Benoit4,
  9. Isabelle Maystadt4,
  10. Charlotte Noakes2,
  11. Alejandro Leal3,8,
  12. Marie Shaw9,
  13. Jozef Gecz9,
  14. Lucy Raymond10,
  15. André Reis3,
  16. Deborah Shears11,
  17. Knut Brockmann12,
  18. Christiane Zweier3
  1. 1Institute of Human Genetics, University Medical Center, Georg August University, Göttingen, Germany
  2. 2Oxford Genetics Laboratories, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
  3. 3Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
  4. 4Centre de Génétique Humaine, Institut de Pathologie et Génétique, Charleroi, Belgium
  5. 5Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Woluwe-Saint-Lambert, Belgium
  6. 6GOLD (Genetics of Learning and Disability) Service, Hunter Genetics, Waratah, New South Wales, Australia
  7. 7University of New South Wales, Sydney, New South Wales, Australia
  8. 8Section of Genetics and Biotechnology, School of Biology and Neuroscience Research Center, University of Costa Rica, San José, Costa Rica
  9. 9School of Medicine, and the Robinson Research Institute, the University of Adelaide, Adelaide, South Australia, Australia
  10. 10Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK
  11. 11Department of Clinical Genetics, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
  12. 12Interdisciplinary Pediatric Center for Children with Developmental Disabilities and Severe Chronic Disorders, University Medical Center, Georg August University, Göttingen, Germany
  1. Correspondence to Dr Christiane Zweier, Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Schwabachanlage 10, Erlangen 91054, Germany; christiane.zweier{at}


Background Heterozygous copy number variants (CNVs) or sequence variants in the contactin-associated protein 2 gene CNTNAP2 have been discussed as risk factors for a wide spectrum of neurodevelopmental and neuropsychiatric disorders. Bi-allelic aberrations in this gene are causative for an autosomal-recessive disorder with epilepsy, severe intellectual disability (ID) and cortical dysplasia (CDFES). As the number of reported individuals is still limited, we aimed at a further characterisation of the full mutational and clinical spectrum.

Methods Targeted sequencing, chromosomal microarray analysis or multigene panel sequencing was performed in individuals with severe ID and epilepsy.

Results We identified homozygous mutations, compound heterozygous CNVs or CNVs and mutations in CNTNAP2 in eight individuals from six unrelated families. All aberrations were inherited from healthy, heterozygous parents and are predicted to be deleterious for protein function. Epilepsy occurred in all affected individuals with onset in the first 3.5 years of life. Further common aspects were ID (severe in 6/8), regression of speech development (5/8) and behavioural anomalies (7/8). Interestingly, cognitive impairment in one of two affected brothers was, in comparison, relatively mild with good speech and simple writing abilities. Cortical dysplasia that was previously reported in CDFES was not present in MRIs of six individuals and only suspected in one.

Conclusions By identifying novel homozygous or compound heterozygous, deleterious CNVs and mutations in eight individuals from six unrelated families with moderate-to-severe ID, early onset epilepsy and behavioural anomalies, we considerably broaden the mutational and clinical spectrum associated with bi-allelic aberrations in CNTNAP2.

  • intellectual disability
  • epilepsy
  • autosomal recessive
  • epileptic encephalopathy

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  • Contributors MS, AC, JH, DL, M-CN, EEP, MD, VB, IM, CN, AL, MS, JG, LR, AR, DS, KB and CZ provided clinical and mutational data. MS and CZ wrote the manuscript. All authors read and agreed with the text.

  • Funding CZ was supported by a grant from the German Research Foundation (DFG, ZW184/1-2) and by the IZKF (Interdisziplinäres Zentrum für Klinische Forschung, E26) Erlangen.

  • Competing interests None declared.

  • Ethics approval Either diagnostic setting or approvals of the respective university ethic committees, for example, ethical board of the medical faculty of Friedrich-Alexander-University Erlangen-Nürnberg.

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