title: Eight further individuals with intellectual disability and epilepsy carrying bi-allelic CNTNAP2 aberrations allow delineation of the mutational and phenotypic spectrum.
abstract: 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.
  
  
  
  Targeted sequencing, chromosomal microarray analysis or multigene panel sequencing was performed in individuals with severe ID and epilepsy.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Institute of Human Genetics, University Medical Center, Georg August University, Göttingen, Germany.
authors.forename: Mateja
authors.initials: M
authors.lastname: Smogavec
authors.affiliation: Oxford Genetics Laboratories, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
authors.forename: Alison
authors.initials: A
authors.lastname: Cleall
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.
authors.forename: Juliane
authors.initials: J
authors.lastname: Hoyer
authors.affiliation: Centre de Génétique Humaine, Institut de Pathologie et Génétique, Charleroi, Belgium.
authors.forename: Damien
authors.initials: D
authors.lastname: Lederer
authors.affiliation: Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Woluwe-Saint-Lambert, Belgium.
authors.forename: Marie-Cécile
authors.initials: MC
authors.lastname: Nassogne
authors.affiliation: GOLD (Genetics of Learning and Disability) Service, Hunter Genetics, Waratah, New South Wales, Australia.|University of New South Wales, Sydney, New South Wales, Australia.
authors.forename: Elizabeth E
authors.initials: EE
authors.lastname: Palmer
authors.affiliation: Centre de Génétique Humaine, Institut de Pathologie et Génétique, Charleroi, Belgium.
authors.forename: Marie
authors.initials: M
authors.lastname: Deprez
authors.affiliation: Centre de Génétique Humaine, Institut de Pathologie et Génétique, Charleroi, Belgium.
authors.forename: Valérie
authors.initials: V
authors.lastname: Benoit
authors.affiliation: Centre de Génétique Humaine, Institut de Pathologie et Génétique, Charleroi, Belgium.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Maystadt
authors.affiliation: Oxford Genetics Laboratories, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Noakes
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.|Section of Genetics and Biotechnology, School of Biology and Neuroscience Research Center, University of Costa Rica, San José, Costa Rica.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Leal
authors.affiliation: School of Medicine, and the Robinson Research Institute, the University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Marie
authors.initials: M
authors.lastname: Shaw
authors.affiliation: School of Medicine, and the Robinson Research Institute, the University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Jozef
authors.initials: J
authors.lastname: Gecz
authors.affiliation: Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
authors.forename: Lucy
authors.initials: L
authors.lastname: Raymond
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Reis
authors.affiliation: Department of Clinical Genetics, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
authors.forename: Deborah
authors.initials: D
authors.lastname: Shears
authors.affiliation: Interdisciplinary Pediatric Center for Children with Developmental Disabilities and Severe Chronic Disorders, University Medical Center, Georg August University, Göttingen, Germany.
authors.forename: Knut
authors.initials: K
authors.lastname: Brockmann
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.
authors.forename: Christiane
authors.initials: C
authors.lastname: Zweier
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D002648:Child; D002675:Child, Preschool; D019465:Craniofacial Abnormalities; D056915:DNA Copy Number Variations; D004252:DNA Mutational Analysis; D004828:Epilepsies, Partial / Q000235:genetics / Q000378:metabolism; D004827:Epilepsy / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D054220:Malformations of Cortical Development / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D013577:Syndrome
chemical_list: C403049:CNTNAP2 protein, human; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins
keywords: CNTNAP2; autosomal recessive; epilepsy; epileptic encephalopathy; intellectual disability