Eight further individuals with intellectual disability and epilepsy carrying bi-allelic CNTNAP2 aberrations allow delineation of the mutational and phenotypic spectrum

J Med Genet. 2016 Dec;53(12):820-827. doi: 10.1136/jmedgenet-2016-103880.

Mateja Smogavec ¹, Alison Cleall ², Juliane Hoyer ³, Damien Lederer ⁴, Marie-Cécile Nassogne ⁵, Elizabeth E Palmer ⁶ ⁷, Marie Deprez ⁴, Valérie Benoit ⁴, Isabelle Maystadt ⁴, Charlotte Noakes ², Alejandro Leal ³ ⁸, Marie Shaw ⁹, Jozef Gecz ⁹, Lucy Raymond ¹⁰, André Reis ³, Deborah Shears ¹¹, Knut Brockmann ¹², Christiane Zweier ³

Affiliations

1 Institute of Human Genetics, University Medical Center, Georg August University, Göttingen, Germany.
2 Oxford Genetics Laboratories, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
3 Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.
4 Centre de Génétique Humaine, Institut de Pathologie et Génétique, Charleroi, Belgium.
5 Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Woluwe-Saint-Lambert, Belgium.
6 GOLD (Genetics of Learning and Disability) Service, Hunter Genetics, Waratah, New South Wales, Australia.
7 University of New South Wales, Sydney, New South Wales, Australia.
8 Section of Genetics and Biotechnology, School of Biology and Neuroscience Research Center, University of Costa Rica, San José, Costa Rica.
9 School of Medicine, and the Robinson Research Institute, the University of Adelaide, Adelaide, South Australia, Australia.
10 Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
11 Department of Clinical Genetics, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
12 Interdisciplinary Pediatric Center for Children with Developmental Disabilities and Severe Chronic Disorders, University Medical Center, Georg August University, Göttingen, Germany.

PMID: 27439707 DOI: 10.1136/jmedgenet-2016-103880

Abstract

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.

Keywords

CNTNAP2; autosomal recessive; epilepsy; epileptic encephalopathy; intellectual disability.

Name
Email *

	Sorry, but the email address you supplied was invalid.