Eight further individuals with intellectual disability and epilepsy carrying bi-allelicCNTNAP2aberrations allow delineation of the mutational and phenotypic spectrum
| Autor: | Christiane Zweier, Valérie Benoit, Alejandro Leal, Marie-Cécile Nassogne, Lucy Raymond, Marie Deprez, Mateja Smogavec, Alison Cleall, Damien Lederer, Elizabeth E. Palmer, Jozef Gecz, Deborah J. Shears, Marie Shaw, Charlotte Noakes, Knut Brockmann, Isabelle Maystadt, Juliane Hoyer, André Reis |
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| Rok vydání: | 2016 |
| Předmět: |
Adult
Male 0301 basic medicine CNTNAP2 Adolescent DNA Copy Number Variations DNA Mutational Analysis Nerve Tissue Proteins Biology Compound heterozygosity Craniofacial Abnormalities 03 medical and health sciences Epilepsy 0302 clinical medicine Intellectual Disability Intellectual disability Genetics medicine Humans Genetic Predisposition to Disease Copy-number variation Allele Child Alleles Genetics (clinical) Infant Membrane Proteins Syndrome Middle Aged Cortical dysplasia medicine.disease Pedigree 3. Good health Malformations of Cortical Development Phenotype 030104 developmental biology Child Preschool Mutation Female Epilepsies Partial 030217 neurology & neurosurgery |
| Zdroj: | Journal of Medical Genetics. 53:820-827 |
| ISSN: | 1468-6244 0022-2593 |
| Popis: | 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 . |
| Databáze: | OpenAIRE |
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