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

Mateja Smogavec, Alison Cleall, Juliane Hoyer, Damien Lederer, Marie Cécile Nassogne, Elizabeth E. Palmer, Marie Deprez, Valérie Benoit, Isabelle Maystadt, Charlotte Noakes, Alejandro Leal, Marie Shaw, Jozef Gecz, Lucy Raymond, André Reis, Deborah Shears, Knut Brockmann, Christiane Zweier

Research output: Contribution to journalArticle

17 Citations (Scopus)

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 biallelic aberrations in CNTNAP2.

LanguageEnglish
Pages820-827
Number of pages8
JournalJournal of Medical Genetics
Volume53
Issue number12
DOIs
Publication statusPublished - 1 Dec 2016
Externally publishedYes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Smogavec, Mateja ; Cleall, Alison ; Hoyer, Juliane ; Lederer, Damien ; Nassogne, Marie Cécile ; Palmer, Elizabeth E. ; Deprez, Marie ; Benoit, Valérie ; Maystadt, Isabelle ; Noakes, Charlotte ; Leal, Alejandro ; Shaw, Marie ; Gecz, Jozef ; Raymond, Lucy ; Reis, André ; Shears, Deborah ; Brockmann, Knut ; Zweier, Christiane. / Eight further individuals with intellectual disability and epilepsy carrying bi-allelic CNTNAP2 aberrations allow delineation of the mutational and phenotypic spectrum. In: Journal of Medical Genetics. 2016 ; Vol. 53, No. 12. pp. 820-827.
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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 biallelic aberrations in CNTNAP2.",
author = "Mateja Smogavec and Alison Cleall and Juliane Hoyer and Damien Lederer and Nassogne, {Marie C{\'e}cile} and Palmer, {Elizabeth E.} and Marie Deprez and Val{\'e}rie Benoit and Isabelle Maystadt and Charlotte Noakes and Alejandro Leal and Marie Shaw and Jozef Gecz and Lucy Raymond and Andr{\'e} Reis and Deborah Shears and Knut Brockmann and Christiane Zweier",
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Smogavec, M, Cleall, A, Hoyer, J, Lederer, D, Nassogne, MC, Palmer, EE, Deprez, M, Benoit, V, Maystadt, I, Noakes, C, Leal, A, Shaw, M, Gecz, J, Raymond, L, Reis, A, Shears, D, Brockmann, K & Zweier, C 2016, 'Eight further individuals with intellectual disability and epilepsy carrying bi-allelic CNTNAP2 aberrations allow delineation of the mutational and phenotypic spectrum', Journal of Medical Genetics, vol. 53, no. 12, pp. 820-827. https://doi.org/10.1136/jmedgenet-2016-103880

Eight further individuals with intellectual disability and epilepsy carrying bi-allelic CNTNAP2 aberrations allow delineation of the mutational and phenotypic spectrum. / Smogavec, Mateja; Cleall, Alison; Hoyer, Juliane; Lederer, Damien; Nassogne, Marie Cécile; Palmer, Elizabeth E.; Deprez, Marie; Benoit, Valérie; Maystadt, Isabelle; Noakes, Charlotte; Leal, Alejandro; Shaw, Marie; Gecz, Jozef; Raymond, Lucy; Reis, André; Shears, Deborah; Brockmann, Knut; Zweier, Christiane.

In: Journal of Medical Genetics, Vol. 53, No. 12, 01.12.2016, p. 820-827.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Eight further individuals with intellectual disability and epilepsy carrying bi-allelic CNTNAP2 aberrations allow delineation of the mutational and phenotypic spectrum

AU - Smogavec, Mateja

AU - Cleall, Alison

AU - Hoyer, Juliane

AU - Lederer, Damien

AU - Nassogne, Marie Cécile

AU - Palmer, Elizabeth E.

AU - Deprez, Marie

AU - Benoit, Valérie

AU - Maystadt, Isabelle

AU - Noakes, Charlotte

AU - Leal, Alejandro

AU - Shaw, Marie

AU - Gecz, Jozef

AU - Raymond, Lucy

AU - Reis, André

AU - Shears, Deborah

AU - Brockmann, Knut

AU - Zweier, Christiane

PY - 2016/12/1

Y1 - 2016/12/1

N2 - 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 biallelic aberrations in CNTNAP2.

AB - 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 biallelic aberrations in CNTNAP2.

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U2 - 10.1136/jmedgenet-2016-103880

DO - 10.1136/jmedgenet-2016-103880

M3 - Article

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JO - Journal of medical genetics

T2 - Journal of medical genetics

JF - Journal of medical genetics

SN - 0022-2593

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