ORIGINAL ARTICLE Eight further individuals with intellectual disability and epilepsy carrying bi-allelic CNTNAP2 aberrations allow delineation of the mutational and phenotypic spectrum 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 For numbered affiliations see end of article. Correspondence to Dr Christiane Zweier, Institute of Human Genetics, Friedrich- Alexander-Universität Erlangen- Nürnberg, Schwabachanlage 10, Erlangen 91054, Germany; christiane.zweier@uk-erlangen. de Received 3 March 2016 Revised 20 May 2016 Accepted 25 June 2016 Published Online First 20 July 2016 To cite: Smogavec M, Cleall A, Hoyer J, et al. J Med Genet 2016;53:820– 827. 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. INTRODUCTION CNTNAP2 is one of the largest genes in the human genome, consisting of 24 exons (NM_014141) and spanning 2.3 Mb on chromosome 7q35-36.1. 1 It encodes contactin-associated protein 2 (CASPR2), a transmembrane protein which is distantly related to the family of neurexins and regulates neuron-glia contact in vertebrates and glia-glia contact in insects. 2 The large extracellular region of CASPR2 contains several domains, including four laminin G domains, two epidermal growth factor-like domains and discoidin/neuropilin and fibrinogen- like domains. The small C-terminal cytoplasmatic part contains a PDZ domain-binding sequence that is supposed to mediate interactions with PDZ-containing proteins. 3 4 CNTNAP2 is highly expressed in the spinal cord and several brain regions, particularly in a cortico-striato-thalamic circuit that is involved in diverse higher-order cog- nitive functions. 5 6 Vertebrate Caspr2 colocalises with potassium channels in the juxtaparanodal regions of Ranvier nodes in myelinated axons. 47 It has roles in brain development and function by being involved in processes such as neuronal migration, dendritic arborisation and spine devel- opment. 8–10 Heterozygous chromosomal aberrations, copy number variants (CNVs) and sequence variants in CNTNAP2 have been implicated as incompletely penetrant risk factors in a wide spectrum of neuro- developmental and neuropsychiatric disorders. These include Tourette syndrome, intellectual dis- ability (ID), autism-spectrum disorders, speech and language impairment, epilepsy and schizophre- nia. 6 11–18 The presence of one or more additional contributing risk factors in symptomatic carriers is likely. 15 19 In contrast, bi-allelic loss-of-function aberrations in CNTNAP2 are convincingly causative of an auto- somal recessive, fully penetrant, severe ID and epi- lepsy disorder. In 2006, Strauss et al 10 reported on nine affected children in the Old Order Amish with a cortical dysplasia focal epilepsy syndrome (MIM#610042), in whom they identified a homo- zygous single bp deletion (c.3709delG), predicted to result in a premature stop codon. The affected individuals presented with mildly delayed motor and age-appropriate cognitive development and language comprehension until the onset of frequent and intractable seizures within the first 2 years of live. Subsequently, deterioration of speech, learning 820 Smogavec M, et al. J Med Genet 2016;53:820–827. doi:10.1136/jmedgenet-2016-103880 Genotype-phenotype correlations on 26 June 2018 by guest. Protected by copyright. http://jmg.bmj.com/ J Med Genet: first published as 10.1136/jmedgenet-2016-103880 on 20 July 2016. Downloaded from