Submission Details

The CNTNAP2 gene has been reported in association with multiple neurodevelopmental disorders and inheritance patterns. We have split curations by inheritance pattern. This assessment focuses on the association of CNTNAP2 with autosomal dominant complex neurodevelopmental disorder. Biallelic deletions and variants in CNTNAP2 cause an autosomal recessive disorder with early onset epilepsy and intellectual disability, sometimes associated with cortical dysplasia (Cortical dysplasia-focal epilepsy syndrome and Pitt-Hopkins like syndrome 1, MIM# 610042 for both phenotypes). The recessive phenotypes will be curated by the ClinGen Epilepsy Gene Curation Expert Panel. CNTNAP2 has been suggested to be involved in autosomal dominant Autism susceptibility (MIM# 612100) based on association studies of common variants and reports of heterozygous chromosomal aberrations, copy number variants (CNVs) and sequence variants. Two papers published in 2008 suggested that common variants in CNTNAP2 were associated with autism (Arking et al. PMID: 18179894; Alarcon et al. PMID: 18179893). However, these association studies were underpowered, and their findings were not validated in larger case-control studies. Also in 2008, Bakkaloglu et al. (PMID: 18179895) reported a de novo inversion of chromosome 7q disrupting CNTNAP2 and AUTS2 in a child with intellectual disability and autism spectrum disorder. Because AUTS2 is involved in autosomal dominant intellectual disability this case cannot be used as evidence. Bakkaloglu et al. (2008) also reported several rare heterozygous sequence variants in individuals with autism, but a follow-up study by the same group (Murdoch et al. 2015, PMID: 25621974) found no increased burden of rare variants in autism compared to controls. Since then, there have been numerous other reports of heterozygous disruption of CNTNAP2 (mostly deletions, but also translocations and truncating variants) in individuals with a broad spectrum of neurodevelopmental and neuropsychiatric disorders, including autism spectrum disorder, intellectual disability, epilepsy, speech and language impairment, Tourette syndrome, obsessive compulsive disorder, attention deficit-hyperactivity disorder, and schizophrenia. However, no excess of rare variants in CNTNAP2 has been reported in cases with any of these disorders compared to healthy controls. These heterozygous variants are unlikely to be deleterious given that they also occur in healthy controls (PMID: 25217958), and many are inherited from unaffected parents (e.g. PMIDs: 17392702, 21827697). In agreement with these findings, CNTNAP2 is not constrained for loss-of-function variants (pLI = 0 in gnomAD v2.1.1). Of note, carrier parents of individuals with autosomal recessive intellectual disability and epilepsy due to biallelic loss-of-function variants (deletions and/or truncating variants) were not noted to have abnormal phenotypes, consistent with the lack of pathogenicity of heterozygous variants (PMIDs: 19896112, 25045150, 26843181, 27439707). No experimental evidence was applicable to this curation as it is not specific to autosomal dominant inheritance and could overlap with autosomal recessive disorders associated with CNTNAP2. In summary, there is no convincing evidence supporting the relationship between CNTNAP2 and autosomal dominant autism spectrum disorder, and more generally autosomal dominant complex neurodevelopmental disorder, so this gene-disease relationship was classified as disputed. This gene-disease pair was originally evaluated by the Intellectual disability and Autism Gene Curation Expert Panel on 9/19/2019 and re-evaluated on 3/16/2021. As a result of this re-evaluation, the original classification of “disputed” did not change. This classification was approved by the ClinGen Intellectual disability and Autism Working Group on March 16, 2021 (SOP Version 8).

The CNTNAP2 gene has been reported in association with multiple neurodevelopmental disorders and inheritance patterns. We have split curations by inheritance pattern. This assessment focuses on the association of CNTNAP2 with autosomal dominant complex neurodevelopmental disorder. Biallelic deletions and variants in CNTNAP2 cause an autosomal recessive disorder with early onset epilepsy and intellectual disability, sometimes associated with cortical dysplasia (Cortical dysplasia-focal epilepsy syndrome and Pitt-Hopkins like syndrome 1, MIM# 610042 for both phenotypes). The recessive phenotypes will be curated by the ClinGen Epilepsy Gene Curation Expert Panel.

CNTNAP2 has been suggested to be involved in autosomal dominant autism susceptibility (MIM# 612100) based on association studies of common variants and reports of heterozygous chromosomal aberrations, copy number variants (CNVs) and sequence variants. Two papers published in 2008 suggested that common variants in CNTNAP2 were associated with autism (Arking et al., PMID: 18179894; Alarcon et al., PMID: 18179893). However, these association studies were underpowered, and their findings were not validated in larger case-control studies. Also in 2008, Bakkaloglu et al. (PMID: 18179895) reported a de novo inversion of chromosome 7q disrupting CNTNAP2 and AUTS2 in a child with intellectual disability and autism spectrum disorder. Because AUTS2 is involved in autosomal dominant intellectual disability this case cannot be used as evidence. Bakkaloglu et al. (2008) also reported several rare heterozygous sequence variants in individuals with autism, but a follow-up study by the same group (Murdoch et al. 2015, PMID: 25621974) found no increased burden of rare variants in autism compared to controls.

Since then, there have been numerous other reports of heterozygous disruption of CNTNAP2 (mostly deletions, but also translocations and truncating variants) in individuals with a broad spectrum of neurodevelopmental and neuropsychiatric disorders, including autism spectrum disorder, intellectual disability, epilepsy, speech and language impairment, Tourette syndrome, obsessive compulsive disorder, attention deficit-hyperactivity disorder, and schizophrenia. However, no excess of rare variants in CNTNAP2 has been reported in cases with any of these disorders compared to healthy controls. These heterozygous variants are unlikely to be deleterious given that they also occur in healthy controls (PMID: 25217958), and many are inherited from unaffected parents (e.g. PMIDs: 17392702, 21827697). In agreement with these findings, CNTNAP2 is not constrained for loss-of-function variants (pLI = 0 in gnomAD v2.1.1). Of note, carrier parents of individuals with autosomal recessive intellectual disability and epilepsy due to biallelic loss-of-function variants (deletions and/or truncating variants) were not noted to have abnormal phenotypes, consistent with the lack of pathogenicity of heterozygous variants (PMIDs: 19896112, 25045150, 26843181, 27439707).

No experimental evidence was applicable to this curation as it is not specific to autosomal dominant inheritance and could overlap with autosomal recessive disorders associated with CNTNAP2.

In summary, there is no convincing evidence supporting the relationship between CNTNAP2 and autosomal dominant autism spectrum disorder, and more generally autosomal dominant complex neurodevelopmental disorder, so this gene-disease relationship was classified as disputed. This gene-disease pair was originally evaluated by the Intellectual disability and Autism Gene Curation Expert Panel on September 19, 2019 and re-evaluated on March 16, 2021. As a result of this re-evaluation, the original classification of disputed did not change. This classification was approved by the ClinGen Intellectual disability and Autism Gene Curation Expert Panel on March 16, 2021 (SOP Version 8).