CNTNAP2

Inheritance Pattern: AR

Disease ID:MONDO:0100038

Submitter: ClinGen

The CNTNAP2 gene is associated with autosomal recessive clinical disorders referred to as cortical dysplasia-focal epilepsy syndrome (CDFE), Pitt-Hopkins like syndrome type 1, or CASPER2 deficiency syndrome in the literature. These disorders share one phenotype number in OMIM (610042). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism(s), inheritance pattern, or phenotypic variability. Therefore, all of the disease entities have been lumped into one disease entity, autosomal recessive complex neurodevelopmental disorder. Of note, this gene has also been implicated in autosomal dominant complex neurodevelopmental disorder, which has been assessed separately. CNTNAP2 was first reported in relation to an autosomal recessive complex neurodevelopmental disorder in 2006 (PMID 16571880). The mechanism for disease is homozygous or compound heterozygous loss of function variants. At least 15 unique variants, including nonsense, frameshift, and exon-level deletions have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in this gene have been reported in at least seven probands in four publications (PMIDs: 16571880, 19896112, 27439707, and 30762603). Variants in this gene segregated with disease in a similarly affected sibling in three of these families. Additionally, the c.3709delG founder variant was identified in six additional family members over multiple generations and in nine additional individuals from seven other Old Order Amish families (PMID 16571880). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease association is supported by an animal model (PMID 21962519). In summary, CNTNAP2 is definitively associated with autosomal recessive complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Epilepsy Gene Curation Expert Panel Working Group on June 15, 2021 (SOP Version 8).

Inheritance Pattern: AR

Disease ID:MONDO:0012400

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0012400

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0012400

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

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).

Inheritance Pattern: AR

Disease ID:MONDO:0012400

Submitter: Illumina

Inheritance Pattern: AR

Disease ID:MONDO:0012400

Submitter: G2P