CNTNAP5 was first reported in relation to disease in 2010 (PMID: 20346443) when a deletion disrupting this gene was identified in a pair of siblings with autism who were also found to have additional microdeletions. Since that time, several other variants in CNTNAP5 have been reported in individuals with various neurodevelopmental presentations including autism, intellectual disability, seizures, and language impairment. Because of this the Intellectual Disability and Autism Gene Curation Expert Panel decided to curate this evidence using the term complex neurodevelopmental disorder.
At least 10 individuals with variants (mainly missense with a few intragenic and intergenic deletion variants) in this gene have been reported (PMIDs: 20346443, 31398340, 35982159, 37007974, 37543562). However, none of them were assigned scores. In some cases, the variants reported were either inherited from unaffected parents or found at high frequencies in gnomAD v4.1. In other cases, the probands had other variants in other genes that could also be suspected to be causative for complex neurodevelopmental disorders. Additionally, there are a few reports of individuals with intragenic copy number variants in this gene; these were also excluded from case level evidence given the presence of the same variants in unaffected family members, or the presence of additional copy number variants in the same proband (PMIDs: 23275889, 32329157, 34553698).
In summary, the evidence supporting the relationship between CNTNAP5 and autosomal dominant complex neurodevelopmental disorder has been disputed and no valid evidence remains to support the claim. More evidence is needed to either support or entirely refute the role CNTNAP5 plays in this disease. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on August 20, 2024 (SOP Version 10).
CNTNAP5 was first reported in relation to disease in 2010 (PMID: 20346443) when a deletion disrupting this gene was identified in a pair of siblings with autism who were also found to have additional microdeletions. Since that time, several other variants in CNTNAP5 have been reported in individuals with various neurodevelopmental presentations including autism, intellectual disability, seizures, and language impairment. Because of this the Intellectual Disability and Autism GCEP decided to curate this evidence using the term complex neurodevelopmental disorder.
At least 10 individuals with variants (mainly missense with a few intragenic and intergenic deletion variants) in this gene have been reported (PMIDs: 20346443, 31398340, 35982159, 37007974, 37543562). However, none of them were assigned scores. In some cases, the variants reported were either inherited from unaffected parents or found at high frequencies in gnomAD v4.1. In other cases, the probands had other variants in other genes that could also be suspected to be causative for complex neurodevelopmental disorders. Additionally, there are a few reports of individuals with intragenic copy number variants in this gene; these were also excluded from case level evidence given the presence of the same variants in unaffected family members, or the presence of additional copy number variants in the same proband (PMIDs: 23275889, 32329157, 34553698).
In summary, the evidence supporting the relationship between CNTNAP5 and autosomal dominant complex neurodevelopmental disorder has been disputed and no valid evidence remains to support the claim. More evidence is needed to either support or entirely refute the role CNTNAP5 plays in this disease. This classification was approved by the ClinGen Intellectual Disability and Autism GCEP on August 20, 2024 (SOP Version 10).
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