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).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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