Homozygous or compound heterozygous variants and/or intragenic deletions within CNTNAP2 gene were associated with Pitt-Hopkins like syndrome 1 (PTHSL1, MIM#610042), with variable features that included intellectual disability (ID), early seizure onset, regression of language ability, and hyper-breathing patterns. Given the lack of typical Pitt-Hopkins craniofacial features and hyper-breathing patterns in most patients, it has recently been proposed that biallelic loss of CNTNAP2 results in a disorder called “CASPR2-deficiency neurodevelopmental disorder”, which includes severe ID, early infantile seizures, language regression, variable presence of autistic features, hyporefexia and ataxia.

While the loss of function mechanism due to biallelic CNTNAP2 variants is well understood, the impact of heterozygous CNTNAP2 variants is more controversial.