Molecular characteristics

Contactin-associated protein-like 2 (CNTNAP2) is one of the largest genes in the human genome located on chromosome 7q35-36.1. It encodes for CASPR2, a member of the neurexin superfamily of cell adhesion proteins. CASPR2 is a presynaptic type 1 transmembrane protein, with a large extracellular and smaller intracellular portion that participates in cell–cell adhesion and synaptic interactions. CNTNAP2 is expressed throughout the developing and adult central nervous system.

Molecular-Pathomechanistic link
•    Mouse studies have uncovered a role for CASPR2 in neuronal migration and postmitotic neuronal development
•    Experimental studies on knock-out mice and in human cell lines support the hypothesis that CASPR2 is involved in neuronal migration, myelination, and neuronal transmission with a reduction in both inhibitory GABAergic neuronal numbers and excitatory neurotransmission

Genotype-phenotype correlation
While the loss of function mechanism due to biallelic CNTNAP2 variants is well understood, the impact of heterozygous CNTNAP2 variants is more controversial.
A growing body of literature over the last two decades underscored a possible role of heterozygous chromosomal translocations and deletions, single nucleotide polymorphisms, and rare heterozygous variants of CNTNAP2 in a wide array of neuropsychiatric disorders.
However, heterozygous CNTNAP2 variations are also present in the healthy population including healthy parents of children with either mono- or biallelic variants.
It has been suggested that the phenotypic picture of each heterozygous variant may result from the combination of two mechanisms: a dominant-negative effect on wild-type CASPR2 function due to endoplasmic reticulum (retention mimicking the homozygous null phenotype) and a loss of function mechanism for adhesion-defective variant proteins, enabling the interaction with their extracellular partners.
It has recently been proposed that “CNTNAP2-related neurodevelopmental disorder” might be an exclusively recessive disorder while the dominant version is becoming weaker with the increase body of evidence in the literature and in human population variant databases.

Diagnostic testing
The diagnosis of “CASPR2-deficiency neurodevelopmental disorder” is confirmed in a proband with compatible clinical characteristics and the identification of homozygous or compound heterozygous pathogenic variants in the CNTNAP2 gene identified by one of the following molecular genetic tests.  

Single gene testing -- Sequencing of CNTNAP2 is performed to detect small intragenic deletions, insertions and missense, nonsense and splice site pathogenic variants.

An epilepsy multigene Next Generation Sequencing (NGS) panel or an autism/intellectual deficiency NGS panel -- The multigene panel includes CNTNAP2 and other genes of interest.

Comprehensive genomic testing -- Genomic testing does not require the clinicians to determine which gene is likely involved. Whole exome sequencing is most commonly used. Whole genome sequencing is also possibly used if deep intronic mutation is suspected.