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The study aims to identify and characterize rare structural variants in the CNTNAP2 gene associated with Pitt–Hopkins–like syndrome.

April 7, 2026Human Genomics0 citationsOpen Access

Compound heterozygous structural variants resulting in CNTNAP2 biallelic loss-of-function: rare mechanisms unveiled by genome sequencing

JFJade FauqueuxUniversité de Lille RCRoseline CaumesUniversité de Lille CCCindy ColsonUniversité de Lille

Key Points

The study aims to identify and characterize rare structural variants in the CNTNAP2 gene associated with Pitt–Hopkins–like syndrome.
Analyzed genomic data from two patients with Pitt–Hopkins–like phenotype.
Performed short-read and long-read genome sequencing to detect variants.
Characterized an intragenic deletion and a paracentric inversion in the CNTNAP2 gene.
Identified biallelic pathogenic variants in the CNTNAP2 gene.
Detected a compound heterozygous structural variant consisting of an intragenic deletion and inversion.
Refined the location of one variant breakpoint using long-read sequencing.

Abstract

The CNTNAP2 gene encodes CASPR2, a transmembrane protein essential for neuronal development and synaptic function. Biallelic pathogenic variants cause Pitt–Hopkins–like syndrome, characterized by intellectual disability, epilepsy, and autistic features. We report two patients with a Pitt–Hopkins–like phenotype carrying compound heterozygous structural variants: an intragenic deletion in trans with a paracentric inversion. Short-read genome sequencing detected both variants, and long-read sequencing refined one breakpoint. Non-reccurent deletions involved exon 3, while CNTNAP2 breakpoints for both inversions were located in intron 1. These findings broaden the mutational spectrum of CNTNAP2 and underscore the value of genome sequencing in identifying complex structural variants.

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