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Updated: Apr 7, 2026

Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease
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Compound heterozygous structural variants resulting in CNTNAP2 biallelic loss-of-function: rare mechanisms unveiled

Jade Fauqueux1, Roseline Caumes1,2, Cindy Colson2

  • 1ULR7364 RADEME, Univ. Lille, FHU-G4 Génomique, F-59000, Lille, France.

Human Genomics
|April 5, 2026
PubMed

Insights

Complex genetic variants in the CNTNAP2 gene are linked to Pitt-Hopkins-like syndrome. Genome sequencing identified novel deletions and inversions, expanding the understanding of this neurodevelopmental disorder.

Area of Science:

  • Genetics
  • Neuroscience
  • Molecular Biology

Background:

  • The CNTNAP2 gene encodes CASPR2, a crucial transmembrane protein for neuronal development and synapse function.
  • Pathogenic variants in CNTNAP2 are associated with Pitt-Hopkins-like syndrome, presenting intellectual disability, epilepsy, and autistic traits.

Purpose of the Study:

  • To investigate the genetic basis of Pitt-Hopkins-like syndrome in two patients.
  • To characterize complex structural variants within the CNTNAP2 gene.
  • To expand the known mutational spectrum of CNTNAP2.

Main Methods:

  • Utilized short-read genome sequencing to detect structural variants.
  • Employed long-read sequencing to refine breakpoint characterization.
  • Analyzed intragenic deletions and paracentric inversions within CNTNAP2.

Main Results:

  • Identified compound heterozygous structural variants in two patients with Pitt-Hopkins-like phenotype.
  • Detected non-recurrent deletions involving exon 3 and paracentric inversions with breakpoints in intron 1 of CNTNAP2.
  • Confirmed the presence of both deletion and inversion variants in trans.

Conclusions:

  • These findings broaden the mutational spectrum of the CNTNAP2 gene.
  • Highlight the utility of comprehensive genome sequencing for identifying complex structural variants.
  • Underscore the role of CNTNAP2 in neurodevelopmental disorders.
Keywords:
CNTNAP2Genome sequencingNeurodevelopmental disordersPitt–Hopkins–like syndromeStructural variants

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