Genotype-phenotype correlation in contactin-associated protein-like 2 (CNTNAP-2) developmental disorder

Area of Science:

• Genetics
• Neuroscience
• Developmental Biology

Background:

• Contactin-associated protein-like 2 (CNTNAP2) encodes CASPR2, a protein crucial for cell adhesion and synaptic function.
• Biallelic loss of CNTNAP2 is linked to Pitt-Hopkins-like syndrome-1, but the role of heterozygous variants is debated.
• Understanding the genotype-phenotype correlation in CNTNAP2 variants is essential for accurate diagnosis and genetic counseling.

Approach:

• Reported 22 novel patients with mono- and biallelic CNTNAP2 variants.
• Conducted a literature review including 50 previously published patients.
• Performed genotype-phenotype correlation analysis to identify significant associations.

Key Points:

• Global developmental delay, intellectual disability, and epilepsy are prevalent in patients with CNTNAP2 variants.
• Epilepsy onset typically occurs within the first two years of life.
• Autism spectrum disorder and neuropsychiatric comorbidities are observed in a significant portion of patients.
• Nonspecific midline brain anomalies are common, with some patients showing temporal lobe abnormalities.

Conclusions:

• Global developmental delay, epilepsy, hyporeflexia, autism spectrum disorder, language impairment, and severe cognitive impairment are significantly associated with biallelic CNTNAP2 variants.
• CNTNAP2-deficiency neurodevelopmental disorder is proposed as an exclusively recessive condition.
• The contribution of heterozygous CNTNAP2 variants to disease is less likely to follow an autosomal dominant inheritance pattern.