A Missense Pathogenic Variant in a Conserved Region of CNTNAP2 Is Associated with Obesity, Seizures, and Language Impairment in a Pakistani Family.

INTRODUCTION: In a consanguineous family, seven siblings born in three sibships showed a syndromic disorder characterized by obesity, seizures, and language impairment phenotypes, which appeared at early age or developed during early childhood.

METHODS: By whole-exome sequencing and subsequent Sanger sequencing, a novel homozygous missense variant (c.3371 T>A [p.Ile1124Asn]) in exon 20 of the CNTNAP2 gene was identified.

RESULTS: The pathogenic variant in this family is located within one of the laminin G-like 4 domains of CASPR2 and may cause loss of hydrophobic interactions of CASPR2 with its partner proteins. Single nucleotide and copy number variants in this gene have previously been related to Gilles de la Tourette syndrome, cortical dysplasia-focal epilepsy syndrome, schizophrenia, Pitt-Hopkins syndrome, and autism spectrum, attention deficit hyperactivity, and obsessive compulsive disorders. Yet, few studies described patients with CNTNAP2 variants showing diet-induced obesity.

CONCLUSION: This report expands the phenotypic spectrum of this rare syndrome and provides deeper insights by documenting the clinical features and genetic findings of the patients.