Identification of CNKSR2 Pathogenic Variant and Detection of Strong XCI in a Female Patient With Severe DEE‐SWAS and Phenotype Expansion in Male Patients

Connector enhancer of kinase suppressor of Ras2 (CNKSR2) is critical in neuronal dendrite growth. Hemizygous pathogenic variants of CNKSR2, which is located at Xp22.12, are associated with intellectual disability, epilepsy, and developmental and epileptic encephalopathy with spike wave activation during sleep. As an X-linked recessive genetic disorder, neurological symptoms usually manifest in males, while female carriers are typically asymptomatic. Here, we report a girl (Patient 1) and boy (Patient 2) with a pathogenic truncated variant of CNKSR2. Patient 1 had intractable epilepsy and severe developmental regression; her electroencephalogram showed continuous spike-and-wave activity during sleep. Whole-genome sequencing (WGS) revealed a heterozygous CNKSR2 c.2134C>T, p.(Arg712Ter) variant (de novo, previously reported), and X-chromosome inactivation analysis of her white blood cell DNA showed marked skewing (85:15). Her clinical symptoms were more severe than those of previously reported female patients, but they improved with ethosuximide and sulthiame treatment. Patient 2 had epilepsy and Angelman syndrome-like symptoms. WGS revealed a Clinical Genetics hemizygous c.492C>A, p (Cys164Ter) CNKSR2 variant (maternal or novel). The strength of the X-chromosome inactivation skewing may be related to severity. These novel pathogenic CNKSR2 variants have expanded the phenotypic spectrum of this disease.