Identification and structural characterisation of a novel mutation in the CNKSR2 gene associated with Houge-Type...

Neurological disorders with overlapping phenotypes pose significant diagnostic challenges, especially the ones that occur on account of rare genetic variants. We hereby report a case of a 16-year-old male with clinical symptoms of severe intellectual disability, excessive appetite, an elongated face with decreased body weight (<-2 SD) and microcephaly (<-3 SD). Behavioral manifestations like attention deficit, hyperactivity, and impulsivity were also observed in the patient. The Exome sequencing of affected child revealed a novel frameshift insertion in the CNKSR2 gene, or connector enhancer of kinase suppressor of Ras 2, which is located on the X chromosome. In consensus with the phenotypes of the patient, this novel variant has an association with Houge type of X-linked intellectual developmental disorder. This is the first case reporting a pathogenic frameshift insertion in CNKSR2 (c.2489dup: p. Arg831Glufs *21) gene that encodes a protein that plays a significant role in neuronal proliferation, migration, and differentiation. The integrative molecular dynamics simulation analyses revealed substantial differences in the structural dynamics and stability between the wild-type protein and its mutant form, resulting in a more rigid protein due to the presence of the mutation. This finding broadens the mutation spectrum of CNKSR2 and the importance of exploring mutations in this gene in association with Intellectual developmental disorders. Early detection of such pathogenic variants in associated genes not only helps with clinical diagnosis and management but also has the potential to avert the birth of another affected individual in the family.