Hemizygous splicing variant in CNKSR2 results in X-linked intellectual developmental disorder

Mol Genet Genomic Med. 2024 Feb;12(2):e2389. doi: 10.1002/mgg3.2389.

Abstract

Background: Intellectual disability (ID) refers to a childhood-onset neurodevelopmental disorder with a prevalence of approximately 1%-3%.

Methods: We performed whole exome sequencing for the patient with ID. And the splicing variant we found was validated by minigene assay.

Results: Here, we report a boy with ID caused by a variant of CNKSR2. His neurological examination revealed hypsarrhythmia via electroencephalography and a right temporal polar arachnoid cyst via brain magnetic resonance imaging. A novel splicing variant in the CNKSR2 gene (NM_014927.5, c.1657+1G>A) was discovered by exome sequencing. The variant caused a 166 bp intron retention between exons 14 and 15, which was validated by a minigene assay. The variant was not reported in public databases such as gnomAD and the Exome Aggregation Consortium.

Conclusions: The variant was predicted to be damaging to correct the translation of the CNKRS2 protein and was classified as likely pathogenic according to the ACMG guidelines.

Keywords: ACMG; CNKSR2; X-linked; intellectual developmental; variant.

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Child
  • Developmental Disabilities / genetics
  • Humans
  • Intellectual Disability* / diagnosis
  • Intellectual Disability* / genetics
  • Male
  • Mental Retardation, X-Linked* / genetics
  • Neurodevelopmental Disorders*
  • RNA Splicing

Substances

  • CNKSR2 protein, human
  • Adaptor Proteins, Signal Transducing