Two heterozygous mutations in the calcium/calmodulin‐dependent serine protein kinase gene (CASK) in cases with developmental disorders

BACKGROUND: The calcium/calmodulin‐dependent serine protein kinase gene (CASK) is an essential gene in mammals, critical for neurodevelopment. The purpose of this study is to expand the understanding of the diagnosis of CASK‐linked disorders. MATERIALS/METHODS: From clinical and genetic mutational analyses, relevant data in 2 Han Chinese patients were collected and analyzed. Real‐time quantitative PCR (RT‐qPCR) was performed to investigate the CASK expression levels in the patients. The X‐chromosome inactivation (XCI) patterns of the patients and their nuclear families were tested by quantitation of methylation of the polymorphic human androgen receptor (HUMARA) locus. RESULTS: Two Han Chinese patients both presented with intellectual disability (ID), microcephaly with pontine and cerebellar hypoplasia (MICPCH). Two de novo mutations of c.82C>T (p.Arg28*) and c.846C>G (p.Tyr282*) in CASK have been investigated and predicted to be deleterious, which have produced truncated proteins. The functional protein association network of STRING (http://string‐db.org) generated three‐dimensional (3D) atomic models based on protein sequences in CASK and two Arg28 and Tyr282 residues were marked. RT‐qPCR showed lower copy numbers of CASK expression in the patients than in their parents, as well as the sex‐ and age‐ matched control groups. Patient 1 showed a skewed XCI pattern, while no related changes noted in patient 2. CONCLUSIONS: Patients carrying different nonsense variants may have different degrees of different clinical phenotypes. This study expands the spectrum of genotype and phenotype correlations of CASK‐linked disorders in the Han Chinese ethnicity and provides new insights into the molecular mechanism.