Clinical and genetic spectrum of CASK-related disorders in Chinese patients

CASK-related disorders are rare X-linked neurological conditions. Heterozygous and hemizygous variants in the CASK gene located at Xp11.4 are strongly associated with developmental delay and intellectual disability. However, no long-term clinical information has been reported in the Chinese population. Here, we delineated the clinical and genetic characteristics of 21 Chinese patients with CASK variants.

We used whole-exome sequencing and copy number variant sequencing to identify CASK variants in 21 Chinese patients (18 females and 3 males). Information on the age, sex, genetic data, feeding situation, growth, developmental conditions, and auxiliary examinations of the cohort was collected.

We identified a total of 20 CASK alterations, 12 of which were novel variants, including five copy number alterations. The clinical phenotypes of the cohort included severe developmental delay, severe intellectual disability, microcephaly, muscle tone abnormalities, feeding difficulties, relatively low weight gain, and seizures. Significant differences in the sex composition of patients with CASK-related neurodevelopmental disorders were noted; compared with male patients, more female patients had CASK-related neurodevelopmental disorders and had relatively mild clinical manifestations. Compared with that in previously reported cohorts in other countries, the age of seizure onset was earlier in the Chinese population with CASK variants, and these patients tended not to suffer from severe ophthalmologic problems.

The present study revealed the clinical and genetic spectrum of 21 Chinese individuals carrying CASK variants. The core clinical phenotypes of the present cohort overlapped with those in previously reported cohorts, but there were several unique features, such as earlier seizure times. The present study emphasized the role of CASK as a disease-causing gene of unexplained intellectual disability.