A novel CASK mutation identified in siblings exhibiting developmental disorders with/without microcephaly

Area of Science:

• Genetics and Molecular Biology
• Neuroscience
• Developmental Biology

Background:

• Mutations in the calcium/calmodulin-dependent serine protein kinase (CASK) gene are linked to various neurological disorders, including intellectual disability (ID), microcephaly with pontine and cerebellar hypoplasia (MICPCH), FG syndrome, X-linked ID, epileptic encephalopathy, and autistic spectrum disorder (ASD).
• Understanding the genetic underpinnings of developmental disorders like ASD is crucial for diagnosis and potential therapeutic strategies.

Purpose of the Study:

• To investigate the genetic causes of developmental disorders in siblings using next-generation sequencing.
• To identify novel mutations in the CASK gene and explore their association with intellectual disability and autistic spectrum disorder.

Main Methods:

• Next-generation sequencing was employed to analyze the genetic makeup of siblings presenting with developmental disorders.
• Radiological examination of the brain was performed to assess for structural abnormalities.
• X-chromosome inactivation (XCI) patterns were analyzed in affected and unaffected family members.

Main Results:

• A novel CASK mutation, c.1424G>T (p.Ser475Ile), was identified in a male patient with ID, ASD, and microcephaly.
• The identified mutation was present in the healthy mother and a younger sister who exhibited ASD but had normal intellectual levels, explained by a paradoxical XCI pattern.
• Brain imaging revealed no structural abnormalities in the affected male patient.

Conclusions:

• The identification of a novel CASK mutation in siblings with ID and/or ASD suggests a significant relationship between CASK gene mutations and the development of ASD.
• X-chromosome inactivation patterns play a crucial role in modulating the phenotypic expression of CASK mutations, influencing intellectual levels and symptom severity.
• Further research and accumulation of data are necessary to fully elucidate the genotype-phenotype correlation in ASD cases associated with CASK mutations.