Novel Variations in the KDM5C Gene Causing X-Linked Intellectual Disability

Area of Science:

• Genetics
• Neurodevelopmental Disorders
• Molecular Biology

Background:

• Intellectual disability (ID) is a complex neurodevelopmental disorder with diverse genetic causes.
• The KDM5C gene plays a crucial role in neuronal development and is associated with X-linked ID.

Purpose of the Study:

• To investigate the pathogenicity of two novel KDM5C gene variations.
• To describe the clinical and neuroimaging findings in affected individuals.
• To review existing literature on KDM5C variations and associated phenotypes.

Main Methods:

• Physical examinations and structural neuroimaging were conducted.
• Exome sequencing was used to identify genetic variations.
• In vitro studies using transfected KDM5C constructs assessed protein function.

Main Results:

• Two novel KDM5C variations (c.2233C>G and c.3392_3393delAG) were identified in two Chinese families with X-linked ID.
• Affected males presented with severe ID, short stature, and facial dysmorphism; one also had epilepsy and autistic spectrum disorder (ASD).
• Mutant KDM5C constructs showed reduced protein expression, stability, and histone demethylase activity.

Conclusions:

• Novel KDM5C variations are associated with X-linked intellectual disability.
• The clinical phenotype, including ID and associated features like ASD, can be variable and may relate to specific KDM5C alterations.