Key points

• Genetic changes (pathogenic variants) in the X chromosomal gene CLCN4 can be associated with a variety of impacts on an individual’s learning, physical and mental health. The extent and severity of CLCN4 related condition is very variable, depending on the type of gene change, the gender of the affected individual, the pathophysiological impact of the genetic change and as yet incompletely understood factors.
• Symptoms of CLCN4-related condition include developmental delay/intellectual disability, autism spectrum disorders, epilepsy, movement disorders and mental health disorders.
• For males, CLCN4 gene variants may be new (de novo) or inherited from a carrier mother who may be completely unaffected or mildly affected.
• For affected females, their CLCN4 gene variant is most typically de novo, although occasionally may be passed on from a mildly affected parent.
• Comprehensive early intervention and specialist education, psychosocial support, therapies for certain symptoms (e.g. antiepileptics, cognitive and behavioural therapies, psychiatric medication such as mood stabilisers), educational and employment support and supportive genetic counselling are important for individuals with CLCN4-related condition.
• Supportive genetic counselling and consideration of referral for psychological or counsellor support for parents with a new diagnosis of CLCN4 related disorder in their family is required.
• CLCN4 encodes the protein CIC-4 which is understood to play important roles in the acidification of endosomes. Identified pathogenic variants alter the function of the CIC-4 protein in cellular models, but more research is required to understand the pathophysiology of CLCN4 related disorder.
• Another name for CLCN4 related disorder is Raynaud-Claes syndrome (OMIM reference 300114)