CLCN4

Inheritance Pattern: XL

Disease ID:MONDO:0010250

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: XL

Disease ID:MONDO:0010250

Submitter: Ambry Genetics

Inheritance Pattern: XL

Disease ID:MONDO:0010250

Submitter: G2P

Inheritance Pattern: XL

Disease ID:MONDO:0100148

Submitter: ClinGen

*CLCN4* is located on chromosome Xp22.2 and encodes ClC-4, a chloride/proton ion exchanger and member of the chloride channel family that is localized in endosomes. *CLCN4* was first reported in relation to X-linked complex neurodevelopmental disorder in 2013 (Veeramah et al., PMID: 23647072). Rare inherited or *de novo* missense and truncating variants have been identified in males and females with a range of neurodevelopmental phenotypes. The clinical features of affected individuals include developmental delay, intellectual disability (varying from borderline to profound), seizures, behavioral disorders including autism or autistic features, infantile hypotonia, mild dysmorphic features, neuroimaging abnormalities, and, in some individuals, progressive neurological manifestations, including movement disorders and spasticity (PMID: 36385166). Females exhibit a wide spectrum of severity, and about half are unaffected. In some families, missense variants are associated with X-linked recessive inheritance and heterozygous females are unaffected or exhibit mild cognitive or psychiatric phenotypes. In other families with inherited *CLCN4* missense variants, females exhibit highly variable phenotypes, ranging from unaffected to severely affected, even within the same family. Females with *de novo* missense variants generally exhibit a more severe phenotype, which overlaps with that observed in males (PMID: 36385166). The differences in clinical severity in females are not explained by X-inactivation status (PMID: 27550844). Most of the reported variants are missense, although a few truncating variants have been reported (PMID: 36385166). Nineteen variants (15 missense, 2 frameshift, 1 exonic deletion, 1 splice region) that have been reported in 20 probands in four publications (PMIDs: 23647072, 25644381, 27550844, 36385166) are included in this curation. Variants in this gene segregated with disease in additional family members. Multiple missense variants are recurrent. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. *CLCN4* pathogenic variants result in a wide range of molecular consequences, and missense variants leading to both loss (LoF) and gain of function (GoF) have been reported. Most variants lead to partial or complete LoF, due to transport dysfunction, protein instability, intracellular trafficking defects, or failure of ClC-4 to oligomerize with CIC-3 (PMIDs: 35721313, 36385166), while other variants result in a toxic GoF, associated with a disrupted gate allowing inward transport at negative voltages (PMID: 36385166). Although genotype-phenotype correlations are still being explored, GoF variants were associated with a severe growth component (short stature and microcephaly), and were more common among affected females than LoF variants (PMID: 36385166). This gene-disease relationship is also supported by biochemical function, protein interactions, functional alterations and rescue experiments in mouse neurons following *Clcn4* knockdown, and a null mouse model. Other members of the CLC chloride channel family are also involved in neurodevelopmental disorders, including *CLCN3*, *CLCN6*, and *CLCN7*. ClC-4 forms heterodimers with ClC-3 that determine its subcellular localization (PMID: 28972156). In summary, there is definitive evidence supporting the relationship between *CLCN4* and X-linked complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was originally evaluated by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on October 20, 2017. It was reevaluated on July 22, 2026 (SOP Version 12). Although new cases and experimental evidence were added, the classification did not change.

Inheritance Pattern: XL

Disease ID:MONDO:0019181

Submitter: Orphanet