ClinGen Dosage Sensitivity Curation Page

CLCN4

  • Curation Status: Complete

Location Information

Select assembly: (NC_000023.10) (NC_000023.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
25644381 Hu et al. 2016 report five unrelated families with variants in CLCN4; four of the families had missense variants, and one family (referred to as MRX49) had a frameshift variant. The frameshift variant segregated with four affected males in the family (a fifth affected male was not tested). Unaffected brothers of these affected individuals were shown not to have the variant. The phenotype of the affected individuals was relatively non-specific; within family MRX49, the degree of intellectual disability ranged from borderline to moderate. The family was said to have no other distinguishing features aside from head circumference over the 97th percentile in 3 of the 5 affected individuals. The authors did perform some functional assays to demonstrate that CLCN4 variants "impair protein functions as indicated by electrophysiological studies and altered differentiation of cultured primary neurons from Clcn4? / ? mice or after mRNA knock-down."
27550844 Palmer et al. 2016 describe several families (X-exome or whole-exome sequencing) with variants in CLCN4, including a previously unreported frameshift variant (Family B) and a deletion of exon 12 (Family J). In family B, the frameshift variant was found in three affected brothers and their unaffected sister and mother. A fourth brother, who is reportedly unaffected, was also found to have the variant; this individual is known to have Klinefelter syndrome, and the authors postulate that the presence of the extra X chromosome contributes to his unaffected status. In family J, the deletion was found in two affected brothers and their unaffected mother. The authors comment that the individuals in the study with variants predicted to result in loss of function are (in general) more mildly affected than those individuals with missense variants, suggesting that "an abnormally functioning CIC-4 antiporter is more deleterious than a reduction in its levels or a complete absence." They also note that "no potential dominant negative effect of CLCN4 missense variants was observed when equal amounts of wild-type and mutant ClC-4 were expressed in Xenopus oocytes."

Haploinsufficiency phenotype comments:

Though this gene technically has three putative loss of function variants reported in two independent publications, the haploinsufficiency score remains at 2 at this time. Little functional evidence is available to characterize the truncating variants - it has not been definitively demonstrated that they result in loss of function. No focal deletions involving CLCN4 have been reported at this time. Additional information is necessary to clarify the role of loss of function variants in this phenotype. Additional relevant literature is summarized below: Veeramah et al. (2013) (PMID:23647072) report a de novo missense variant in a male patient (Proband C) presenting with persistent, refractory seizures; severe developmental delay; diffuse/multifocal bi-hemispheric abnormalities on EEG, and normal brain MRI. The authors report that the variant (Gly544Arg) acts as a loss of function variant: "When expressed in Xenopus oocytes, the Gly544Arg mutation almost abolished the outwardly rectifying ClC-4 currents that are mediated by electrogenic 2Cl?/H+-exchange (Friedrich et al., 1999; Scheel et al.,2005) (Figure 2B), identifying it as a loss-of-function mutation." 8/2018: HGMD , and Google Scholar checked, relevant literature describing new families other than the major ones reviewed above not seen The mutation spectrum consists primarily of frameshift, missense and splice site variants and one single-exon deletion (no nonsense variants have reported). Majority of variants described are loss of function. With respect to the missense variants, to date there is no functional data implicating CLCN4 as having a potential dominant-negative effect.

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.