ClinGen Dosage Sensitivity Curation Page

CLCN4

Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function 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."

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.

Evidence for Triplosenstive Phenotype

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.

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.