ClinGen Dosage Sensitivity Curation Page

CHM

Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function phenotype
PubMed ID Description
33538369 Zeitz et al. (2021) describe a French cohort of 45 families, 25 of which carry novel variants, in the context of 822 previously reported choroideremia (CHM) families. Most of the variants represent loss?of?function variants with eleven families having large (i.e. ?6?kb) genomic deletions; 18 small insertions, deletions or insertion deletions; 6 nonsense variants; 8 splice site variants; and 2 missense variants likely to affect splicing. Similarly, 822 previously published families carry mostly loss?of?function variants. These variants and other recurrent variants span all exons of CHM.
27070432 Sanchez-Alcudia et al. (2016) characterized 36 families with CHM and identified 28 different variants. Most of the families (31%, 22/36) carried hemizygous nucleotide substitutions that corresponded mostly to nonsense mutations (36%, 13/36), although splicing mutations (11%, 4/36), frameshift (11%, 4/36) and missense (3%, 1/36) variants were also identified. The remainder of the families (13/36) carried genomic deletions involving complete or partial deletion of the gene. Of note, a 455.6 kb deletion at chromosome region Xq21.2 (arr[GRCh37] Xq21.2(84847610?85303270)x0) exclusively encompassing the entire CHM gene was detected. A de novo previously described translocation was also found.

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.