ClinGen Dosage Sensitivity Curation Page

CHM

  • Curation Status: Complete

Location Information

Select assembly: (NC_000023.10) (NC_000023.11)
  • Haploinsufficiency score: 3
  • Strength of Evidence (disclaimer): Sufficient evidence for dosage pathogenicity
  • Haploinsufficiency Phenotype: CHOROIDEREMIA; CHM
Evidence for haploinsufficiency 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.

Haploinsufficiency phenotype comments:

Choroideremia (CHM) is characterized by progressive chorioretinal degeneration in affected males and milder signs in carrier females. A recent study (PMID: 31181178) has shown female carriers of choroideremia can present with a wide range of clinical phenotypes and disease severity, from mild to severe disease similar to males. Symptoms in affected individuals evolve from night blindness to peripheral visual field loss, with central vision preserved until late in life.

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.