ClinGen Dosage Sensitivity Curation Page

CYBB

  • Curation Status: Complete

Location Information

  • Xp21.1-p11.4
  • GRCh37/hg19 chrX: 37,639,270-37,672,714
  • View: NCBI | Ensembl | UCSC
  • GRCh38/hg38 chrX: 37,780,017-37,813,461
  • View: NCBI | Ensembl | UCSC
Select assembly: (NC_000023.10) (NC_000023.11)

Haploinsufficiency phenotype comments:

Mutations in CYBB are the most common causes of chronic granulomatous disease (CGD). A large number of variants (>600) have been reported for CYBB that cause the X-linked form of CGD. A large-scale review of variation within this gene demonstrates variants ranging from single nucleotide variations to deletions of several megabases (PMID: 20729109). The majority are loss of function variants (e.g. 75% are nonsense, del/dup, splicing variants (PMID: 30716179) and about 12?15% of the mutations in CYBB result from de novo mutations ((PMID: 20729109), thus there are overwhelming case and genetic evidence supporting haploinsufficiency of CYBB. Some female carriers have been shown to manifest a disease phenotype. See GeneReviews for relevant primary literature and review, as well as a discussion of known genotype-phenotype correlations. Of note, intragenic duplications have been identified in patients with CGD, likely due to a loss of function mechanism (PMID:22924696, 22382877).

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

Triplosensitivity phenotype comment:

Focal whole gene duplications have not been reported in association with CGD or other phenotypes; however, intragenic duplications have been identified in patients with CGD, likely due to a loss of function mechanism.

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.