ClinGen Dosage Sensitivity Curation Page

FMR1

  • Curation Status: Complete

Location Information

Select assembly: (NC_000023.10) (NC_000023.11)

Haploinsufficiency phenotype comments:

Loss of function mutations in FMR1 are associated with Fragile X syndrome. Up to 1% of mutations are partial or whole gene deletions. Males are always affected and about 50% of females will have intellectual disability. See Gene Reviews. In addition, unmethylated premutation alleles (CGG expansions of 55-200) in FMR1 are associated with primary ovarian insufficiency and Fragile-X-associated tremor/ataxia syndrome. These types of mutations would not be detected by microarray.

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 duplications of FMR1 alone have not been reported. It is included within a large 5 Mb duplication syndrome, PMID: 19844254.

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.