ClinGen Dosage Sensitivity Curation Page

Xp21.2 region (includes NR0B1)

  • Curation Status: Complete
  • id: ISCA-46302
  • Date last evaluated: 2020-07-22
  • Issue Type: ClinGen Region Curation
  • ClinGen Haploinsufficiency Score: 0
  • ClinGen Triplosensitivity Score: 3


Location Information

  • Xp21.2
  • GRCh37/hg19 chrX: 30,195,000-30,355,000
  • View: NCBI | Ensembl | UCSC

GRCh37/hg19 chrX: 30,195,000-30,355,000 ()

  • Haploinsufficiency score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Haploinsufficiency phenotype comments:

Loss of the NR0B1 gene alone has been associated with adrenal hypoplasia congenita. Please see the separate curation for the NR0B1 gene (ISCA-4997) for a complete description of the evidence supporting haploinsufficiency of the NR0B1 gene.

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 triplosensitivity phenotype
PubMed ID Description
22518125 Barbaro M et al. (2012) reported 3 individuals of 46,XY sex reversal in a 6 generations English family with inheritance through seven 46,XX fertile carriers of an NR0B1/DAX1 locus duplication. Another 9 healthy 46,XX females in this family also carry this duplication. The duplication has a minimal and maximal size of 679 kb and 687 kb, respectively. In addition to NR0B1, this duplication contains the MAGEB genes, CXorf21, GK and part of the 3? region of the MAP3K7IP3 gene. The carrier mothers are all healthy.
17504899 Barbaro M et al., (2007) reported two Iranian individuals with isolated XY gonadal dysgenesis in an X-linked inheritance pattern had a NR0B1 locus duplications (637kb), including MAGEB, NR0B1, CXorf21, GK and part of the 3? region of the MAP3K7IP3 gene. The carrier fertile mother had NR0B1 overexpression without skewed X-inactivation or impaired ovarian function. Later study in 2008 (PMID: 18384427) confirmed the healthy mother carries the same duplication. This article supports DAX1 duplication as the genetic cause of gonadal dysgenesis, even if a role for the MAGEB genes cannot be completely excluded.
20685758 Ledig S et al., (2010) reported a case (case 52) with a duplication of 729kb on DAX1/NORB1 locus including 5 other genes, MAGEB4, MAGEB1, CXorf21, GK and MAP3K7IP3 from cohort of 26 patients with 46, XY gonadal dysgenesis.

Triplosensitivity phenotype comment:

This region was created to capture the various cases that have been reported describing duplications of varying sizes of this genomic region in individuals with 46,XY sex reversal. The coordinates roughly correspond to the 160 kb minimal critical region containing the NR0B1 gene (also known as DAX1) and the MAGEB gene cluster described in Bardoni et al. (1994) (PMID:7951319). Note that cases counted for evidence in this curation may be larger than this, but typically include the NR0B1 gene and at least one of the MAGEB genes. While NR0B1 is suspected to be the causative gene, to date there have not been any reported duplications involving this gene alone, and the effects of the other genes on the phenotype cannot be ruled out. See GeneReviews http://www.ncbi.nlm.nih.gov/books/NBK1547/ and PMID 22518125 for a recent review of the literature. Additional evidence includes: PMID: 18384427 Barbaro M et al., (2008) reported. One Italian individual of 46, XY gonadal dysgenesis, and the healthy mother of the two Iranian sisters from previous study (PMID: 17504899) carry a Xp21.2 duplication containing 4 MAGEB genes, CXorf21, GK, partial MAP3K71P3. NR0B1 is the strongest candidate for causing reversal if duplicated in XY subjects. PMID: 21408189 White S et al., (2011) reported one case (case 13) with DAX/NROB1 locus duplication of 771kb by array study on a cohort of 23 patients with 46,XY gonadal dysgenesis. PMID: 7951319 Bardoni B et al., (1994) identified a 160-kb minimal common region denoted dosage sensitive sex reversal that, if duplicated, causes sex reversal. This region contains the MAGEB genes and the DAX1 (now known as NR0B1) gene. This is the minimal duplication reported. NR0B1 gene is 5kb in length.

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.