ClinGen Dosage Sensitivity Curation Page

EBP

  • Curation Status: Complete

Location Information

Select assembly: (NC_000023.10) (NC_000023.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
11038443 Ikegawa et al (2000) screened for EBP mutations in five sporadic female patient with X-linked dominant Chondrodysplasia punctate using PCR amplification of coding and flanking regions of EBP followed by sequencing analysis. All five patients have EBP mutations including 3 nonsense mutations and 2 missense mutations. Functional studies showed abnormal sterol profile in the individuals with nonsense mutation consistent with a defect in EBP (delta8-delta7-sterol isomerase) function.
12509714 Herman et al (2002) detected EBP mutations in 22 out of 26 females with clinical diagnosis of X-linked dominant Chondrodysplasia punctate using PCR amplification of coding and flanking regions of EBP followed by sequencing. Functional studies (delta8-delta7-sterol isomerase level) were performed in 20 mutation positive patients and all showed abnormal profile. Among the mutations tested, 6 are nonsense and 3 are frameshift mutations which are expected to produce functional null alleles. Eight of the patients with expected null allele has no family history.
10942423 Has et al (2000) screened EBP mutations in seven independent families with X-linked dominant Chondrodysplasia punctate using direct sequencing and restriction enzyme analysis. Three nonsense, two frame shift, on deletion in exon 4 and one insertion in exon 5 were detected. At least three families in this study showed 3-4 observed segregations.

Haploinsufficiency phenotype comments:

Loss of function mutations, including nonsense, frameshift, and splice-site mutations, in EBP cause chondrodysplasia punctata, X-linked dominant. At least 95% of liveborn individuals are female as these mutations typically cause male lethality. See GeneReviews for complete clinical information. The association of EBP and X-linked dominant chondrodysplasia punctate was found through linkage study and mouse model (Traupe et al-PMID:1355069; Derry et al-PMID: 10391218), thus later case reports are all based on the direct sequencing results of EBP. To date, 93 variants were listed in HGMD with the vast majority being sequence level variants including nonsense, missense, splicing variants, small deletions and duplications. Most variants are associated with X-linked dominant chondrodysplasia punctate (CDPX2) characterized by ichthyosis, chondrodysplasia punctata, cataracts and short stature. CDPX2 is usually lethal in males and survival in these males was assumed due to postzygotic mosaicism. Two variants of EBP in HGMD have also been associated with X-linked recessive MEND syndrome characterized by intellectual disability, short stature, scoliosis, digital abnormalities, cataracts, and dermatologic abnormalities, in which males are hemizygous for a nonmosaic hypomorphic EBP allele. (PMID: 24459047)

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 EBP have not been described.

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.