ClinGen Dosage Sensitivity Curation Page

EBP

Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function 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.

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 Triplosenstive Phenotype

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.

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.