Submission Details

X-linked

10/04/2019

The EBP gene is located on chromosome X at Xp11.23 and encodes 3-beta-hydroxysteroid-Delta(8),Delta(7)-isomerase protein, an integral membrane protein located in the endoplasmic reticulum that functions as a sterol isomerase, catalysing the conversion of Delta8-sterols to Delta7-isomers in the final steps of the production of cholesterol. The EBP gene was first reported in relation to X-linked dominant chondrodysplasia punctata in 1999 (10391218: Derry et al. 1999). At least seven unique variants, including six null variants and one missense variant (six of which were de novo) have been reported in three studies (10391218: Derry et al. 1999; 22121851: Cañueto et al. 2012; 25754886 Lefebvre et al. 2015). Evidence supporting this gene-disease relationship includes case-level data and experimental data. X-linked dominant chondrodysplasia punctata arises almost exclusively in females and is usually lethal in males, although a few male patients have been reported who carry somatic mosaicism in EBP or present with Klinefleter syndrome. Genotype to phenotype correlation remains uncertain. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. Of note, this gene has also been implicated in MEND syndrome. This gene-disease relationship will be assessed separately. This gene-disease relationship is supported by at least one mouse model, Td, where heterozygous male mice exhibit severe skeletal defects, lack intestines and suffer prenatal lethality and heterozygous females are small, have patches of hyperkeratotic skin, absent hair, mild skeletal defects including craniofacial dysmorphia and asymmetric ophthalmia, thereby recapitulating features of the human condition (10391218: Derry et al. 1999). Furthermore, transgenic expression of wild-type EBP in the presence of the variant form is sufficient to rescue the tattered phenotype of males and heterozygous females (11309666: Means et al. 2001). In summary, the EBP gene is definitively associated with X-linked dominant chondrodysplasia punctate. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

22121851 25754886 10391218 11309666