EBP

Inheritance Pattern: XL

Disease ID:MONDO:0020603

Submitter: PanelApp Australia

Inheritance Pattern: XL

Disease ID:MONDO:0010498

Submitter: PanelApp Australia

Inheritance Pattern: XL

Disease ID:MONDO:0010498

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: XL

Disease ID:MONDO:0010498

Submitter: ClinGen

*EBP* encodes a key enzyme involved in the cholesterol biosynthesis pathway. Variants in EBP have been reported in patients with X-linked dominant chondrodysplasia punctata 2 and X-linked recessive MEND syndrome (male EBP disorder with neurologic defects). X-linked chondrodysplasia punctata 2 (also known as Conradi-Hunermann-Happle syndrome) primarily affects females and is lethal *in utero* in males, although a few affected males with 47,XXY karyotype or somatic mosaicism have been reported. It is associated with a significant deficiency of EBP function. Non-mosaic hypomorphic missense variants in males cause MEND syndrome, comprising neurologic and structural malformations without chondrodysplasia punctata. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, these disorders are curated separately due to differences in inheritance pattern, molecular mechanism and phenotypic variability. This curation focuses on MEND syndrome. *EBP* was first reported in relation to MEND syndrome in 2003 (Milunsky *et al.*, PMID: 12503101). Affected males are hemizygous for a non-mosaic hypomorphic EBP allele resulting in a defect in sterol biosynthesis but retaining some residual enzyme activity. The clinical features are highly variable, and include intellectual disability, facial dysmorphisms, digital abnormalities, cataracts, dermatologic abnormalities, structural brain abnormalities, other congenital abnormalities, and early death in a subset of individuals. Individuals with MEND syndrome also have increased plasma concentration of 8(9)-cholestenol and 8-dehydrocholesterol. Carrier females typically do not have clinical manifestations of the disorder but may show biochemical abnormalities. Missense variants in this gene have been reported in 7 unrelated male probands with MEND syndrome in 6 publications (PMIDs: 12503101, 20949533, 23852825, 24459067, 24700572, 27276700), including 3 multigenerational pedigrees with multiple affected males. The mechanism of disease is partial loss of function. This gene-disease relationship is also supported by protein interaction with WLS (PMID: 28734904), recently involved in syndromic intellectual disability. In summary, there is definitive evidence supporting the relationship between EBP and MEND syndrome. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on September 7, 2022 (SOP Version 9).

Inheritance Pattern: XL

Disease ID:MONDO:0020603

Submitter: G2P

Inheritance Pattern: XL

Disease ID:MONDO:0026782

Submitter: Illumina

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.

Inheritance Pattern: XL

Disease ID:MONDO:0010498

Submitter: Genomics England PanelApp

Inheritance Pattern: XL

Disease ID:MONDO:0020603

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: XL

Disease ID:MONDO:0020603

Submitter: Orphanet

Inheritance Pattern: XL

Disease ID:MONDO:0010498

Submitter: Orphanet