BCOR

Inheritance Pattern: XL

Disease ID:MONDO:0010261

Submitter: G2P

Inheritance Pattern: XL

Disease ID:MONDO:0010261

Submitter: PanelApp Australia

Inheritance Pattern: XL

Disease ID:MONDO:0010261

Submitter: ClinGen

The BCOR gene is located on chromosome X at Xp11.4 and encodes the BCL6 corepressor, a POZ/zinc finger transcription repressor that is involved in transcription co-repression and is required for germinal center formation. The BCOR gene was first reported in relation to X-linked oculofaciocardiodental and Lenz microphthalmia syndromes in 2004 (Ng et al., PMID 15004558). Evidence supporting these gene-disease relationships includes case-level data and experimental data. Variants in this gene have been reported in at least nine probands in three publications (Hilton et al., 2009 PMID 19367324; Kraus et al., 2018 PMID 30450806; Ragge et al., 2019 PMID 29974297). At least seven unique variants have been reported in humans, including six predicted null variants in female patients and one recurrent missense variant in male patients. De novo occurrence and inheritance from an affected mother have been reported in females, while male patients typically inherit the missense variant from unaffected mothers. More evidence is available in the literature, but the maximum score for genetic and experimental evidence (12 pts) has been reached. The mechanism for BCOR-related syndromic microphthalmia is not completely understood; however, loss of function and haploinsufficiency appear to play an important role. This gene-disease association is also supported by expression in relevant tissues during embryogenesis, and data from a non-human model organisms, including zebrafish and Xenopus knockdown models and a conditional knockout mouse model (Ng et al., 2004 PMID 15004558; Wamstad & Bardwell, 2007 PMID 17344103; Hilton et al., 2007 PMID 17517692; Hamline et al., 2020 PMID 32692983). In summary, BCOR is definitively associated with X-linked syndromic microphthalmia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. Lumping and Splitting: Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no clear difference in the phenotypic variability or molecular mechanism(s) underlying the disease entities: oculofaciocardiodental syndrome (MONDO:0017125) and Lenz-type microphthalmia (MONDO:0018924). There is phenotypic variability seen in both male and female patients, and the body systems affected are similar in males and females and include ocular, cardiac, and skeletal defects, developmental delays and some facial dysmorphisms (Ragge et al., 2019 PMID 29974297). Although null variants cause the disease in females, while missense variants appear to be causative in males, it is suggested that the underlying mechanism is LoF with less severe effect of missense variants and male lethality with null variants (Ng et al., 2004 PMID 15004558; Ragge et al., 2019 PMID 29974297). Male lethality was recently confirmed in a knockout mouse line (Hamline et al., 2020 PMID 32692983).

Inheritance Pattern: XL

Disease ID:MONDO:0010261

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: XL

Disease ID:MONDO:0010261

Submitter: Ambry Genetics

Inheritance Pattern: XL

Disease ID:MONDO:0010261

Submitter: Orphanet

Inheritance Pattern: Unknown

Disease ID:MONDO:0010261

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: XL

Disease ID:MONDO:0010261

Submitter: Illumina

Inheritance Pattern: XL

Disease ID:MONDO:0018924

Submitter: Orphanet