BGN

Inheritance Pattern: XL

Disease ID:MONDO:0010515

Submitter: Ambry Genetics

Inheritance Pattern: XL

Disease ID:MONDO:0010515

Submitter: Ambry Genetics

Inheritance Pattern: XL

Disease ID:MONDO:0010248

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: XL

Disease ID:MONDO:0010515

Submitter: ClinGen

Variants in *BGN* have been reported in individuals with X-linked Meester-Loeys syndrome (MLS), X-linked familial thoracic aortic aneurysm and dissection (TAAD), and X-linked spondyloepimetaphyseal dysplasia (SEMDX). Given differences in molecular mechanism and phenotypes between TAAD/MLS and SEMDX, a split curation for SEMDX will be curated separately by the Skeletal Disorders GCEP in the future. Missense variants not affecting splicing have mainly been associated with SEMDX, whereas loss-of-function variants have been associated with TAAD/MLS. This current curation will be for the lumped disease entity of *BGN*-related syndromic thoracic aortic aneurysm and dissection. *BGN* was first reported in relation to aortic disease in mice in 2007 (PMID: 17502576) and in humans with X-linked syndromic thoracic aortic aneurysms and dissections in 2017 (PMID: 27632686). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Eight variants reported in eight probands from two publications are included in this curation (PMIDs: 27632686, 38531898). Variants included nonsense, frameshift, deletions, and splicing variants. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. In humans, Meester *et al.* (2017) described five families with loss-of-function variants in *BGN* who had an X-linked severe syndromic form of thoracic aortic aneurysms and dissections, including features such as joint hypermobility, hypertelorism, malar hypoplasia, joint contractures, and reduced bone density (PMID: 27632686). Two male probands with very early onset aortic disease and mild skeletal dysplasia had *BGN* deletions spanning exons 2-8 that extended into the 5’ untranslated region of the *ATP2B3* gene, resulting in use of the *BGN* 5’-UTR to drive *ATP2B3* expression in skin fibroblasts (PMID: 38531898). *ATP2B3* has been associated with X-linked cerebellar ataxia and is not expressed in control skin fibroblasts. These two probands were not scored for this curation due to extragenic involvement. In 2024, Meester *et al.* described an additional 13 probands and their relatives, and showed that *BGN* variants have reduced penetrance and variable expressivity. Some individuals had only subtle syndromic features or presented with aortic disease as late as 70 years old (PMID: 38531898). In addition to previous features described, some individuals also had peripheral or cerebral arterial aneurysms or dissections. In line with X-linked inheritance, disease was more penetrant in hemizygous males compared to heterozygous females. This study also showed loss of biglycan protein expression on western blot from skin fibroblasts of multiple individuals with the described *BGN* variants. The mechanism of pathogenicity appears to be loss-of-function, although one missense variant of uncertain significance was reported in a family with arterial aneurysms, joint hypermobility, and musculoskeletal injuries/pain (PMID: 41465473). This gene-disease relationship is also supported by animal models and expression studies. Using immunohistochemistry and immunoelectron microscopy, Heegaard *et al.* (2007) showed that biglycan is detected in the aortic walls of wildtype mice, with the adventitia being the major site of biglycan deposition (PMID: 17502576). In *BGN*-knockout male mice, necrocopies following sudden death revealed major hemorrhage in the thoracic (82%) or abdominal (18%) cavity. Histology showed aortic rupture involving intimal and medial tears and dissection between media and adventitia (PMID: 17502576). In another study in *BGN*-knockout mice, radiographic, microradiographic, and histological analyses showed that the epiphyseal and metaphyseal trabecular structures in the femora, tibiae, and vertebrae of 6 month old mice were thinner, fewer, and poorly connected to each other compared to wild type. In addition, bone volume/total tissue volume was reduced to below 50% of wildtype. Total ash weight (mineral content) was also reduced in mutant long bones. These findings supported that disruption of *BGN* leads to an osteoporosis-like phenotype in mice (PMID: 9731537). Additionally, stained aortic tissue from two individuals with loss-of-function *BGN* variants showed increased phosphorylated SMAD2 positive nuclei (a specific marker of activated canonical TGF-β signaling) compared to controls, and was similar to aortic tissue from a proband with Loeys-Dietz syndrome (PMID: 27632686). Increased pSMAD2 and TGF-β signaling has also been observed in aortic tissue affected by thoracic aortic aneurysm and dissection, Marfan syndrome, and Loeys-Dietz syndrome (PMIDs: 18852674, 21493862, 29682117, 30037098). This gene-disease pair was originally evaluated by the Heritable Thoracic Aortic Aneurysm and Dissection Gene Curation Expert Panel on December 22, 2016. It was reevaluated on February 6, 2026. As a result of this reevaluation, the classification changed from Limited to Strong with the addition of new case-level and experimental evidence as described above. In summary, there is strong evidence supporting the relationship between *BGN* and X-linked syndromic thoracic aortic aneurysm. This classification was approved by the ClinGen Heritable Thoracic Aortic Aneurysm and Dissection subgroup of the Hereditary Cardiovascular Gene Curation Expert Panel on the meeting date February 6, 2026 (SOP Version 11).

Inheritance Pattern: XL

Disease ID:MONDO:0010248

Submitter: Ambry Genetics

Inheritance Pattern: XL

Disease ID:MONDO:0010515

Submitter: Genomics England PanelApp

Inheritance Pattern: XL

Disease ID:MONDO:0010515

Submitter: Illumina

Inheritance Pattern: XL

Disease ID:MONDO:0010515

Submitter: G2P

Inheritance Pattern: Unknown

Disease ID:MONDO:0019625

Submitter: ClinGen

Inheritance Pattern: XL

Disease ID:MONDO:0010248

Submitter: Ambry Genetics

Inheritance Pattern: XL

Disease ID:MONDO:0010248

Submitter: Orphanet

Inheritance Pattern: XL

Disease ID:MONDO:0010248

Submitter: G2P