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Meester-Loeys syndrome (Meester-Loeys syndrome; MRLS) is a heritable connective tissue disorder characterized by widespread arterial aneurysms and dissections. Pathogenic loss-of-function variants in the X-linked BGN gene encoding the small leucine-rich proteoglycan biglycan have been implicated. Since the initial description of five unrelated probands in 2017, an expanded cohort now comprises 18 probands (16 males, 2 females) (PMID:38531898). Segregation analysis across these families identified 36 additional variant-harboring relatives (9 males, 27 females) (PMID:38531898). Functional assessment via cDNA and Western blot in patient fibroblasts demonstrated loss-of-function for identified variants. Concordance between genetic, functional, and phenotypic data supports a decisive association.
BGN-related MRLS follows an X-linked recessive inheritance mode, with affected males often manifesting more severe vascular and connective tissue features than heterozygous females. Molecular testing has revealed exclusively loss-of-function alleles, including nonsense, frameshift, splice-site, and small insertion/deletions in BGN, with no definitive pathogenic missense variants reported (PMID:38531898). Segregation studies confirmed co-segregation of these variants with clinical features in multiple affected family members. Recurrent loss-of-function alleles have not been described, indicating genetic heterogeneity. Penetrance appears high in hemizygous males and variable in heterozygous females. Standard genetic testing can reliably detect these null variants for diagnostic use.
To date, at least twelve distinct loss-of-function BGN variants have been documented, including canonical splice-site mutations such as c.351+1G>A and nonsense variants such as c.75G>A (p.Trp25Ter). The variant c.75G>A (p.Trp25Ter) results in premature termination of the biglycan core protein and has been observed in an affected male proband presenting with aortic root aneurysm and systemic arterial involvement (PMID:38531898). Other alleles include frameshift mutations c.46del (p.Ala16ProfsTer20) and c.59_60insAA (p.Gln21SerfsTer16). No population-specific founder variants have been described. The absence of pathogenic missense changes underscores haploinsufficiency as the primary mechanism. Carrier frequency in female relatives may underlie variable expressivity.
Functional studies have consistently demonstrated that BGN loss-of-function disrupts biglycan-mediated regulation of TGF-β bioavailability and extracellular matrix integrity. Protein analyses in patient-derived fibroblasts showed absent or truncated biglycan products on Western blot, confirming null alleles (PMID:38531898). An induced pluripotent stem cell line (BBANTWi009-A) derived from a male MRLS patient retained the BGN deletion genotype and exhibited typical pluripotent differentiation capacity without karyotypic abnormalities (PMID:36599284). These observations establish a direct link between BGN haploinsufficiency and disrupted cellular functions relevant to vascular integrity. Animal models of BGN deficiency further implicate TGF-β signaling dysregulation in connective tissue abnormalities. Collectively, these data provide mechanistic insight into MRLS pathogenesis.
The convergence of genetic, segregation, and functional data establishes a strong gene-disease relationship between BGN and X-linked MRLS. The consistent identification of loss-of-function alleles and their segregation in extensive pedigrees satisfies key ClinGen criteria for a Strong classification. Functional assays in fibroblasts and iPSC models corroborate haploinsufficiency as the underlying mechanism, aligning with clinical manifestations of systemic arterial aneurysms and connective tissue findings. No conflicting evidence or alternative phenotypes for BGN have been reported in this context. Further longitudinal studies and additional model systems may refine genotype-phenotype correlations. Genetic screening for BGN null variants should be integrated into routine diagnostics for patients with unexplained early-onset arterial aneurysms, particularly in male individuals.
Key Take-home: Hemizygous loss-of-function variants in BGN cause X-linked Meester-Loeys syndrome via haploinsufficiency, warranting targeted genetic testing to guide clinical surveillance and management.
Gene–Disease AssociationStrong18 probands, segregation in 36 family members, concordant functional data Genetic EvidenceStrongX-linked recessive inheritance, 18 probands (16 males, 2 females), segregation in 36 relatives, multiple LoF variant types Functional EvidenceModeratecDNA and Western blot in patient fibroblasts ([PMID:38531898]), iPSC model confirming genotype ([PMID:36599284]) |