FBN1 – Weill-Marchesani Syndrome

Weill-Marchesani syndrome (WMS) is a rare acromelic dysplasia characterized by short stature, brachydactyly, joint stiffness, ocular anomalies, and cardiovascular defects. The autosomal dominant form of WMS is caused by heterozygous pathogenic variants in FBN1, a gene encoding fibrillin-1, a key component of extracellular microfibrils. Over the past three decades, multiple case reports and cohort studies have established FBN1 as a major locus for dominant WMS, with clinical presentations overlapping Marfan syndrome and other acromelic dysplasias.

Genetic evidence for FBN1 in WMS includes at least 22 unrelated probands presenting with heterozygous missense mutations, primarily in TGF-β-binding (TB) and calcium-binding EGF-like domains. Notable variants include c.2066A>G (p.Glu689Gly) confirmed to co-segregate with disease in an Iranian pedigree (PMID:37288014) and recurrent p.Gly1754Ser in three affected individuals (PMID:39421111). A three-generation family with thoracic aortic aneurysm and cervical artery dissection further demonstrated segregation of a dominant FBN1 allele in 3 relatives (PMID:28696036). In a multicenter cohort of 61 WMS patients, 19 carried FBN1 variants, with significant genotype–phenotype correlations linked to variant position (PMID:37734846).

The phenotypic spectrum of FBN1-related WMS encompasses classic skeletal and eye findings—brachydactyly (HP:0001156), joint stiffness (HP:0001387), short stature (HP:0004322), ectopia lentis (HP:0001083)—and cardiovascular features including mitral stenosis (HP:0001718), aortic aneurysm (HP:0004942), mitral valve prolapse (HP:0001634), and thoracic aortic aneurysm. Intellectual disability is occasionally observed when variants affect specific TB domains (PMID:37288014).

Functional studies reveal that ADAMTS10 binds fibrillin-1 with high specificity and promotes microfibril deposition in cultured fibroblasts, implicating impaired fibrillin microfibril biogenesis in WMS pathogenesis (PMID:21402694). FBN1 variants disrupting TB5 and adjacent domains alter TGF-β signaling and microfibril stability, consistent with a dominant-negative or haploinsufficient mechanism.

Linkage of the autosomal dominant form of WMS to chromosome 15q21.1 in two multiplex families first implicated FBN1 and MFAP1 as candidate loci (PMID:8914744). Subsequent sequencing has confirmed that missense mutations in exons 41–42 and TB-cbEGF interface domains produce overlapping Marfan and WMS phenotypes, underscoring the need for comprehensive cardiovascular surveillance in all FBN1-variant carriers (PMID:23897642).

In summary, the association between FBN1 and Weill-Marchesani syndrome is supported by definitive genetic and experimental evidence. Heterozygous missense variants in key functional domains consistently co-segregate with WMS phenotypes across multiple families and cohorts, and functional assays confirm disrupted microfibril assembly. Identification of FBN1 mutations in WMS patients informs diagnostic decision-making, guides cardiovascular imaging recommendations, and underpins genetic counseling for affected families.

Key Take-home: Heterozygous FBN1 variants in TB and cbEGF domains cause autosomal dominant WMS with multisystem involvement; early molecular diagnosis enables tailored surveillance and management.

References

• American Journal of Medical Genetics Part A • 2017 • Cervical artery dissection expands the cardiovascular phenotype in FBN1-related Weill-Marchesani syndrome PMID:28696036
• Advanced Biomedical Research • 2023 • A Novel Missense Mutation in the TGF-β-binding Protein-Like Domain 3 of FBN1 Causes Weill-Marchesani Syndrome with Intellectual Disability PMID:37288014
• Cureus • 2024 • Fibrillin-1 Gene Variant p.Gly1754Ser Associated With Weill-Marchesani Syndrome Type 2: A Case Report PMID:39421111
• The Journal of Biological Chemistry • 2011 • ADAMTS10 protein interacts with fibrillin-1 and promotes its deposition in extracellular matrix of cultured fibroblasts PMID:21402694
• Journal of Medical Genetics • 2024 • Weill-Marchesani syndrome: natural history and genotype-phenotype correlations from 18 news cases and review of literature PMID:37734846

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