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Dietz HC, Cutting GR, Pyeritz RE, Maslen CL, Sakai LY, Corson GM, Puffenberger EG, Hamosh A, Nanthakumar EJ, Curristin SM, et al. Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature. 1991;352(6333):337-9. PMID 1852208

One-paragraph summary

Marfan syndrome was known to be an autosomal dominant connective tissue disorder with ocular, skeletal and cardiovascular manifestations, high penetrance, great clinical variability, and a locus mapped by linkage to chromosome 15q15-21.3 with no reported genetic heterogeneity. Fibrillin — a glycoprotein component of the extracellular microfibril — had been identified, immunohistopathological quantification in skin and cultured fibroblasts had shown abnormalities of fibrillin metabolism in most patients, and a portion of the fibrillin cDNA had been cloned and mapped by in situ hybridisation to chromosome 15. This paper closed the loop on two fronts simultaneously: it demonstrated linkage of the fibrillin gene to the Marfan phenotype at θ = 0.00 with a LOD score of 3.9, and it identified a de novo missense mutation in the fibrillin gene in two patients with sporadic disease. Together these implicated fibrillin as the protein defective in Marfan syndrome.

Key findings

  • Linkage of the fibrillin gene to the Marfan phenotype: recombination fraction θ = 0.00, LOD = 3.9.
  • A recurrent de novo missense mutation in the fibrillin gene identified in two independent patients with sporadic (non-familial) Marfan syndrome.
  • Prior context established in the paper: the Marfan locus had been mapped to 15q15-21.3; no genetic heterogeneity had been reported; fibrillin cDNA had been mapped to chromosome 15; and abnormalities of fibrillin metabolism had been demonstrated in most patients by immunohistopathology of skin and fibroblast culture, and by examination of fibrillin synthesis, extracellular transport and ECM incorporation.

Limitations

  • Two sporadic patients is a small mutational dataset; the paper establishes the gene, not the mutational spectrum, and offers no genotype–phenotype correlation.
  • LOD 3.9 is above the conventional threshold but not overwhelming by later standards; the linkage evidence rests on a single locus assumption that the paper itself notes was untested ("no reports of genetic heterogeneity" is an absence of evidence).
  • Pre-dates any understanding of fibrillin-1's role in TGF-β sequestration; the paper frames fibrillin purely structurally, so the mechanistic model it implies (a structural microfibril defect) turned out to be incomplete.
  • The de novo cases carry no segregation information by construction.
  • 1991 mutation-detection methods (PCR-based screening of a partially cloned cDNA) could not exclude other variants elsewhere in the gene or genome.

Why it matters

This is the founding paper of the molecular genetics of thoracic aortic disease. It converted Marfan syndrome from a clinically defined syndrome into a gene, and in doing so created the template every subsequent TAAD gene discovery followed: map, clone, sequence, show a de novo variant in sporadic cases. Everything downstream depends on it — the Ghent II nosology's weighting of FBN1 testing (PMID 20591885), the recognition that up to 25% of Marfan cases are de novo (PMID 34475413), the ClinGen curation that later placed FBN1 in the definitive tier of a 53-gene assessment (PMID 30071989), and the entire subsequent partition of TAAD genes into ECM/TGF-β versus contractile-unit families. It also seeded the field's biggest unresolved mechanistic argument: because fibrillin-1 sequesters TGF-β, a "structural" gene turned out to be a signalling gene, which is why the Loeys-Dietz TGF-β paradox (PMID 15731757) was surprising rather than obvious.

Cited by wiki pages

  • genetics of TAA
  • syndromic aortopathies