FBN1 – Neonatal Marfan syndrome

Fibrillin-1, encoded by FBN1, is an extracellular matrix glycoprotein essential for microfibril integrity. Heterozygous pathogenic variants in FBN1 cause the spectrum of Marfan syndrome, with the most severe presentation classified as neonatal Marfan syndrome (nMFS). nMFS is autosomal dominant and manifests in early infancy with severe mitral/tricuspid valve insufficiency, rapidly progressive aortic root dilatation, arachnodactyly, loose skin, crumpled ears and pulmonary emphysema leading to death within the first year of life.

Clinical Validity

Genetic testing of nMFS cohorts has identified pathogenic FBN1 variants in at least 60 unrelated probands, clustering predominantly in exons 24–32 (PMID:21135753). Multi-family studies demonstrate de novo and familial segregation of missense and splicing mutations with complete penetrance in affected offspring. Complementary functional assays confirm a dominant-negative mechanism via impaired EGF-like domain folding and calcium binding in mutant fibrillin-1 monomers.

Genetic Evidence

nMFS follows an autosomal dominant inheritance pattern with both de novo and inherited mutations. Segregation data are robust, though specific counts of affected relatives are limited in singleton reports. Case series report over 60 probands harbouring missense substitutions of critical cysteine residues and splice site mutations leading to exon skipping. Variant spectrum includes missense changes (e.g., c.3331T>C (p.Cys1111Arg) (PMID:27138491)), splice donor/acceptor site variants, and large in-frame deletions affecting cbEGF domains. Recurrent hotspots in exons 25–26 underscore genotype–phenotype correlations.

Functional Evidence

Biophysical studies of recombinant fibrillin-1 EGF-like domains (e.g., TB6-cbEGF32) reveal that calcium-binding site mutations disrupt domain folding and increase backbone flexibility, supporting a dominant-negative effect on microfibril assembly (PMID:9383409). Cellular assays show that certain cysteine-substitution variants are retained in the endoplasmic reticulum, reducing extracellular matrix deposition of fibrillin-1 and recapitulating the nMFS phenotype in vitro (PMID:8894692).

Conflicting Evidence

No substantive disputes have been reported regarding the causative role of FBN1 variants in nMFS. Some FBN1 mutations can present with milder phenotypes (e.g., MASS, isolated ectopia lentis), but clustering of mutations in the neonatal region (exons 24–32) remains a consistent discriminator for nMFS.

Integration & Clinical Utility

The convergence of extensive proband data, familial segregation, and concordant functional assays establishes FBN1 pathogenic variants as a definitive cause of nMFS. Diagnostic genetic testing should target exons 24–32 for missense and splice site alterations, with attention to critical cysteine residues. Early molecular diagnosis informs prognosis, guides multidisciplinary management, and supports genetic counseling. In research and commercial settings, FBN1 variant interpretation benefits from established genotype–phenotype correlations in nMFS.

Key Take-home: Heterozygous FBN1 mutations in the neonatal hotspot exons 24–32 cause a definitive, autosomal dominant nMFS phenotype with rapid cardiovascular decline and high infant mortality, underscoring the importance of targeted genetic and functional assessment.

References

• Pediatric Research • 2011 • Prognosis factors in probands with an FBN1 mutation diagnosed before the age of 1 year. PMID:21135753
• BMC Pediatrics • 2016 • A novel fibrillin-1 gene missense mutation associated with neonatal Marfan syndrome: a case report and review of the mutation spectrum. PMID:27138491
• Chemistry & Biology • 1995 • Fibrillin domain folding and calcium binding: significance to Marfan syndrome. PMID:9383409
• Human Molecular Genetics • 1996 • Mutant fibrillin-1 monomers lacking EGF-like domains disrupt microfibril assembly and cause severe marfan syndrome. PMID:8894692

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