TGFB3 – Rienhoff syndrome

Transforming growth factor beta 3 (TGFB3) is a secreted cytokine involved in extracellular matrix regulation and vascular development. Heterozygous TGFB3 variants underlie syndromic connective tissue disorders with variable cardiovascular involvement. Rienhoff syndrome (MONDO:0014262) is characterized by distal arthrogryposis, hypotonia and vascular anomalies. The autosomal dominant inheritance and pleiotropic phenotypes suggest a dosage-sensitive role for TGFB3 in human development.

A founder NM_003239.5(TGFB3):c.787G>C (p.Asp263His) variant was identified in 27 individuals from five unrelated families originating in Flanders (Campine region) carrying a shared 1.92–4.14 Mb haplotype, indicating a common ancestor >400 years ago (27 individuals,PMID:37719708). Variable clinical features encompassed connective tissue signs, hypertrophic cardiomyopathy, bicuspid aortic valve and septal defects.

Cardiovascular manifestations showed low penetrance: only 4/27 carriers developed significant aortic aneurysm or dissection (PMID:37719708). In one pedigree, a 31-year-old male had type A dissection; in another, males aged 65 and 80 underwent a Bentall procedure and exhibited aortic diameters of 50 mm and 43 mm, respectively. These findings support autosomal dominant segregation across five families with at least 22 additional affected relatives.

No variant-specific functional assay of p.Asp263His has been reported. However, murine studies demonstrate that integrin‐mediated activation of latent TGFβ3 is essential for vascular morphogenesis, implying that disruption of the integrin‐binding Asp263 residue may impair cytokine activation (PMID:18343643).

There are no reports disputing the pathogenicity of c.787G>C (p.Asp263His) in the context of Rienhoff syndrome. The robust segregation and founder nature of this variant, combined with mechanistic plausibility, support a strong gene–disease relationship.

In conclusion, heterozygous c.787G>C (p.Asp263His) in TGFB3 is strongly associated with Rienhoff syndrome, exhibiting autosomal dominant inheritance with variable connective tissue and cardiovascular phenotypes. Genetic testing for TGFB3 should be considered in patients with unexplained distal arthrogryposis or aortic aneurysms to guide diagnosis and family screening.

References

• Frontiers in Genetics • 2023 • Variable clinical expression of a Belgian TGFB3 founder variant suggests the presence of a genetic modifier. PMID:37719708
• Mechanisms of Development • 2008 • TGFbeta1 and TGFbeta3 are partially redundant effectors in brain vascular morphogenesis. PMID:18343643

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