TGFBR2 – Loeys-Dietz syndrome

Loeys-Dietz syndrome (LDS) is an autosomal dominant aortopathy characterised by arterial tortuosity and aneurysms, hypertelorism, and bifid uvula or cleft palate, caused by heterozygous mutations in the TGFBR2 gene. Pathogenic variants cluster in the serine/threonine kinase domain and are identified in multiple unrelated families with clear segregation ([PMID:16928994]).

Inheritance is autosomal dominant, with at least 52 affected families and 40 index probands harbouring TGFBR2 mutations, including recurrent missense changes in kinase‐domain residues ([PMID:16928994]). Segregation across multigenerational pedigrees confirms co-segregation of these missense variants with LDS features in affected relatives.

Case series and single-patient reports have identified >100 probands with TGFBR2 missense variants such as c.1582C>T (p.Arg528Cys) presenting with early-onset LDS manifestations including craniosynostosis, aortic root dilatation, hypertelorism, cleft palate, and skeletal anomalies ([PMID:19875893]).

Functional assays in cellular and in vitro models demonstrate that LDS-associated TGFBR2 variants disrupt receptor kinase activity and downstream SMAD2 phosphorylation. In particular, the novel V419L variant delays SMAD2 activation and reduces TGF-β-induced transcriptional responses, confirming pathogenicity through impaired canonical signalling ([PMID:28679693]).

Quantitative analyses of multiple TGFBR2 mutations show dominant-negative effects on Smad versus ERK signalling balance, correlating with phenotypic severity and supporting a haploinsufficiency/dominant-negative mechanism in LDS and related aortopathies ([PMID:21098638]).

No studies to date substantially dispute the association between TGFBR2 mutations and LDS. Taken together, the genetic and functional evidence establishes TGFBR2 as a definitive cause of LDS, highlighting the importance of early genetic testing for diagnosis, family screening, and management.

Key Take-home: Heterozygous pathogenic variants in TGFBR2 definitively underlie autosomal dominant Loeys-Dietz syndrome, and genetic confirmation enables early surveillance and tailored cardiovascular intervention.

References

• The New England journal of medicine • 2006 • Aneurysm syndromes caused by mutations in the TGF-beta receptor PMID:16928994
• Cold Spring Harbor molecular case studies • 2017 • Functional validation reveals the novel missense V419L variant in TGFBR2 associated with Loeys-Dietz syndrome (LDS) impairs canonical TGF-β signaling PMID:28679693
• Journal of cell science • 2010 • Quantitative analysis of TGFBR2 mutations in Marfan-syndrome-related disorders suggests a correlation between phenotypic severity and Smad signaling activity PMID:21098638

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