TGFBR1 – Loeys-Dietz Syndrome

Loeys-Dietz syndrome (LDS) is a rare autosomal dominant connective tissue disorder characterized by aggressive arterial aneurysms and dissections, arterial tortuosity, hypertelorism, and bifid uvula or cleft palate (PMID:16928994). Heterozygous variants in the transforming growth factor β receptor type I gene (TGFBR1) underlie LDS type I (MONDO:0018954), disrupting subcellular TGF-β signaling and predisposing to life-threatening vasculopathy.

Genetic evidence includes identification of TGFBR1 variants in over 50 unrelated probands across multicenter cohorts (PMID:16928994; PMID:19542084). Variants encompass missense, splice-site, and truncating changes clustering in the serine/threonine kinase domain and extracellular ligand-binding region. For example, the recurrent missense variant c.1459C>T (p.Arg487Trp) segregates with disease in multigenerational families and has been reported in multiple ethnically diverse cohorts.

Segregation analyses in multigenerational pedigrees demonstrate co-segregation of TGFBR1 variants with LDS features in at least 24 additional affected relatives (PMID:19542084). De novo and inherited cases confirm autosomal dominant transmission with variable expressivity.

Functional assays support a dominant-negative or loss-of-function mechanism, with splice-site variants causing differential exon skipping, truncated in frame proteins, and paradoxical upregulation of TGF-β signaling in patient aortic tissue (PMID:29706644; PMID:30701076). iPSC-derived smooth muscle cell models of the TGFBR1^Ala230Thr variant recapitulate lineage-specific contractile defects and identify rapamycin and activin A as potential therapeutic modulators (PMID:34346740). Rescue experiments confirm TGFBR1’s critical role in SMC differentiation and extracellular matrix integrity.

No studies refute the TGFBR1–LDS association. The evidence meets ClinGen criteria for a Strong gene-disease association, with robust genetic and experimental support.

Key Take-home: Heterozygous TGFBR1 pathogenic variants cause autosomal dominant LDS with aggressive vascular manifestations; early genetic testing and surveillance enable timely surgical and medical interventions.

References

• The New England journal of medicine • 2006 • Aneurysm syndromes caused by mutations in the TGF-beta receptor. PMID:16928994
• Journal of Medical Genetics • 2009 • Analysis of multigenerational families with thoracic aortic aneurysms and dissections due to TGFBR1 or TGFBR2 mutations. PMID:19542084
• European Journal of Human Genetics • 2018 • Distinct variants affecting differential splicing of TGFBR1 exon 5 cause either Loeys-Dietz syndrome or multiple self-healing squamous epithelioma. PMID:29706644
• Human Genome Variation • 2019 • Activation of TGF-β signaling in an aortic aneurysm in a patient with Loeys-Dietz syndrome caused by a novel loss-of-function variant of TGFBR1. PMID:30701076
• Circulation • 2021 • hiPSC Modeling of Lineage-Specific Smooth Muscle Cell Defects Caused by TGFBR1A230T Variant, and Its Therapeutic Implications for Loeys-Dietz Syndrome. PMID:34346740
• European Journal of Human Genetics • 2023 • Truncating variants in the penultimate exon of TGFBR1 escaping nonsense-mediated mRNA decay cause Loeys-Dietz syndrome. PMID:36599937

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