TGFB3 – Loeys‐Dietz syndrome type V

Loeys-Dietz syndrome (LDS) is an autosomal dominant systemic connective tissue disorder characterised by early and aggressive vascular disease including aortic aneurysms and dissections, craniofacial anomalies, skeletal overgrowth, and cutaneous findings. Type V LDS has recently been linked to heterozygous variants in TGFB3 through multiple case reports and functional studies.

In a three-member family with marfanoid features overlapping LDS, exome sequencing identified a novel TGFB3 missense mutation, c.898C>G (p.Arg300Gly), which segregated in the father and two affected children presenting with tall stature, arachnodactyly, hyperextensible joints, hypertelorism, and bifid uvula in the absence of aortic involvement (PMID:26184463). This finding expanded the phenotypic spectrum of TGFB3-related disorders and suggested opposing effects of Arg300 substitutions on TGF-β signalling.

Subsequent independent reports described a Loeys-Dietz type V patient with thoracic aortic aneurysm carrying the heterozygous variant c.787G>C (p.Asp263His) in TGFB3, demonstrating preservation of iPSC pluripotency and normal karyotype in patient-derived lines (PMID:36356561). A separate case report of recurrent coronary artery fistulae identified a novel c.730G>A (p.Glu244Lys) mutation in TGFB3, absent from gnomAD and considered pathogenic based on evolutionary conservation and clinical correlation (PMID:34659991).

The mutational landscape of TGFB3 in LDS now includes more than four missense substitutions at key functional residues (Arg300, Asp263, Glu244) and several truncating alleles (e.g., c.109A>T (p.Lys37Ter), c.436del (p.Leu146fs)) reported in unrelated patients (PMID:29392890). Recurrence of codon 300 variants across individuals supports a gain-of-function mechanism, whereas loss-of-function alleles are associated with distinct hypomorphic syndromes.

Mechanistic studies in mouse models demonstrate partial redundancy yet essential roles for TGFβ3 in vascular morphogenesis, with Tgfb1(RGE/RGE); Tgfb3(–/–) embryos exhibiting severely perturbed brain vasculature and embryonic lethality, underscoring the importance of ligand activation in vivo (PMID:18343643). These findings align with clinical observations of TGF-β dysregulation in LDS patients carrying TGFB3 variants.

Collectively, three unrelated probands and one multiplex family provide moderate genetic evidence for TGFB3 as a causative gene in Loeys-Dietz syndrome type V, supported by segregation data and consistent variant recurrence. Functional concordance between human genotypes and animal models further corroborates pathogenicity, justifying inclusion of TGFB3 in diagnostic panels for connective tissue disorders. TGFB3 variant analysis enables genetic confirmation, informs risk stratification, and guides early surveillance for vascular complications in LDS type V.

References

• Molecular and Cellular Probes • 2015 • Exome sequencing identifies a novel heterozygous TGFB3 mutation in a disorder overlapping with Marfan and Loeys-Dietz syndrome. PMID:26184463
• Stem Cell Research • 2022 • Generation of a human TGFB3-hIPSC line, BBANTWi010-A, from a Loeys-Dietz syndrome type V patient. PMID:36356561
• Cureus • 2021 • Recurrent Coronary Artery Fistulae and a Novel Transforming Growth Factor Beta-3 Mutation. PMID:34659991
• Human Mutation • 2018 • A mutation update on the LDS-associated genes TGFB2/3 and SMAD2/3. PMID:29392890
• Mechanisms of Development • 2008 • TGFbeta1 and TGFbeta3 are partially redundant effectors in brain vascular morphogenesis. PMID:18343643

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