TGFB2 – Loeys-Dietz Syndrome Type 4

Loeys-Dietz syndrome type 4 (LDS4) is an autosomal dominant connective tissue disorder characterized by late-onset thoracic aortic aneurysm, skeletal anomalies, and systemic features due to heterozygous TGFB2 variants (PMID:25163805).

Initial reports identified a novel splice acceptor mutation c.839-1G>A (p.Gly280AspfsTer41) in a 57-year-old proband and her two affected daughters presenting with joint hypermobility, scoliosis, high palate, dural ectasia, and mitral valve prolapse without early dissection (PMID:25163805). A separate family harbored a 1-bp duplication c.1165dupA (p.Thr389AsnfsTer13) segregating in three relatives with thoracic aortic aneurysms and craniofacial dysmorphism, confirming haploinsufficiency as the underlying mechanism (PMID:24193348).

The TGFB2 variant spectrum includes loss-of-function alleles—splice site, frameshift, and nonsense mutations—and a recurrent missense change c.958C>T (p.Arg320Cys), the latter causing paradoxical upregulation of TGF-β1/2 expression in aortic tissue (PMID:27782106). These variants are typically private and demonstrate full penetrance with variable expressivity.

Clinical manifestations span aortic root aneurysm (HP:0002616) and general aneurysm (HP:0004942), arterial tortuosity, hypertelorism, bifid uvula, high palate (HP:0000218), joint hypermobility (HP:0001382), striae distensae, and occasional ectopia lentis (PMID:32462795; PMID:37677958).

Functional assays show that intronic variants reduce canonical TGFB2 transcript levels, leading to loss of ligand and downstream haploinsufficiency (PMID:39737004), whereas the p.Arg320Cys missense allele enhances TGF-β signaling on immunofluorescence and western blot of patient aortic tissue (PMID:27782106).

Animal and cellular models, including mice with Tgfb2 haploinsufficiency exhibiting vascular and developmental anomalies and three-dimensional smooth muscle cell constructs, reinforce TGFB2’s role in aortic wall integrity and confirm haploinsufficiency as the primary mechanism (PMID:35426477).

Together, multiple unrelated families, segregation data, and concordant functional studies establish a strong, definitive association between TGFB2 variants and Loeys-Dietz syndrome type 4. Key take-home: TGFB2 should be routinely included in genetic testing panels for heritable thoracic aortopathies and connective tissue disorders.

References

• BMC Medical Genetics • 2014 • Further delineation of Loeys-Dietz syndrome type 4 in a family with mild vascular involvement and a TGFB2 splicing mutation. PMID:25163805
• European Journal of Human Genetics • 2014 • A 1-bp duplication in TGFB2 in three family members with a syndromic form of thoracic aortic aneurysm. PMID:24193348
• European Journal of Human Genetics • 2016 • A missense TGFB2 variant p.(Arg320Cys) causes a paradoxical and striking increase in aortic TGFB1/2 expression. PMID:27782106
• American Journal of Medical Genetics Part A • 2020 • Ectopia lentis in Loeys-Dietz syndrome type 4. PMID:32462795
• Cirugía y Cirujanos • 2023 • Anesthetic management of a child with Loeys-Dietz syndrome undergoing complete aortic arch replacement. PMID:37677958
• Frontiers in Genetics • 2024 • Novel variant alters splicing of TGFB2 in family with features of Loeys-Dietz syndrome. PMID:39737004
• Cardiology in Review • 2024 • Genetic Problems, Diagnosis, and Cardiovascular Manifestations of Loeys-Dietz Syndrome. PMID:37126428

Evidence Based Scoring (AI generated)