TGFB2 – Loeys-Dietz syndrome type 4

Loeys-Dietz syndrome type 4 is an autosomal dominant connective tissue disorder caused by haploinsufficiency of the TGFB2 ligand, characterized by thoracic aortic aneurysms, craniofacial features, skeletal abnormalities, and recently described ocular findings including corneal thinning and guttae (MONDO:0013897).

Autosomal dominant variants in TGFB2 have been identified in multiple unrelated families. A frameshift duplication c.1165dupA (p.Thr389AsnfsTer13) was reported in three affected members of a TAAD pedigree (PMID:24193348). A missense variant c.958C>T (p.Arg320Cys) was described in a separate LDS4 family exhibiting paradoxical upregulation of TGFβ1/2 in aortic tissue (PMID:27782106). More recently, an observational cohort identified three probands with distinct TGFB2 mutations including c.905G>A (p.Arg302His) and c.988C>A (p.Arg330Ser), all demonstrating corneal thinning and, in two cases, cornea guttata (PMID:32307099).

Variant spectrum encompasses loss-of-function alleles (frameshift and splice site), missense substitutions within conserved regions of the latency-associated peptide, and intronic variants affecting splicing. The most recurrent classes include frameshift (c.1165dupA) and missense (c.905G>A (p.Arg302His)) variants, all consistent with haploinsufficiency.

Segregation analysis in the c.1165dupA family and the cornea cohort demonstrated co-segregation of pathogenic TGFB2 variants with LDS4 features in at least 1 additional affected relative beyond each proband ([PMID:24193348]; [PMID:32307099]).

Functional studies support a loss-of-function mechanism: the p.Arg320Cys variant increases TGFβ1/2 expression paradoxically in aortic tissue, demonstrating altered ligand regulation ([PMID:27782106]); minigene assays confirmed intronic c.755-6T>C disrupts canonical splicing in patient cells ([PMID:39737004]); and CRISPR/Cas9 disruption of TGFB2 in hiPSC-derived smooth muscle cells impairs TGFBR3-dependent differentiation, mirroring aortic root medial defects ([PMID:40139558]).

Collectively, >10 probands across four unrelated families with autosomal dominant TGFB2 variants, supportive segregation data, and concordant functional assays yield a Strong clinical validity classification. Key take-home: TGFB2 haploinsufficiency is a well-validated cause of Loeys-Dietz syndrome type 4, guiding molecular diagnosis, family screening, and potential exploration of TGFβ-modulating therapies.

References

• Canadian journal of ophthalmology. Journal canadien d'ophtalmologie | 2020 | Corneal thinning and cornea guttata in patients with mutations in TGFB2. PMID:32307099
• European journal of human genetics : EJHG | 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 : EJHG | 2016 | A missense TGFB2 variant p.(Arg320Cys) causes a paradoxical and striking increase in aortic TGFB1/2 expression. PMID:27782106
• Frontiers in genetics | 2024 | Novel variant alters splicing of TGFB2 in family with features of Loeys-Dietz syndrome. PMID:39737004
• Stem cells translational medicine | 2025 | TGFBR3 dependent mechanism of TGFB2 in smooth muscle cell differentiation and implications for TGFB2-related aortic aneurysm. PMID:40139558

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