Novel Biallelic <i>TGFBR3</i> Mutation in Brothers Presenting With Craniosynostosis

Craniosynostosis is characterized by premature fusion of cranial sutures, often with a complex genetic basis. While multiple genes have been implicated, the role of TGFBR3 mutations remains largely uncharacterized in human craniosynostosis. We report two Kuwaiti male siblings, born to consanguineous parents, who presented with syndromic features including craniosynostosis involving the lambdoid and posterior sagittal sutures, hypertelorism, midface hypoplasia, bilateral low-set ears, undescended testes, and developmental hip dysplasia. Duo whole exome sequencing research re-analysis identified a novel homozygous nonsense variant segregating with the phenotype in TGFBR3 (NM_003243.4: c.2418G>A, p.Trp806Ter), which encodes the betaglycan protein. Functional studies were performed to assess the pathogenicity of the variant. Expression of the mutant TGFBR3 in HEK293T cells demonstrated correct plasma membrane localization but revealed a truncated protein lacking its intracellular C-terminus. The mutant receptor retained canonical co-receptor function. In luciferase reporter assays, both wild-type and mutant TGFBR3 enhanced TGF-β1, TGF-β2, and TGF-β3 signaling. Mutant TGFBR3 produced an increase in luciferase activity relative to wild type only at the highest TGFβ1 concentration tested (10 pM). At lower TGFβ1 concentrations (0.1 and 1 pM) and across all concentrations of TGFβ2 and TGFβ3, mutant and wild-type receptors behaved similarly. This is the first report implicating a biallelic TGFBR3 nonsense variant in a syndromic, autosomal recessive form of craniosynostosis in a Middle Eastern population. The premature stop codon truncates the C-terminal region of the protein, perhaps disrupting critical regulatory or interaction domains. Our results suggest that dysregulated TGFβ signaling via the intracellular C-terminus of the protein may represent a novel pathogenic mechanism in cranial suture biology.

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