Identification of a Pathogenic TGFBR2 Variant in a Patient With Loeys–Dietz Syndrome

Xiao Chen,Abdulrahman Mustafa Ahmed Al-Raimi,Ying Jiang,Feng Zhu,Xiaobin Liu,Xiang Wang,Yu Song,Xi Luo,Long Wu,Shan Deng

doi:10.3389/fgene.2020.00479

Xiao Chen, Abdulrahman Mustafa Ahmed Al-Raimi + Show 8 more

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https://doi.org/10.3389/fgene.2020.00479

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Abstract

Loeys–Dietz syndrome (LDS) is a rare connective tissue genetic disorder that is caused by a pathogenic variant in genes of transforming growth factor (TGF) beta receptor 1 (TGFBR1), TGFBR2, mothers against decapentaplegic homolog 2 (SMAD2), SMAD3, TGFB2, or TGFB3. It is characterized by aggressive vascular pathology, aneurysms, arterial tortuosity, bifid uvula, hypertelorism, and cleft palate. Here we present a 42-year-old female patient with LDS. The patient underwent rapidly progressing artery aneurysms and life-threatening aortic dissection. Spontaneous fracture of the first metatarsal bone was noted in her medical record. Physical examination revealed a delayed wound healing on her left abdomen. Considering these clinical manifestations, we speculated that there was a genetic defect in the connective tissue, which provides strength and flexibility to structures such as bones, skins, ligaments, and blood vessels. Thus, whole exome sequencing (WES) was performed on the proband and revealed a heterozygous missense pathogenic variant (c.1613T > C/p.Val538Ala) in TGFBR2, which was a de novo variant in the proband as confirmed by the segregation analysis in parental samples. Although this variant was discovered and associated with the phenotype of LDS previously, the pathogenicity of the variant had not been confirmed by cellular functional assay yet. To further validate the effects of the variant in vitro, we assessed the canonical TGF-β signaling pathway in mutant cells. Our results showed that the p.Val538Ala variant significantly decreased TGF-β-induced gene transcription and the phosphorylation of Smad2, which were consistent with other pathogenic variants of TGFBR2. In conclusion, this study demonstrates that the p.Val538Ala pathogenic variant in TGFBR2 leads to aberrant TGF-β signaling and LDS in this patient.

Highlights

Loeys–Dietz syndrome (MIM#609192, LDS) is an inherited autosomal dominant connective tissue disorder with a broad phenotypic spectrum of cardiovascular, skeletal, craniofacial, and cutaneous manifestations (Loeys et al, 2005, 2006)
We reported a case of a 42-year-old female who underwent recurrent and life-threatening artery aneurysm and dissection, spontaneous bone fracture, and delayed wound healing
After five filters of the variants data for whole exome sequencing (WES) data, 347 variants from 267 genes were kept. These genes were associated with the phenotype of “aortic dissection; artery aneurysm” by Phenolyzer, and the result revealed one heterozygous T-to-C transition c.1613T > C in TGFBR2 (Supplementary Figure S1), which leads to a substitution of valine to alanine at codon 538 (p.Val538Ala) in the TGFBR2 kinase domain (Figure 1C)

Summary

INTRODUCTION

Loeys–Dietz syndrome (MIM#609192, LDS) is an inherited autosomal dominant connective tissue disorder with a broad phenotypic spectrum of cardiovascular, skeletal, craniofacial, and cutaneous manifestations (Loeys et al, 2005, 2006). After five filters of the variants data for WES data, 347 variants from 267 genes were kept These genes were associated with the phenotype of “aortic dissection; artery aneurysm” by Phenolyzer, and the result revealed one heterozygous T-to-C transition c.1613T > C in TGFBR2 (Supplementary Figure S1), which leads to a substitution of valine to alanine at codon 538 (p.Val538Ala) in the TGFBR2 kinase domain (Figure 1C). This variant is a raw variant which is absent in population databases including Genome Aggregation Database (gnomAD), Exome Aggregation Consortium (ExAC), Exome Sequencing Project (ESP), and 1000 Genomes.

DISCUSSION

MATERIALS AND METHODS

Findings

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