Genotype-Phenotype Correlation Insights Through Molecular Modeling Analysis in a Patient with Loeys-Dietz Syndrome

TL;DR

A patient with Loeys-Dietz syndrome had a genetic variant in TGFB2 that caused structural changes in the protein, leading to aortic aneurysms and highlighting the need for accurate diagnosis.

Contribution

The study identifies a novel pathogenic variant in TGFB2 and its structural impact through molecular modeling in a patient with Loeys-Dietz syndrome.

Findings

A de novo heterozygous variant c.896G>A in TGFB2 was found to cause p.Arg299Gln substitution.

Molecular modeling showed the variant has destabilizing effects on the 3D structure of the TGF-β protein.

The variant is linked to LDS type 4 and expands understanding of genotype-phenotype correlations.

Abstract

Background: Pathogenic variants within the gene encoding transforming growth factor β (TGF-β) are responsible for Loeys-Dietz syndrome (LDS), a heritable thoracic aortic disease sharing clinical features with Marfan syndrome, including craniofacial and skeletal abnormalities as well as aortic root aneurysms and dissections. In contrast to Marfan syndrome patients, who rarely develop aneurysms or dissections beyond the aortic root, LDS patients frequently exhibit vessel aneurysms in locations other than the aortic root. Here, we report the case of a 61-year-old patient who initially presented with marfanoid characteristics and an aortic root aneurysm and was presumed to have Marfan syndrome two decades ago. Later, the patient developed an abdominal aorta aneurysm, necessitating endovascular repair and stent placement. That fact raised doubts regarding the initial diagnosis of Marfan syndrome, and we decided to investigate the genetic cause of the disorder. Methods: Genetic testing was performed using WES analysis and Sanger sequencing. Results: The genetic analysis detected a de novo heterozygous pathogenic variant c.896G>A in exon 5 of the TGFB2 gene, resulting in the amino acid substitution p. Arg299Gln that has devastating destabilizing structural effects on 3D folding of the protein, as demonstrated by the molecular modeling study we performed. This variant is pathogenic for LDS type 4, partially consistent with the patient’s clinical presentation. Conclusions: Our case emphasizes the significance of precise clinical assessment and genetic verification in patients exhibiting marfanoid characteristics. Furthermore, our findings contribute to the understanding of the diverse clinical spectrum associated with this specific pathogenic variant of TGFB2, underscoring the importance of detailed clinical assessment in expanding knowledge of genotype-phenotype correlations. Accurate diagnosis is crucial for tailored and appropriate management of individuals with heritable thoracic aortic diseases.

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