Genomic observations of a rare/pathogenic SMAD3 variant in Loeys–Dietz syndrome 3 confirmed by protein informatics and structural investigations

John E. Richter, Ayesha Samreen, Charitha Vadlamudi, Haytham Helmi, Ahmed N. Mohammad, Klaas Wierenga, Stephanie Hines, Paldeep S. Atwal, Thomas R. Caulfield

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

Background and objectives: Loeys–Dietz syndrome 3, also known as aneurysms—osteoarthritis syndrome, is an autosomal dominant genetic connective tissue disease caused by pathogenic variants in SMAD3, a transcription factor involved in TGF-β signaling. This disorder is characterized by early-onset osteoarthritis and arterial aneurysms. Common features include scoliosis, uvula abnormalities, striae, and velvety skin. Materials and Methods: The pathogenicity of a variant of uncertain significance in the SMAD3 gene was evaluated (variant c.220C > T) through personalized protein informatics and molecular studies. Results: The case of a 44-year-old male, who was originally presumed to have Marfan syndrome, is presented. An expanded gene panel determined the probable cause to be a variant in SMAD3, c.220C > T (p.R74W). His case was complicated by a history of stroke, but his phenotype was otherwise characteristic for Loeys–Dietz syndrome 3. Conclusion: This case emphasizes the importance of comprehensive genetic testing to evaluate patients for connective tissue disorders, as well as the potential benefit of utilizing a protein informatics platform for the assessment of variant pathogenicity.

Original languageEnglish (US)
Article number137
JournalMedicina (Lithuania)
Volume55
Issue number5
DOIs
StatePublished - May 2019

Keywords

  • Case report
  • Loeys-Dietz syndrome 3 (LDS3)
  • Molecular genomics
  • Pathogenicity
  • Protein informatics
  • SMA-and MAD-related protein 3 (SMAD3)

ASJC Scopus subject areas

  • Medicine(all)

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