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 Caulfield

Research output: Contribution to journalArticle

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 1 2019

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Informatics
Virulence
Uvula
Marfan Syndrome
Proteins
Connective Tissue Diseases
Genetic Testing
Scoliosis
Osteoarthritis
Connective Tissue
Genes
Aneurysm
Transcription Factors
Stroke
Phenotype
Skin

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)

Cite this

Genomic observations of a rare/pathogenic SMAD3 variant in Loeys–Dietz syndrome 3 confirmed by protein informatics and structural investigations. / Richter, John E.; Samreen, Ayesha; Vadlamudi, Charitha; Helmi, Haytham; Mohammad, Ahmed N.; Wierenga, Klaas; Hines, Stephanie; Atwal, Paldeep S.; Caulfield, Thomas.

In: Medicina (Lithuania), Vol. 55, No. 5, 137, 01.05.2019.

Research output: Contribution to journalArticle

Richter, John E. ; Samreen, Ayesha ; Vadlamudi, Charitha ; Helmi, Haytham ; Mohammad, Ahmed N. ; Wierenga, Klaas ; Hines, Stephanie ; Atwal, Paldeep S. ; Caulfield, Thomas. / Genomic observations of a rare/pathogenic SMAD3 variant in Loeys–Dietz syndrome 3 confirmed by protein informatics and structural investigations. In: Medicina (Lithuania). 2019 ; Vol. 55, No. 5.
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