TY - JOUR
T1 - Genomic observations of a rare/pathogenic SMAD3 variant in Loeys–Dietz syndrome 3 confirmed by protein informatics and structural investigations
AU - Richter, John E.
AU - Samreen, Ayesha
AU - Vadlamudi, Charitha
AU - Helmi, Haytham
AU - Mohammad, Ahmed N.
AU - Wierenga, Klaas
AU - Hines, Stephanie
AU - Atwal, Paldeep S.
AU - Caulfield, Thomas R.
N1 - Publisher Copyright:
© 2019 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2019/5
Y1 - 2019/5
N2 - 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.
AB - 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.
KW - Case report
KW - Loeys-Dietz syndrome 3 (LDS3)
KW - Molecular genomics
KW - Pathogenicity
KW - Protein informatics
KW - SMA-and MAD-related protein 3 (SMAD3)
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U2 - 10.3390/medicina55050137
DO - 10.3390/medicina55050137
M3 - Article
C2 - 31096651
AN - SCOPUS:85066821159
SN - 1010-660X
VL - 55
JO - Medicina (Lithuania)
JF - Medicina (Lithuania)
IS - 5
M1 - 137
ER -