Novel SMAD3 p.Arg386Thr genetic variant co‐segregating with thoracic aortic aneurysm and dissection

Abstract

Background Pathogenic variants in the SMAD3 gene affecting the TGF‐β/SMAD3 signaling pathway with aortic vessel involvement cause Loeys‐Dietz syndrome 3, also known as aneurysms–osteoarthritis syndrome. Methods Description of clinical history of a family in Sweden using clinical data, DNA sequencing, bioinformatics, and pedigree analysis. Results We report a novel SMAD3 variant, initially classified as a genetic variant of uncertain clinical significance (VUS), and later found to be co‐segregating with aortic dissection in the family. The index patient presented with a dissecting aneurysm of the aorta including the ascending, descending, and abdominal parts. Genotype analysis revealed a heterozygous missense SMAD3 variant: NM_005902.3(SMAD3): c.11576G > C (p.Arg386Thr). The same variant was also identified in a 30 years old formalin‐fixed paraffin‐embedded block of tissue from a second cousin, who died at 26 years of age from a dissecting aneurysm of the aorta. Conclusion A “variant of uncertain significance” according to the ACMG guidelines has always a scope for reappraisal. Genetic counselling to relatives, and the offering of surveillance service is important to families with aortic aneurysm disease. The report also highlight the potential use of FFPE analysis from deceased relatives to help in the interpretation of variants.

Known pathogenic gene variants and new candidates detected in Sudden Unexpected Infant Death using Whole Genome Sequencing

“…SMAD3 is also regulated by serotonin (55) which has been implicated in SUID (56). Variants in this gene have been described in patients that died of sudden cardiac death, heart failure and aortic aneurysm (57)(58)(59)(60)(61).…”

“…SMAD3 is also regulated by serotonin (Chen, 2014) which has been implicated in SUID (Cummings, 2019). Variants in this gene have been described in patients that died of sudden cardiac death, heart failure and aortic aneurysm (Loeys, 2018; Engström, 2020; Ou, 2020; Hanna, 2021; Humeres, 2022).…”

Applying multi-omics techniques to the discovery of biomarkers for acute aortic dissection

“…Of these, exome sequencing revealed that SMAD3 mutations cause 2% of familial thoracic aortic aneurysms and dissections (TAAD) ( 67 ). As a result of the identification of fresh missense mutations in SMAD3’s evolutionarily conserved areas, Loeys-Dietz syndrome (LDS) type 3 has also been more precisely identified ( 68 , 69 ). Similarly, a nonsense variant and four missense variants in the MH2 structural domain of SMAD2 ( 70 ) and a heterozygous missense variant in the MH1 structural domain of SMAD4 were detected by sequencing in patients with sporadic thoracic aortic disease and published as first reports ( 71 ), perhaps in relation to its important role in the proliferation of vascular smooth muscle cells (VSMCs), extracellular matrix maintenance and vascular remodeling related ( 72 ).…”

Functional analysis of cell lines derived from SMAD3-related Loeys-Dietz Syndrome patients provides insights into genotype-phenotype relations

“…LDS3 is characterized by aneurysms and tortuosity of the aorta and/or middle-sized arteries, accompanied by osteoarthritis (5,6). Currently, over 60 different P/LP variants in SMAD3 have been identified in LDS3 families (24)(25)(26)(27)(28), including missense, truncating and splicing variants, and intragenic and whole gene deletions (24,29,30). Interestingly, large phenotypic variation is described between LDS3 families, suggesting that, among others, genotype and ancestry might play a role.…”