Department of Clinical Genetics and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
Department of Cardiothoracic and Vascular Surgery and Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.
Mol Genet Genomic Med. 2020 Apr;8(4):e1089. doi: 10.1002/mgg3.1089. Epub 2020 Feb 5.
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.
Description of clinical history of a family in Sweden using clinical data, DNA sequencing, bioinformatics, and pedigree analysis.
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.
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.
SMAD3 基因中的致病性变异会影响 TGF-β/SMAD3 信号通路，导致涉及主动脉血管的 Loeys-Dietz 综合征 3 型，也称为动脉瘤-骨关节炎综合征。
使用临床数据、DNA 测序、生物信息学和家系分析描述瑞典一个家族的临床病史。
我们报告了一种新的 SMAD3 变异，最初被归类为遗传变异意义不明（VUS），后来发现与该家族的主动脉夹层共分离。该指数患者表现为主动脉夹层，包括升主动脉、降主动脉和腹主动脉。基因型分析显示杂合错义 SMAD3 变异：NM_005902.3(SMAD3):c.11576G>C(p.Arg386Thr)。同样的变异也在一个 30 岁的远房表亲的福尔马林固定石蜡包埋组织块中被发现，他在 26 岁时死于主动脉夹层。
根据 ACMG 指南，“意义不明的变异”始终有重新评估的空间。对有主动脉瘤疾病的亲属进行遗传咨询和提供监测服务很重要。该报告还强调了从已故亲属中进行 FFPE 分析以帮助解释变异的潜在用途。
