Low yield of genetic testing for known vascular connective tissue disorders in patients with fibromuscular dysplasia

Abstract

Patients with fibromuscular dysplasia (FMD) may have clinical features consistent with Mendelian vascular connective tissue disorders. The yield of genetic testing for these disorders among patients with FMD has not been determined. A total of 216 consecutive patients with FMD were identified. Clinical characteristics were collected and genetic test results reviewed for abnormalities in the following genes: transforming growth factor-β receptor 1 and 2 (TGFβR1 and TGFβR2), collagen 3A1, fibrillin-1, smooth muscle α-actin 2, and SMAD3. A total of 63 patients (63/216; 29.2%) were referred for genetic counseling with testing performed in 35 (35/63; 55.6%). The percentage of patients with a history of arterial or aortic dissection, history of aortic aneurysm, systemic features of a connective tissue disorder, and a family history of sudden death was significantly larger in the group that underwent genetic testing (62.9% vs 18.2%, p < 0.001; 8.6% vs 1.7%, p = 0.02; 51.4% vs 17.1%, p < 0.001; and 42.9% vs 22.7%, p = 0.04, respectively). Two patients were found to have distinct variants in the TGFβR1 gene (c.611 C>T, p.Thr204lle and c.1285 T>C, p.Tyr429His). The yield of genetic testing for vascular connective tissue disorders was low in a high-risk subset of FMD patients. However, two patients with a similar phenotype had novel and distinct variants in the TGFβR1 gene, a finding which merits further investigation.

Fibromuscular Dysplasia: State of the Science and Critical Unanswered Questions

“…Poloskey and colleagues 49 demonstrated that the prevalence of genetic mutations associated with connective tissue disorders, including the COL31A gene, transforming growth factor (TGF)-β1 and β2 genes, and the ACTA2 gene, was negligible in an FMD cohort. In their case series, however, they report 2 patients with distinct novel point mutations in the TGF-β receptor type 1 gene, mutations of which have been associated with inherited aneurysmal disease.…”

“…In their case series, however, they report 2 patients with distinct novel point mutations in the TGF-β receptor type 1 gene, mutations of which have been associated with inherited aneurysmal disease. 49,50 Both patients with these TGF-β receptor type 1 mutations had multifocal disease (medial fibroplasia), had suffered carotid or vertebral artery dissection, had ascending aortic dilatation, and had a family history of sudden death. 49 In summary, evidence supports a genetic basis for susceptibility to FMD.…”

“…49,50 Both patients with these TGF-β receptor type 1 mutations had multifocal disease (medial fibroplasia), had suffered carotid or vertebral artery dissection, had ascending aortic dilatation, and had a family history of sudden death. 49 In summary, evidence supports a genetic basis for susceptibility to FMD. Multiple barriers have impeded the identification and characterization of genes that may contribute to FMD.…”

“…49 Because TGF-β signaling is important in vascular wall remodeling and aneurysm formation, the use of ARBs as first-line therapy in the management of FMD is reasonable until the relationship between TGF-β and FMD is clarified.…”

Revisiting Fibromuscular Dysplasia

“…Accordingly, it may be postulated that there is a continuum between both forms and that, alongside with environmental factors, genetic factors may also contribute to the pathogenesis of apparently sporadic FMD. Earlier case-control studies failed to show an association between FMD and variants of genes coding for components of the renin-angiotensin system 51 and extracellular matrix, 52 including α-1 antitrypsin. 53 However, a large association study looking for enrichment in gene variants in patients with sporadic FMD compared with controls disclosed a significant association between multifocal FMD and 3 genes coding for muscle proteins (OBSCN, DYNC2H1, and MYLK), one of them (MYLK) also involved in familial thoracic aortic dissection, and a fourth one associated with susceptibility to Moyamoya disease (RNF213).…”