New insights into the molecular diagnosis and management of heritable thoracic aortic aneurysms and dissections

Abstract

Since the identification of the fibrillin-1 gene as the causal gene for Marfan syndrome, our knowledge of molecular genetics and the applicability of genetic testing for heritable thoracic aneurysms and dissections (H-TAD) in clinical practice have increased substantially. Several new syndromes related to H-TAD have been described and the list of mutated genes in syndromal and nonsyndromal H-TAD is rapidly expanding. This knowledge has led to a significant improvement of our insight into the underlying pathophysiology of H-TAD resulting in new opportunities for targeted treatment, as well as in improved risk stratification. Clinicians involved in the care for H-TAD patients require a basic knowledge of the disease entities and need to be correctly informed on the applicability of genetic testing in their patients and families. Gene-tailored treatment and management should now be considered as part of good clinical practice. We provide a systematic overview of genetic H-TAD entities and practical recommendations for genetic testing and patient management.

Good performance of the criteria of American College of Medical Genetics and Genomics/Association for Molecular Pathology in prediction of pathogenicity of genetic variants causing thoracic aortic aneurysms and dissections

“…Out of 22 variants identified using TAAD-specific panel and predicted to be P/LP by ACMG and/or VarSome only one variant (in the HCN4 gene) wouldn't have been found if universal cardiac panel was used. This observation supports previous reports suggesting that use of smaller gene panels consisting of the most frequently mutated genes may be a cost-effective strategy as a first step of the genetic diagnosis for TAAD patients [17].…”

Clinical utility of a next generation sequencing panel assay for Marfan and Marfan‐like syndromes featuring aortopathy

“…Identifying a genetic cause for the disorder in these patients is important because it can help define a more appropriate medical course of action. Specifically, molecular results can be used to guide proper management, surveillance, and treatment of patients through the use of interventional surgery and/or targeted medication to alter the natural course of the disorder [Campens et al, ]. Mutation identification is also important for at‐risk family members who may need to be monitored as well.…”

“…Molecular genetic testing is often required for timely and accurate diagnosis of individuals with Marfan or Marfan‐like syndromes. Understanding the genetic origin of aortopathy is important because it can guide proper management and treatment of patients through use of interventional surgery and/or targeted medication before an aortic event occurs [Campens et al, ]. Because of the phenotypic overlap and genetic heterogeneity of diseases featuring aortopathy, we developed a 10‐gene (Table ) next generation sequencing (NGS) panel assay for the molecular diagnosis of these disorders [Wooderchak‐Donahue et al, ].…”

Characterization of Two Novel Intronic Variants Affecting Splicing in FBN1-Related Disorders

“…Current treatment includes losartan 50 mg/day (single dose) and nebivolol 50 mg/day (single dose), without significant side effects. The last heart ultrasound, at 27 years, showed a stable dilatation of the aortic root (48 mm; Z score 171.13 = 4.66 SD [11]) with normal ascending aorta (34 mm), minimal insufficiency of the aortic valve, prolapse of the anterior mitral leaflet with minimal insufficiency, and mild insufficiency of the tricuspid valve. Dilatation of the aortic root (48 × 43 mm) was also confirmed by angio-computer tomography.…”

“…A heart ultrasound repeatedly showed normal aortic diameters, prolapse, and mild insufficiency of the mitral valve. At 47 years, aortic root diameter was 36 mm (Z score 1.26 SD [11]). Routine ophthalmologic assessments always excluded lens dislocations.…”