Evaluating the Feasibility of Screening Relatives of Patients Affected by Nonsyndromic Thoracic Aortic Diseases: The REST Study

Abstract

Background Diseases of the thoracic aorta are characterized by a familial etiology in up to 30% of the cases. Nonsyndromic thoracic aorta diseases (NS‐TADs) lack overt clinical signs and systemic features, which hinder early detection and prompt surgical intervention. We hypothesize that tailored genetic testing and imaging of first‐degree and second‐degree relatives of patients affected by NS‐TADs may enable early diagnosis and allow appropriate surveillance or intervention. Methods and Results We conducted a feasibility study involving probands affected by familial or sporadic NS‐TADs who had undergone surgery, which also offered screening to their relatives. Each participant underwent a combined imaging (echocardiogram and magnetic resonance imaging) and genetic (whole exome sequencing) evaluation, together with physical examination and psychological assessment. The study population included 16 probands (8 sporadic, 8 familial) and 54 relatives (41 first‐degree and 13 second‐degree relatives) with median age 48 years (range: 18–85 years). No syndromic physical features were observed. Imaging revealed mild‐to‐moderate aortic dilation in 24% of relatives. A genetic variant of uncertain significance was identified in 3 families. Imaging, further phenotyping, or a form of secondary prevention was indicated in 68% of the relatives in the familial group and 54% in the sporadic group. No participants fulfilled criteria for aortic surgery. No differences between baseline and 3‐month follow‐up scores for depression, anxiety, and self‐reported quality of life were observed. Conclusions In NS‐TADs, imaging tests, genetic counseling, and family screening yielded positive results in up to 1 out of 4 screened relatives, including those in the sporadic NS‐TAD group. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03861741.

Barriers to cascade screening in people at risk of Thoracic Aortic Disease: a mixed methods evaluation from the DECIDE-TAD initiative

“…Up to 30% of first- and second-degree relatives of people with TAD will also have recognised mutations or aortic aneurysms. (5)…”

“…Up to 30% of first-and second-degree relatives of people with TAD will also have recognised mutations or aortic aneurysms. (5) Cascade screening, where relatives undergo genetic tests and imaging significantly reduces mortality through detection of latent disease, effective secondary prevention, and early treatment (6). It is recommended by treatment guidelines if the proband is aged < 60 years at presentation, or if there is a family history.…”

Preventing Acute Aortic Dissections: The Power of Familial Screening and Risk Assessment

“…In this issue of the Journal of the American Heart Association (JAHA) , Abbasciano et al investigated the feasibility of a multifaceted TAD screening program that integrated thoracic aortic imaging for at‐risk relatives of NS‐TAD probands, exome sequencing for TAD probands, and psychological and quality of life assessments. 17 This study included 16 probands with NS‐TAD (8 familial; 8 sporadic) and 54 FDRs and second‐degree relatives who underwent thoracic aortic imaging via transthoracic echocardiogram (n=54) and magnetic resonance imaging (n=43). Approximately 62% of the probands were male with median ages of 68.5 and 67.5 years in the familial and sporadic groups, respectively.…”

“…In addition to aortic imaging, exome sequencing was pursued for the 16 probands with NS‐TAD to detect pathogenic variants that could be used for predictive cascade genetic testing in relatives and to identify variants of uncertain significance that may prompt additional phenotyping or segregation studies. 17 After filtering variants by allele frequency and predicted functional impact, they identified 14 variants (9 variants of uncertain significance, 5 benign) in 32 genes included on the National Institutes of Health Genomic Medicine Service Aortopathy Panel. No pathogenic or likely pathogenic variants were identified.…”

“…This study by Abbasciano et al further confirms the significant burden of TAD in at‐risk FDRs and second‐degree relatives. 17 Additionally, they integrated other critical components of TAD risk assessment including genetic variant analysis, clinical risk factor assessment, psychological well‐being, and quality of life. When genetic or clinical risk factors such as hypertension are identified in at‐risk relatives, secondary prevention strategies can be implemented to reduce aortic dissection risk.…”