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.

Keywords: familial thoracic aortic aneurysm and dissection; genetic screening; whole exome sequencing.

Figures

Figure 1. Consolidated Standards of Reporting Trials diagram for study recruitment and follow‐up.

In 2 relatives a sufficient amount of blood could not be collected because of poor peripheral vasculature; the proband tested negative for variants in these cases. FDR indicates first‐degree relative; MRI, magnetic resonance imaging; SDR, second‐degree relative; and TTE, transthoracic echocardiogram.

Figure 2. Summary of the findings related to the imaging study procedures.

Fifty‐four participants underwent transthoracic echocardiogram as part of the study procedures, and 43 had both echocardiogram and MRI. Thirteen imaging diagnoses of mild‐to‐moderate aortic dilatation were reached. FDR indicates first‐degree relative; MRI, magnetic resonance imaging; SDR, second‐degree relative; and TTE, transthoracic echocardiogram.

Figure 3. Flow chart describing the variant filtering and evaluation process.

The complete list was reduced by filtering for (in order) type of variant (synonymous vs nonsynonymous), rarity in gnomAD (less vs more than 5% of the general population), predicted impact of the mutation (high/moderate vs low impact), classification in ClinVar (pathogenic/likely pathogenic/uncertain significance vs benign/likely benign) and evaluated finally according to the American College of Medical Genetics and Genomics criteria. ACMG indicates American College of Medical Genetics and Genomics; VUS, variant of uncertain significance; and VUS‐LP‐P, variant of uncertain significance likely pathogenic‐pathogenic.

Figure 4. Summary of the findings related to the genetic test study procedures.

After ACMG evaluation and multidisciplinary team discussion, 3 participants were rephenotyped by a clinical geneticist where deep phenotyping might alter variant classification. FDR indicates first‐degree relative; SDR, second degree relative; and VUS, variant of uncertain significance.

Figure 5. Summary of the overall study findings.

Sixteen families of patients with nonsyndromic thoracic aortic disease (NS‐TAD) were involved in a feasibility study to evaluate a combined approach to screening for aortopathy. Results showed an aortic dilatation in 24% and a genotype that required rephenotyping in 15% of the relatives respectively. Thirteen participants required imaging follow‐up, and 3 families a further clinical genetics reevaluation. FDR indicates first‐degree relative; MRI, magnetic resonance imaging; SDR, second degree relative; TTE, transthoracic echocardiogram; and VUS, variant of uncertain significance.