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

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.

first degree relative

nonsyndromic thoracic aortic disease

second degree relative

thoracic aortic disease

variant of uncertain significance

Clinical Perspective

What Is New?

A screening initiative, combining genetics and imaging, could potentially optimize surveillance and management of nonsyndromic thoracic aortic disease patients, with no major psychological impact.

What Are the Clinical Implications?

Nonsyndromic thoracic aortic diseases (NS‐TAD) have a high mortality when presenting as emergencies; nonetheless, clear guidance on how to conduct surveillance is currently lacking.

In this study, testing 70 relatives of patients affected by NS‐TADs confirmed that there is often a familial etiology.

This supports screening initiatives in families of patients with NS‐TADs.

Diseases of the thoracic aorta (TADs) account for 1% to 2% of all deaths in the Western countries and occur in approximately 1% of the general population, , although prevalence might be even higher according to recent series. TADs are often silent entities with a mortality of almost 80% when presenting as life‐threatening emergencies. , , Consequently, early recognition and treatment are crucial elements for improving patient survival. , Unlike syndromic TADs, nonsyndromic TADs (NS‐TADs) lack overt clinical signs and systemic features, hindering early detection and prompt surgical intervention. , Although both the European and American guidelines recommended the screening of first‐degree relatives of a subject affected by TAD, tailored imaging and genetic screening programs have not been standardized to date. , , As a result, there is uncertainty around the screening of relatives with regard to screening modality, prognosis, and genetic counseling. , Therefore, the present study aimed to investigate the feasibility of a tailored imaging and genetic testing approach in relatives of probands affected by both sporadic and familial NS‐TAD.

Methods

Study Design and Participants

The present study is a single‐center, prospective, and noninterventional feasibility study, and it is registered at Clinicaltrials.gov (NCT03508505). Its detailed protocol with definition criteria is reported in Data S1 through S4, and it was approved by the East Midlands—Derby Research Ethics Committee (18/EM/0287). The data that support the findings of this study are available from the corresponding author upon reasonable request. Briefly, the study population consisted of probands affected by NS‐TAD with at least 2 first‐degree (FDR) or second‐degree (SDR) relatives (in order to maximize recruitment in each of the families) aged ≥16 years willing to participate in the study screening program. Probands with a previous diagnosis of syndromic TAD or those affected by aortic lesions associated with other aortic etiologies, including trauma and infections, were excluded. The target recruitment included at least 8 probands with familial and 8 with sporadic NS‐TADs. Participants were identified through the surgical database of the Glenfield Hospital (Leicester, United Kingdom) between January 2016 and December 2018 and subsequently were approached initially by mail and then by telephone consultation. Up to 8 FDRs and SDRs for each identified proband were enrolled. All participants were screened by a complete clinical evaluation (clinical history and examination), genetic tests, and imaging (transthoracic echocardiography [TTE] and magnetic resonance imaging [MRI]) for the presence of NS‐TADs.

The present study was approved by the Health Research Authority (HRA; East Midlands—Derby n. 18.EM.0287—IRAS 247434), and complies with the Consolidated Standards of Reporting Trials (CONSORT) Statement (Figure 1).

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.

Clinical Assessment, Familial and Genetic Counseling

At the first study visit, after informed consent, all recruited participants underwent a detailed clinical evaluation, including cardiological, ophthalmological, and orthopedic assessments (when needed) to identify any syndromic features. Questionnaires assessing participants’ perception and comprehension of each part of the study, health‐related self‐assessed Quality of Life questionnaire, a Patient Health Questionnaire, and a Generalized Anxiety Disorder Assessment form were completed and assessed at baseline and at 3 months. Genetic counseling was offered to all participants before the recruitment, to discuss possible outcomes including variants of uncertain significance (VUSs) and incidental findings (eg, a section of the genetic code missing that includes another important gene as well) with a wider impact for the patient or family as well as implications for health insurance. Any genetic variants of uncertain significance were discussed by a multidisciplinary team, including 2 clinical geneticists, a cardiac surgeon, and a bioinformatician. Following this discussion, participants with VUSs that warranted further phenotyping were seen in an outpatient clinic along with their relatives, where results were communicated and contextualized by a clinical geneticist.

Imaging Tests

TTE was performed by a trained sonographer. Aortic diameter was measured from the parasternal long‐axis view at the level of aortic annulus, sinuses of Valsalva, widest level of the ascending aorta, aortic arch, and descending aorta. , Aortic index and Z score were calculated according to the published standards. , , MRI of the thoracic aorta on a 3T research scanner was performed in all relatives able to attend the local hospital facility. All images used retrospective ECG gating unless arrhythmias were present in which case prospective gating was used. To decrease the breath‐hold duration for the patient, parallel imaging was used in all acquisitions. In patients with poor breath‐holding, spatial resolution was decreased and free breathing allowed (increasing the averages to 3 for cine imaging). The internal diameters of the ascending and descending aorta were measured at the level of the pulmonary bifurcation, and aortic distensibility analysis was performed as per previous recommendations. ,

The adopted aortic values of references to define aortic dilatation are reported in the Tables S1 through S3.

Genetic Testing

A peripheral venous blood sample was obtained and stored at −80 °C for batch preparations of DNA suitable for genetic analysis. Samples from participants were processed internally, via a fully automated pipeline (QIAGEN QIAsymphony, Hilden, Germany), and externally subjected to whole‐exome sequencing, on DNBseq platform (BGI Hong Kong Tech Solution NGS Lab, Hong Kong), where a high‐throughput sequencing was performed for each captured library independently, to ensure that each sample would meet the desired average fold‐coverage (x100). The bioinformatic workflow consisted of alignment, variant calling, and quality check through bwa, GATK4, and Haplotype Caller, respectively. Variants were annotated with snpEff (only high and moderate impact), dbNSFP, and ClinVar. , , Variants were evaluated in line with the American College of Medical Genetics and Genomics guidelines for variant interpretation, the Association for Clinical Genomic Science Best Practice Guidelines for variant classification in rare disease, and the FBN1 Specific Variant Interpretation Guidelines from 2018. Cascade sequencing was performed only when a VUS was detected in a proband.

Statistical Analysis

Continuous data are reported as mean±SD or median (range), and categorical data as number and/or percentage. Wilcoxon rank sum test, Kruskal‐Wallis test, and unpaired t test were adopted for comparisons, as appropriate. Correlations between patient characteristics and aortic dilatation rate were assessed by Spearman’s method. All statistical tests were 2 sided and a P<0.05 is described as statistically significant. Statistical analyses were performed using the ggplot2, dplyr, and desctools packages of R software (version 4.0; R Foundation for Statistical Computing, Vienna, Austria). , , ,

Results

Participants and Characteristics

A total of 276 probands operated on for TAD were identified (Figure 1), and 99 were eligible for the study criteria and approached by mail (Figure 1).

Thirty‐four probands indicated a willingness to participate in the screening project (34% uptake), identifying 102 relatives who were approached by mail. However, 18 families were excluded because there were fewer than 2 eligible relatives available to be enrolled. Therefore, the final patient population included 16 probands (8 sporadic, 8 familial) and 54 relatives (41 FDRs and 13 SDRs). Of these, 70 underwent clinical examination, 68 (97%) blood sample collection for genetic testing, 54 (100% of the relatives) underwent echocardiography, 43 (80% of the relatives) underwent MRI screening, and 41 (59%) completed the psychological assessment (Figure 1).

The screened population had a median age of 49 years (range: 18 to 85 years), and 59% were women. Baseline characteristics are detailed in Table 1. As part of the physical examination, every participant underwent a series of tests to calculate the Beighton score for joint hypermobility with a mean of (0.98 ± 1.72). The prevalence of possible syndromic features detected during the clinical assessment are reported in Figure S1.

Table 1

Study Population Characteristics With Results From Physical Examination of Participants

	Familial		Sporadic		Participants
Variables*	Probands N=8	Relatives N=28	Probands N=8	Relatives N=26	Total N=70
Age, y	68.5 (51–74)	39.0 (18–85)	67.5 (41–84)	46.5 (20–77)	48.5 (18–85)
Sex	5 women; 3 men	22 women; 6 men	1 woman; 7 men	13 women; 13 men	41 women; 29 men
Height, cm	168.0 (160–177)	168.5 (156–184)	171.5 (155–183)	173.0 (157–204)	170 (155–204)
Weight, kg	70.3 (57–177)	63.8 (51–105)	83.6 (65–119)	80.0 (53–150)	71.5 (51.0–150.0)
Body mass index, kg/m2	25.3 (22.3–33.2)	22.8 (19.9–33.0)	29.9 (21.7–38.4)	25.9 (21.0–44.3)	24.8 (19.9–44.3)
Body surface area, m2	1.8 (1.6–2.2)	1.7 (1.5–2.2)	1.9 (1.7–2.3)	2.0 (1.5–2.7)	1.8 (1.5–2.7)
Systolic blood pressure, mm Hg	160.5 (124–202)	132.5 (96–177)	145 (109–172)	123.5 (96–171)	130.0 (96–202)
Diastolic blood pressure, mm Hg	98.5 (80–119)	87.0 (64–105)	93 (72–100)	83.0 (58–116)	86.0 (58–119)
Antihypertensive medications	8 (100%)	2 (7%)	8 (100%)	6 (23%)	24 (34%)
Beta blockers	5 (63%)	0 (0%)	4 (50%)	1 (4%)	10 (14%)
Angiotensin‐converting enzyme inhibitor/angiotensin receptor blocker	5 (63%)	2 (7%)	5 (63%)	3 (12%)	15 (21%)
Myocardial infarction	1 (13%)	0 (0%)	1 (13%)	1 (4%)	3 (4%)
Diabetes	0 (0%)	0 (0%)	0 (0%)	0 (0%)	0 (0%)
Cerebrovascular accident or transient ischemic attack	1 (13%)	0 (0%)	2 (25%)	0 (0%)	3 (4%)
Smoking	0 smokers 4 ex‐smokers	2 smokers 4 ex‐smokers	0 smokers 6 (ex‐smokers)	2 smokers 4 ex‐smokers	4 smokers 18 ex‐smokers
Chronic obstructive pulmonary disease	0 (0%)	1 (4%)	2 (25%)	4 (15%)	7 (10%)
Impaired mobility	0 (0%)	0 (0%)	1 (13%)	0 (0%)	1 (1%)
Renal disease	0 (0%)	0 (0%)	1 (13%)	1 (4%)	2 (3%)
Peripheral vascular disease	1 (13%)	0 (0%)	0 (0%)	0 (0%)	1 (1%)

Data expressed as median (range) and percentage or count.

Imaging

The data obtained from imaging evaluations are summarized in Tables 2 and 3. Among all 54 relatives subjected to TTE, 10 (19%) were diagnosed with an aortic dilatation. Five (18%) out of 28 relatives were in the familial group, and 5 (19%) out of 26 in the sporadic ones. In the familial group, the aortic dilatation was detected in 3 (17%) FDRs and 2 (20%) SDRs, respectively. In the sporadic group, aortic dilatation was observed in 4 (21%) FDRs and 1 (14%) SDRs, respectively.

Table 2

Imaging Features From First‐ and Second‐Degree Relatives Involved in the Study

Imaging test	Measure*	All	Familial	Sporadic
Echocardiogram	End systolic diameter, mm	31.4 (5.4)	31.8 (4.5)	31.1 (6.3)
	End diastolic diameter, mm	46.2 (5.2)	45.4 (4.8)	47.1 (5.6)
	Septum thickness, mm	9.6 (2.0)	9.2 (2.3)	10.1 (1.7)
	Left ventricular ejection fraction, %	60.5 (5.8)	59.8 (3.3)	61.4 (7.6)
	E/A ratio	1.2 (0.4)	1.2 (0.4)	1.2 (0.3)
	Annulus, mm	22.7 (3.1)	21 (2.7)	24.3 (2.8)
	SOV, mm	30.8 (4.8)	29.4 (5)	32.4 (4.1)
	Ascending aorta, mm	30.8 (5.0)	29.5 (4.6)	32.2 (5.2)
	Distal arch, mm	24.2 (3.9)	23.9 (3.3)	24.5 (4.6)
	Abdominal aorta, mm	17.1 (2.7)	16.7 (2)	17.5 (3.2)
MRI (3‐chambers view)	Annulus, mm	22.0 (2.7)	20.9 (2.1)	23.4 (2.8)
	SOV, mm	32.1 (4.8)	30.5 (5.4)	33.7 (3.6)
	Ascending aorta, mm	28.1 (5.1)	26.8 (5.3)	29.3 (4.5)
MRI (left ventricular outflow tract view)	Annulus, mm	23.8 (3.3)	22.4 (2.2)	25.5 (3.5)
	SOV, mm	32.8 (4.8)	31.7 (4.8)	34.2 (4.5)
	Ascending aorta, mm	28.9 (5.4)	27.6 (5.3)	30.3 (5.1)
MRI (distensibility)	Ascending aorta Distensibility (10−3 mm Hg−1)	5.1 (3.23)	5 (3.2)	5.2 (3.4)
	Descending aorta Distensibility (10−3 mm Hg−1)	5.3 (2.62)	5 (2.3)	5.6 (2.9)

MRI indicates magnetic resonance imaging; and SOV, sinuses of Valsalva.

Data are reported as mean (SD).

Table 3

Results from the Imaging and Genetic Tests

Variables	Familial			Sporadic
	FDR N (%)	SDR N (%)	Total N (%)	FDR N (%)	SDR N (%)	Total N (%)
Consented	18	10	28	19	7	26
History of smoking	1 (6%)	1 (10%)	2 (7%)	2 (11%)	0 (0%)	2 (8%)
Hypertension (at clinical assessment)	8 (44%)	5 (50%)	13 (46%)	6 (32%)	2 (29%)	8 (31%)
Antihypertensive medications	1 (6%)	1 (10%)	2 (7%)	4 (21%)	2 (29%)	6 (23%)
Underwent transthoracic echocardiogram	18 (100%)	10 (100%)	28 (100%)	19 (100%)	7 (100%)	26 (100%)
Aortic dilatation on echo	3 (17%)	2 (20%)	5 (18%)	4 (21%)	1 (14%)	5 (19%)
Underwent MRI	13 (72%)	8 (80%)	21 (75%)	15 (79%)	7 (100%)	22 (85%)
Aortic dilatation on MRI	2 (15%)	2 (25%)	4 (19%)	3 (20%)	1 (14%)	4 (18%)
Abnormal distensibility (MRI)	1 (8%)	0 (0%)	1 (5%)	3 (20%)	1 (14%)	4 (18%)
Genetic analysis finding	4 (22%)	2 (20%)	6 (21%)	2 (11%)	0 (0%)	2 (8%)
Genes affected	NOTCH1, FBN1			FBN1
Disease variant	VUS	VUS	VUS	VUS	VUS	VUS
New positive genotype or phenotype	7 (54%)	4 (40%)	11 (39%)	8 (42%)	1 (14%)	9 (35%)
Imaging surveillance indicated (based on MRI)	2 (11%)	2 (20%)	4 (14%)	3 (20%)	1 (14%)	4 (15%)
Genetic medicine review indicated	4 (22%)	2 (20%)	6 (21%)	2 (11%)	0 (0%)	2 (8%)
Indication for surgery	0 (0%)	0 (0%)	0 (0%)	0 (0%)	0 (0%)	0 (0%)
Secondary prevention indicated	8 (44%)	5 (50%)	13 (54%)	7 (37%)	2 (29%)	9 (35%)
Any surgery, prevention, imaging, or genetic surveillance	12 (67%)	7 (70%)	19 (68%)	12 (63%)	2 (29%)	14 (54%)

FDR indicates first‐degree relative; MRI, magnetic resonance imaging; SDR, second‐degree relative; TTE, transthoracic echocardiography; and VUS, variant of uncertain significance.

Among the 43 (79%) relatives who underwent MRI, 8 (19%) were diagnosed with an aortic dilatation, including 4 (19%) out of 21 in the familial group, and 4 (18%) out of 22 in the sporadic group. In the familial NS‐TAD group, the aortic dilatation was confirmed in 5 (18%) FDRs and 2 (25%) SDRs, respectively. In the sporadic NS‐TAD group, the aortic dilatation was observed in 3 (20%) FDRs and 1 (14%) SDRs. MRI scanning provided additional phenotypic information in 6 screened relatives. MRI sequences allowed distensibility calculations in 38 (88%) scans. Aortic distensibility was abnormal for the ascending segment in 5 out of 38 scans (1/17 (13%)) from the familial group and 4/21 (19%) in the sporadic cohort; in the descending segment, distensibility was abnormal in 3 out of 38 scans (none of 17 participants from the familial cohort and 3/21 (14%) participants in the sporadic cohort). Aortic tortuosity was described in 1 case.

Agreement between MRI and TTE diagnoses was explored in an error matrix (Table S4). Taking the MRI positive results as confirmed cases of aortic dilatation, in our population TTE had 75% sensitivity and 97% specificity.

Overall, imaging tests identified 13 new cases with dilated aortas from all the 54 (24%) tested FDRs and SDRs. Family trees related to the sporadic and familial cohorts are presented in Figures S2 and S3. Figure 2 visually summarizes the imaging findings across all families involved in the study. In the 8 families of probands affected by familial NS‐TAD, 6 (21%) relatives had aortic dilatation, with 4 out of 18 (22%) FDRs and 2 out of 10 (20%) SDRs affected. In the 8 families of probands affected by sporadic NS‐TAD, 7 out of 26 (27%) had aortic dilatation with 6 out of 19 (32%) among FDRs and 1 out of 7 (14%) among SDRs. At least 1 relative in each (familial or sporadic) family was identified as affected by an aortic dilation. However, no participants fulfilled criteria for aortic surgery at the current time.

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.

Sixty‐eight participants (16/16 probands, 52/54 relatives, 34/36 familial, 34/34 sporadic, 35/37 FDR, and 17/17 SDR) underwent blood sample collection for the purpose of genetic testing. Analysis of the data occurred in probands initially. A Sankey chart demonstrating the analysis of the genetic test results is depicted in Figure 3. From the regions within the gene panel 431 variants were identified. Among these, 224 (52%) were nonsynonymous consequences (therefore the redundancy of the genetic code and the flexibility of protein formation would not compensate the mutation), and 207 (48%) were synonymous.

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.

Fifty‐nine (26%) of these variants were predicted to have high or moderate effects using snpEff variant predictor. Variants with this high/moderate impact rating occurred in 22 out of the 32 genes in the National Health Service Genomic Medicine Service aortopathy panel. Three of the 59 had no rsIDs in dbSNP151 database. Twenty‐eight of the 59 variants were considered to be rare (5% frequency based on gnomAD v2.1 exome and UK10K data in dbNSFP4.0 database, with 9 having no frequency data). After exclusion of benign and likely benign variants using ClinVar (pathogenic/likely pathogenic/uncertain significance versus benign/likely benign), a total of 14 variants were identified for interpretation according to the American College of Medical Genetics and Genomics guidelines (Table S5). Of these, 9 fulfilled the criteria for classification as a VUS and the rest were classified as benign or likely benign.

Figure 4 visually summarizes the findings from the genetic tests conducted in the enrolled families.

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.

Among the 8 families affected by familial NS‐TAD, 2 (25%) out of 8 probands demonstrated a finding of a VUS confirmed by variant interpretation according to the American College of Medical Genetics and Genomics criteria, which required additional phenotyping. , to look for specific features which might alter the classification. Four (100%) out of 4 FDRs and 2 (40%) out of 5 SDRs in these families shared the same variant identified in the proband. The genes involved were NOTCH1 and FBN1. Among the 8 families of probands affected by sporadic NS‐TAD, in 1 (13%) a VUS that required additional phenotyping was identified, with 2 (100%) out of 2 FDRs sharing the same variant as the proband. The gene involved was FBN1.

Clinical phenotyping did not provide support for these variants.

Assessments of Comprehension, Acceptability, Quality of Life, Anxiety, and Depression

There was no difference between baseline and 3‐month follow‐up scores for depression, anxiety, and self‐reported quality of life. Only the perception of general health from the Quality of Life questionnaire was significantly lower at follow‐up (P=0.009) (Table S6). Levels of comprehension and perception were comparable between probands and relatives, with the exception of the answer to “Becoming aware of the purpose of this study caused me uneasiness,” which was reported as true more often in the relative cohort (P=0.047).

Combined Clinical Assessment, Imaging, and Genetic Testing

The results of cascade tests in relatives (along with details related to the probands’ diseases and imaging diagnoses) are reported in Table 3 and Table S7. In the familial NS‐TAD group, 8 (44%) out of 18 FDRs and 5 (50%) out of 10 SDRs had clinical risk factors that required secondary prevention. In detail, 4 (22%) FDRs and 2 (20%) SDRs had either positive imaging tests, requiring ongoing surveillance, or a VUS requiring repeat phenotyping by a clinical geneticist. Overall, 12 (67%) FDR and 7 (70%) SDR required at least 1 subsequent management intervention (surveillance, repeat phenotyping, surgery, and/or secondary prevention).

In the sporadic NS‐TAD group, 7 (37%) FDRs and 2 (29%) SDRs had clinical risk factors that required secondary prevention, whereas 6 (32%) FDRs and 1 (14%) SDR had positive imaging tests, requiring ongoing surveillance. Two (11%) FDRs had a VUS requiring repeat phenotyping and future variant review. No FDRs or SDRs had both abnormal imaging and a VUS. Overall, 12 (63%) FDRs and 2 (29%) SDRs required at least 1 subsequent management intervention (Figure 5).

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.

Discussion

The present study demonstrated the feasibility of cascade screening for relatives of probands affected by nonsyndromic thoracic aortic diseases. Although the uptake was only 34%, the detection of clinical aortopathy rate was significant, with 24% of screened relatives demonstrating a potential phenotype disease on imaging. The cascade testing identified 61% of relatives requiring further management, including surveillance, clinical genetics, surgery, or secondary prevention.

The major strength of the study was the inclusion of comprehensive clinical, imaging, and genetic testing, in an unselected cohort of probands with NS‐TAD and their relatives. To our knowledge this is the first study to have included both sporadic and familial NS‐TAD forms. Participants in the familial group were shorter with lower body mass index and had higher blood pressure readings despite similar levels of treatment for hypertension. Genetic testing did not detect any clinically actionable results (besides the necessity to rephenotype 3 participants to confirm the lack of clinical signs of syndromic conditions) but this is likely to be because of the sample size in the study. The frequency of positive imaging tests was comparable in both familial and sporadic forms, highlighting the potential benefits of routine cascade screening in the often‐overlooked sporadic group.

The study also had low levels of attrition for all of the assessments, allowing comparison of different testing modalities. TTE provided a specificity of 97% and a sensitivity of 75% for aortic dilatation as defined by the MRI gold standard. Abdominal aorta could be visualized by TTE in 85% of the participants, with no abdominal aortic dilatation diagnosed in our cohort. The lower specificity was offset by higher uptake in the TTE group (100% versus 79%, respectively) and the overall numbers of new disease phenotypes identified were the same for both modalities. In addition, false negatives and positives were attributable to diameters close to the limits of normal ranges indicating that diminished diagnostic accuracy may not be clinically important, particularly where repeat scans can be undertaken relatively cheaply compared with MRI. MRI provides useful additional data on distensibility and tortuosity that may have additional prognostic value; however, this requires further validation. Finally, the study demonstrated no effect of cascade screening on participant anxiety and depression levels. A small difference in 1 domain of the Quality of Life questionnaire that did not favor screening will need to be confirmed in an adequately powered study. This finding, were it confirmed on a larger population, might warrant the need for an increased care in communicating the screening rationale (and possibly the results) to specific categories of subjects. This is particularly meaningful given the relatively young age of participants and also has implications for assessments of cost‐effectiveness in any future study.

The major limitation of the study was the small sample size, and there is no certainty that these results would be representative of the findings of a larger study. The present study was restricted to a single center without an established inherited cardiovascular disease service, and therefore uptake rates and detection rates may be higher than in some other centers. Moreover, the approach to cascade screening adopted in the study and the necessity for additional phenotyping of some participants do not reflect the standard management adopted in a clinical context and are mainly due to the research nature of the procedures described. These limitations not withstanding, however, the data suggest that cascade screening is feasible, is safe, and does identify relatives who require ongoing surveillance and secondary prevention.

The study provided useful insights into the potential barriers to the wider introduction of such a program. First, uptake was low, accounting for 34%, possibly attributable to the limited understanding of the familial basis of TAD in people with the disease, but also more broadly, in primary and tertiary care. This suggests that education and overcoming institutional and individual barriers to cascade screening will be important components of any wider initiative. Decision support tools are increasingly used to help people make decisions around genetic testing in particular. Potential participants were also approached by mail, sometimes several years after the index admission of the proband. Uptake may be higher in the acute setting, as recommended by a recent Delphi exercise. Second, in those probands who expressed an interest in the study, the uptake of cascade screening in their FDR and SDR was high, accounting for 54% of participants. This may reflect the desire of people at risk to know more about their likelihoods of developing the disease. As a matter of fact, cascade screening was identified as top research priority for aortic dissection survivors and their families in a recent survey (Aortic Dissection Awareness UK, personal communication). Third, the study identified participants with disease phenotypes and no detected genetic abnormality. This points toward a potential unmet need for further research into the interaction between genetic and environmental factors in the natural history of the condition. Finally, and accepting the limited power of the study sample size, the data constitute a potential argument in favor of imaging tests in FDRs and SDRs of both sporadic and familial groups. In contemporary clinical practice in the United Kingdom and United States, genetic and imaging testing are typically restricted to FDRs of familial cases in the first instance. , ,

Other larger studies in sporadic disease have reached similar conclusions. Our work suggests that a clinical geneticist review should be sought where imaging results point toward a family history of the disease, to undertake phenotyping and aid variant interpretation. A final comment is that given the age of the participants and their comorbidities, only 1 out of the 3 probands who needed rephenotyping would have undergone testing according to the latest revision of the criteria of the National Genomic Test Directory.

Conclusions

In conclusion, NS‐TADs are conditions with an often‐unrecognized genetic etiology. Cascade testing could return positive results in up to 1 out of 4 relatives, even in families with a first case of aortic dissection. A tailored, focused screening program could potentially be helpful in optimizing surveillance, medical management, and prophylactic surgical intervention when required, by combining a careful review of a potential familial component with an imaging assessment that should be extended to SDRs.

Sources of Funding

The present work was supported via the Van Geest Development Fund (years 2017–2018) from the University of Leicester (United Kingdom). Research echocardiograms were provided by the National Institute for Health Research Leicester Biomedical Research Centre, along with the support for appointing a Clinical Research Fellow (R.A.) following the project. This work was also supported by the British Heart Foundation [CH/12/1/29419 and AA18/3/34220 to GJM].

Disclosures

None.

Data S1–S4

Table S1–S7

Figure S1–S3

Click here for additional data file.