Analysis of Genetic Contribution to Thoracic Aortic Aneurysm or Dissection in a Prospective Cohort of Familial and Sporadic Cases in East China

doi:10.21203/rs.3.rs-1548216/v1

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Research Article

Analysis of Genetic Contribution to Thoracic Aortic Aneurysm or Dissection in a Prospective Cohort of Familial and Sporadic Cases in East China

https://doi.org/10.21203/rs.3.rs-1548216/v1

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Background. Thoracic aortic aneurysm or dissection (TAAD) is a group of life-threatening diseases. Genetic etiology lead to some special characteristics on age of onset, clinical phenotype, and timing of intervention. Herein, we initiated a prospective trial to determine the prevalence of pathogenic variants in TAAD patients and to elucidate the traits related to harboring pathogenic variants. One hundred and one unrelated TAAD patients were sequenced and analyzed for 23 TAAD associated genes using a targeted PCR and next generation sequencing-based panel.

Results. A total of 47 variants were identified in 52 TAAD patients (51.5%) including 6 pathogenic, 1 likely pathogenic and 40 variants of uncertain significance. The pathogenic or likely pathogenic (P/LP) variants in 4 disease-causing genes were carried by 1 familial and 6 sporadic cases (6.9%). Besides one familial TAAD, the FBN1 gene also harbored more than half of the P/LP variants in sporadic ones. The individuals with the age of onset less than 50 years and normotension massively increased the genetic risk.

Conclusions. The TAAD cases with younger age at diagnosis and normotension were more likely to carry a P/LP variant, thus routine genetic testing will be beneficial to better prognosis through a genetically personalized care prior to acute rupture or dissection.

Thoracic Aortic Aneurysm or dissection

High-Throughput DNA Sequencing

TAAD Genetics

Sporadic TAAD

Thoracic aortic diseases that progress to dissection or rupture manifest a clinical disastrous course with an unacceptable high morbidity and mortality [1]. Approximately 21% of patients presenting with aortic dissection die suddenly before seeking medical care [2], and 51% pass away in the transferred facility or en route [3]. Acute surgery is the unique option of the in-hospital patients with type A aortic dissection; however, its overall mortality rate ranges from 8–24% [4]. Compared to acute treatment, the repair of intact thoracic aorta has less than 3% perioperative mortality rate and over 85% 5-year survival rate [5] [6]. Therefore, the diagnosis and treatment prior to acute rupture or dissection are likely to better clinical outcomes.

Currently, the American and European guidelines recommend that the threshold for considering surgical intervention is given by thoracic ascending aortic diameter 5.5cm [7, 8]. However, acute aortic events occur in more than half of patients who do not meet the criteria for prophylactic surgery as widely reported [9] [10]. In response to this, the lower bound less than 5.0cm were given to the timing of surgery for syndrome disorders such as Marfan (MFS), Loeys-Dietz (LDS) and Ehlers-Danlos (EDS) [11]. Meanwhile, some non-syndromic familial thoracic aortic aneurysm and dissection (ns-FTAAD) with manifestations restricted to the aorta are also known as high risk of dissection at diameters less than 5.0cm [12, 13]. Therefore, genetic indicators might be required to decide the optimal timing for surgical repair to avoid acute aortic events.

The genetic studies over the past two decades identified that both ns-FTAAD and syndromic thoracic aortic aneurysm or dissection (s-TAAD) is predominately single-gene hereditary in an autosomal dominant fashion [12]. Syndromic TAAD are caused by the pathogenic variants in those genes associated with the dysfunction of extracellular matrix and TGF-β signaling; Marfan syndrome (FBN1), Loeys-Dietz syndrome (TGFBR1, TGFBR2, SMAD3, TGFB2), Ehlers-Danlos syndrome (COL1A1, COL1A2, COL3A1, COL5A1 and COL5A2), arterial tortuosity syndrome (SLC2A10), Shprintzen-Goldberg syndrome (SKI) and cutis laxa (EFEMP2, ELN) [12]. In comparison, the majority of ns-FTAAD arise from pathogenic variants in genes with the functionality of artery; Five causative genes were identified in TAAD families; ACTA2, MYH11, MYLK and PRKG1 encode components of the contractile apparatus in vascular smooth muscle cell, and LOX encodes an extracellular matrix cross-linking enzyme [14–17]. Besides, some ns-FTAAD families can be explained by the variants in the s-TAAD causative genes such as FBN1, TGFBR1, TGFBR2, SMAD3, and TGFB2 etc [11]. The genetic testing of those genes can thus contribute to making a definitive diagnosis, further to decide the timing of prophylactic surgery, and finally to optimize clinical management.

Herein, we analyzed 23 known causative genes of TAAD in a cohort of 101 cases from East China using the multiplex PCR targeted amplicon enrichment and deep-coverage massively parallel DNA sequencing, providing insight into the prevalence and clinical characteristics of causative gene carriers.

Characteristics of patients

The study enrolled 101 consecutive patients presented with thoracic aortic diseases including 7 thoracic aortic aneurysms (6.8%) and 94 acute aortic syndromes (AAS; 93.1%); the AAS patients consisted of 89 aortic dissections, 2 intramural haematoma and 3 penetrating aortic ulcer (Table 1). About 63.7% patients with thoracic aortic dissection (TAD) had concurrent thoracic aortic aneurysm (TAA). According to Stanford classification, 60 out of 89 cases involve the ascending aorta (type A), and the remaining does the descending aorta (type B). Risk factors of TAAD were investigated including sex, blood pressure and family history et al (Table 1). Male composed 81.2% (82) of the cohort. Seventy-three patients (72.3%) had hypertension; 78.6% of them were male. Only one case had a positive family history of aortic disease, bicuspid valve and coronary artery disease, respectively.

Table 1

Baseline characteristics of the cohort (n = 101).
Clinical Characteristics of the cohort	Mean ± SD or No.(%) patients
Age (years)	57 ± 14 [13–80]
< 50 years at TAAD onset	29(28.7)
> 50 years at TAAD onset	72(71.3)
Gender
Male	82(81.2)
Female	19(18.8)
Thoracic Aortic disease
Aortic aneurysm	7(6.9)
Acutic Aortic syndrome	94(93.1)
Aortic dissection	91(88.1)
Stanford Type A	60(59.4)
Stanford Type B	29(28.7)
Aortic dissection and aneurysm	58(57.4)
Intramural haematoma	2(2.0)
Penetrating aortic ulcer	3(3.0)
Suspected Syndrome	2(0.2)
Aortic doctus diameter	40.3(7.7)
Z score ≥ 2	46(45.5)
-2 < Z score < 2	49(48.5)
Z score≤-2	2(0.02)
Risk Factors and Comorbidities:
Proven Positive Family history of Aortic Disease	1(0.1)
Marfan syndrome	2(0.2)
Hypertension	73(72.3)
Smoke history	32(31.7)
Hyperlipidaemia	49(48.5)
Diabetes	51(49.5)
Bicuspid valve	1(0.1)
Coronary Artery Disease	1(0.1)
Hypothyroidism	0(0.0)
Gastroesophageal Reflux Disease	0(0.0)
Chronic Obstructive Pulmonary Disease	0(0.0)

Variants identified by IMPATT assay

The study uncovered that 79 out of 101 patients (78.2%) carried the non-synonymous variants (Table 2). Fifty-six (55.4%) harbored the ones with MAF thresholds less than 0.1% in either worldwide super-populations or East/South Asian population. Of them, 6 patients carried more than 1 variant and 17 patients shared 4 variants(Additional file 3 and 4). Thus, the total number of analyzed variants in the whole cohort was 69 including 6 pathogenic variants, 1 likely pathogenic variants and 62 variant of uncertain significance(VUS) (Table 3). Fifteen of 23 targeted genes harbored alternations; of which, the largest number of VUS and P/LP variants were in the FBN1 gene, and the highest overall proportion of P/LP variants for each gene were also in the FBN1 gene (22.2%) (Fig. 1A).

Table 2

Summary of the variants harboring by the TAAD patients.
Variable	No. Patients	Percentage
Negative for non-synonymous variants	22	21.8%
Positive for non-synonymous variants	79	78.2%
Number of mutations/variants identified in total:
Variant related to genetic code
Missense(no. of variants)	71
Frameshift(no. of variants)	2
Nonsense(no. of variants)	2
Variant related to polymorphism type
SNP(no. of variants)	71
Insertion(no. of variants)	1
Deletion(no. of variants)	5
Note: The no. is the abbreviation of Number and TAAD is the one of thoracic aortic aneurysm and dissection.

Table 3

Summary of patients with the variants.
101 individuals with
Mutation/variants identified with MAF > 0.1%	23
Mutation/variants identified with MAF < 0.1%	56
Pathogenic	6
FBN1	3
MYH11	1
MYLK	1
SMAD3	1
Likely pathogenic	1
FBN1	1
Uncertain significance	49
ACTA2	2
COL1A1	2
COL1A2	1
COL5A1	5
COL5A2	1
ELN	2
FBN1	14
FBN2	3
MYH11	7
MYLK	8
NOTCH1	5
SKI	3
SLC1A10	2
SMAD3	6
TGFBR1	3

Table 4

Pathogenic and likely pathogenic variants identified by the IMPATT assay.
No.	Age,Sex	Gene Affected	Variant(DNA Sequence)	Variant (Protein level)	Functional Category	Aortic Pathology	Clinical diagnosis	Classification	Previously reported?	Family History
TAAD_6	13,M	FBN1	c.114delA	p.Ala39fs	frameshift	Aortic root aneurysm	Marfan	Pathologic	No	No
TAAD_61	57,F	FBN1	c.273T > A	p.Asp91Glu	missense	Type A aortic dissection	N/A	Likely Pathologic	No	No
TAAD_81	20,M	FBN1	c.1285C > T	p.Arg429*	stop gained	Aortic root aneurysm	Marfan	Pathologic	No	Yes
TAAD_89	50,M	MYLK	c.2736delG	p.Lys913fs	frameshift	Ascending aortic aneurysm	N/A	Pathologic	No	No
TAAD_90	47,M	SMAD3	c.139C > T	p.Gln47*	stop gained	Ascending aortic aneurysm	N/A	Pathologic	No	No
TAAD_98	33,M	MYH11	c.3787_3789delAAG	p.Lys1263del	deletion	Type A aortic dissection	N/A	Pathologic	No	No
TAAD_102	30,M	FBN1	c.7988G > C	p.Cys2663Ser	missense	Type A aortic dissection	Marfan	Pathologic	No	No

Seven variants were considered to be P/LP: 4 variants in the FBN1 gene; and 1 in each of MYH11, MYLK, and SMAD3 genes. Excepted for two in FBN1, the P/LP variants were not associated with syndromic phenotype. Four VUS were repeatedly identified in TAAD patients: FBN1 c.1217T > A (p. Leu406His) in 8 patients (6 Type A, 2 Type B), SMAD3 c.1180T > A (p. Cys394Ser) in 4 (Type A), MYH11 c. 1729A > C (p. Lys577Gln) in 3 (Type A), and SKI c.2189C > T (p. Pro730Leu) in 2 (1 Type A, 1 Type B) (Additional file 3); these was in sharp contrast that those variant never existed in healthy Chinese [35]. According to protein function prediction from Provean, SIFT, PolyPhen2 and MutationTaster, all variants had a deleterious effect on protein function except for FBN1 c.1217T > A (p.Leu406His). In spite of this, FBN1 c.1217T > A might be associated with TAAD if considering its median age at diagnosis of 48.5 years significantly less than 57 in no variation (NV) group (P = 0.0273).

Genotype-phenotype correlation with P/LP variants

To determine which TAAD patients could benefit from genetic testing, we took the clinical characteristics of the P/LP carriers into consideration. As for age at diagnosis, younger patients would be more likely to identify a deleterious variant. The median age at diagnosis was 33 years for P/LP carriers, which were less than 57 years for VUS carriers (P = 0.0013) and 57 for NV group (P = 0.0014) (Fig. 1B). The patients under the age of 50 were more likely to find a P/LP alteration (6 of 32) than those over 50 years (1 of 69) (P = 0.0045) (Fig. 1C). But no significant difference was found at the percentage of P/LP variants between the sexes.

Except for age-of-onset, three cardiovascular risk factors also were analyzed the possibility of identifying a P/PL alteration among TAAD patients. Genetics contributed to a much larger percentage of those normotensive cases (6 of 22) than ones with hypertension (1 of 77) (P = 0.0004). However, the probability of detecting deleterious mutations was not likely to link with whether blood lipid and blood glucose are normal or not. Besides, several traits of aortic pathology were considered including aortic doctus diameter, the presence of aneurysm, and dissection location. We did not found that the likelihood of carrying a P/LP variant was associated with Z scores of aortic doctus diameter more than 2, presence of aneurysm and Stanford Type A. Overall, our results suggested the execution of genetic testing in TAAD patients who met either of two conditions: age-of-onset less than 50 years and no hypertension.

The present study reported on the results of a one-year prospective trial aimed to determine the prevalence of genetic abnormalities in thoracic aortic disease according to the data of consecutively enrolled 101 unrelated patients from department of cardiovascular surgery. Since the cost was free, all patients in whom IMPATT assay was recommended were able to have the test done, and subsequently defines 5.9% as the total frequency of P/LP variants among 23 known TAAD genes. This frequency is similar to 3.9% and 4.9% reported previously, respectively, in a whole exome sequencing for 102 TAAD patients [36] and in a large cohort study of 1025 TAAD cases [34]. Even we met the most stringent criteria of the ClinGen framework only including 9 definitive causes[37], the percentage of P/LP variants was still close to the above two studies [34, 36]. A mixed cohort of sporadic and familial cases in South China had been previously reported with the total frequency of deleterious mutations (22.5%, 34/151) [38], of which was far greater than the prevalence of P/LP variants in our and two other studies as above described [34] [36]. However, if considering that the deleterious mutations being identified from 129 candidate genes with little evidence reported for disease-causing TAAD in the majority of genes, the total frequency could remain enormously overvalued in South China [37]. Besides, we repeatedly identified some VUS in TAAD patients but never found in local healthy people, indicating the importance of the genetic aspects in thoracic aortic disease.

The FBN1 gene was the most contributor to TAAD cases harboring 4 out of 7 P/LP variants. Three carriers with a P/LP variant in FBN1 met the clinical criteria for MFS diagnosis by the 2010 revised Ghent nosology criteria [18], of which two displayed typical MFS involving multiple organ systems and the other one manifested isolated strictly to ascending aorta with dilatation of the aortic root. Noteworthy, one of two typical MFS carried a spontaneous mutation that were not present in his parents and four siblings [39]. In contrast, the final one carrier did not even have a dilatation of the aortic root. Consistent with our observation, FBN1 pathogenic mutations have been proven to link with a wide range of phenotypic variabilities from single organ involvement to multiorgan dysfunction syndrome; the dysfunction of FBN1 is a common pathogenesis of aortic disease in MFS, FTAAD and sporadic TAAD[40] [41] [42]. The type and location of pathogenic FBN1 variants affected TAAD progress [41], consequently giving some insight into prognostic stratification of TAAD cases based on the variants. Moreover, it is very likely that a variation in FBN1 arises spontaneously, sometimes performs not full penetrance and involves different organ among the same variant carriers [39] [43], indicating a big complication on tracking a family history.

As an important risk factor of TAAD [44], genetic disorders involving the connective tissue was in the requisition of genetic testing to identify inborn error. To study the clinical features of high-risk individuals harboring a mutation prone to dissect would be beneficial to improve the efficiency. Two risks were statistically significant to link with the genetic disorders including the age at diagnosis less than 50 years and no hypertension (Table 5). The median age of onset of P/LP carriers was much lower than the rest of the cohort, consistent with an observation in a large cohort [34]. Compared with the age at diagnosis in familial (56.8 years) and sporadic (64.3 years) cases, lower age of onset within P/LP carriers again proved that genetic defects accelerated TAAD progression[34]. Correspondingly, genetic defects were 12.9 times (95% CI: 1.6242-103.0541, P = 0.0156) more likely to be in the patients before the age of 50 years old than those after 50 years old in this study.

Table 5

Relative risk of carrying a P/LP variant according to diverse phenotype
	Total	P/LP (percentage)	RR (95% CI)	P-value
Age-of-onset, < 50	32	6 (18.8)	12.9375 (1.6242-103.0541)	0.0156
Female	19	1 (5.3)	0.7193 (0.0919–5.6288)	0.7536
Normotension	22	6 (27.3)	21.0000 (2.6676–165.3160)	0.0038
Normolipidemia	30	2 (6.7)	7.5758 (0.3755-152.8386)	0.1865
Normoglycemia	36	2 (5.6)	2.8333 (0.2669–30.0762)	0.1256
Z scores of aortic doctus diameter, >2	46	5 (10.9)	5.5435 (0.6722–45.7129)	0.1116
presence of aortic aneurysm	66	5 (7.6)	1.3258 (0.2709–6.4870)	0.7278
Stanford Type A	60	3(5.0)	0.7750 (0.1366–4.3974)	0.7750

Hypertension was strongly associated with incident thoracic aortic dissection [44]. The wall tension of aorta was directly proportional to blood pressure, thus explaining why hypertension is a major risk factor for TAAD [45]. Hypertension accelerated the usual histopathologic changes in aorta associated with TAAD [7]. When TAAD patients’ aorta was on the normal circumferential stress, our study showed that the possibility of vascular inborn error was over 21.0 times (2.668-165.316, P = 0.0038) higher than those with hypertension.

Although linking aortic root enlargement to aortic dissection seems straightforward, we found no significant association between variant categories and three aortic traits including Z scores of aortic doctus diameter, presence of aneurysm, and dissection location. It has been proven that some pathogenic variants, such as MYLK [46], were not always preceded by obvious aortic dilatation. Moreover, arterial hypertension, as a predisposing condition for the development of thoracic aorta aneurysms, further make the association more complex [7].

Our study is subject to a number of limitation. First, the number of P/LP variants might be underestimated if taken stringent criteria on variant classification in the guidelines of the American College of Medical Genetics and Genomics (ACMG) into consideration. Several VUS variants carried by more than 1 patient in this study were never present in population databases, and a part of them were classified as VUS associated with ns-FTAAD in previously reports. Although extremely rare variants in causative gene are often disease related, however, diagnostic uncertainty was apparent solely based on the genetic technology itself indicating the need for high-throughput functional assay so as to systematically classify genetic alterations [47] [48]. Moreover, our IMPATT assay specially analyzed the coding sequences and intron/exon boundaries of the 23 TAAD genes (Additional file 1), but neglected non-coding variants in spite of their known small effects on disease; subsequently, genome-wide sequencing could enrich understanding TAAD-related genetic factor. Furthermore, we were unable to track the cause of death for these deceased parents of the patients due to limited local medical resources before 2000, not to mention family history of aortic disease. Further studies will aim to correlate VUS carriers’ attention to family history based on future follow-up.

The study identified that the frequency of genetic cause was 5.9% among 101 TAAD cases in the prospective cohort. The positive carriers were non-syndromic manifestations of TAAD except for two typical MFS. Two clinical features, age under 50 years at diagnosis and no hypertension, were found to increase the likelihood of harboring P/LP variants. If taken the potential for spontaneous mutation and unknown family history into consideration, the highly positive rate of a P/LP variant among the special individuals suggested that the routine genetic screening still was worth to be recommended.

Ethical compliance

All procedures performed in this study involving human participants were in accordance with the Declaration of Helsinki (as revised in 2013).

Patient profile

The patients who were diagnosed with TAAD by cardiovascular surgeons at Heart Medical Centre of First Affiliated Hospital of Gannan Medical University, Jiangxi, China, between August 2020 and August 2021 were included in this study (clinical trial registration no. ChiCTR2000034841 [clinicaltrials.gov]). The patient was included if he had TAAD aged less than 80 years, and was excluded when one of the following exists: pseudo-aneurysm, heart surgery history, bone marrow transplantation, exogenous transfusion in the past six months, and pregnancy. All participants were collected peripheral blood samples before surgery. MFS diagnoses were made according to the 2010 revised Ghent nosology criteria [18].

Targeted Exon Sequencing

The alterations in the known TAAD-associated genes were profiled using our IMPATT assay (Integrated Mutation Profiling of Actionable TAAD Targets), which utilizes the multiplex PCR targeted amplicon enrichment and deep-coverage massively parallel DNA sequencing. The coordinates of 23 targeted genes in Table S1 were determined using the human reference genome (NCBI GRCh37) [19]. Custom primers for the multiplexed PCR approach were designed to enrich 754 amplicon covering all protein-coding exons plus 15bp adjacent intron padding of the targeted genes using Illumina’s DesignStudio Sequencing Assay Designer. The total targeted DNA length was 80.86kb. The average amplicon length was 123bp with 48% GC content. The library was prepared using two primer pools for multiplex PCR, were indexed using index adapters, further amplified, and combined in preparation for PE150 sequencing in HiSeq XTen platform as described in the manufacture’s AmpliSeq for Illumina workflow (Illumina, San Diego, CA).

Read Mapping, Variant Calling & Annotation

The sequencing read quality was assessed using FASTQC. Primer sequences were trimmed from FASTQ files using cutPrimers [20] prior to read mapping to the human GRCh37/hg reference sequence using the Burrows-Wheeler Aligner V0.5.17 [21]. After removal of potential PCR duplicates (Picard, http://picard.sourceforge.net) and realignment (GATK)[22], mutations were called and filtered using SAMtools[23], GATK3.7[22], Pindel[24], BreakDancer[25] and CNVnator[26]. All variants were annotated according to the control population of the 1000 Genomes Project (2014 October release)[27], ExAC r0.3.1[28], EVS(https://evs.gs.washington.edu/EVS/), the disease databases of ClinVar[29], and OMIM[30].

Variant and Sample Filtering

Synonymous variants and intronic variants outside splice sites were not considered for downstream analysis only when they were annotated as pathogenic or disease-causing in ClinVar[29] or HMGD[31]. Variants with minor allele frequency (MAF) thresholds more than 0.1% in either worldwide super-populations or East/South Asian population of ExAC r0.3.1[28] datasets were excluded. Samples with less than 80% of target bases covered by more than 60 reads were precluded from downstream analysis.

Pathogenicity Assignment

Variants passing filters were assigned to one of four categories: either ‘pathogenic’, ‘likely pathogenic’, ‘VUS’ or ‘likely benign’ based on ACMG[32].

In particular, a variant was considered as a pathogenic mutation if it had (I) is already reported as disease causing in HGMD or pathogenic in ClinVar, (II) results in the same amino acid substitution as an HGMD disease causing mutation or ClinVar pathogenic variant, (III) was a de novo mutation if nonsense (i.e., had an in-frame and out-of-frame deletion/insertion, the splice site mutations affected the canonical splice sequence, or it was shown to alter splicing on an mRNA level), (IV) was missense and either affecting/creating cysteine residues or affecting conserved residues of the EGF consensus sequence in FBN1 [33], (V) a substitution of a glycine residue within a GlyXY repeat in collagen triple helical domain, (VI) an insertion of amino acids disrupting the GlyXY repeat sequence in collagens, and (VII) alteration of a key residue in a protein feature in keeping with previously ascribed molecular mechanisms for a given gene [34]. The pathogenic/likely pathogenic (P/LP) variants and four VUS were confirmed by Sanger sequencing (Table S2).

Statistical Analysis

The Fisher’s exact test was used for the assessment of categorical variables between different groups. And, non-parametric phenotypic continuous measurements were analysed using the unpaired Wilcoxon rank-sum test. P values less than 0.05 were considered statistically significant (two-sided). All calculations were performed using SPSS 24.0 software.

AAS: acute aortic syndromes

EDS: Ehlers-Danlos Syndrome

ns-FTAAD: non-syndromic familial thoracic aortic aneurysm and dissection

MFS: Marfan Syndrome

LDS: Loeys-Dietz Syndrome

NV: no variation

P/LP: pathogenic or likely pathogenic

s-TAAD: syndromic thoracic aortic aneurysm or dissection

TAA: thoracic aortic aneurysm

TAAD: thoracic aortic aneurysm or dissection

VUS: variant of uncertain significance

Availability of data and materials

The datasets generated during the current study are available from the corresponding author on reasonable request.

Acknowledgements

We gratefully thank all participants for their supports to this research.

Funding

The work was financially supported by the Department of Science and Technology of Jiangxi Province (No. 20213BCJ22001), the National Natural Science Foundation of China (No. 31671288; 81960326), the Science and Technology Project of Jiangxi Health Committee (No. 202130676), and the Innovation Team of Gannan Medical University (No. TD201902).

Contributions

ZL and YD developed the study concept and the design. All patients were interviewed and examined by JX, ZL, YZ, CT, ZD, ZL, JY, WL, and WX. Data and sample collection was conducted by YW, TD, XZ, MP, YQ, XL, TC, PL, KL and YH. YD wrote the manuscript. All authors read and approved the final manuscript.

Ethics declarations

Ethics approval and consent to participate

The study was approved by the ethics committee at the First Affiliated Hospital of Gannan Medical University (No. 201713104150) and informed consent was taken from all the patients.

Consent for publication

All data reported are aggregated and no individual data are reported in the manuscript.

Competing interests

The authors have no conflicts of interest to declare.

Data access

All P/LP variants have been submitted to ClinVar database (SUB10857128). Detailed phenotype and genotype data is available on request.

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Analysis of Genetic Contribution to Thoracic Aortic Aneurysm or Dissection in a Prospective Cohort of Familial and Sporadic Cases in East China

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Version 1

Abstract

Figures

Background

Results

Characteristics of patients

Variants identified by IMPATT assay

Genotype-phenotype correlation with P/LP variants

Discussion

Conclusions

Methods

Ethical compliance

Patient profile

Targeted Exon Sequencing

Read Mapping, Variant Calling & Annotation

Variant and Sample Filtering

Pathogenicity Assignment

Statistical Analysis

Abbreviations

Declarations

References

Supplementary Files

Status:

Version 1