Impact of Pathogenic FBN1 Variant Types on the Progression of Aortic Disease in Patients With Marfan Syndrome
2018; Wolters Kluwer; Volume: 11; Issue: 6 Linguagem: Inglês
10.1161/circgen.117.002058
ISSN2574-8300
AutoresNorifumi Takeda, Ryo Inuzuka, Sonoko Maemura, Hiroyuki Morita, Kan Nawata, Daishi Fujita, Yuki Taniguchi, Haruo Yamauchi, Hiroki Yagi, Masayoshi Kato, Hiroshi Nishimura, Yoichiro Hirata, Yuichi Ikeda, Hidetoshi Kumagai, Eisuke Amiya, Hironori Hara, Takayuki Fujiwara, Hiroshi Akazawa, Junichi Suzuki, Yasushi Imai, Ryozo Nagai, Shinichi Takamoto, Yasunobu Hirata, Minoru Ōno, Issei Komuro,
Tópico(s)Cardiovascular Issues in Pregnancy
ResumoHomeCirculation: Genomic and Precision MedicineVol. 11, No. 6Impact of Pathogenic FBN1 Variant Types on the Progression of Aortic Disease in Patients With Marfan Syndrome Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplementary MaterialsFree AccessResearch ArticlePDF/EPUBImpact of Pathogenic FBN1 Variant Types on the Progression of Aortic Disease in Patients With Marfan Syndrome Norifumi Takeda, MD, PhD, Ryo Inuzuka, MD, PhD, Sonoko Maemura, MD, Hiroyuki Morita, MD, PhD, Kan Nawata, MD, PhD, Daishi Fujita, MD, PhD, Yuki Taniguchi, MD, PhD, Haruo Yamauchi, MD, PhD, Hiroki Yagi, MD, PhD, Masayoshi Kato, MD, PhD, Hiroshi Nishimura, MD, PhD, Yoichiro Hirata, MD, PhD, Yuichi Ikeda, MD, PhD, Hidetoshi Kumagai, MD, PhD, Eisuke Amiya, MD, PhD, Hironori Hara, MD, PhD, Takayuki Fujiwara, MD, Hiroshi Akazawa, MD, PhD, Jun-ichi Suzuki, MD, PhD, Yasushi Imai, MD, PhD, Ryozo Nagai, MD, PhD, Shinichi Takamoto, MD, PhD, Yasunobu Hirata, MD, PhD, Minoru Ono, MD, PhD and Issei Komuro, MD, PhD Norifumi TakedaNorifumi Takeda Department of Cardiovascular Medicine (N.T., S.M., H.M., D.F., H. Yagi, M.K., H.N., Y. Ikeda, H.K., E.A., H.H., T.F., H.A., J.-i.S., I.K.), , Ryo InuzukaRyo Inuzuka Department of Pediatrics (R.I., Y.H.) , Sonoko MaemuraSonoko Maemura Department of Cardiovascular Medicine (N.T., S.M., H.M., D.F., H. Yagi, M.K., H.N., Y. Ikeda, H.K., E.A., H.H., T.F., H.A., J.-i.S., I.K.), , Hiroyuki MoritaHiroyuki Morita Department of Cardiovascular Medicine (N.T., S.M., H.M., D.F., H. Yagi, M.K., H.N., Y. Ikeda, H.K., E.A., H.H., T.F., H.A., J.-i.S., I.K.), , Kan NawataKan Nawata Department of Cardiac Surgery (K.N., H. Yamauchi, M.O.) , Daishi FujitaDaishi Fujita Department of Cardiovascular Medicine (N.T., S.M., H.M., D.F., H. Yagi, M.K., H.N., Y. Ikeda, H.K., E.A., H.H., T.F., H.A., J.-i.S., I.K.), , Yuki TaniguchiYuki Taniguchi Department of Orthopedic Surgery (Y.T.) , Haruo YamauchiHaruo Yamauchi Department of Cardiac Surgery (K.N., H. Yamauchi, M.O.) , Hiroki YagiHiroki Yagi Department of Cardiovascular Medicine (N.T., S.M., H.M., D.F., H. Yagi, M.K., H.N., Y. Ikeda, H.K., E.A., H.H., T.F., H.A., J.-i.S., I.K.), , Masayoshi KatoMasayoshi Kato Department of Cardiovascular Medicine (N.T., S.M., H.M., D.F., H. Yagi, M.K., H.N., Y. Ikeda, H.K., E.A., H.H., T.F., H.A., J.-i.S., I.K.), , Hiroshi NishimuraHiroshi Nishimura Department of Cardiovascular Medicine (N.T., S.M., H.M., D.F., H. Yagi, M.K., H.N., Y. Ikeda, H.K., E.A., H.H., T.F., H.A., J.-i.S., I.K.), , Yoichiro HirataYoichiro Hirata Department of Pediatrics (R.I., Y.H.) , Yuichi IkedaYuichi Ikeda Department of Cardiovascular Medicine (N.T., S.M., H.M., D.F., H. Yagi, M.K., H.N., Y. Ikeda, H.K., E.A., H.H., T.F., H.A., J.-i.S., I.K.), , Hidetoshi KumagaiHidetoshi Kumagai Department of Cardiovascular Medicine (N.T., S.M., H.M., D.F., H. Yagi, M.K., H.N., Y. Ikeda, H.K., E.A., H.H., T.F., H.A., J.-i.S., I.K.), Department of Advanced Clinical Science and Therapeutics (H.K., J.-i.S.) , Eisuke AmiyaEisuke Amiya Department of Cardiovascular Medicine (N.T., S.M., H.M., D.F., H. Yagi, M.K., H.N., Y. Ikeda, H.K., E.A., H.H., T.F., H.A., J.-i.S., I.K.), , Hironori HaraHironori Hara Department of Cardiovascular Medicine (N.T., S.M., H.M., D.F., H. Yagi, M.K., H.N., Y. Ikeda, H.K., E.A., H.H., T.F., H.A., J.-i.S., I.K.), , Takayuki FujiwaraTakayuki Fujiwara Department of Cardiovascular Medicine (N.T., S.M., H.M., D.F., H. Yagi, M.K., H.N., Y. Ikeda, H.K., E.A., H.H., T.F., H.A., J.-i.S., I.K.), , Hiroshi AkazawaHiroshi Akazawa Department of Cardiovascular Medicine (N.T., S.M., H.M., D.F., H. Yagi, M.K., H.N., Y. Ikeda, H.K., E.A., H.H., T.F., H.A., J.-i.S., I.K.), , Jun-ichi SuzukiJun-ichi Suzuki Department of Cardiovascular Medicine (N.T., S.M., H.M., D.F., H. Yagi, M.K., H.N., Y. Ikeda, H.K., E.A., H.H., T.F., H.A., J.-i.S., I.K.), Department of Advanced Clinical Science and Therapeutics (H.K., J.-i.S.) , Yasushi ImaiYasushi Imai The University of Tokyo Hospital, Tokyo, Japan. Division of Clinical Pharmacology, Department of Pharmacology (Y. Imai) Division of Cardiovascular Medicine, Department of Internal Medicine (Y. Imai), , Ryozo NagaiRyozo Nagai Jichi Medical University, Shimotsuke, Tochigi, Japan. Jichi Medical University, Shimotsuke, Tochigi, Japan (R.N.). , Shinichi TakamotoShinichi Takamoto Mitsui Memorial Hospital, Tokyo, Japan (S.T.). , Yasunobu HirataYasunobu Hirata Tokyo Teishin Hospital, Tokyo, Japan (Y.H.). , Minoru OnoMinoru Ono Department of Cardiac Surgery (K.N., H. Yamauchi, M.O.) and Issei KomuroIssei Komuro Department of Cardiovascular Medicine (N.T., S.M., H.M., D.F., H. Yagi, M.K., H.N., Y. Ikeda, H.K., E.A., H.H., T.F., H.A., J.-i.S., I.K.), Originally published30 May 2018https://doi.org/10.1161/CIRCGEN.117.002058Circulation: Genomic and Precision Medicine. 2018;11:e002058AbstractBackground:Marfan syndrome can cause life-threatening aortic complications. We investigated the relationship between FBN1 genotype and severe aortopathy (aortic root replacement, type A dissections, and related death).Methods:We evaluated 248 patients with pathogenic or likely pathogenic FBN1 variants. The variants were classified as haploinsufficient type (HI, n=93) or dominant-negative type (DN, n=155) based on their location and predicted amino acid alterations, and we examined the effects of the FBN1 genotype on severe aortic events (aortic root replacement, type A dissections, and related death).RESULTS:The cumulative event-free probability was significantly lower in the HI group than in the DN group (adjusted hazard ratio, 2.1; 95% confidence interval, 1.4 -3.2; P<0.001). Male patients were at a greater than two-fold increased risk in both genotypes. In addition, after identifying deleterious variants among DN patients, we found that those with variants affecting or creating Cysteine residues and in-frame Deletion variants in exons 25–36 and 43–49 (DN-CD group) had a 6.3-fold higher risk compared with DN-nonCD patients (P<0.0001), which was comparable to or more deleterious than HI patients (P=0.062). Furthermore, DN-CD + HI patients had larger aortic root Z-scores than DN-nonCD patients (P<0.05 for <20 years; P<0.01 for 20–40 years), and males under 20 years old were more likely to develop aneurysms with higher rate of change in Z-score than females (P 70 years. Surgical replacement of the aorta is recommended when the aortic diameter is ≥45 to 50 mm1–3; however, it remains difficult to precisely predict when and how fast their aneurysms grow to a size at which surgery is indicated or rupture occurs. Thus, patients spend their childhood and adolescence under tremendous amounts of anxiety, despite receiving regular outpatient treatment, which includes β-blockers and angiotensin II receptor blockers, such as losartan.Up to 97% of patients with MFS who fulfil the Ghent criteria have pathogenic variants in the FBN1 gene,2 which encodes a major component of the extracellular matrix microfibril, namely fibrillin-1. MFS has been traditionally considered to result from the structural weakness of connective tissue. On the other hand, recent investigations on molecular mechanisms indicate that increased TGF-β (transforming growth factor-β) activity also plays a crucial role in the pathogenesis of MFS; fibrillin-1 can regulate TGF-β bioavailability, and the dysregulation of TGF-β contributes to the major extraocular features of MFS.4 However, details regarding how FBN1 variants and altered TGF-β signaling are genetically and functionally involved in pathogenesis remain to be fully elucidated.More than 3000 pathogenic variants, which are mostly unique among families, have been identified in the FBN1 gene. The penetrance of FBN1 variants for MFS is generally high, but phenotype prediction from variant types of the FBN1 gene has been a challenging task. However, though strong correlations between ectopia lentis and variants affecting or creating cysteine residues have been repeatedly reported in many publications,5 practical guidelines that consider the relationship between genotype and phenotype have yet to be established.Some recent studies have shown that patients with haploinsufficient type (HI) FBN1 variants, such as nonsense and frameshift variants that presumably cause nonsense-mediated mRNA decay, have more severe aortic phenotypes than those with missense variants.5–9 However, further studies are warranted to replicate and extend these findings before introduction into clinical practice. In this study, we examined the effects of the FBN1 genotype on severe aortic events (aortic root replacement, type A dissections, and related death) and the progression of aortic root dilatation in 248 patients with pathogenic FBN1 variants.MethodsThe data, analytic methods, and study materials will not be made available to other researchers for purposes of reproducing the results or replicating the procedures.Study Population and DNA Sequence AnalysisWe performed genetic analysis for FBN1 gene variants (NM_000138.4) using Sanger sequencing in those suspected to have MFS.10 In the present study, we enrolled consecutive patients with pathogenic or likely pathogenic FBN1 variants detected on genetic analysis performed between September 2006 and May 2017. The variants were classified as pathogenic or likely pathogenic based on the American College of Medical Genetics and Genomics−Association for Molecular Pathology classification guideline.11 After excluding 12 patients with insufficient clinical information on the aortic events from 260 patients with pathogenic or likely pathogenic FBN1 variants, 248 patients were studied. This study was approved by the institutional ethics committee (G-1538).2Pathogenic Variant ClassificationThe pathogenic variants were classified under 2 main categories, HI and dominant-negative type (DN), based on their location and predicted amino acid alterations. Variants creating a premature termination codon or presumably abolishing the transcription of the gene were classified under the HI group and included (1) nonsense variants, (2) out-of-frame insertion or deletion variants, (3) out-of-frame exon-skipping variants caused by the splice donor site (eg, intron +1G or +2T) or splice acceptor site (eg, intron −1G or −2A), and (4) initiation codon variants (c.2T>A). Although these pathogenic HI variants are expected to cause haploinsufficiency because of nonsense-mediated mRNA decay in nonsense variants, out-of-frame insertion or deletion variants, and out-of-frame exon-skipping variants caused by the splice donor or splice acceptor site and failure of protein translation in initiation codon variants, these are not molecularly proven. Variants classified under the DN group included (5) missense variants, (6) in-frame insertion or deletion variants, and (7) in-frame exon skipping variants, which are expected to exert DN effects.Clinical DataClinical data were retrospectively collected based on patients' medical records kept at the University of Tokyo Hospital. Major manifestations and positive pertinent findings at the start of their continued hospital follow-up were classified into 1 of the following 11 categories based on their medical reports: (a) family history of MFS, (b) ectopia lentis, (c) tall stature, long limbs, and arachnodactylia, (d) kyphoscoliosis, (e) pectus carinatum and pectus excavatum, (f) pneumothorax, (g) mitral valve prolapse, (h) aortic dissection (type B), (i) aortic dilatation and aortic regurgitation, (j) aortic dissection (type A), and (k) others or unknown.Severe aortic events were defined as occurrence of aortic root replacement, type A dissections and related death, and the event-free survival was calculated by sex using the Kaplan–Meier method. The aortic root diameter was measured at the referring hospital or our institute using transthoracic echocardiography at the level of the sinuses of Valsalva. Comparable echocardiographic data were obtained from the intact aortic root, and the last data for patient with severe aortic events were obtained only when data within 1 year before dissection or immediately before prophylactic aortic root surgery were available. To normalize the aortic root diameter to the patients' age and body size, age- and body surface area–adjusted echocardiographic aortic Z score (<20, 20–40, and ≥40 years of age) was calculated as described previously.12Statistical AnalysesData are presented as median (interquartile range [IQR]), median (95% confidence intervals [CI]), or number of participants (percentage). Comparisons between continuous and ordinal variables were made using the Wilcoxon rank-sum test. Comparisons between paired continuous variables were made using the Wilcoxon matched-pairs signed-rank test. Comparisons between categorical variables were made using the Fisher exact test. The event-free curve of the first aortic complication (aortic dissection, aortic surgery, and related death) was constructed using the Kaplan–Meier method and compared using the log-rank test. Univariate and multivariate Cox proportional hazards regression analyses were used to assess the relation between the FBN1 genotype and aortic events. P values <0.05 were considered statistically significant. We applied the Benjamini and Hochberg false discovery rate method13 to derive corrected P values to address the issue of multiple testing among 3 genetic groups. Statistical analyses were conducted with R, version 3.4.1 (R Foundation).ResultsBaseline CharacteristicsA total of 248 patients (128 men and 120 women; age range, 2–80 years; median age, 31.3 years [IQR, 19.1–42.9]) from 202 Japanese families who had pathogenic or likely pathogenic FBN1 variants were studied (Table I in the Data Supplement). Among 248 patients, 225 (90.7%) patients fulfilled the revised Ghent criteria, whereas the remaining 23 (9.3%) children were enrolled as potential MFS considering their clinical and genetic features. Among these patients, 209 (84.3%) patients fulfilled the revised Ghent criteria without including genetic variant information. To examine the effects of pathogenic FBN1 variant types on the progression of aortic aneurysms and dissections, patients were subcategorized into 2 groups according to the predicted effects on protein structure and function: those carrying HI FBN1 variants and those with loss-of-function variants through a DN mechanism. However, the distinction had not been validated by comparing genomic DNA with complementary DNA from the mRNA of patient tissues (eg, aortic tissues and cultured fibroblasts from skin biopsies).Among the 248 participants, 139 (56.0%) had already been diagnosed with MFS or potential MFS by the referring hospital. Variant types, age at the start of follow-up, and major manifestations or positive pertinent findings for continued hospital follow-up of both groups (DN, n=155 from 122 families; HI, n=93 from 80 families) are summarized in Figure 1. The HI group included slightly more men than women (male percentage, 60.2% versus 46.5% in the HI and DN groups, respectively; P=0.037). Although no significant difference in the median age range was found between the 2 groups (Figure 1B), major manifestations or positive pertinent findings for continued hospital follow-up differed among age groups in both genotype groups (DN, P<0.0001; HI, P<0.001; Figure 1C). Younger patients were often followed up because of ectopia lentis, marfanoid stature, and skeletal disorders, whereas disorders related to aortic events gradually increased with age. The large number of DN patients aged 0 to 6 years were being followed up for MFS, which presumably reflects the high prevalence of ectopia lentis in DN infants (Figure 1B and 1C).Download figureDownload PowerPointFigure 1. Genetic characteristics and clinical information at the start of the continued hospital follow-up.FBN1 genetic types (A) and age distribution at the start of follow-up (B) and the major manifestations or positive pertinent findings at the start of their continued hospital follow-up (C) in the dominant-negative (DN; left) and haploinsufficient type (HI; right) groups: (a) family history of Marfan syndrome, (b) ectopia lentis, (c) tall stature, long limbs, and arachnodactylia, (d) kyphoscoliosis, (e) pectus carinatum and pectus excavatum, (f) pneumothorax, (g) mitral valve prolapse, (h) aortic dissection (type B), (i) aortic dilatation and aortic regurgitation, (j) aortic dissection (type A), and (k) others or unknown.Clinical Characteristics During Follow-UpClinical features and the incidence rate of aortic events (cardiovascular death, aortic dissection, and aortic surgery) from birth to the last follow-up visit or date of death are summarized in the Table. Patients with HI FBN1 variants were less likely to have ectopia lentis (P<0.001) and more likely to have a history of pneumothorax (P=0.025). Although prophylactic surgical replacement of the aorta has been generally recommended for those having an aortic diameter ≥45 mm at our institute,1 including pediatric patients, intensive medical treatment had been continued in 10 patients who had an aortic diameter of 45 to 50 mm (DN, n=7 [4.5%]; HI, n=3 [3.2%]).Table. Clinical Characteristics of Patients With Pathogenic FBN1 Variants During the Follow-Up PeriodVariablesDN Group (n=155)HI Group (n=93)P ValueAge at the last follow-up, y; range33.6 (19.0–46.8); range, 2–8026.8 (19.1–37.0); range, 7–670.051Cardiovascular events and features Death2 (1.3)00.53 Aortic dissection (type A)19 (12.3)9 (9.7)0.68 Prophylactic aortic root and ascending replacements38 (24.5)31 (33.3)0.15 Aortic dissection (type B) and thoracoabdominal aortic repair27 (17.4)14 (15.1)0.73 Mitral valve repair5 (3.2)5 (5.4)0.51 Mitral prolapse65/140 (46.4)43/81 (53.1)0.40Other features Ectopia lentis72/130 (55.4)18/65 (27.7)<0.001 Pneumothorax31/138 (22.5)28/75 (37.3)0.025 Kyphoscoliosis77/140 (55.0)49/78 (62.8)0.32 Pectus carinatum and excavatum67/141 (47.5)48/81 (59.3)0.097DN indicates dominant-negative type variants; and HI, haploinsufficient type variants.Patients With HI FBN1 Variants Have Increased Risk for Aortic ComplicationsFigure 2 shows Kaplan–Meier curves for the cumulative risk of severe aortic events (type A aortic dissections, aortic root replacement, and the aorta-related death). The median event-free survival period from birth for men and women was 31.0 (95% CI, 26.0–34.0) and 41.0 years (95% CI, 32.7–45), respectively, in the HI group and 41.0 (95% CI, 33.0–46.0) and 55.0 years (95% CI, 49.0–66.0), respectively, in the DN group. The risk of severe aortic events was significantly higher in the HI group than in the DN group (unadjusted hazard ratio [HR], 2.1; 95% CI, 1.4–3.1; P<0.001) and in men than in women (unadjusted HR, 2.3; 95% CI, 1.5–3.5; P<0.0001). On multivariate analysis, the HI group (adjusted HR, 2.1; 95% CI, 1.4–3.2; P<0.001) and male sex (adjusted HR, 2.4; 95% CI, 1.6–3.6; P<0.0001) were independently associated with a risk of severe aortic events.Download figureDownload PowerPointFigure 2. Kaplan–Meier estimates of the probability of the first severe aortic event from birth in patients with Marfan syndrome based on the combination of the FBN1 (dominant-negative [DN] or haploinsufficient type [HI]) genotype and sex. Aortic events include type A aortic dissection, aortic root replacement, and aorta-related death.Identification of a Group at High Risk for Severe Aortic Events Among DN PatientsCertain premature termination codon-containing transcripts that escape nonsense-mediated mRNA decay might be relatively stable and affect clinical outcomes differently,14 especially in HI patients with variants at the C-terminal side. However, the location of HI variants did not affect the probability of severe aortic events (Figure I in the Data Supplement).Subsequently, to identify patients at high risk for aortic events, we examined the genotype of 12 patients who had developed type A aortic dissection (n=1) and had undergone aortic root replacement (n=11) before the age of 20 years. Among the 7 DN variants (Figure 3A), 6 affecting conserved cysteine residues (4 variants affecting cysteine residues and 2 deletion variants [in-frame exon skipping]) were localized within tandem arrays of cb-EGF (calcium-binding epidermal growth factor)-like domains (exons 25–36 and 43–49) in the middle of the FBN1 gene (abbreviated as DN-CD variants henceforth; Figure 3B). Among 46 children (<20 years of age) with DN variants, severe aortic event-free probability was significantly lower in 17 with DN-CD variants compared with 29 with DN-nonCD variants (P=0.011), as expected. Thus, we subsequently tested whether DN-CD variants are deleterious even in the remaining109 DN patients aged ≥20 years. Consistent with the pediatric cohort, the cumulative event-free survival was significantly lower in DN-CD (n=11) than in DN-nonCD (n=98) patients (P<0.001; Figure II in the Data Supplement), suggesting that among DN patients, those with DN-CD variants might be at increased risk for severe aortic events.Download figureDownload PowerPointFigure 3. Clinical and genetic characteristics of dominant-negative (DN) patients with aortic events <20 y of age.A, List of patients. B, Schematic representation of the fibrillin-1 domain structure, and location of DN variants in patients listed in (A). DN variants that did and did not affect conserved cysteine residues are indicated by down arrows (red, variant affecting a cysteine residue; blue, exon deletion) and black up arrows, respectively. Down arrows cluster in the cb-EGF (calcium-binding epidermal growth factor)-like domains (exons 25–36 and 43–49, green lines) in the middle of the FBN1 gene. Thus, variants affecting or creating cysteine residues and in-frame deletion variants in the central cb-EGF domains (exons 25–36 and 43–49, green lines) were defined as DN-CD in the present study. DA(A) indicates type A aortic dissection; EGF, epidermal growth factor-like; F, female; M, male; and TB, transforming growth factor-β binding protein-like.Risk Assessment for Severe Aortic Events Based on the Newly Identified Genetic Subgroups and SexFigure 4 shows that the median event-free survival period from birth (freedom from severe aortic events) was 30.0 years (95% CI, 19.0–42.0) for the DN-CD (n=28), 33.0 years (95% CI, 30.0–37.2) for the HI (n=93), and 52.0 years (95% CI, 43.0–57.0) for the DN-nonCD groups (n=127). Both DN-CD (unadjusted HR, 5.5; 95% CI, 2.9–10.5; corrected P value, <0.0001) and HI patients (unadjusted HR, 2.7; 95% CI, 1.7–4.2; corrected P value, <0.0001) had significantly higher risks of severe aortic events compared with DN-nonCD patients, whereas the difference between HI and DN-CD was not statistically significant (corrected P value, 0.062). Moreover, as shown in Figure III in the Data Supplement, DN-CD variants seemed to be more deleterious than variants within the so-called neonatal (or severe form) region, exons 24–3215,16 (11 patients were included in both groups).Download figureDownload PowerPointFigure 4. Kaplan–Meier estimates comparing the probability of the first severe aortic event between genotypes. Cumulative aortic event-free probability of 28 dominant-negative (DN)-CD patients (green), 93 haploinsufficient type (HI) patients (red), and 127 DN-nonCD patients (blue).On multivariate analysis, the newly identified genetic subgroups (adjusted HR, 6.3; 95% CI, 3.3–11.8; P<0.0001 for DN-CD versus DN-nonCD; adjusted HR, 2.8; 95% CI, 1.8–4.4; P<0.0001 for HI versus DN-nonCD) and male sex (adjusted HR, 2.6; 95% CI, 1.7–4.0; P<0.0001) were independently associated with a risk of severe aortic events. Even when type B aortic dissection was included in the severe aortic events, similar results were obtained for the genetic subgroups (adjusted HR, 5.5; 95% CI, 2.9–10.3; P<0.0001 for DN-CD versus DN-nonCD; adjusted HR, 2.8; 95% CI, 1.8–4.4; P<0.0001 for HI versus DN-nonCD) and for male sex (adjusted HR, 2.2; 95% CI, 1.4–3.3; P=0.0002).Moreover, multivariate analysis for the risk of severe aortic events (not including type B dissection) for only 202 index cases provided similar results for the genetic subgroups (adjusted HR, 6.1; 95% CI, 3.2–11.7; P<0.0001 for DN-CD versus DN-nonCD; adjusted HR, 3.0; 95% CI, 1.9–4.9; P<0.0001 for HI versus DN-nonCD) and for male sex (adjusted HR, 2.8; 95% CI, 1.8–4.4; P<0.0001).Rapid Aortic Root Diameter Growth in DN-CD, HI, and Male PatientsTo further validate the impact of deleterious DN-CD and HI variants, we analyzed aortic root diameters measured through echocardiography when the aortic root was intact (if available). Data immediately before severe aortic events were obtained from 58 patients in the prophylactic surgery group (n=69) and 8 patients in type A or related death group (n=28). All data for the 151 aortic event-free patients (n=151) were available at least once. Figure IV in the Data Supplement shows the intact aortic root sizes at the last measuring times (age) of each patient, with their subsequent aortic outcomes. Aortic root diameters appeared to become larger until ≈40 years of age, with men having larger values (Figure V in the Data Supplement), and most patients underwent aortic root surgery when the aortic root size exceeded 45 to 50 mm.Subsequently, we analyzed the relation between the FBN1 genotype and aortic root Z scores stratified by age (<20 and 20–40 years of age). Because the available body size data (height and weight) from the referring hospital were limited, especially in pediatric patients, data from patients with deleterious variants (DN-CD and HI) were collectively analyzed. DN-CD+HI patients had higher Z scores than DN-nonCD patients in both age groups (Figure 5).Download figureDownload PowerPointFigure 5. Aortic Z scores of dominant-negative (DN)-nonCD and DN-CD+haploinsufficient type (HI) patients.Z scores for those 3 years of follow-up data until 20 years of age and whose initial aortic root diameter was <40 mm (Figure 6). The aortic growth rate (millimeter per year) was higher in men than in women (men, 1.35 [IQR, 0.79–1.66]; women, 0.71 [IQR, 0.32–1.08]; P=0.0034; Figure 6A and 6B). A comparison of rate of changes in Z score showed that the Z score increased in men between the first and last echocardiography but remained unchanged in women (men, P<0.001; women, P=0.24; Figure 6C and 6D). These results suggested that male patients 3 y of follow-up data available until 20 y of age. (A and C) Individual aortic root diameters (A), Z scores (C), and the age at measurement are plotted and connected. B, Growth rates of aortic root diameters (mm per y) in patients shown in (A). D, Paired bar graph showing the change in Z scores between the first and last echocardiography in patients shown in (C).DiscussionThe objective of this study is to elucidate the impact of the FBN1 genotype in MFS on the incidence of severe aortic events (aortic root replacement, type A dissections, and related death). Our results confirmed the main conclusion of the previous studies tha
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