RESUMO
PURPOSE: Marfan syndrome (MFS) is a connective tissue disorder in which several systems are affected with great phenotypic variability. Although known to be associated with pathogenic variants in the FBN1 gene, few genotype-phenotype correlations have been found in proband studies only. METHODS: In 1,575 consecutive MFS probands and relatives from the most comprehensive database worldwide, we established survival curves and sought genotype-phenotype correlations. RESULTS: A risk chart could be established with clinical and genetic data. Premature termination codon variants were not only associated with a shorter life expectancy and a high lifelong risk of aortic event, but also with the highest risk of severe scoliosis and a lower risk for ectopia lentis (EL) surgery. In-frame variants could be subdivided according to their impact on the cysteine content of fibrillin-1 with a global higher severity for cysteine loss variants and the highest frequency of EL surgery for cysteine addition variants. CONCLUSION: This study shows that FBN1 genotype-phenotype correlations exist for both aortic and extra-aortic features. It can be used for optimal risk stratification of patients with a great importance for genetic counseling and personalized medicine. This also provides additional data for the overall understanding of the role of fibrillin-1 in various organs.
Assuntos
Síndrome de Marfan , Estudos de Coortes , Fibrilina-1/genética , Fibrilinas , Estudos de Associação Genética , Genótipo , Humanos , Síndrome de Marfan/genética , Proteínas dos Microfilamentos/genética , Mutação , FenótipoRESUMO
PURPOSE: Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening disease with often unrecognized inherited forms. We sought to identify novel pathogenic variants associated with autosomal dominant inheritance of TAAD. METHODS: We analyzed exome sequencing data from 35 French TAAD families and performed next-generation sequencing capture panel of genes in 1114 unrelated TAAD patients. Functional effects of pathogenic variants identified were validated in cell, tissue, and mouse models. RESULTS: We identified five functional variants in THSD4 of which two heterozygous variants lead to a premature termination codon. THSD4 encodes ADAMTSL6 (member of the ADAMTS/L superfamily), a microfibril-associated protein that promotes fibrillin-1 matrix assembly. The THSD4 variants studied lead to haploinsufficiency or impaired assembly of fibrillin-1 microfibrils. Thsd4+/- mice showed progressive dilation of the thoracic aorta. Histologic examination of aortic samples from a patient carrying a THSD4 variant and from Thsd4+/- mice, revealed typical medial degeneration and diffuse disruption of extracellular matrix. CONCLUSION: These findings highlight the role of ADAMTSL6 in aortic physiology and TAAD pathogenesis. They will improve TAAD management and help develop new targeted therapies.
Assuntos
Aneurisma da Aorta Torácica , Dissecção Aórtica , Proteínas ADAM , Dissecção Aórtica/genética , Animais , Aneurisma da Aorta Torácica/genética , Exoma/genética , Fibrilina-1/genética , Humanos , CamundongosRESUMO
PURPOSE: Heritable thoracic aortic aneurysms and dissections (hTAAD) are life-threatening complications of well-known syndromic diseases or underdiagnosed nonsyndromic heritable forms (nshTAAD). Both have an autosomal dominant transmission and are genetically heterogeneous. Our objective was to describe the relevance of molecular diagnosis in these patients and the contribution of each gene in nshTAAD. METHODS: Two hundred twenty-six consecutive nshTAAD probands, either young (<45 years) sporadic or familial cases were included. A next-generation sequencing capture panel comprising 23 known disease-causing genes was performed. RESULTS: Class 4 or 5 variants were identified in 18% of the nshTAAD probands, while class 3 variants were found in 10% of them. The yield in familial cases was greater than in sporadic cases. SMAD3 and FBN1 genes were the major disease-causing genes. Unexpectedly, no premature termination codon variant was identified in the FBN1 gene. Furthermore, we report for the first time that aortic dissection or surgery occurred significantly more often and earlier in probands with a class 4 or 5 pathogenic variant. CONCLUSION: This study indicates that genetic screening using NGS is efficient in young and familial nshTAAD. The presence of a pathogenic variant has a possible predictive value, which needs to be further investigated because it may influence care.
Assuntos
Aneurisma da Aorta Torácica/genética , Dissecção Aórtica/genética , Fibrilina-1/genética , Proteína Smad3/genética , Adolescente , Adulto , Idoso , Dissecção Aórtica/diagnóstico , Dissecção Aórtica/fisiopatologia , Aneurisma da Aorta Torácica/diagnóstico , Criança , Códon sem Sentido/genética , Feminino , Predisposição Genética para Doença , Testes Genéticos/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Patologia Molecular/métodos , Linhagem , Adulto JovemRESUMO
BACKGROUND: Marfan syndrome (MFS) is an autosomal-dominant connective tissue disorder usually associated with heterozygous mutations in the gene encoding fibrillin-1 (FBN1). Homozygous and compound heterozygous cases are rare events and have been associated with a clinical severe presentation. OBJECTIVES: Report unexpected findings of homozygosity and compound heterozygosity in the course of molecular diagnosis of heterozygous MFS and compare the findings with published cases. METHODS AND RESULTS: In the context of molecular diagnosis of heterozygous MFS, systematic sequencing of the FBN1 gene was performed in 2500 probands referred nationwide. 1400 probands carried a heterozygous mutation in this gene. Unexpectedly, among them four homozygous cases (0.29%) and five compound heterozygous cases (0.36%) were identified (total: 0.64%). Interestingly, none of these cases carried two premature termination codon mutations in the FBN1 gene. Clinical features for these carriers and their families were gathered and compared. There was a large spectrum of severity of the disease in probands carrying two mutated FBN1 alleles, but none of them presented extremely severe manifestations of MFS in any system compared with carriers of only one mutated FBN1 allele. This observation is not in line with the severe clinical features reported in the literature for four homozygous and three compound heterozygous probands. CONCLUSION: Homozygotes and compound heterozygotes were unexpectedly identified in the course of molecular diagnosis of MFS. Contrary to previous reports, the presence of two mutated alleles was not associated with severe forms of MFS. Although homozygosity and compound heterozygosity are rarely found in molecular diagnosis, they should not be overlooked, especially among consanguineous families. However, no predictive evaluation of severity should be provided.
Assuntos
Fibrilina-1/genética , Síndrome de Marfan/diagnóstico , Síndrome de Marfan/genética , Patologia Molecular , Alelos , Códon sem Sentido , Feminino , Predisposição Genética para Doença , Testes Genéticos , Heterozigoto , Homozigoto , Humanos , Masculino , Síndrome de Marfan/patologia , Mutação de Sentido Incorreto/genética , LinhagemRESUMO
BACKGROUND: This cross-sectional controlled study aims to assess health-related quality of life (HRQoL) of children and adolescents with a molecular diagnosis of Marfan syndrome (MFS) or related disorders and to evaluate the factors associated with HRQoL in this population. Sixty-three children with MFS and 124 age- and sex-matched healthy children were recruited. HRQoL was assessed using the Pediatric Quality of Life Inventory (PedsQL™) generic questionnaire. The correlation between HRQoL scores and the different continuous parameters (age, body mass index, disease severity, systemic score, aortic sinus diameter, and aerobic physical capacity) was evaluated using Pearson's or Spearman's coefficient. A multiple linear regression analysis was performed on the two health summary self-reported PedsQL™ scores (physical and psychosocial) to identify the factors associated with HRQoL in the MFS group. RESULTS: Except for emotional functioning, all other domains of HRQoL (psychosocial and physical health, social and school functions) were significantly lower in children with MFS compared to matched healthy children. In the MFS group, the physical health summary score was significantly lower in female than in male patients (self-report: absolute difference [95%CI] = -8.7 [-17.0; -0.47], P = 0.04; proxy-report: absolute difference [95%CI] = -8.6 [-17.3; 0.02], P = 0.05) and also negatively correlated with the systemic score (self-report: R = -0.24, P = 0.06; proxy-report: R = -0.29, P = 0.03) and with the height Z-score (proxy-report: R = -0.29, P = 0.03). There was no significant difference in the physical health summary scores between the different genetic subgroups. In the subgroup of 27 patients who performed a cardiopulmonary exercise test, self- and proxy-reported physical health summary scores were highly correlated with their aerobic physical capacity assessed by peak oxygen consumption (VO2max) and ventilatory anaerobic threshold (VAT). In the multivariate analysis, the most important independent predictors of decreased physical health were increased height, decreased body mass index, decreased VAT and use of prophylactic therapy. CONCLUSIONS: This study reports an impaired HRQoL in children and adolescents with MFS or related conditions, in comparison with matched healthy children. Educational and rehabilitation programs must be developed and evaluated to improve exercise capacity and HRQoL in these patients. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03236571 . Registered 28 July 2017.
Assuntos
Síndrome de Marfan , Qualidade de Vida , Humanos , Síndrome de Marfan/fisiopatologia , Masculino , Feminino , Estudos Transversais , Criança , Adolescente , Inquéritos e QuestionáriosRESUMO
Until recently, the disease known to be associated with THOC2 mutations was Intellectual developmental disorder, X-linked 12 (MIM300957). However, recently, fetal arthrogryposis multiplex congenita has been associated with a specific splice site mutation in the THOC2 gene. We report a family with the same splice site mutation in the THOC2 gene involved in fetal arthrogryposis as well. We provide the first description of the muscular phenotype of this disease which reveals the presence of cytoplasmic bodies. Our findings expand the clinical phenotype of THOC2 gene related defects.
Assuntos
Artrogripose , Deficiência Intelectual , Splicing de RNA , Proteínas de Ligação a RNA , Humanos , Artrogripose/diagnóstico , Artrogripose/genética , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Mutação , Fenótipo , Proteínas de Ligação a RNA/genética , Masculino , Recém-NascidoRESUMO
BACKGROUND: Pathogenic variants in MYH11 are associated with either heritable thoracic aortic aneurysm and dissection (HTAAD), patent ductus arteriosus (PDA) syndrome, or megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS). METHODS AND RESULTS: We report a family referred for molecular diagnosis with HTAAD/PDA phenotype in which we found a variant at a non-conserved position of the 5' donor splice site of intron 32 of MYH11 potentially altering splicing (NM_002474.3:c.4578+3A>C). Although its cosegregation with disease was observed, it remained of unknown significance. Later, aortic surgery in the proband gave us the opportunity to perform a transcript analysis. This showed a skipping of the exon 32, an RNA defect previously reported to be translated to an in-frame loss of 71 amino acids and a dominant-negative effect in the smooth muscle myosin rod. This RNA defect is also reported in 3 other HTAAD/PDA pedigrees. CONCLUSION: This report confirms that among rare variants in MYH11, skipping of exon 32 is recurrent. This finding is of particular interest to establish complex genotype-phenotype correlations where some alleles are associated with autosomal dominant HTAAD/PDA, while others result in recessive or dominant visceral myopathies.
Assuntos
Aneurisma da Aorta Torácica/genética , Dissecção Aórtica/genética , Permeabilidade do Canal Arterial/genética , Cadeias Pesadas de Miosina/genética , Sítios de Splice de RNA , Dissecção Aórtica/patologia , Aneurisma da Aorta Torácica/patologia , Permeabilidade do Canal Arterial/patologia , Éxons , Humanos , Masculino , Mutação , Splicing de RNA , Adulto JovemRESUMO
Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder with considerable inter- and intra-familial clinical variability. The contribution of inherited modifiers to variability has not been quantified. We analyzed the distribution of 23 clinical features in 1306 well-phenotyped MFS patients carrying FBN1 mutations. We found strong correlations between features within the same system (i.e., ophthalmology vs. skeletal vs. cardiovascular) suggesting common underlying determinants, while features belonging to different systems were largely uncorrelated. We adapted a classical quantitative genetics model to estimate the heritability of each clinical feature from phenotypic correlations between relatives. Most clinical features showed strong familial aggregation and high heritability. We found a significant contribution by the major locus on the phenotypic variance only for ectopia lentis using a new strategy. Finally, we found evidence for the "Carter effect" in the MFS cardiovascular phenotype, which supports a polygenic model for MFS cardiovascular variability and indicates additional risk for children of MFS mothers with an aortic event. Our results demonstrate that an important part of the phenotypic variability in MFS is under the control of inherited modifiers, widely shared between features within the same system, but not among different systems. Further research must be performed to identify genetic modifiers of MFS severity.
Assuntos
Ectopia do Cristalino/genética , Fibrilina-1/genética , Fibrilinas/genética , Síndrome de Marfan/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Aorta/metabolismo , Aorta/patologia , Ectopia do Cristalino/fisiopatologia , Feminino , Genótipo , Humanos , Masculino , Síndrome de Marfan/fisiopatologia , Proteínas dos Microfilamentos/genética , Pessoa de Meia-Idade , Mutação/genética , Fenótipo , Adulto JovemRESUMO
BACKGROUND: Pathogenic SMAD3 variants are responsible for a cardiovascular phenotype, mainly thoracic aortic aneurysms and dissections. Precocious identification of the vascular risk such as aortic dilatation in mutated patients has a major impact in terms of management, particularly to avoid dissection and sudden death. These vascular damages are classically associated with premature osteoarthritis and skeletal abnormalities. However, variable expressivity and incomplete penetrance are common with SMAD3 variants. METHODS: To investigate the clinical variability observed within SMAD3 patients, we reviewed the phenotypic and genetic data of 22 new patients from our Centre and of 133 patients reported in the literature. From this cohort of 155 mutated individuals, we first aimed to delineate an estimated frequency of the main clinical signs associated with SMAD3 pathogenic variants and, then, to look for genotype-phenotype correlations, mainly to see if the aortic phenotype (AP) could be predicted by the SMAD3 variant type. RESULTS: We showed, herein, the absence of correlation between the SMAD3 variant type and the occurrence of an AP in patients. CONCLUSION: Therefore, this report brings additional data for the genotype-phenotype correlations of SMAD3 variants and the need to explore in more detail the effects of genetic modifiers that could influence the phenotype.
Assuntos
Síndrome de Loeys-Dietz/genética , Fenótipo , Proteína Smad3/genética , Adolescente , Adulto , Criança , Feminino , Humanos , Síndrome de Loeys-Dietz/patologia , Masculino , Pessoa de Meia-Idade , MutaçãoRESUMO
BACKGROUND: Aortic risk has not been evaluated in patients with Marfan syndrome and documented pathogenic variants in the FBN1 gene. OBJECTIVES: This study sought to describe aortic risk in a population with Marfan syndrome with pathogenic variants in the FBN1 gene as a function of aortic root diameter. METHODS: Patients carrying an FBN1 pathogenic variant who visited our reference center at least twice were included, provided they had not undergone aortic surgery or had an aortic dissection before their first visit. Aortic events (aortic surgery or aortic dissection) and deaths were evaluated during the 2 years following each patient visit. The risk was calculated as the number of events divided by the number of years of follow-up. RESULTS: A total of 954 patients were included (54% women; mean age 23 years). During follow-up (9.1 years), 142 patients underwent prophylactic aortic root surgery, 5 experienced type A aortic dissection, and 12 died (noncardiovascular causes in 3, unknown etiology in 3, post-operative in 6). When aortic root diameter was <50 mm, risk for proven type A dissection (0.4 events/1,000 patient-years) and risk for possible aortic dissection (proven aortic dissection plus death of unknown cause, 0.7 events/1,000 patients-years) remained low in this population that was treated according to guidelines. Three type A aortic dissections occurred in this population during the 8,594 years of follow-up, including 1 in a patient with a tubular aortic diameter of 50 mm, but none in patients with a family history of aortic dissection. The risk for type B aortic dissection in the same population was 0.5 events/1,000 patient-years. CONCLUSIONS: In patients with FBN1 pathogenic variants who receive beta-blocker therapy and who limit strenuous exercise, aortic risk remains low when maximal aortic diameter is <50 mm. The risk of type B aortic dissection is close to the remaining risk of type A aortic dissection in this population, which underlines the global aortic risk.
Assuntos
Aorta/patologia , Aneurisma Aórtico/etiologia , Dissecção Aórtica/etiologia , Fibrilina-1/genética , Síndrome de Marfan/complicações , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Aorta/cirurgia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Síndrome de Marfan/mortalidade , Síndrome de Marfan/patologia , Síndrome de Marfan/cirurgia , Pessoa de Meia-Idade , Procedimentos Cirúrgicos Profiláticos , Medição de Risco , Adulto JovemRESUMO
BACKGROUND: Both bicuspid aortic valve (BAV) and Marfan syndrome have been associated with aortic dissection risk, but it is unknown whether the presence of BAV is associated with an increased aortic risk in patients with an FBN1 gene mutation. We evaluated aortic diameters, aortic valve function, and aortic shape in Marfan syndrome patients with and without BAV and reported aortic events during follow-up. METHODS: All patients with an FBN1 gene mutation evaluated in our clinic were included. Aortic root diameters were measured, and the aortic valve was studied using echocardiography at each visit. RESULTS: Of the 1437 patients with an FBN1 gene mutation, 26 patients (1.8%) had a BAV. Both aortic root maximal diameter and normalized Z score were larger at all ages, in patients with BAV when compared with patients with tricuspid aortic valve. Prophylactic aortic root surgery tended to be performed in younger patients when BAV was present, although aortic diameter threshold was similar in the 2 populations. No aortic dissection was observed in Marfan syndrome patients with BAV. CONCLUSIONS: In patients with a FBN1 mutation, BAV is associated with larger aortic root diameter, with no difference in evolution of Z score with age. We found a trend towards prophylactic aortic root surgery at younger ages but similar aortic diameter thresholds without occurrence of aortic dissection. We did not find any evidence for lowering aortic diameter thresholds used to propose preventive aortic root surgery in the presence of BAV in patients with FBN1 mutations.
Assuntos
Aorta/fisiopatologia , Aneurisma Aórtico/epidemiologia , Valva Aórtica/anormalidades , Doenças das Valvas Cardíacas/epidemiologia , Síndrome de Marfan/epidemiologia , Remodelação Vascular , Adolescente , Adulto , Aorta/diagnóstico por imagem , Aneurisma Aórtico/diagnóstico por imagem , Aneurisma Aórtico/fisiopatologia , Valva Aórtica/diagnóstico por imagem , Doença da Válvula Aórtica Bicúspide , Criança , Ecocardiografia , Feminino , Fibrilina-1/genética , Predisposição Genética para Doença , Doenças das Valvas Cardíacas/diagnóstico por imagem , Humanos , Masculino , Síndrome de Marfan/diagnóstico , Síndrome de Marfan/genética , Mutação , Paris/epidemiologia , Prevalência , Prognóstico , Fatores de Risco , Fatores de Tempo , Adulto JovemRESUMO
In recent years, simple renal cysts have been associated with an increased risk of aortic aneurysms. There is little data regarding aortic dilation in patients with autosomal dominant polycystic kidney disease (ADPKD). The aim of this study was to compare Sinuses of Valsalva (SoV) and tubular ascending aorta diameters in ADPKD patients with matched controls. From 2008 to 2016, 61 consecutive ADPKD patients who had an echocardiogram performed in our institution were matched 1:1 with controls for sex, age, blood pressure, and ß-blocker therapy use. SoV and tubular ascending aorta were measured at end-diastole, using the leading-edge to leading-edge convention. Paired t Tests were used for quantitative variables and McNemar-tests for qualitative variables. The mean age of patients was 56 ± 12 years, 54% were men, 38% received ß-blockers, and mean systolic and diastolic BP were 137 ± 25 and 78 ± 19 mm Hg. SoV diameters were significantly larger in ADPKD patients than in controls (36.4 ± 4.1 vs 34.0 ± 3.7 mm, p <0.0001). The Z-scores (normalized for sex, age, and body surface area) were significantly higher in ADPKD patients, both for SoV and tubular ascending aorta. Moreover, aortic aneurysms, as defined by a Z score >2 standard deviations, were present in 27 ADPKD patients (44%) versus 9 controls (15%, p <0.001). In conclusion, there is an increased prevalence of aortic aneurysms in ADPKD patients as compared with controls matched for common confounding factors for aortic dilation.
Assuntos
Aorta/diagnóstico por imagem , Aneurisma Aórtico/complicações , Aneurisma Aórtico/diagnóstico por imagem , Rim Policístico Autossômico Dominante/complicações , Seio Aórtico/diagnóstico por imagem , Adulto , Estudos de Casos e Controles , Dilatação Patológica/diagnóstico por imagem , Ecocardiografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , PrevalênciaRESUMO
BACKGROUND: The natural history of aortic diseases in patients with TGFBR1 or TGFBR2 mutations reported by different investigators has varied greatly. In particular, the current recommendations for the timing of surgical repair of the aortic root aneurysms may be overly aggressive. METHODS AND RESULTS: The Montalcino Aortic Consortium, which includes 15 centers worldwide that specialize in heritable thoracic aortic diseases, was used to gather data on 441 patients from 228 families, with 176 cases harboring a mutation in TGBR1 and 265 in TGFBR2. Patients harboring a TGFBR1 mutation have similar survival rates (80% survival at 60 years), aortic risk (23% aortic dissection and 18% preventive aortic surgery), and prevalence of extra-aortic features (29% hypertelorism, 53% cervical arterial tortuosity, and 27% wide scars) when compared with patients harboring a TGFBR2 mutation. However, TGFBR1 males had a greater aortic risk than females, whereas TGFBR2 males and females had a similar aortic risk. Additionally, aortic root diameter prior to or at the time of type A aortic dissection tended to be smaller in patients carrying a TGFBR2 mutation and was ≤45 mm in 6 women with TGFBR2 mutations, presenting with marked systemic features and low body surface area. Aortic dissection was observed in 1.6% of pregnancies. CONCLUSIONS: Patients with TGFBR1 or TGFBR2 mutations show the same prevalence of systemic features and the same global survival. Preventive aortic surgery at a diameter of 45 mm, lowered toward 40 in females with low body surface area, TGFBR2 mutation, and severe extra-aortic features may be considered.