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1.
Am J Obstet Gynecol ; 2021 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-33493488

RESUMO

BACKGROUND: Ovarian cancer risk in BRCA1 and BRCA2 mutation carriers has been shown to decrease with longer duration of oral contraceptive use. Although the effects of using oral contraceptives in the general population are well established (approximately 50% risk reduction in ovarian cancer), the estimated risk reduction in mutation carriers is much less precise because of potential bias and small sample sizes. In addition, only a few studies on oral contraceptive use have examined the associations of duration of use, time since last use, starting age, and calendar year of start with risk of ovarian cancer. OBJECTIVE: This study aimed to investigate in more detail the associations of various characteristics of oral contraceptive use and risk of ovarian cancer, to provide healthcare providers and carriers with better risk estimates. STUDY DESIGN: In this international retrospective study, ovarian cancer risk associations were assessed using oral contraceptives data on 3989 BRCA1 and 2445 BRCA2 mutation carriers. Age-dependent-weighted Cox regression analyses were stratified by study and birth cohort and included breast cancer diagnosis as a covariate. To minimize survival bias, analyses were left truncated at 5 years before baseline questionnaire. Separate analyses were conducted for each aspect of oral contraceptive use and in a multivariate analysis, including all these aspects. In addition, the analysis of duration of oral contraceptive use was stratified by recency of use. RESULTS: Oral contraceptives were less often used by mutation carriers who were diagnosed with ovarian cancer (ever use: 58.6% for BRCA1 and 53.5% BRCA2) than by unaffected carriers (ever use: 88.9% for BRCA1 and 80.7% for BRCA2). The median duration of use was 7 years for both BRCA1 and BRCA2 carriers who developed ovarian cancer and 9 and 8 years for unaffected BRCA1 and BRCA2 carriers with ovarian cancer, respectively. For BRCA1 mutation carriers, univariate analyses have shown that both a longer duration of oral contraceptive use and more recent oral contraceptive use were associated with a reduction in the risk of ovarian cancer. However, in multivariate analyses, including duration of use, age at first use, and time since last use, duration of oral contraceptive use proved to be the prominent protective factor (compared with <5 years: 5-9 years [hazard ratio, 0.67; 95% confidence interval, 0.40-1.12]; >10 years [hazard ratio, 0.37; 95% confidence interval, 0.19-0.73]; Ptrend=.008). The inverse association between duration of use and ovarian cancer risk persisted for more than 15 years (duration of ≥10 years; BRCA1 <15 years since last use [hazard ratio, 0.24; 95% confidence interval, 0.14-0.43]; BRCA1 >15 years since last use [hazard ratio, 0.56; 95% confidence interval, 0.18-0.59]). Univariate results for BRCA2 mutation carriers were similar but were inconclusive because of limited sample size. CONCLUSION: For BRCA1 mutation carriers, longer duration of oral contraceptive use is associated with a greater reduction in ovarian cancer risk, and the protection is long term.

2.
Eur J Hum Genet ; 2021 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-33437034

RESUMO

Uncertainty is increasingly discussed during genetic counseling due to innovative techniques, e.g., multigene panel testing. Discussions about uncertainty may impact counselees variably, depending on counselors' communication styles. Ideally, the discussion of uncertainty enables counselees to cope with uncertainty and make well-informed decisions about testing. We examined the impact of how counselors convey uncertainty and address counselees' uncertainty, and explored the role of individual characteristics. Therefore, a randomized controlled experiment using videos was conducted. Former counselees (N = 224) viewed one video depicting a genetic consultation about multigene panel testing. The extent of counselors' communication of uncertainty (comprehensive vs. the essence) and their response to counselees' uncertainty expressions (providing information vs. providing space for emotions vs. normalizing and counterbalancing uncertainty) were systematically manipulated. Individual characteristics, e.g., uncertainty tolerance, were assessed, as well as outcome variables (primary outcomes: feelings of uncertainty and information recall). No effects were found on primary outcomes. Participants were most satisfied when the essence was communicated, combined with providing information or providing space responses (p = 0.002). Comprehensive information resulted in less perceived steering toward testing (p = 0.005). Participants with lower uncertainty tolerance or higher trait anxiety were less confident about their understanding when receiving comprehensive information (p = 0.025). Participants seeking information experienced less uncertainty (p = 0.003), and trusted their counselor more (p = 0.028), when the counselor used information providing responses. In sum, the impact of discussing uncertainty primarily depends on individual characteristics. Practical guidelines should address how to tailor the discussion of uncertainty.

3.
JMIR Res Protoc ; 10(1): e24414, 2021 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-33480862

RESUMO

BACKGROUND: BRCA1/2 mutation carriers are recommended to undergo risk-reducing salpingo-oophorectomy (RRSO) at 35 to 45 years of age. RRSO substantially decreases ovarian cancer risk, but at the cost of immediate menopause. Knowledge about the potential adverse effects of premenopausal RRSO, such as increased risk of cardiovascular disease, osteoporosis, cognitive dysfunction, and reduced health-related quality of life (HRQoL), is limited. OBJECTIVE: The aim of this study is to assess the long-term health effects of premenopausal RRSO on cardiovascular disease, bone health, cognitive functioning, urological complaints, sexual functioning, and HRQoL in women with high familial risk of breast or ovarian cancer. METHODS: We will conduct a multicenter cross-sectional study with prospective follow-up, nested in a nationwide cohort of women at high familial risk of breast or ovarian cancer. A total of 500 women who have undergone RRSO before 45 years of age, with a follow-up period of at least 10 years, will be compared with 250 women (frequency matched on current age) who have not undergone RRSO or who have undergone RRSO at over 55 years of age. Participants will complete an online questionnaire on lifestyle, medical history, cardiovascular risk factors, osteoporosis, cognitive function, urological complaints, and HRQoL. A full cardiovascular assessment and assessment of bone mineral density will be performed. Blood samples will be obtained for marker analysis. Cognitive functioning will be assessed objectively with an online neuropsychological test battery. RESULTS: This study was approved by the institutional review board in July 2018. In February 2019, we included our first participant. As of November 2020, we had enrolled 364 participants in our study. CONCLUSIONS: Knowledge from this study will contribute to counseling women with a high familial risk of breast/ovarian cancer about the long-term health effects of premenopausal RRSO. The results can also be used to offer health recommendations after RRSO. TRIAL REGISTRATION: ClinicalTrials.gov NCT03835793; https://clinicaltrials.gov/ct2/show/NCT03835793. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/24414.

4.
Int J Cardiol ; 306: 56-60, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32145937

RESUMO

BACKGROUND: 22q11.2 Deletion syndrome (22q11.2DS) is common in patients with tetralogy of Fallot (TOF) or pulmonary atresia with ventricular septal defect (PA/VSD) and is associated with worse outcomes in children. Whether this impaired prognosis is also translated into adulthood is unknown, as data in adult patients are limited. We aimed to compare long-term outcomes in adults with TOF or PA/VSD both with and without 22q11.2DS. METHODS: This study prospectively followed a nationwide multicenter cohort of TOF or PA/VSD patients with genetically confirmed presence or absence of 22q11.2DS, from inclusion in the Dutch national CONCOR registry for adults with congenital heart disease (CHD) onward. Outcome measures included all-cause mortality, cardiac mortality, need for pulmonary valve replacement (PVR), ventricular arrhythmias (VA), pacemaker implantation, and ICD implantation. RESULTS: In total, 479 patients were included (277 (58%) male, median age 28 [IQR; 21-37] years, 62 (13%) with PA/VSD, 34 (7%) with 22q11.2DS). During a median follow-up of 11 [IQR; 6-13] years, 52 (11%) patients died (8 with 22q11.2DS and 44 without 22q11.2DS). Patients with 22q11.2DS had significant decreased survival after 12 years (76% [95% CI; 62-93]) compared to patients without 22q11.2DS (89% [95% CI; 86-92], p = 0.008). 22q11.2DS was associated with increased risk of all-cause mortality and cardiac-mortality, independent of age, sex, and PA/VSD. No association was found between 22q11.2DS and late complications i.e. PVR, VA, pacemaker, or ICD implantation. CONCLUSIONS: Adults with TOF or PA/VSD with 22q11.2DS have a significantly worse survival than adults without this deletion. In patients with TOF or PA/VSD, genetic analysis for the presence of 22q11.2DS is important for risk stratification and genetic counseling.

6.
Breast Cancer Res ; 22(1): 8, 2020 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-31948486

RESUMO

BACKGROUND: The effect of risk-reducing salpingo-oophorectomy (RRSO) on breast cancer risk for BRCA1 and BRCA2 mutation carriers is uncertain. Retrospective analyses have suggested a protective effect but may be substantially biased. Prospective studies have had limited power, particularly for BRCA2 mutation carriers. Further, previous studies have not considered the effect of RRSO in the context of natural menopause. METHODS: A multi-centre prospective cohort of 2272 BRCA1 and 1605 BRCA2 mutation carriers was followed for a mean of 5.4 and 4.9 years, respectively; 426 women developed incident breast cancer. RRSO was modelled as a time-dependent covariate in Cox regression, and its effect assessed in premenopausal and postmenopausal women. RESULTS: There was no association between RRSO and breast cancer for BRCA1 (HR = 1.23; 95% CI 0.94-1.61) or BRCA2 (HR = 0.88; 95% CI 0.62-1.24) mutation carriers. For BRCA2 mutation carriers, HRs were 0.68 (95% CI 0.40-1.15) and 1.07 (95% CI 0.69-1.64) for RRSO carried out before or after age 45 years, respectively. The HR for BRCA2 mutation carriers decreased with increasing time since RRSO (HR = 0.51; 95% CI 0.26-0.99 for 5 years or longer after RRSO). Estimates for premenopausal women were similar. CONCLUSION: We found no evidence that RRSO reduces breast cancer risk for BRCA1 mutation carriers. A potentially beneficial effect for BRCA2 mutation carriers was observed, particularly after 5 years following RRSO. These results may inform counselling and management of carriers with respect to RRSO.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/epidemiologia , Mutação , Salpingo-Ooforectomia/métodos , Adulto , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Estudos de Coortes , Feminino , Humanos , Incidência , Agências Internacionais , Menopausa , Pessoa de Meia-Idade , Estudos Prospectivos , Comportamento de Redução do Risco
7.
Breast Cancer Res Treat ; 177(3): 723-733, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31302855

RESUMO

BACKGROUND: In healthy BRCA1/2 mutation carriers, bilateral risk-reducing mastectomy (BRRM) strongly reduces the risk of developing breast cancer (BC); however, no clear survival benefit of BRRM over BC surveillance has been reported yet. METHODS: In this Dutch multicenter cohort study, we used multivariable Cox models with BRRM as a time-dependent covariable to estimate the associations between BRRM and the overall and BC-specific mortality rates, separately for BRCA1 and BRCA2 mutation carriers. RESULTS: During a mean follow-up of 10.3 years, 722 out of 1712 BRCA1 (42%) and 406 out of 1145 BRCA2 (35%) mutation carriers underwent BRRM. For BRCA1 mutation carriers, we observed 52 deaths (20 from BC) in the surveillance group, and 10 deaths (one from BC) after BRRM. The hazard ratios were 0.40 (95% CI 0.20-0.90) for overall mortality and 0.06 (95% CI 0.01-0.46) for BC-specific mortality. BC-specific survival at age 65 was 93% for surveillance and 99.7% for BRRM. For BRCA2 mutation carriers, we observed 29 deaths (7 from BC) in the surveillance group, and 4 deaths (no BC) after BRRM. The hazard ratio for overall mortality was 0.45 (95% CI 0.15-1.36). BC-specific survival at age 65 was 98% for surveillance and 100% for BRRM. CONCLUSION: BRRM was associated with lower mortality than surveillance for BRCA1 mutation carriers, but for BRCA2 mutation carriers, BRRM may lead to similar BC-specific survival as surveillance. Our findings support a more individualized counseling based on BRCA mutation type.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/etiologia , Neoplasias da Mama/prevenção & controle , Heterozigoto , Mutação , Mastectomia Profilática , Neoplasias da Mama/mortalidade , Neoplasias da Mama/cirurgia , Feminino , Mutação em Linhagem Germinativa , Humanos , Mortalidade , Países Baixos/epidemiologia , Prognóstico , Mastectomia Profilática/métodos , Vigilância em Saúde Pública , Comportamento de Redução do Risco
8.
BMJ ; 365: l1652, 2019 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-31088823

RESUMO

OBJECTIVE: To investigate the incidence and characteristics of breast cancer in transgender people in the Netherlands compared with the general Dutch population. DESIGN: Retrospective, nationwide cohort study. SETTING: Specialised tertiary gender clinic in Amsterdam, the Netherlands. PARTICIPANTS: 2260 adult trans women (male sex assigned at birth, female gender identity) and 1229 adult trans men (female sex assigned at birth, male gender identity) who received gender affirming hormone treatment. MAIN OUTCOME MEASURES: Incidence and characteristics (eg, histology, hormone receptor status) of breast cancer in transgender people. RESULTS: The total person time in this cohort was 33 991 years for trans women and 14 883 years for trans men. In the 2260 trans women in the cohort, 15 cases of invasive breast cancer were identified (median duration of hormone treatment 18 years, range 7-37 years). This was 46-fold higher than in cisgender men (standardised incidence ratio 46.7, 95% confidence interval 27.2 to 75.4) but lower than in cisgender women (0.3, 0.2 to 0.4). Most tumours were of ductal origin and oestrogen and progesterone receptor positive, and 8.3% were human epidermal growth factor 2 (HER2) positive. In 1229 trans men, four cases of invasive breast cancer were identified (median duration of hormone treatment 15 years, range 2-17 years). This was lower than expected compared with cisgender women (standardised incidence ratio 0.2, 95% confidence interval 0.1 to 0.5). CONCLUSIONS: This study showed an increased risk of breast cancer in trans women compared with cisgender men, and a lower risk in trans men compared with cisgender women. In trans women, the risk of breast cancer increased during a relatively short duration of hormone treatment and the characteristics of the breast cancer resembled a more female pattern. These results suggest that breast cancer screening guidelines for cisgender people are sufficient for transgender people using hormone treatment.


Assuntos
Neoplasias da Mama/epidemiologia , Estrogênios/efeitos adversos , Transexualidade/tratamento farmacológico , Adulto , Antagonistas de Androgênios/uso terapêutico , Neoplasias da Mama Masculina/epidemiologia , Estrogênios/uso terapêutico , Feminino , Humanos , Incidência , Masculino , Países Baixos/epidemiologia , Estudos Retrospectivos , Fatores de Risco , Testosterona/uso terapêutico , Adulto Jovem
9.
Br J Cancer ; 119: 357-363, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29937543

RESUMO

BACKGROUND: The effect of in vitro fertilisation (IVF) on breast cancer risk for BRCA1/2 mutation carriers is rarely examined. As carriers may increasingly undergo IVF as part of preimplantation genetic diagnosis (PGD), we examined the impact of ovarian stimulation for IVF on breast cancer risk in BRCA1/2 mutation carriers. METHODS: The study population consisted of 1550 BRCA1 and 964 BRCA2 mutation carriers, derived from the nationwide HEBON study and the nationwide PGD registry. Questionnaires, clinical records and linkages with the Netherlands Cancer Registry were used to collect data on IVF exposure, risk-reducing surgeries and cancer diagnosis, respectively. Time-dependent Cox regression analyses were conducted, stratified for birth cohort and adjusted for subfertility. RESULTS: Of the 2514 BRCA1/2 mutation carriers, 3% (n = 76) were exposed to ovarian stimulation for IVF. In total, 938 BRCA1/2 mutation carriers (37.3%) were diagnosed with breast cancer. IVF exposure was not associated with risk of breast cancer (HR: 0.79, 95% CI: 0.46-1.36). Similar results were found for the subgroups of subfertile women (n = 232; HR: 0.73, 95% CI: 0.39-1.37) and BRCA1 mutation carriers (HR: 1.12, 95% CI: 0.60-2.09). In addition, age at and recency of first IVF treatment were not associated with breast cancer risk. CONCLUSION: No evidence was found for an association between ovarian stimulation for IVF and breast cancer risk in BRCA1/2 mutation carriers.


Assuntos
Neoplasias da Mama/etiologia , Fertilização In Vitro/efeitos adversos , Genes BRCA1 , Genes BRCA2 , Heterozigoto , Mutação , Indução da Ovulação , Adulto , Idoso , Neoplasias da Mama/genética , Feminino , Humanos , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Risco
10.
Eur J Hum Genet ; 26(6): 848-857, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29483665

RESUMO

This observational study aimed to investigate whether the reported association between family history (FH) of breast cancer (BC) or ovarian cancer (OC) and OC risks in BRCA1/2 mutation carriers can be explained by mutation position on the gene. In total, 3310 female BRCA1/2 mutation carriers participating in a nationwide prospective cohort (Hereditary Breast and Ovarian Cancer in the Netherlands) were included. FH was classified according to cancer occurrence in first-degree relatives (BC only, OC only, both, neither) and mutations were classified according to their position on the gene (OC cluster region (OCCR), BC cluster region, neither). The main outcome was OC occurrence. Cox proportional-hazard models were applied to investigate the association between FH and OC risks before and after adjusting for mutation position. Of all women included, 202 were diagnosed with OC. A BC-only FH tended to be associated with lower OC risks when compared with a FH without BC/OC (HR: 0.79, 95% CI: 0.52-1.17; HR: 0.59, 95% CI: 0.33-1.07 for BRCA1 and BRCA2, respectively) while an OC-only FH tended to be associated with higher risks (HR: 1.58, 95% CI: 0.90-2.77; HR: 1.75, 95% CI: 0.70-4.37 for BRCA1 and BRCA2, respectively). After adjusting for mutation position, association between FH and OC risks was slightly smaller in magnitude (HR: 0.85, 95% CI: 0.55-1.30; HR: 0.64, 95% CI: 0.34-1.21 for BC-only FH in BRCA1 and BRCA2, respectively; HR: 1.46, 95% CI: 0.80-2.68; HR: 1.49, 95% CI: 0.44-4.02 for OC-only FH in BRCA1 and BRCA2, respectively), indicating that mutation position explains only part of the association. Considering the magnitude of the observed trend, we do not believe FH should be used to change counseling regarding OC prevention.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/genética , Neoplasias Ovarianas/genética , Adulto , Idoso , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/patologia , Estudos de Coortes , Feminino , Predisposição Genética para Doença , Humanos , Anamnese , Pessoa de Meia-Idade , Mutação , Países Baixos , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/patologia , Fatores de Risco
11.
Eur Heart J ; 39(12): 1015-1022, 2018 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-29106500

RESUMO

Aims: Congenital heart defects (CHD) affect almost 1% of all live born children and the number of adults with CHD is increasing. In families where CHD has occurred previously, estimates of recurrence risk, and the type of recurring malformation are important for counselling and clinical decision-making, but the recurrence patterns in families are poorly understood. We aimed to determine recurrence patterns, by investigating the co-occurrences of CHD in 1163 families with known malformations, comprising 3080 individuals with clinically confirmed diagnosis. Methods and results: We calculated rates of concordance and discordance for 41 specific types of malformations, observing a high variability in the rates of concordance and discordance. By calculating odds ratios for each of 1640 pairs of discordant lesions observed between affected family members, we were able to identify 178 pairs of malformations that co-occurred significantly more or less often than expected in families. The data show that distinct groups of cardiac malformations co-occur in families, suggesting influence from underlying developmental mechanisms. Analysis of human and mouse susceptibility genes showed that they were shared in 19% and 20% of pairs of co-occurring discordant malformations, respectively, but none of malformations that rarely co-occur, suggesting that a significant proportion of co-occurring lesions in families is caused by overlapping susceptibility genes. Conclusion: Familial CHD follow specific patterns of recurrence, suggesting a strong influence from genetically regulated developmental mechanisms. Co-occurrence of malformations in families is caused by shared susceptibility genes.


Assuntos
Anormalidades Múltiplas/genética , Predisposição Genética para Doença , Cardiopatias Congênitas/genética , Sistema de Registros , Anormalidades Múltiplas/epidemiologia , Adulto , Europa (Continente)/epidemiologia , Feminino , Cardiopatias Congênitas/epidemiologia , Humanos , Recém-Nascido , Masculino , Morbidade/tendências , Linhagem , Fatores de Risco
12.
Mol Genet Metab ; 118(2): 123-7, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27067449

RESUMO

X-linked adrenoleukodystrophy (ALD), a progressive neurodegenerative disease, is caused by mutations in ABCD1 and characterized by very-long-chain fatty acids (VLCFA) accumulation. In male patients, an increased plasma VLCFA levels in combination with a pathogenic mutation in ABCD1 confirms the diagnosis. Recent studies have shown that many women with ALD also develop myelopathy. Correct diagnosis is important for management including genetic counseling. Diagnosis in women can only be confirmed when VLCFA levels are elevated or when a known pathogenic ABCD1 mutation is identified. However, in 15-20% of women with ALD VLCFA plasma levels are not elevated. Demonstration that a novel sequence variant is pathogenic can be a challenge when VLCFA levels are in the normal range. Here we report two women with a clinical presentation compatible with ALD, an ABCD1 variation (p.Arg17His and p.Ser358Pro) of unknown significance, but with normal VLCFA levels. We developed a diagnostic test that is based on generating clonal cell lines that express only one of the two alleles. Subsequent biochemical studies enabled us to show that the two sequence variants were not pathogenic, thereby excluding the diagnosis ALD in these women. We conclude that the clonal approach is an important addition to the existing diagnostic array.


Assuntos
Membro 1 da Subfamília D de Transportadores de Cassetes de Ligação de ATP/genética , Adrenoleucodistrofia/diagnóstico , Adrenoleucodistrofia/genética , Triagem de Portadores Genéticos/métodos , Membro 1 da Subfamília D de Transportadores de Cassetes de Ligação de ATP/metabolismo , Adrenoleucodistrofia/sangue , Adulto , Alelos , Linhagem Celular , Análise Mutacional de DNA , Ácidos Graxos/sangue , Feminino , Variação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Peroxissomos/metabolismo , Doenças da Medula Espinal/diagnóstico , Doenças da Medula Espinal/genética
13.
Am J Med Genet A ; 164A(11): 2732-8, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25099673

RESUMO

Atrial septal defect (ASD) is the most common congenital heart defect clinically characterized by an opening in the atrial septum. Mutations in GATA4, TBX5, and NKX2-5 underlie this phenotype. Here, we report on the identification of a novel -6 G>C mutation in the highly conserved Kozak sequence in the 5'UTR of GATA4 in a small family presenting with two different forms of ASD. This is the first time a mutation in the Kozak sequence has been linked to heart disease. Functional assays demonstrate reduced GATA4 translation, though the GATA4 transcript levels remain normal. This leads to a reduction of GATA4 protein level, consequently diminishing the ability of GATA4 to transactivate target genes, as demonstrated by using the GATA4-driven Nppa (ANF) promoter. In conclusion, we identified a mutation in the GATA4 Kozak sequence that likely contributes to the pathogenesis of ASD. In general, it points to the importance of accurate protein level regulation during heart development and emphasizes the need to analyze the entire transcribed region when screening for mutations.


Assuntos
Fator de Transcrição GATA4/genética , Comunicação Interatrial/genética , Mutação , Motivos de Nucleotídeos , Regiões Promotoras Genéticas , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Análise Mutacional de DNA , Eletrocardiografia , Feminino , Fator de Transcrição GATA4/metabolismo , Genótipo , Comunicação Interatrial/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Biossíntese de Proteínas , Ativação Transcricional , Adulto Jovem
14.
Fetal Diagn Ther ; 36(1): 59-68, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24903004

RESUMO

INTRODUCTION: Bicuspid aortic valve (BAV) is common in Turner syndrome (TS). In adult TS, 82-95% of BAVs have fusion of the right and left coronary leaflets. Data in fetal stages are scarce. The purpose of this study was to gain insight into aortic valve morphology and associated cardiovascular abnormalities in a fetal TS cohort with adverse outcome early in development. MATERIAL AND METHODS: We studied post-mortem heart specimens of 36 TS fetuses and 1 TS newborn. RESULTS: BAV was present in 28 (76%) hearts. BAVs showed fusion of the right and left coronary leaflet (type 1 BAV) in 61%, and fusion of the right coronary and non-coronary leaflet (type 2 BAV) in 39%. There were no significant differences in occurrence of additional cardiovascular abnormalities between type 1 and type 2 BAV. However, all type 2 BAV hearts showed ascending aorta hypoplasia and tubular hypoplasia of the B segment, as opposed to only 55 and 64% of type 1 BAV hearts, respectively. DISCUSSION: The proportion of type 2 BAV seems higher in TS fetuses than in adults. Fetal type 2 BAV hearts all had severe aortic pathology, possibly contributing to a worse prognosis of type 2 than type 1 BAV in TS.


Assuntos
Valva Aórtica/anormalidades , Coração Fetal/anormalidades , Coração Fetal/patologia , Doenças das Valvas Cardíacas/patologia , Síndrome de Turner/patologia , Valva Aórtica/embriologia , Valva Aórtica/patologia , Anormalidades Cardiovasculares/embriologia , Anormalidades Cardiovasculares/patologia , Feminino , Coração Fetal/embriologia , Coração/embriologia , Doenças das Valvas Cardíacas/embriologia , Humanos , Recém-Nascido , Síndrome de Turner/embriologia
15.
Circ Cardiovasc Genet ; 6(4): 347-53, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23876493

RESUMO

BACKGROUND: Association between the C677T polymorphism of the methylene tetrahydrofolate reductase (MTHFR) gene and congenital heart disease (CHD) is contentious. METHODS AND RESULTS: We compared genotypes between CHD cases and controls and between mothers of CHD cases and controls. We placed our results in context by conducting meta-analyses of previously published studies. Among 5814 cases with primary genotype data and 10 056 controls, there was no evidence of association between MTHFR C677T genotype and CHD risk (odds ratio [OR], 0.96 [95% confidence interval, 0.87-1.07]). A random-effects meta-analysis of all studies (involving 7697 cases and 13 125 controls) suggested the presence of association (OR, 1.25 [95% confidence interval, 1.03-1.51]; P=0.022) but with substantial heterogeneity among contributing studies (I(2)=64.4%) and evidence of publication bias. Meta-analysis of large studies only (defined by a variance of the log OR <0.05), which together contributed 83% of all cases, yielded no evidence of association (OR, 0.97 [95% confidence interval, 0.91-1.03]) without significant heterogeneity (I(2)=0). Moreover, meta-analysis of 1781 mothers of CHD cases (829 of whom were genotyped in this study) and 19 861 controls revealed no evidence of association between maternal C677T genotype and risk of CHD in offspring (OR, 1.13 [95% confidence interval, 0.87-1.47]). There was no significant association between MTHFR genotype and CHD risk in large studies from regions with different levels of dietary folate. CONCLUSIONS: The MTHFR C677T polymorphism, which directly influences plasma folate levels, is not associated with CHD risk. Publication biases appear to substantially contaminate the literature with regard to this genetic association.


Assuntos
Cardiopatias Congênitas/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Polimorfismo de Nucleotídeo Único , Alelos , Estudos de Coortes , Bases de Dados Genéticas , Ácido Fólico/sangue , Predisposição Genética para Doença , Genótipo , Cardiopatias Congênitas/patologia , Humanos , Razão de Chances , Fatores de Risco
16.
Am J Med Genet C Semin Med Genet ; 163C(3): 178-84, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23794396

RESUMO

Left ventricular noncompaction (LVNC) is a relatively common genetic cardiomyopathy, characterized by prominent trabeculations with deep intertrabecular recesses in mainly the left ventricle. Although LVNC often occurs in an isolated entity, it may also be present in various types of congenital heart disease (CHD). The most prevalent CHD in LVNC is Ebstein anomaly, which is a rare form of CHD characterized by apical displacement and partial fusion of the septal and posterior leaflet of the tricuspid valve with the ventricular septum. Several reports of sporadic as well as familial cases of Ebstein anomaly associated with LVNC have been reported. Recent studies identified mutations in the MYH7 gene, encoding the sarcomeric ß-myosin heavy chain protein, in patients harboring this specific phenotype. Here, we will review the association between Ebstein anomaly, LVNC and mutations in MYH7, which seems to represent a subtype of Ebstein anomaly with autosomal dominant inheritance and variable penetrance.


Assuntos
Miosinas Cardíacas/genética , Anomalia de Ebstein/genética , Ventrículos do Coração/anormalidades , Miocárdio Ventricular não Compactado Isolado/genética , Cadeias Pesadas de Miosina/genética , Anomalia de Ebstein/complicações , Genes Dominantes , Humanos , Miocárdio Ventricular não Compactado Isolado/complicações , Mutação , Fenótipo
17.
Am J Med Genet A ; 161A(7): 1628-37, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23696448

RESUMO

For adult patients with congenital heart disease (CHD), knowledge about the origin and inheritance of their CHD is important. Clinical geneticists may play a significant role in their care. We explored the diagnostic yield of clinical genetic consultation of adult CHD patients, patients' motivations for the consultation, implications for reproductive decisions, patients' evaluation of the impact of provided information, and satisfaction with counseling. Chart review was performed on all adult patients referred for CHD to our clinical genetics department between 2000 and 2011 (n = 90). Additionally, a questionnaire was sent to those patients referred between 2005 and 2011 (n = 64), of which 46 useful questionnaires were returned (72% response). Of patients without an etiological diagnosis at referral (n = 83), 17 (20%) were eventually diagnosed with syndromic CHD, 6 (7%) with nonsyndromic monogenetic CHD and 45 (54%) with nonsyndromic multifactorial CHD. The diagnosis remained undetermined in 15 (18%) patients. Half of patients who returned the questionnaire had purposefully postponed having children until after genetic consultation and 13% had changed their mind about having children or not after the consultation. Counseling was valued positively. In this study, we showed the added value of clinical genetic consultation in the care for adult CHD patients: it improves diagnostics by establishing an etiological diagnosis and associated recurrence risk in a substantial proportion of patients and leads to more informed reproductive decisions. With new genetic testing technologies an etiological diagnosis may be established in an increasing number of patients in the near future.


Assuntos
Cardiopatias Congênitas/diagnóstico , Adulto , Aconselhamento Genético , Testes Genéticos , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/psicologia , Humanos , Satisfação do Paciente , Médicos , Encaminhamento e Consulta , Inquéritos e Questionários
18.
Nat Genet ; 45(7): 822-4, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23708191

RESUMO

We carried out a genome-wide association study (GWAS) of congenital heart disease (CHD). Our discovery cohort comprised 1,995 CHD cases and 5,159 controls and included affected individuals from each of the 3 major clinical CHD categories (with septal, obstructive and cyanotic defects). When all CHD phenotypes were considered together, no region achieved genome-wide significant association. However, a region on chromosome 4p16, adjacent to the MSX1 and STX18 genes, was associated (P = 9.5 × 10⁻7) with the risk of ostium secundum atrial septal defect (ASD) in the discovery cohort (N = 340 cases), and this association was replicated in a further 417 ASD cases and 2,520 controls (replication P = 5.0 × 10⁻5; odds ratio (OR) in replication cohort = 1.40, 95% confidence interval (CI) = 1.19-1.65; combined P = 2.6 × 10⁻¹°). Genotype accounted for ~9% of the population-attributable risk of ASD.


Assuntos
Cromossomos Humanos Par 4 , Loci Gênicos , Predisposição Genética para Doença , Cardiopatias Congênitas/genética , Cardiopatias/genética , Comunicação Interatrial/genética , Anormalidades Múltiplas/genética , Animais , Estudos de Casos e Controles , Cromossomos Humanos Par 4/genética , Estudos de Coortes , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Cardiopatias/congênito , Humanos , Masculino , Camundongos , Fenótipo
19.
Hum Mol Genet ; 22(7): 1473-81, 2013 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-23297363

RESUMO

We conducted a genome-wide association study to search for risk alleles associated with Tetralogy of Fallot (TOF), using a northern European discovery set of 835 cases and 5159 controls. A region on chromosome 12q24 was associated (P = 1.4 × 10(-7)) and replicated convincingly (P = 3.9 × 10(-5)) in 798 cases and 2931 controls [per allele odds ratio (OR) = 1.27 in replication cohort, P = 7.7 × 10(-11) in combined populations]. Single nucleotide polymorphisms in the glypican 5 gene on chromosome 13q32 were also associated (P = 1.7 × 10(-7)) and replicated convincingly (P = 1.2 × 10(-5)) in 789 cases and 2927 controls (per allele OR = 1.31 in replication cohort, P = 3.03 × 10(-11) in combined populations). Four additional regions on chromosomes 10, 15 and 16 showed suggestive association accompanied by nominal replication. This study, the first genome-wide association study of a congenital heart malformation phenotype, provides evidence that common genetic variation influences the risk of TOF.


Assuntos
Cromossomos Humanos Par 12/genética , Cromossomos Humanos Par 13/genética , Estudo de Associação Genômica Ampla , Tetralogia de Fallot/genética , Estudos de Casos e Controles , Feminino , Frequência do Gene , Loci Gênicos , Humanos , Desequilíbrio de Ligação , Masculino , Polimorfismo de Nucleotídeo Único
20.
PLoS One ; 7(12): e52685, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23285148

RESUMO

NKX2-5 is a homeodomain-containing transcription factor implied in both heart and thyroid development. Numerous mutations in NKX2-5 have been reported in individuals with congenital heart disease (CHD), but recently a select few have been associated with thyroid dysgenesis, among which the p.A119S variation. We sequenced NKX2-5 in 303 sporadic CHD patients and 38 families with at least two individuals with CHD. The p.A119S variation was identified in two unrelated patients: one was found in the proband of a family with four affected individuals with CHD and the other in a sporadic CHD patient. Clinical evaluation of heart and thyroid showed that the mutation did not segregate with CHD in the familial case, nor did any of the seven mutation carriers have thyroid abnormalities. We tested the functional consequences of the p.A119S variation in a cellular context by performing transactivation assays with promoters relevant for both heart and thyroid development in rat heart derived H10 cells and HELA cells. There was no difference between wildtype NKX2-5 and p.A119S NKX2-5 in activation of the investigated promoters in both cell lines. Additionally, we reviewed the current literature on the topic, showing that there is no clear evidence for a major pathogenic role of NKX2-5 mutations in thyroid dysgenesis. In conclusion, our study demonstrates that p.A119S does not cause CHD or TD and that it is a rare variation that behaves equal to wildtype NKX2-5. Furthermore, given the wealth of published evidence, we suggest that NKX2-5 mutations do not play a major pathogenic role in thyroid dysgenesis, and that genetic testing of NKX2-5 in TD is not warranted.


Assuntos
Proteínas de Homeodomínio/genética , Mutação , Disgenesia da Tireoide/genética , Fatores de Transcrição/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Sequência de Aminoácidos , Animais , Núcleo Celular/metabolismo , Criança , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Feminino , Proteína Homeobox Nkx-2.5 , Proteínas de Homeodomínio/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Regiões Promotoras Genéticas , Transporte Proteico , Alinhamento de Sequência , Fatores de Transcrição/metabolismo , Ativação Transcricional , Adulto Jovem
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