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2.
Nat Commun ; 10(1): 2837, 2019 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-31253775

RESUMO

The diagnostic yield of exome and genome sequencing remains low (8-70%), due to incomplete knowledge on the genes that cause disease. To improve this, we use RNA-seq data from 31,499 samples to predict which genes cause specific disease phenotypes, and develop GeneNetwork Assisted Diagnostic Optimization (GADO). We show that this unbiased method, which does not rely upon specific knowledge on individual genes, is effective in both identifying previously unknown disease gene associations, and flagging genes that have previously been incorrectly implicated in disease. GADO can be run on www.genenetwork.nl by supplying HPO-terms and a list of genes that contain candidate variants. Finally, applying GADO to a cohort of 61 patients for whom exome-sequencing analysis had not resulted in a genetic diagnosis, yields likely causative genes for ten cases.


Assuntos
Regulação da Expressão Gênica/fisiologia , Predisposição Genética para Doença , Análise de Sequência de RNA/métodos , Transcriptoma , Bases de Dados de Ácidos Nucleicos , Humanos , Modelos Genéticos , Análise de Componente Principal , Software , Interface Usuário-Computador
3.
Int J Cardiol ; 258: 243-248, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29452988

RESUMO

BACKGROUND: Thoracic aortic aneurysm (TAA) is a potentially life-threatening disorder with a strong genetic component. The number of genes implicated in TAA has increased exponentially over the last decade. Approximately 20% of patients with TAA have a positive family history. As most TAA remain asymptomatic for a long time, screening of at risk relatives is warranted to prevent complications. Existing international guidelines lack detailed instructions regarding genetic evaluation and family screening of TAA patients. We aimed to develop a consensus document to provide medical guidance for all health care professionals involved in the recognition, diagnosis and treatment of patients with thoracic aortic disease and their relatives. METHODS: A multidisciplinary panel of experts including cardiologists, cardiothoracic surgeons, clinical geneticists and general practitioners, convened to review and discuss the current literature, guidelines and clinical practice on genetic testing and family screening in TAA. RESULTS: There is a lack of high-quality evidence in the literature. This consensus statement, based on the available literature and expert opinions, summarizes our recommendations in order to standardize and optimize the cardiogenetic care for patients and families with thoracic aortic disease. In particular, we provide criteria to identify those patients most likely to have a genetic predisposition, and discuss the preferred modality and frequency of screening in their relatives. CONCLUSIONS: Age, family history, aortic size and syndromic features determine who is advised to have genetic testing as well as screening of first-degree relatives. There is a need for more prospective multicenter studies to optimize current recommendations.


Assuntos
Aneurisma da Aorta Torácica/genética , Consenso , Prova Pericial/normas , Família , Predisposição Genética para Doença/genética , Assistência ao Paciente/normas , Aneurisma da Aorta Torácica/epidemiologia , Aneurisma da Aorta Torácica/terapia , Prova Pericial/métodos , Predisposição Genética para Doença/epidemiologia , Humanos , Países Baixos/epidemiologia , Assistência ao Paciente/métodos
4.
Pediatrics ; 140(4)2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28939701

RESUMO

BACKGROUND: Rapid diagnostic whole-genome sequencing has been explored in critically ill newborns, hoping to improve their clinical care and replace time-consuming and/or invasive diagnostic testing. A previous retrospective study in a research setting showed promising results with diagnoses in 57%, but patients were highly selected for known and likely Mendelian disorders. The aim of our prospective study was to assess the speed and yield of rapid targeted genomic diagnostics for clinical application. METHODS: We included 23 critically ill children younger than 12 months in ICUs over a period of 2 years. A quick diagnosis could not be made after routine clinical evaluation and diagnostics. Targeted analysis of 3426 known disease genes was performed by using whole-genome sequencing data. We measured diagnostic yield, turnaround times, and clinical consequences. RESULTS: A genetic diagnosis was obtained in 7 patients (30%), with a median turnaround time of 12 days (ranging from 5 to 23 days). We identified compound heterozygous mutations in the EPG5 gene (Vici syndrome), the RMND1 gene (combined oxidative phosphorylation deficiency-11), and the EIF2B5 gene (vanishing white matter), and homozygous mutations in the KLHL41 gene (nemaline myopathy), the GFER gene (progressive mitochondrial myopathy), and the GLB1 gene (GM1-gangliosidosis). In addition, a 1p36.33p36.32 microdeletion was detected in a child with cardiomyopathy. CONCLUSIONS: Rapid targeted genomics combined with copy number variant detection adds important value in the neonatal and pediatric intensive care setting. It led to a fast diagnosis in 30% of critically ill children for whom the routine clinical workup was unsuccessful.


Assuntos
Diagnóstico Tardio/prevenção & controle , Doenças Genéticas Inatas/diagnóstico , Genômica/métodos , Terapia Intensiva Neonatal/métodos , Análise de Sequência de DNA/métodos , Estado Terminal , Feminino , Seguimentos , Doenças Genéticas Inatas/genética , Marcadores Genéticos , Humanos , Recém-Nascido , Masculino , Mutação , Projetos Piloto , Estudos Prospectivos , Fatores de Tempo
5.
Pharmacogenomics ; 18(10): 987-1001, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28639488

RESUMO

AIM: To explore the role of pharmacogenetics in determining the risk of congenital heart anomalies (CHA) with prenatal use of serotonin reuptake inhibitors. METHODS: We included 33 case-mother dyads and 2 mother-only (child deceased) cases of CHA in a case-only study. Ten genes important in determining fetal exposure to serotonin reuptake inhibitors were examined: CYP1A2, CYP2C9, CYP2C19, CYP2D6, ABCB1, SLC6A4, HTR1A, HTR1B, HTR2A and HTR3B. RESULTS: Among the exposed cases, polymorphisms that tended to be associated with an increased risk of CHA were SLC6A4 5-HTTLPR and 5-HTTVNTR, HTR1A rs1364043, HTR1B rs6296 and rs6298 and HTR3B rs1176744, but none reached statistical significance due to our limited sample sizes. CONCLUSION: We identified several polymorphisms that might potentially affect the risk of CHA among exposed fetuses, which warrants further investigation.


Assuntos
Cardiopatias Congênitas/induzido quimicamente , Exposição Materna/efeitos adversos , Variantes Farmacogenômicos , Polimorfismo de Nucleotídeo Único , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Inibidores de Captação de Serotonina/efeitos adversos , Feminino , Desenvolvimento Fetal/efeitos dos fármacos , Genótipo , Cardiopatias Congênitas/genética , Humanos , Recém-Nascido , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética , Inibidores de Captação de Serotonina/farmacocinética , Inibidores de Captação de Serotonina/uso terapêutico
6.
BMC Pregnancy Childbirth ; 17(1): 120, 2017 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-28410576

RESUMO

BACKGROUND: Pharmacogenetics is an emerging field currently being implemented to improve safety when prescribing drugs. While many women who take drugs during pregnancy would likely benefit from such personalized drug therapy, data is lacking on the awareness towards pharmacogenetics among women. We aim to determine the level of knowledge and acceptance of formerly pregnant women in the Netherlands regarding pharmacogenetics and its implementation, and their interest in pharmacogenetic research. METHODS: A population-based survey using postal questionnaires was conducted among formerly pregnant women in the Northern parts of the Netherlands. A total of 986 women were invited to participate. RESULTS: Of the 219 women who returned completed questionnaires (22.2% response rate), only 22.8% had heard of pharmacogenetics, although the majority understood the concept (64.8%). Women who had experience with drug side-effects were more likely to know about pharmacogenetics [OR = 2.06, 95% CI 1.16, 3.65]. Of the respondents, 53.9% were positive towards implementing pharmacogenetics in their future drug therapy, while 46.6% would be willing to participate in pharmacogenetic research. Among those who were either not willing or undecided in this regard, their concerns were about the consequences of the pharmacogenetic test, including the privacy and anonymity of their genetic information. CONCLUSION: The knowledge and attitude regarding the concept of pharmacogenetics among our population of interest is good. Also, their interest in pharmacogenetic research provides opportunities for future research related to drug use during pregnancy and fetal outcome.


Assuntos
Conhecimentos, Atitudes e Prática em Saúde , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Farmacogenética , Saúde da Mulher , Adulto , Feminino , Humanos , Países Baixos/epidemiologia , Satisfação do Paciente , Cuidado Pré-Natal , Inquéritos e Questionários
7.
Eur J Hum Genet ; 25(6): 694-701, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28422132

RESUMO

16q24 deletion involving the ANKRD11 gene, ranging from 137 kb to 2 Mb, have been associated with a microdeletion syndrome characterized by variable cognitive impairment, autism spectrum disorder, facial dysmorphisms with dental anomalies, brain abnormalities essentially affecting the corpus callosum and short stature. On the other hand, patients carrying either deletions encompassing solely ANKRD11 or its loss-of-function variants were reported in association with the KBG syndrome, characterized by a very similar phenotype, including mild-to-moderate intellectual disability, short stature and macrodontia of upper incisors, with inter and intrafamilial variability. To assess whether the haploinsufficiency of ANKRD11-flanking genes, such as ZFPM1, CDH15 and ZNF778, contributed to either the severity of the neurological impairment or was associated with other clinical features, we collected 12 new cases with a 16q24.2q24.3 deletion (de novo in 11 cases), ranging from 343 kb to 2.3 Mb. In 11 of them, the deletion involved the ANKRD11 gene, whereas in 1 case only flanking genes upstream to it were deleted. By comparing the clinical and genetic features of our patients with those previously reported, we show that the severity of the neurological phenotype and the frequency of congenital heart defects characterize the deletions that, besides ANKRD11, contain ZFPM1, CDH15 and ZNF778 as well. Moreover, the presence of thrombocytopenia and astigmatism should be taken into account to distinguish between 16q24 microdeletion syndrome and KBG syndrome. The single patient not deleted for ANKRD11, whose phenotype is characterized by milder psychomotor delay, cardiac congenital malformation, thrombocytopenia and astigmatism, confirms all this data.


Assuntos
Anormalidades Múltiplas/genética , Doenças do Desenvolvimento Ósseo/genética , Deleção Cromossômica , Cromossomos Humanos Par 16/genética , Haploinsuficiência , Deficiência Intelectual/genética , Proteínas Repressoras/genética , Anormalidades Dentárias/genética , Fatores de Transcrição/genética , Anormalidades Múltiplas/diagnóstico , Adolescente , Adulto , Doenças do Desenvolvimento Ósseo/diagnóstico , Caderinas/genética , Criança , Diagnóstico Diferencial , Facies , Feminino , Humanos , Deficiência Intelectual/diagnóstico , Masculino , Proteínas Nucleares/genética , Fenótipo , Anormalidades Dentárias/diagnóstico , Fatores de Transcrição/metabolismo
8.
PLoS One ; 12(3): e0173530, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28288183

RESUMO

BACKGROUND: A number of transporter proteins are expressed in the placenta, and they facilitate the placental transfer of drugs. The inhibition of P-glycoprotein (P-gp) was previously found to be associated with an increase in the risk of congenital anomalies caused by drug substrates of this transporter. We now explore the role of other placental transporter proteins. METHODS: A population-based case-referent study was performed using cases with congenital anomalies (N = 5,131) from EUROCAT Northern Netherlands, a registry of congenital anomalies. The referent population (N = 31,055) was selected from the pregnancy IADB.nl, a pharmacy prescription database. RESULTS: Ten placental transporters known to have comparable expression levels in the placenta to that of P-gp, were selected in this study. In total, 147 drugs were identified to be substrates, inhibitors or inducers, of these transporters. Fifty-eight of these drugs were used by at least one mother in our cases or referent population, and 28 were used in both. The highest user rate was observed for the substrates of multidrug resistance-associated protein 1, mainly folic acid (6% of cases, 8% of referents), and breast cancer resistance protein, mainly nitrofurantoin (2.3% of cases, 2.9% of referents). In contrast to P-gp, drug interactions involving substrates of these transporters did not have a significant effect on the risk of congenital anomalies. CONCLUSIONS: Some of the drugs which are substrates or inhibitors of placental transporters were commonly used during pregnancy. No significant effect of transporter inhibition was found on fetal drug exposure, possibly due to a limited number of exposures.


Assuntos
Anormalidades Congênitas/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Placenta/metabolismo , Interações de Medicamentos , Feminino , Humanos , Masculino , Gravidez
9.
Eur J Hum Genet ; 25(1): 43-51, 2016 01.
Artigo em Inglês | MEDLINE | ID: mdl-27804958

RESUMO

Verheij syndrome, also called 8q24.3 microdeletion syndrome, is a rare condition characterized by ante- and postnatal growth retardation, microcephaly, vertebral anomalies, joint laxity/dislocation, developmental delay (DD), cardiac and renal defects and dysmorphic features. Recently, PUF60 (Poly-U Binding Splicing Factor 60 kDa), which encodes a component of the spliceosome, has been discussed as the best candidate gene for the Verheij syndrome phenotype, regarding the cardiac and short stature phenotype. To date, only one patient has been reported with a de novo variant in PUF60 that probably affects function (c.505C>T leading to p.(His169Tyr)) associated with DD, microcephaly, craniofacial and cardiac defects. Additional patients were required to confirm the pathogenesis of this association and further delineate the clinical spectrum. Here we report five patients with de novo heterozygous variants in PUF60 identified using whole exome sequencing. Variants included a splice-site variant (c.24+1G>C), a frameshift variant (p.(Ile136Thrfs*31)), two nonsense variants (p.(Arg448*) and p.(Lys301*)) and a missense change (p.(Val483Ala)). All six patients with a PUF60 variant (the five patients of the present study and the unique reported patient) have the same core facial gestalt as 8q24.3 microdeletions patients, associated with DD. Other findings include feeding difficulties (3/6), cardiac defects (5/6), short stature (5/6), joint laxity and/or dislocation (5/6), vertebral anomalies (3/6), bilateral microphthalmia and irido-retinal coloboma (1/6), bilateral optic nerve hypoplasia (2/6), renal anomalies (2/6) and branchial arch defects (2/6). These results confirm that PUF60 is a major driver for the developmental, craniofacial, skeletal and cardiac phenotypes associated with the 8q24.3 microdeletion.


Assuntos
Nanismo/genética , Cardiopatias Congênitas/genética , Deficiência Intelectual/genética , Fatores de Processamento de RNA/genética , Proteínas Repressoras/genética , Adolescente , Criança , Pré-Escolar , Deleção Cromossômica , Cromossomos Humanos Par 8/genética , Nanismo/fisiopatologia , Exoma/genética , Feminino , Mutação da Fase de Leitura , Cardiopatias Congênitas/fisiopatologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Deficiência Intelectual/fisiopatologia , Masculino , Fenótipo , Processamento de RNA/genética
10.
Int J Mol Sci ; 17(8)2016 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-27529241

RESUMO

Serotonin reuptake inhibitors (SRIs) are often prescribed during pregnancy. Previous studies that found an increased risk of congenital anomalies, particularly congenital heart anomalies (CHA), with SRI use during pregnancy have created concern among pregnant women and healthcare professionals about the safety of these drugs. However, subsequent studies have reported conflicting results on the association between CHA and SRI use during pregnancy. These discrepancies in the risk estimates can potentially be explained by genetic differences among exposed individuals. In this review, we explore the potential pharmacogenetic predictors involved in the pharmacokinetics and mechanism of action of SRIs, and their relation to the risk of CHA. In general, the risk is dependent on the maternal concentration of SRIs and the foetal serotonin level/effect, which can be modulated by the alteration in the expression and/or function of the metabolic enzymes, transporter proteins and serotonin receptors involved in the serotonin signalling of the foetal heart development. Pharmacogenetics might be the key to understanding why some children exposed to SRIs develop a congenital heart anomaly and others do not.


Assuntos
Cardiopatias Congênitas/induzido quimicamente , Cardiopatias Congênitas/genética , Farmacogenética , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/genética , Inibidores de Captação de Serotonina/efeitos adversos , Feminino , Humanos , Gravidez , Primeiro Trimestre da Gravidez/fisiologia , Fatores de Risco
11.
Dis Model Mech ; 9(4): 413-25, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26822476

RESUMO

Lipoprotein-related receptor protein 2 (LRP2) is important for development of the embryonic neural crest and brain in both mice and humans. Although a role in cardiovascular development can be expected, the hearts ofLrp2knockout (KO) mice have not yet been investigated. We studied the cardiovascular development ofLrp2KO mice between embryonic day 10.5 (E10.5) and E15.5, applying morphometry and immunohistochemistry, using antibodies against Tfap2α (neural crest cells), Nkx2.5 (second heart field), WT1 (epicardium derived cells), tropomyosin (myocardium) and LRP2. TheLrp2KO mice display a range of severe cardiovascular abnormalities, including aortic arch anomalies, common arterial trunk (persistent truncus arteriosus) with coronary artery anomalies, ventricular septal defects, overriding of the tricuspid valve and marked thinning of the ventricular myocardium. Both the neural crest cells and second heart field, which are essential for the lengthening and growth of the right ventricular outflow tract, are abnormally positioned in theLrp2KO. This explains the absence of the aorto-pulmonary septum, which leads to common arterial trunk and ventricular septal defects. Severe blebbing of the epicardial cells covering the ventricles is seen. Epithelial-mesenchymal transition does occur; however, there are fewer WT1-positive epicardium-derived cells in the ventricular wall as compared to normal, coinciding with the myocardial thinning and deep intertrabecular spaces. LRP2 plays a crucial role in cardiovascular development in mice. This corroborates findings of cardiac anomalies in humans withLRP2mutations. Future studies should reveal the underlying signaling mechanisms in which LRP2 is involved during cardiogenesis.


Assuntos
Cardiopatias Congênitas/embriologia , Cardiopatias Congênitas/patologia , Coração/embriologia , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/deficiência , Animais , Movimento Celular , Embrião de Mamíferos/anormalidades , Embrião de Mamíferos/patologia , Endotélio Vascular/embriologia , Endotélio Vascular/patologia , Feminino , Imunofluorescência , Ventrículos do Coração/embriologia , Ventrículos do Coração/patologia , Imagem Tridimensional , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Cardiovasculares , Miocárdio/patologia , Crista Neural/patologia , Pericárdio/embriologia , Pericárdio/patologia
12.
Genet Med ; 18(9): 914-23, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-26820064

RESUMO

PURPOSE: We aimed to determine the prevalence and phenotypic spectrum of NOTCH1 mutations in left-sided congenital heart disease (LS-CHD). LS-CHD includes aortic valve stenosis, a bicuspid aortic valve, coarctation of the aorta, and hypoplastic left heart syndrome. METHODS: NOTCH1 was screened for mutations in 428 nonsyndromic probands with LS-CHD, and family histories were obtained for all. When a mutation was detected, relatives were also tested. RESULTS: In 148/428 patients (35%), LS-CHD was familial. Fourteen mutations (3%; 5 RNA splicing mutations, 8 truncating mutations, 1 whole-gene deletion) were detected, 11 in familial disease (11/148 (7%)) and 3 in sporadic disease (3/280 (1%)). Forty-nine additional mutation carriers were identified among the 14 families, of whom 12 (25%) were asymptomatic. Most of these mutation carriers had LS-CHD, but 9 (18%) had right-sided congenital heart disease (RS-CHD) or conotruncal heart disease (CTD). Thoracic aortic aneurysms (TAAs) occurred in 6 mutation carriers (probands included 6/63 (10%)). CONCLUSION: Pathogenic mutations in NOTCH1 were identified in 7% of familial LS-CHD and in 1% of sporadic LS-CHD. The penetrance is high; a cardiovascular malformation was found in 75% of NOTCH1 mutation carriers. The phenotypic spectrum includes LS-CHD, RS-CHD, CTD, and TAA. Testing NOTCH1 for an early diagnosis in LS-CHD/RS-CHD/CTD/TAA is warranted.Genet Med 18 9, 914-923.


Assuntos
Cardiopatias Congênitas/genética , Insuficiência Cardíaca/genética , Síndrome do Coração Esquerdo Hipoplásico/genética , Receptor Notch1/genética , Adolescente , Adulto , Idoso , Aorta/fisiopatologia , Aneurisma da Aorta Torácica/genética , Aneurisma da Aorta Torácica/fisiopatologia , Criança , Pré-Escolar , Feminino , Cardiopatias Congênitas/fisiopatologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Síndrome do Coração Esquerdo Hipoplásico/fisiopatologia , Masculino , Pessoa de Meia-Idade , Mutação , Linhagem
13.
Drug Saf ; 38(7): 651-9, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26017034

RESUMO

INTRODUCTION: Drug use in pregnancy is very common but may cause harm to the fetus. The teratogenic effect of a drug is partly dependent on the drug level in the fetal circulation, which is associated with the transport across the placenta. Many drugs are substrates of P-glycoprotein (P-gp), an efflux transporter that acts as a protective barrier for the fetus. We aim to identify whether drug interactions associated with P-gp promote any changes in fetal drug exposure, as measured by the risk of having children with congenital anomalies. METHODS: In this study, cases (N = 4634) were mothers of children with congenital anomalies registered in the EUROCAT Northern Netherlands registry, and the reference population were mothers of children (N = 25,126) from a drug prescription database (IADB.nl). RESULTS: Drugs that are associated with P-gp transport were commonly used in pregnancy in cases (10 %) and population (12 %). Several drug classes, which are substrates for P-gp, were shown to have a higher user rate in mothers of cases with specific anomalies. The use of this subset of drugs in combination with other P-gp substrates increased the risk for specific anomalies (odds ratio [OR] 4.17, 95 % CI 1.75-9.91), and the addition of inhibitors further increased the risk (OR 13.03, 95 % CI 3.37-50.42). The same pattern of risk increment was observed when the drugs were analyzed separately according to substrate specificity. CONCLUSIONS: The use of drugs associated with P-gp transport was common during pregnancy. For several drug classes associated with specific anomalies, P-gp-mediated drug interactions are associated with an increased risk for those specific anomalies.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Anormalidades Induzidas por Medicamentos/etiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Exposição Materna/efeitos adversos , Placenta/metabolismo , Medicamentos sob Prescrição/efeitos adversos , Anormalidades Induzidas por Medicamentos/diagnóstico , Anormalidades Induzidas por Medicamentos/metabolismo , Transporte Biológico , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Interações de Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/metabolismo , Feminino , Humanos , Masculino , Países Baixos , Razão de Chances , Gravidez , Medicamentos sob Prescrição/classificação , Sistema de Registros , Medição de Risco , Fatores de Risco
14.
Am J Med Genet A ; 164A(12): 3003-9, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25257999

RESUMO

Since 2004, CHD7 mutations have been a known cause of CHARGE (Coloboma, Heart defects, Atresia of choane, Retardation of growth and development, Genital hypoplasia, Ear anomalies) syndrome, but the full clinical spectrum of CHD7 mutations is only now gradually emerging. CHD7 mutations have been identified in patients who do not fulfill the clinical criteria for CHARGE syndrome and in patients with overlapping syndromes. Variable congenital heart defects occur in the majority of patients with CHD7 mutations, with an overrepresentation of atrioventricular septal defects and conotruncal heart defects. This prompted us to study CHD7 in 46 patients with these heart defects and one other feature of CHARGE syndrome. We identified two CHD7 variants that were inherited from a healthy parent (c.3778 + 17C > T, c.7294G > A), but no pathogenic CHD7 mutations. We conclude that CHD7 mutations are not a major cause of the atrioventricular septal defects and conotruncal heart defects, not even if one extra phenotypic feature of CHARGE syndrome is present. Therefore, CHD7 analysis should not be performed routinely in this group of patients. However, we do recommend adding CHD7 to massive parallel sequencing gene panels for diagnostic work in patients with syndromic heart defects.


Assuntos
DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Cardiopatias Congênitas/genética , Defeitos dos Septos Cardíacos/genética , Fenótipo , Feminino , Humanos , Masculino , Mutação Puntual/genética
15.
Circ Cardiovasc Genet ; 6(3): 248-54, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23677905

RESUMO

BACKGROUND: Loss-of-function mutations in CHD7 cause Coloboma, Heart Disease, Atresia of Choanae, Retardation of Growth and/or Development, Genital Hypoplasia, and Ear Abnormalities With or Without Deafness (CHARGE) syndrome, a variable combination of multiple congenital malformations including heart defects. Heart defects are reported in 70% to 92% of patients with a CHD7 mutation, but most studies are small and do not provide a detailed classification of the defects. We present the first, detailed, descriptive study on the cardiac phenotype of 299 patients with a CHD7 mutation and discuss the role of CHD7 in cardiac development. METHODS AND RESULTS: We collected information on congenital heart defects in 299 patients with a pathogenic CHD7 mutation, of whom 220 (74%) had a congenital heart defect. Detailed information on the heart defects was available for 202 of these patients. We classified the heart defects based on embryonic cardiac development and compared the distribution to 1007 equally classified nonsyndromic heart defects of patients registered by EUROCAT, a European Registry of Congenital Anomalies. Heart defects are highly variable in patients with CHD7 mutations, but atrioventricular septal defects and conotruncal heart defects are over-represented. Sex did not have an effect on the presence of heart defects, but truncating CHD7 mutations resulted in a heart defect significantly more often than missense or splice-site mutations (χ², P<0.001). CONCLUSIONS: CHD7 plays an important role in cardiac development, given that we found a wide range of heart defects in 74% of a large cohort of patients with a CHD7 mutation. Conotruncal defects and atrioventricular septal defects are over-represented in patients with CHD7 mutations compared with patients with nonsyndromic heart defects.


Assuntos
DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Cardiopatias Congênitas/enzimologia , Estudos de Coortes , DNA Helicases/metabolismo , Proteínas de Ligação a DNA/metabolismo , Feminino , Coração/embriologia , Cardiopatias Congênitas/embriologia , Cardiopatias Congênitas/genética , Humanos , Lactente , Masculino , Mutação , Fenótipo
16.
J Med Genet ; 50(8): 500-6, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23592887

RESUMO

BACKGROUND: Childhood-onset pulmonary arterial hypertension (PAH) is rare and differs from adult-onset disease in clinical presentation, with often unexplained mental retardation and dysmorphic features (MR/DF). Mutations in the major PAH gene, BMPR2, were reported to cause PAH in only 10-16% of childhood-onset patients. We aimed to identify more genes associated with childhood-onset PAH. METHODS: We studied 20 consecutive cases with idiopathic or heritable PAH. In patients with accompanying MR/DF (n=6) array-comparative genomic hybridisation analysis was performed, with the aim of finding common deletion regions containing candidate genes for PAH. Three patients had overlapping deletions of 17q23.2. TBX2 and TBX4 were selected from this area as candidate genes and sequenced in all 20 children. After identifying TBX4 mutations in these children, we subsequently sequenced TBX4 in a cohort of 49 adults with PAH. Because TBX4 mutations are known to cause small patella syndrome (SPS), all patients with newly detected TBX4 mutations were screened for features of SPS. We also screened a third cohort of 23 patients with SPS for PAH. RESULTS: TBX4 mutations (n=3) or TBX4-containing deletions (n=3) were detected in 6 out of 20 children with PAH (30%). All living patients and two parents with TBX4 mutations appeared to have previously unrecognised SPS. In the adult PAH-cohort, one TBX4 mutation (2%) was detected. Screening in the cohort of (predominantly adult) SPS patients revealed no PAH. CONCLUSIONS: These data indicate that TBX4 mutations are associated with childhood-onset PAH, but that the prevalence of PAH in adult TBX4 mutation carriers is low.


Assuntos
Doenças do Desenvolvimento Ósseo/genética , Quadril/anormalidades , Hipertensão Pulmonar/genética , Ísquio/anormalidades , Mutação , Patela/anormalidades , Proteínas com Domínio T/genética , Doenças do Desenvolvimento Ósseo/complicações , Criança , Pré-Escolar , Estudos de Coortes , Hipertensão Pulmonar Primária Familiar , Feminino , Predisposição Genética para Doença , Humanos , Hipertensão Pulmonar/complicações , Hipertensão Pulmonar/epidemiologia , Lactente , Masculino
17.
Biol Reprod ; 88(1): 24, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23153566

RESUMO

The importance of maternal cholesterol as an exogenous cholesterol source for the growing embryo was first reported in studies of Smith-Lemli-Opitz syndrome. Although most of the fetus's cholesterol is synthesized by the fetus itself, there is now growing evidence that during the first weeks of life, when most organs develop, the fetus largely depends on maternal cholesterol as its cholesterol source. The maternal-fetal cholesterol transport mechanism, by transporters in both the yolk sac and placenta, is becoming better understood. This minireview summarizes current insights on maternal-fetal cholesterol transport based on in vitro and in vivo studies. As the prevalence of maternal diseases, such as diabetes, obesity, and the metabolic syndrome that adversely affect maternal cholesterol levels, is now rapidly reaching epidemic proportions, we urgently need to determine the impact of these maternal conditions on the developing human fetus.


Assuntos
Colesterol/metabolismo , Troca Materno-Fetal/fisiologia , Transporte Biológico/fisiologia , Feminino , Desenvolvimento Fetal/fisiologia , Humanos , Gravidez
18.
Am J Obstet Gynecol ; 207(3): 202.e19-25, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22728028

RESUMO

OBJECTIVE: Cholesterol is crucial for fetal development. To gain more insight into the origin of the fetal cholesterol pool in early human pregnancy, we determined cholesterol and its precursors in the amniotic fluid of uncomplicated, singleton human pregnancies. STUDY DESIGN: Total sterols were characterized by gas chromatography-mass spectrometry in the second-trimester amniotic fluid of 126 healthy fetuses from week 15 until week 22. RESULTS: The markers of cholesterol biosynthesis, lanosterol, dihydrolanosterol, and lathosterol, were present in low levels until the 19th week of gestation, after which their levels increased strongly. ß-sitosterol, a marker for maternal-fetal cholesterol transport, was detectable in the amniotic fluid. The total cholesterol levels increased slightly between weeks 15 and 22. CONCLUSION: Our results support the hypothesis that during early life the fetus depends on maternal cholesterol supply because endogenous synthesis is relatively low. Therefore, maternal cholesterol can play a crucial role in fetal development.


Assuntos
Líquido Amniótico/química , Troca Materno-Fetal , Esteróis/análise , Esteróis/metabolismo , Feminino , Humanos , Gravidez , Segundo Trimestre da Gravidez , Estudos Retrospectivos , Esteróis/biossíntese
19.
Heart ; 98(6): 474-9, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22294555

RESUMO

OBJECTIVE: To study the influence of a possible interaction between maternal smoking and high body mass index (BMI) on the occurrence of specific congenital heart anomalies (CHA) in offspring. DESIGN: Case-control study. SETTING: Data from a population-based birth defects registry in the Netherlands. PATIENTS: Cases were 797 children and fetuses born between 1997 and 2008 with isolated non-syndromic CHA. They were classified into five cardiac subgroups: septal defects (n=349), right ventricular outflow tract obstructive anomalies (n=126), left ventricular outflow tract obstructive anomalies (n=139), conotruncal defects (n=115) and other CHA (n=68). Controls were 322 children and fetuses with chromosomal anomalies without cardiac anomalies. MAIN OUTCOME MEASURES: Investigation of whether an interaction between maternal smoking and high BMI influences the occurrence of CHA in offspring by calculation of the synergy factors and 95% CIs. RESULTS: As opposed to smoking or high BMI alone, the risk for CHA in the offspring of women with high BMI (≥25 kg/m(2)) who also smoked was significantly increased. The adjusted OR was 2.65 (95% CI 1.20 to 5.87) for all CHA, 2.60 (95% CI 1.05 to 6.47) for septal defects and 3.58 (95% CI 1.46 to 8.79) for outflow tract anomalies. The interaction between maternal high BMI and smoking contributed significantly to the occurrence of all offspring-CHA combined, and to the occurrence of all cardiac subgroup anomalies except right ventricular outflow tract obstructive anomalies. CONCLUSIONS: Maternal overweight and smoking may have a synergistic adverse effect on the development of the fetal heart. Overweight women who wish to become pregnant should be strongly encouraged to stop smoking and to lose weight.


Assuntos
Índice de Massa Corporal , Cardiopatias Congênitas/etiologia , Fumar/efeitos adversos , Adulto , Estudos de Casos e Controles , Feminino , Coração/embriologia , Humanos , Recém-Nascido , Masculino , Gravidez , Estudos Retrospectivos , Fatores de Risco
20.
Eur J Hum Genet ; 20(2): 161-5, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21934709

RESUMO

The correct interpretation of copy number gains in patients with developmental delay and multiple congenital anomalies is hampered by the large number of copy number variations (CNVs) encountered in healthy individuals. The variable phenotype associated with copy number gains makes interpretation even more difficult. Literature shows that inheritence, size and presence in healthy individuals are commonly used to decide whether a certain copy number gain is pathogenic, but no general consensus has been established. We aimed to develop guidelines for interpreting gains detected by array analysis using array CGH data of 300 patients analysed with the 105K Agilent oligo array in a diagnostic setting. We evaluated the guidelines in a second, independent, cohort of 300 patients. In the first 300 patients 797 gains of four or more adjacent oligonucleotides were observed. Of these, 45.4% were de novo and 54.6% were familial. In total, 94.8% of all de novo gains and 87.1% of all familial gains were concluded to be benign CNVs. Clinically relevant gains ranged from 288 to 7912 kb in size, and were significantly larger than benign gains and gains of unknown clinical relevance (P < 0.001). Our study showed that a threshold of 200 kb is acceptable in a clinical setting, whereas heritability does not exclude a pathogenic nature of a gain. Evaluation of the guidelines in the second cohort of 300 patients revealed that the interpretation guidelines were clear, easy to follow and efficient.


Assuntos
Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Hibridização Genômica Comparativa , Variações do Número de Cópias de DNA , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/genética , Estudos de Coortes , Feminino , Humanos , Masculino , Guias de Prática Clínica como Assunto
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