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1.
Neth Heart J ; 19(2): 85-88, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21461037

RESUMO

Expectations are high that increasing knowledge of the genetic basis of cardiovascular disease will eventually lead to personalised medicine-to preventive and therapeutic interventions that are targeted to at-risk individuals on the basis of their genetic profiles. Most cardiovascular diseases are caused by a complex interplay of many genetic variants interacting with many non-genetic risk factors such as diet, exercise, smoking and alcohol consumption. Since several years, genetic susceptibility testing for cardiovascular diseases is being offered via the internet directly to consumers. We discuss five reasons why these tests are not useful, namely: (1) the predictive ability is still limited; (2) the risk models used by the companies are based on assumptions that have not been verified; (3) the predicted risks keep changing when new variants are discovered and added to the test; (4) the tests do not consider non-genetic factors in the prediction of cardiovascular disease risk; and (5) the test results will not change recommendations of preventive interventions. Predictive genetic testing for multifactorial forms of cardiovascular disease clearly lacks benefits for the public. Prevention of disease should therefore remain focused on family history and on non-genetic risk factors as diet and physical activity that can have the strongest impact on disease risk, regardless of genetic susceptibility.

2.
J Med Genet ; 43(7): e35, 2006 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16816022

RESUMO

We report on a multigenerational family with isolated Hirschsprung's disease (HSCR). Five patients were affected by either short segment or long segment HSCR. The family consists of two main branches: one with four patients (three siblings and one maternal uncle) and one with one patient. Analysis of the RET gene, the major gene involved in HSCR susceptibility, revealed neither linkage nor mutations. A genome wide linkage analysis was performed, revealing suggestive linkage to a region on 4q31-q32 with a maximum parametric multipoint LOD score of 2.7. Furthermore, non-parametric linkage (NPL) analysis of the genome wide scan data revealed a NPL score of 2.54 (p = 0.003) for the same region on chromosome 4q (D4S413-D4S3351). The minimum linkage interval spans a region of 11.7 cM (12.2 Mb). No genes within this chromosomal interval have previously been implicated in HSCR. Considering the low penetrance of disease in this family, the 4q locus may be necessary but not sufficient to cause HSCR in the absence of modifying loci elsewhere in the genome. Our results suggest the existence of a new susceptibility locus for HSCR at 4q31.3-q32.3.


Assuntos
Cromossomos Humanos Par 4 , Predisposição Genética para Doença , Doença de Hirschsprung/genética , Mapeamento Cromossômico , Feminino , Genes Dominantes , Humanos , Masculino , Países Baixos , Linhagem , Proteínas Proto-Oncogênicas c-ret/genética
4.
Am J Med Genet ; 87(2): 99-114, 1999 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-10533024

RESUMO

We describe clinical, pathological and radiological findings in 15 cases of sporadic and familial lower spine agenesis with additional anomalies of the axial skeleton and internal organs and speculate about the cause and pathogenesis of this malformation complex. We show that all of these findings are defects of blastogenesis, originate in the primary developmental field and/or the progenitor fields, thus representing polytopic field defects. This concept appears applicable in our cases and makes such terms such as "caudal regression syndrome" or "axial mesodermal dysplasia spectrum" redundant.


Assuntos
Anormalidades Múltiplas , Vértebras Lombares/anormalidades , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/embriologia , Anormalidades Múltiplas/mortalidade , Adulto , Consanguinidade , Evolução Fatal , Feminino , Feto/anormalidades , Feto/diagnóstico por imagem , Idade Gestacional , Humanos , Lactente , Recém-Nascido , Vértebras Lombares/diagnóstico por imagem , Vértebras Lombares/embriologia , Masculino , Radiografia , Síndrome
5.
Hum Mutat ; 13(4): 301-10, 1999.
Artigo em Inglês | MEDLINE | ID: mdl-10220144

RESUMO

Congenital long QT syndrome (cLQTS) is electrocardiographically characterized by a prolonged QT interval and polymorphic ventricular arrhythmias (torsade de pointes). These cardiac arrhythmias may result in recurrent syncopes, seizure, or sudden death. LQTS can occur either as an autosomal dominant (Romano Ward) or as an autosomal recessive disorder (Jervell and Lange-Nielsen syndrome). Mutations in at least five genes have been associated with the LQTS. Four genes, encoding cardiac ion channels, have been identified. The most common forms of LQTS are due to mutations in the potassium-channel genes KCNQ1 and HERG. We have screened 24 Dutch LQTS families for mutations in KCNQ1 and HERG. Fourteen missense mutations were identified. Eight of these missense mutations were novel: three in KCNQ1 and five in HERG. Novel missense mutations in KCNQ1 were Y184S, S373P, and W392R and novel missense mutations in HERG were A558P, R582C, G604S, T613M, and F640L. The KCNQ1 mutation G189R and the HERG mutation R582C were detected in two families. The pathogenicity of the mutations was based on segregation in families, absence in control individuals, the nature of the amino acid substitution, and localization in the protein. Genotype-phenotype studies indicated that auditory stimuli as trigger of cardiac events differentiate LQTS2 and LQTS1. In LQTS1, exercise was the predominant trigger. In addition, a number of asymptomatic gene defect carriers were identified. Asymptomatic carriers are still at risk of the development of life-threatening arrhythmias, underlining the importance of DNA analyses for unequivocal diagnosis of patients with LQTS.


Assuntos
Proteínas de Transporte de Cátions , Proteínas de Ligação a DNA , Síndrome do QT Longo/genética , Mutação de Sentido Incorreto , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Canais de Potássio/genética , Transativadores , Análise Mutacional de DNA , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go , Ligação Genética , Haplótipos , Humanos , Canais de Potássio KCNQ , Canal de Potássio KCNQ1 , Repetições de Microssatélites , Países Baixos , Linhagem , Polimorfismo Genético , Homologia de Sequência de Aminoácidos , Regulador Transcricional ERG
6.
J Am Coll Cardiol ; 33(2): 327-32, 1999 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-9973011

RESUMO

OBJECTIVE: This study was performed to identify a possible relationship between genotype and phenotype in the congenital familial long QT syndrome (cLQTS). BACKGROUND: The cLQTS, which occurs as an autosomal dominant or recessive trait, is characterized by QT-interval prolongation on the electrocardiogram and torsade de pointes arrhythmias, which may give rise to recurrent syncope or sudden cardiac death. Precipitators for cardiac events are exercise or emotion and occasionally acoustic stimuli. METHODS: The trigger for cardiac events (syncope, documented cardiac arrhythmias, sudden cardiac death) was analyzed in 11 families with a familial LQTS and a determined genotype. RESULTS: The families were subdivided in KVLQT1-related families (LQTS1, n = 5) and HERG (human ether-a-gogo-related gene)-related families (LQTS2, n = 6) based on single-strand conformation polymorphism analysis and sequencing. Whereas exercise-related cardiac events dominate the clinical picture of LQTS1 patients, auditory stimuli as a trigger for arrhythmic events were only seen in LQTS2 patients. CONCLUSIONS: Arrhythmic events triggered by auditory stimuli may differentiate LQTS2 from LQTS1 patients.


Assuntos
Estimulação Acústica , Proteínas de Transporte de Cátions , Proteínas de Ligação a DNA , Síndrome do QT Longo/diagnóstico , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Canais de Potássio/genética , Transativadores , Adulto , Idoso , Idoso de 80 Anos ou mais , DNA/análise , Sondas de DNA/química , Morte Súbita Cardíaca/etiologia , Progressão da Doença , Canal de Potássio ERG1 , Eletrocardiografia , Canais de Potássio Éter-A-Go-Go , Feminino , Seguimentos , Genótipo , Frequência Cardíaca , Humanos , Canais de Potássio KCNQ , Canal de Potássio KCNQ1 , Síndrome do QT Longo/etiologia , Síndrome do QT Longo/genética , Masculino , Mutação , Fenótipo , Polimorfismo Conformacional de Fita Simples , Regulador Transcricional ERG
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