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1.
Fam Cancer ; 15(4): 563-70, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-26880076

RESUMO

Familial adenomatous polyposis (FAP) is a dominantly inherited syndrome caused by germline mutations in the APC gene and characterized by the development of multiple colorectal adenomas and a high risk of developing colorectal cancer (CRC). The severity of polyposis is correlated with the site of the APC mutation. However, there is also phenotypic variability within families with the same underlying APC mutation, suggesting that additional factors influence the severity of polyposis. Genome-wide association studies identified several single nucleotide polymorphisms (SNPs) that are associated with CRC. We assessed whether these SNPs are associated with polyp multiplicity in proven APC mutation carriers. Sixteen CRC-associated SNPs were analysed in a cohort of 419 APC germline mutation carriers from 182 families. Clinical data were retrieved from the Dutch Polyposis Registry. Allele frequencies of the SNPs were compared for patients with <100 colorectal adenomas versus patients with ≥100 adenomas, using generalized estimating equations with the APC genotype as a covariate. We found a trend of association of two of the tested SNPs with the ≥100 adenoma phenotype: the C alleles of rs16892766 at 8q23.3 (OR 1.71, 95 % CI 1.05-2.76, p = 0.03, dominant model) and rs3802842 at 11q23.1 (OR 1.51, 95 % CI 1.03-2.22, p = 0.04, dominant model). We identified two risk variants that are associated with a more severe phenotype in APC mutation carriers. These risk variants may partly explain the phenotypic variability in families with the same APC gene defect. Further studies with a larger sample size are recommended to evaluate and confirm the phenotypic effect of these SNPs in FAP.


Assuntos
Proteína da Polipose Adenomatosa do Colo/genética , Cromossomos Humanos Par 11 , Cromossomos Humanos Par 8 , Neoplasias Colorretais/genética , Adenoma/genética , Polipose Adenomatosa do Colo/genética , Adulto , Frequência do Gene , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Mutação , Polimorfismo de Nucleotídeo Único
3.
J Med Genet ; 43(10): 793-7, 2006 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16613914

RESUMO

BACKGROUND: Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant disease exhibiting multifocal vascular telangiectases and arteriovenous malformations. The majority of cases are caused by mutations in either the endoglin (ENG) or activin receptor-like kinase 1 (ALK1, ACVRL1) genes; both members of the transforming growth factor (TGF)-beta pathway. Mutations in SMAD4, another TGF-beta pathway member, are seen in patients with the combined syndrome of juvenile polyposis (JP) and HHT (JP-HHT). METHODS: We sought to determine if HHT patients without any apparent history of JP, who were undergoing routine diagnostic testing, would have mutations in SMAD4. We tested 30 unrelated HHT patients, all of whom had been referred for DNA based testing for HHT and were found to be negative for mutations in ENG and ALK1. RESULTS: Three of these people harboured mutations in SMAD4, a rate of 10% (3/30). The SMAD4 mutations were similar to those found in other patients with the JP-HHT syndrome. CONCLUSIONS: The identification of SMAD4 mutations in HHT patients without prior diagnosis of JP has significant and immediate clinical implications, as these people are likely to be at risk of having JP-HHT with the associated increased risk of gastrointestinal cancer. We propose that routine DNA based testing for HHT should include SMAD4 for samples in which mutations in neither ENG nor ALK1 are identified. HHT patients with SMAD4 mutations should be screened for colonic and gastric polyps associated with JP.


Assuntos
Proteína Smad4/genética , Telangiectasia Hemorrágica Hereditária/genética , Receptores de Activinas Tipo II/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/genética , Análise Mutacional de DNA , Endoglina , Testes Genéticos , Humanos , Pólipos Intestinais/genética , Pessoa de Meia-Idade , Mutação , Pólipos/genética , Receptores de Superfície Celular/genética
4.
Am J Med Genet A ; 140(3): 284-90, 2006 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-16411219

RESUMO

We describe a unique case of achondroplasia with associated complications, including severe respiratory problems. Molecular analysis of the fibroblast growth factor receptor type 3 (FGFR3) gene in this patient showed the common p.G380R mutation and a second novel p.L377R mutation. An allele-specific PCR demonstrated that these mutations were on the same allele (cis). Both mutations were not present in the parents and appear to have occurred de novo. To our knowledge, this is the first report in the literature on an achondroplasia patient with two FGFR3 mutations on the same allele.


Assuntos
Acondroplasia/genética , Mutação , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Acondroplasia/complicações , Alelos , Sequência de Bases , Análise Mutacional de DNA , Evolução Fatal , Humanos , Lactente , Recém-Nascido , Masculino , Mutação de Sentido Incorreto , Síndrome do Desconforto Respiratório do Recém-Nascido/complicações
5.
J Med Genet ; 43(4): 371-7, 2006 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16155196

RESUMO

Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant disorder characterised by vascular malformations in multiple organ systems, resulting in mucocutaneous telangiectases and arteriovenous malformations predominantly in the lungs (pulmonary arteriovenous malformation; PAVM), brain (cerebral arteriovenous malformation; CAVM), and liver (hepatic arteriovenous malformation; HAVM). Mutations in the ENG and ALK-1 genes lead to HHT1 and HHT2 respectively. In this study, a genotype-phenotype analysis was performed. A uniform and well classified large group of HHT patients and their family members were screened for HHT manifestations. Groups of patients with a clinically confirmed diagnosis and/or genetically established diagnosis (HHT1 or HHT2) were compared. The frequency of PAVM, CAVM, HAVM, and gastrointestinal telangiectases were determined to establish the genotype-phenotype relationship. The analysis revealed differences between HHT1 and HHT2 and within HHT1 and HHT2 between men and women. PAVMs and CAVMs occur more often in HHT1, whereas HAVMs are more frequent in HHT2. Furthermore, there is a higher prevalence of PAVM in women compared with men in HHT1. In HHT1 and HHT2, there is a higher frequency of HAVM in women. HHT1 has a distinct, more severe phenotype than HHT2. There is a difference in the presence of symptoms between men and women. With these data, genetic counselling can be given more accurately when the family mutation is known.


Assuntos
Receptores de Activinas Tipo II/genética , Antígenos CD/genética , Receptores de Superfície Celular/genética , Telangiectasia Hemorrágica Hereditária/diagnóstico , Adulto , Malformações Arteriovenosas/classificação , Malformações Arteriovenosas/epidemiologia , Malformações Arteriovenosas/genética , Análise Mutacional de DNA , Endoglina , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Fenótipo , Fatores Sexuais , Telangiectasia Hemorrágica Hereditária/epidemiologia , Telangiectasia Hemorrágica Hereditária/genética
6.
Hum Genet ; 116(1-2): 8-16, 2005 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-15517393

RESUMO

Hereditary hemorrhagic telangiectasia (HHT) or Rendu-Osler-Weber disease is an autosomal dominant disorder characterized by an aberrant vascular development. The resulting vascular lesions range from smaller mucocutaneous telangiectases to large visceral arteriovenous malformations, especially in the skin, lung, gastrointestinal tract and the brain. Mutations in the genes encoding endoglin (ENG, chromosome 9q34) and activin A receptor type-like kinase 1 (ALK-1, also named ACVRL1, chromosome 12q13) are associated with HHT1 and HHT2, respectively. We report here on the genetic and molecular heterogeneity found in the HHT population in the Netherlands. Probands of 104 apparently unrelated families were studied and we performed sequence analysis on both the ENG gene and ALK-1 gene. In most of the probands, we found a mutation in one of the two genes: 53% in the ENG gene and 40% in the ALK-1 gene. In 7% of the families no ENG or ALK1 mutation was found. The mutations detected were deletions, insertions, nonsense, missense and splice site mutations. The majority were novel mutations.


Assuntos
Receptores de Ativinas Tipo I/genética , Telangiectasia Hemorrágica Hereditária/genética , Molécula 1 de Adesão de Célula Vascular/genética , Receptores de Activinas Tipo II , Sequência de Aminoácidos , Antígenos CD , Análise Mutacional de DNA , Endoglina , Humanos , Dados de Sequência Molecular , Países Baixos , Receptores de Superfície Celular , Alinhamento de Sequência
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