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1.
Clin Genet ; 86(3): 246-51, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24003905

RESUMO

Nager syndrome belongs to the group of acrofacial dysostosis, which are characterized by the association of craniofacial and limb malformations. Recently, exome sequencing studies identified the SF3B4 gene as the cause of this condition in most patients. SF3B4 encodes a highly conserved protein implicated in mRNA splicing and bone morphogenic protein (BMP) signaling. We performed SF3B4 sequencing in 14 families (18 patients) whose features were suggestive of Nager syndrome and found nine mutations predicted to result in loss-of-function. SF3B4 is the major gene responsible for autosomal dominant Nager syndrome. All mutations reported predict null alleles, therefore precluding genotype-phenotype correlations. Most mutation-negative patients were phenotypically indistinguishable from patients with mutations, suggesting genetic heterogeneity.


Assuntos
Predisposição Genética para Doença/genética , Haploinsuficiência/genética , Disostose Mandibulofacial/genética , Fenótipo , Proteínas de Ligação a RNA/genética , Sequência de Bases , Feminino , Genes Dominantes/genética , Humanos , Masculino , Disostose Mandibulofacial/patologia , Dados de Sequência Molecular , Mutação/genética , Fatores de Processamento de RNA , Análise de Sequência de DNA
3.
Clin Genet ; 84(6): 507-21, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23506379

RESUMO

The association of marfanoid habitus (MH) and intellectual disability (ID) has been reported in the literature, with overlapping presentations and genetic heterogeneity. A hundred patients (71 males and 29 females) with a MH and ID were recruited. Custom-designed 244K array-CGH (Agilent®; Agilent Technologies Inc., Santa Clara, CA) and MED12, ZDHHC9, UPF3B, FBN1, TGFBR1 and TGFBR2 sequencing analyses were performed. Eighty patients could be classified as isolated MH and ID: 12 chromosomal imbalances, 1 FBN1 mutation and 1 possibly pathogenic MED12 mutation were found (17%). Twenty patients could be classified as ID with other extra-skeletal features of the Marfan syndrome (MFS) spectrum: 4 pathogenic FBN1 mutations and 4 chromosomal imbalances were found (2 patients with both FBN1 mutation and chromosomal rearrangement) (29%). These results suggest either that there are more loci with genes yet to be discovered or that MH can also be a relatively non-specific feature of patients with ID. The search for aortic complications is mandatory even if MH is associated with ID since FBN1 mutations or rearrangements were found in some patients. The excess of males is in favour of the involvement of other X-linked genes. Although it was impossible to make a diagnosis in 80% of patients, these results will improve genetic counselling in families.


Assuntos
Testes Genéticos/métodos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Síndrome de Marfan/diagnóstico , Síndrome de Marfan/genética , Adolescente , Adulto , Criança , Pré-Escolar , Hibridização Genômica Comparativa , Análise Citogenética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Estudos Prospectivos , Análise de Sequência de DNA , Inativação do Cromossomo X , Adulto Jovem
4.
Prenat Diagn ; 32(13): 1318-23, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23147988

RESUMO

OBJECTIVES: Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder with manifestations mainly involving the skeletal, ocular, and cardiovascular systems. The phenotypic variability observed in MFS makes genetic counselling difficult. Prenatal diagnosis (PND) and preimplantation genetic diagnosis are technically feasible when a causal mutation is identified, but both raise many ethical questions in this condition. Little is known about opinions and practices in such reproductive issues in MFS. The goal of this study was to report on patients' points of view and geneticists' standard practices. METHODS: Two different questionnaires were produced. RESULTS: Fifty geneticists filled in the questionnaire. Twenty-two per cent thought that PND was acceptable, 72% debatable and 6% not acceptable. Preimplantation genetic diagnosis was more often reported acceptable (34% of answers). Results varied according to the physician's experience with the disease. Fifty-four answers were collected for patients' questionnaires. Most of them (74%) were favourable to the development of prenatal testing, and believed that the choice should be given to parents. However, only a minority would opt for prenatal diagnosis for themselves. CONCLUSION: This study showed that the majority of patients were in favour of PND and that opinions among practitioners varied widely, but that overall, practitioners favoured a systematic multidisciplinary evaluation of the couple's request.


Assuntos
Genética Médica/estatística & dados numéricos , Síndrome de Marfan/diagnóstico , Pais/psicologia , Diagnóstico Pré-Implantação/psicologia , Diagnóstico Pré-Natal/psicologia , Adolescente , Adulto , Feminino , França , Humanos , Masculino , Síndrome de Marfan/psicologia , Pessoa de Meia-Idade , Inquéritos e Questionários , Adulto Jovem
5.
J Med Genet ; 43(5): 401-5, 2006 May.
Artigo em Inglês | MEDLINE | ID: mdl-16443854

RESUMO

BACKGROUND: Costello syndrome (CS) is a rare multiple congenital abnormality syndrome, associated with failure to thrive and developmental delay. One of the more distinctive features in childhood is the development of facial warts, often nasolabial and in other moist body surfaces. Individuals with CS have an increased risk of malignancy, suggested to be about 17%. Recently, mutations in the HRAS gene on chromosome 11p13.3 have been found to cause CS. METHODS: We report here the results of HRAS analysis in 43 individuals with a clinical diagnosis of CS. RESULTS: Mutations were found in 37 (86%) of patients. Analysis of parental DNA samples was possible in 16 cases for both parents and in three cases for one parent, and confirmed the mutations as de novo in all of these cases. Three novel mutations (G12C, G12E, and K117R) were found in five cases. CONCLUSIONS: These results confirm that CS is caused, in most cases, by heterozygous missense mutations in the proto-oncogene HRAS. Analysis of the major phenotypic features by mutation suggests a potential correlation between malignancy risk and genotype, which is highest for patients with an uncommon (G12A) substitution. These results confirm that mutation testing for HRAS is a reliable diagnostic test for CS.


Assuntos
Anormalidades Múltiplas/diagnóstico , Proteínas Proto-Oncogênicas p21(ras)/genética , Anormalidades Múltiplas/genética , Adolescente , Adulto , Criança , Pré-Escolar , Análise Mutacional de DNA , Diagnóstico Diferencial , Feminino , Genótipo , Humanos , Lactente , Peptídeos e Proteínas de Sinalização Intracelular/genética , Síndrome de Noonan/diagnóstico , Síndrome de Noonan/genética , Fenótipo , Proteína Tirosina Fosfatase não Receptora Tipo 11 , Proteínas Tirosina Fosfatases/genética , Proto-Oncogene Mas , Síndrome
6.
Genet Couns ; 13(3): 319-25, 2002.
Artigo em Inglês | MEDLINE | ID: mdl-12416640

RESUMO

Ectrodactyly and phocomelia are well known limbs malformations. They can be a part of various syndromes, and are more often transmitted with dominant autosomal Inheritance with variable expression and Incomplete penetrance. Different loci have been Identified for ectrodactyly (SHFM1 at 7q21.3q22.1, SHFM2 at Xq26, SHFM3 at 10q24q25, SHFM4 at 3q27), and two genes are known (DSS1 for SHFM1, p63 for SHFM4). We report the case of a 33 year-old female affected with the association of ectrodactyly and phocomelia. It could be a "new" association, or a mild or partial expression of the syndrome Including ectrodactyly, phocomelia, deafness and sinusal arythmia.


Assuntos
Anormalidades Múltiplas/genética , Displasia Ectodérmica/genética , Ectromelia/genética , Deformidades Congênitas da Mão/genética , Anormalidades Múltiplas/patologia , Adulto , Criança , Displasia Ectodérmica/complicações , Displasia Ectodérmica/patologia , Ectromelia/complicações , Ectromelia/patologia , Feminino , Dedos/anormalidades , Genes Dominantes , Deformidades Congênitas da Mão/complicações , Deformidades Congênitas da Mão/patologia , Humanos
7.
Arch Pediatr ; 9(10): 1059-63, 2002 Oct.
Artigo em Francês | MEDLINE | ID: mdl-12462839

RESUMO

Costello syndrome is a sporadic development anomaly suggesting a genetic determinism. Main features include characteristic facial features, mental retardation, growth retardation, cutis laxa, heart malformation, and peri-orificial papillomata. In previous reported cases, the frequency of tumors is 15%, which argues for a screening protocol. The occurrence of a tumor in a child with growth retardation and cutis laxa must be reminiscent of Costello syndrome. The determinism of this syndrome is still unknown, and the hypothesis of an inactivation of a tumor suppressor gene is to be considered.


Assuntos
Anormalidades Múltiplas/patologia , Transtornos do Crescimento , Deficiência Intelectual , Neoplasias/etiologia , Criança , Pré-Escolar , Face/anormalidades , Feminino , Genes Supressores de Tumor , Humanos , Lactente , Recém-Nascido , Masculino , Fenótipo
8.
Arch Pediatr ; 20(11): 1193-1200, 2013 Nov.
Artigo em Francês | MEDLINE | ID: mdl-24090671

RESUMO

Diagnosing Marfan syndrome in young children is difficult because of the great variability of expression of the disease and because the phenotype evolves over the life course. The goal of this retrospective study was to describe the first clinical symptoms in children under 10 years of age with Marfan syndrome and to evaluate the pertinence of the new 2010 Ghent criteria in comparison with the 1996 criteria. Seventeen patients under 10 by the time of the first medical examination were included. All children had an FBN1 gene mutation that was secondarily demonstrated. Clinical data including ophthalmological, cardiac, and orthopaedic examinations obtained during the first medical examination were analyzed. The most frequent abnormalities encountered were high arched palate (82%), arachnodactyly (71%), and flatfoot (59%). Aortic aneurysm (47%) and ectopic lens (35%) were also seen at the time of diagnosis. According to the 2010 Ghent criteria, the diagnosis of Marfan syndrome could be obtained in 71% of patients after identification of the mutation of the FBN1 gene, whereas only 59% of patients were diagnosed using the older criteria. All organs can be affected during childhood. An early diagnosis is essential in order to set up specific management.


Assuntos
Síndrome de Marfan/diagnóstico , Aneurisma Aórtico/etiologia , Aracnodactilia/etiologia , Criança , Pré-Escolar , Ectopia do Cristalino/etiologia , Fácies , Feminino , Fibrilina-1 , Fibrilinas , Pé Chato/etiologia , Tórax em Funil/etiologia , Humanos , Lactente , Instabilidade Articular/etiologia , Masculino , Síndrome de Marfan/genética , Proteínas dos Microfilamentos/genética , Mutação , Palato/anormalidades , Estudos Retrospectivos
10.
Clin Genet ; 66(2): 83-93, 2004 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15253756

RESUMO

Although obesity shows high heritability, we are aware of only a small number of genes that affect adipose mass in humans. Genetic syndromes with obesity represent unique opportunities to gain insight into the control of energy balance. The majority of obesity syndromes can be distinguished by the presence of mental retardation. We performed a systematic search of such syndromes and reviewed the literature with a focus on distinguishing clinical features, the characteristics of their obesity, and the underlying pathogenetic mechanisms. We predict that the study of these conditions will shed light on common forms of obesity.


Assuntos
Deficiência Intelectual/complicações , Obesidade/complicações , Obesidade/genética , Aberrações Cromossômicas , Expressão Gênica , Doenças Genéticas Ligadas ao Cromossomo X/complicações , Humanos , PubMed , Síndrome
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