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1.
Hum Genet ; 125(5-6): 581-90, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19296131

RESUMO

Dihydropyrimidine dehydrogenase (DPD) deficiency is an infrequently described autosomal recessive disorder of the pyrimidine degradation pathway and can lead to mental and motor retardation and convulsions. DPD deficiency is also known to cause a potentially lethal toxicity following administration of the antineoplastic agent 5-fluorouracil. In an ongoing study of 72 DPD deficient patients, we analysed the molecular background of 5 patients in more detail in whom initial sequence analysis did not reveal pathogenic mutations. In three patients, a 13.8 kb deletion of exon 12 was found and in one patient a 122 kb deletion of exon 14-16 of DPYD. In the fifth patient, a c.299_302delTCAT mutation in exon 4 was found and also loss of heterozygosity of the entire DPD gene. Further analysis demonstrated a de novo deletion of approximately 14 Mb of chromosome 1p13.3-1p21.3, which includes DPYD. Haploinsufficiency of NTNG1, LPPR4, GPSM2, COL11A1 and VAV3 might have contributed to the severe psychomotor retardation and unusual craniofacial features in this patient. Our study showed for the first time the presence of genomic deletions affecting DPYD in 7% (5/72) of all DPD deficient patients. Therefore, screening of DPD deficient patients for genomic deletions should be considered.


Assuntos
Cromossomos Humanos Par 1/genética , Deficiência da Di-Hidropirimidina Desidrogenase/genética , Di-Hidrouracila Desidrogenase (NADP)/genética , Rearranjo Gênico , Deleção de Sequência , Sequência de Bases , Pré-Escolar , Hibridização Genômica Comparativa , Análise Mutacional de DNA , Éxons , Feminino , Humanos , Hibridização in Situ Fluorescente , Lactente , Masculino , Dados de Sequência Molecular , Pirimidinas/análise
2.
J Med Genet ; 44(12): 787-90, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17630404

RESUMO

OBJECTIVE: The aim of this study was to determine if there is a significant difference in the risk of developing Wilms tumour between patients with submicroscopic and those with visible deletions of the WT1 tumour suppressor gene. METHODS: To determine which subjects had WT1 deletions, high-resolution chromosomal deletion analysis of the 11p13 region was carried out in 193 people with aniridia. The rationale for this was that aniridia is caused by loss of function of one copy of the PAX6 gene, and although most patients with aniridia have intragenic mutations, a proportion has deletions that also include the nearby WT1 gene. Fluorescence in situ hybridisation (FISH) analysis of patients with aniridia identifies people with WT1 deletions regardless of whether they have Wilms tumour, allowing the deletion size to be correlated with clinical outcome. RESULTS: Wilms tumour was not observed in any case without a WT1 deletion. Of subjects in whom WT1 was deleted, 77% with submicroscopic deletions (detectable only by high-resolution FISH analysis) presented with Wilms tumour compared with 42.5% with visible deletions (detectable by microscopy). This difference was significant. CONCLUSIONS: High-resolution deletion analysis is a useful tool for assessing the risk of Wilms tumour in neonates with aniridia. People with submicroscopic WT1 deletions have a significantly increased risk of Wilms tumour, and a high level of vigilance should be maintained in such cases.


Assuntos
Aniridia/genética , Cromossomos Humanos Par 11/genética , Deleção de Genes , Genes do Tumor de Wilms , Neoplasias Renais/genética , Tumor de Wilms/genética , Adolescente , Adulto , Idade de Início , Criança , Pré-Escolar , Quebra Cromossômica , Cromossomos Humanos Par 11/ultraestrutura , Proteínas do Olho/genética , Feminino , Seguimentos , Predisposição Genética para Doença , Proteínas de Homeodomínio/genética , Humanos , Hibridização in Situ Fluorescente , Lactente , Neoplasias Renais/epidemiologia , Masculino , Microscopia , Fator de Transcrição PAX6 , Fatores de Transcrição Box Pareados/deficiência , Fatores de Transcrição Box Pareados/genética , Proteínas Repressoras/genética , Tumor de Wilms/epidemiologia
3.
Am J Ment Retard ; 110(4): 253-67, 2005 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15941363

RESUMO

A prospective assessment following a step-wise protocol in 281 patients with unexplained cognitive delay was used to assess diagnostic possibilities. Diagnostic procedures were complex and required a multidisciplinary approach. One third of diagnoses was established based on clinical history and physical exam only; for another third, clinical history and physical exam provided essential clues for additional investigations; and a third were established by additional investigations only. The likelihood to reach a diagnosis did not depend on the severity of mental retardation. We found that in a tertiary care center, a diagnosis can be established in 1 out of every 2 patients. Clinical history and physical examination are the most important instruments to reach a diagnosis.


Assuntos
Deficiência Intelectual/etiologia , Encaminhamento e Consulta , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Diagnóstico Diferencial , Feminino , Humanos , Deficiência Intelectual/genética , Masculino , Fenótipo , Estudos Prospectivos , Fatores de Risco , Estatística como Assunto , Escalas de Wechsler
4.
Am J Med Genet A ; 136(1): 76-80, 2005 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-15889415

RESUMO

We report on a family with six persons in three generations who have mild mental retardation, behavioral problems, seizures, hearing loss, strabismus, dental anomalies, hypermobility, juvenile hallux valgus, and mild dysmorphic features. Classical cytogenetic analysis showed a partial duplication of chromosome 13q, array comparative genomic hybridization showed the duplication to span approximately 21 Mb, ranging from chromosome band 13q21.31 to 13q31.1. The relatively mild presentation of this large duplication may be explained by the relative paucity of genes in the chromosome region involved. Genotype-phenotype correlations in patients with similar partial 13q duplications are inconsistent. Emerging cytogenetic techniques will allow more reliable genotype-phenotype correlations.


Assuntos
Aberrações Cromossômicas , Cromossomos Humanos Par 13/genética , Hibridização de Ácido Nucleico/métodos , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Adolescente , Adulto , Criança , Pré-Escolar , Bandeamento Cromossômico , Saúde da Família , Feminino , Duplicação Gênica , Genoma Humano , Genótipo , Perda Auditiva/patologia , Humanos , Hibridização in Situ Fluorescente , Deficiência Intelectual/patologia , Cariotipagem , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Síndrome , Anormalidades Dentárias
5.
Eur J Hum Genet ; 11(9): 643-51, 2003 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12939649

RESUMO

Cryptic subtelomeric chromosome rearrangements play an important role in the aetiology of mental retardation, congenital anomalies, miscarriages and neoplasia. To facilitate a comprehensive molecular-cytogenetic analysis of these extremely gene-rich and mutation-prone chromosome regions, novel multicolour fluorescence in situ hybridisation (FISH) techniques are being developed. As yet, subtelomeric FISH methods have either had limited multiplicities, making it necessary to perform many hybridisations per patient, or a limited scope of analysable chromosome mutation types, thus not detecting some aberration types such as pericentric inversions or very small aberrations. COBRA (COmbined Binary RAtio) labelling is a generic multicolour FISH technique that combines ratio and combinatorial labelling to attain especially high multiplicities with few fluorochromes. The Subtelomere COBRA FISH method ("S-COBRA FISH") described here detects efficiently all 41 BAC and PAC FISH probes necessary for a complete subtelomere screening in only two hybridisations. It was applied to the analysis of 10 cases with known and partially known aberrations and successfully detected balanced and unbalanced translocations, deletions and an unbalanced pericentric inversion in a mosaic situation. The ability of S-COBRA FISH to efficiently detect all types of balanced and unbalanced subtelomeric chromosome aberrations makes it the most comprehensive diagnostic procedure for human subtelomeric chromosome regions described to date.


Assuntos
Aberrações Cromossômicas , Rearranjo Gênico/genética , Hibridização in Situ Fluorescente/métodos , Telômero/genética , Humanos , Cariotipagem
6.
Am J Med Genet ; 110(1): 65-72, 2002 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-12116274

RESUMO

A patient with hypotonia, blepharophimosis, ptosis, a bulbous nose, a long philtrum, upturned corners of the mouth, and mild developmental delay was found to have a small subtelomeric deletion of the long arm of chromosome 14 (q32.31-qter). In comparing her phenotype with previously reported patients with similar 14q deletions, due to either a linear deletion or to a ring chromosome 14, a clinically recognizable terminal 14q microdeletion syndrome was evident. Due to the limited number of cases reported, it was not possible to assign specific features to specific regions of terminal 14q. The comparison of features in cases with a linear deletion of 14qter (n = 19) to those in cases with a deletion due to a ring chromosome 14 (n = 23), both with the same breakpoint in 14q, showed that seizures and retinitis pigmentosa have been found only in patients with ring chromosomes. Several hypotheses are put forward to explain this difference: mitotic instability of ring chromosomes; a telomere position effect in ring chromosomes in which the 14p telomere silences nearby gene(s) on the q-arm; and dose-dependent gene(s) involved in seizures and retinitis pigmentosa located on the short arm of chromosome 14. In our opinion, only seizures may be explained by the mitotic instability of ring chromosomes, while both seizures and retinitis pigmentosa may be explained by silencing of gene(s) on 14q by the 14p telomere; the third hypothesis seems unlikely to explain either symptom.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 14/genética , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Blefarofimose/patologia , Pré-Escolar , Deficiências do Desenvolvimento/patologia , Feminino , Seguimentos , Humanos , Hibridização in Situ Fluorescente , Lactente , Recém-Nascido , Cariotipagem , Hipotonia Muscular/patologia , Síndrome
7.
J Pediatr Hematol Oncol ; 24(3): 205-10, 2002.
Artigo em Inglês | MEDLINE | ID: mdl-11990307

RESUMO

Despite intensive therapy, the survival of children with medulloblastoma remains disappointing. Moreover, children who survive are affected by serious long-term sequelae of treatment that impair their quality of life. In search of chromosomal aberrations indicative of sites involved in oncogenic transformation and in an attempt to find reliable prognostic markers, the authors analyzed 15 medulloblastomas by comparative genomic hybridization. All neoplasms showed chromosomal abnormalities. The most frequent losses were 17p (7/15 tumors), 8p and 11p (6/15), 10p, 1lq, 16q, and 20q (5/15), and 20p (4/15). Gains were recurrently found at 7q (10/15 tumors), 17q and 18q (9/15 tumors), 7p and 13q (7/15), 18p (6/15), and 1q, 4q, 6q. and 9p (5/15 tumors). Four tumors showed loss of 17p together with gain of 17q, suggesting an isochromosome 17q. High-level amplifications were seen at 1p34, 5p15, 13q34, and 18p11 (one tumor each), and at 2p15 in two tumors, one of which was proven to be N-Myc amplification. The overall pattern of alterations found in this study confirms the findings of other studies and adds two novel regions with chromosomal gains, at 13q and 18q. Previous reports on the relation between 17q gain and survival could not be confirmed, whereas amplification of N-myc or L-myc seems to indicate poor clinical outcome.


Assuntos
Neoplasias Cerebelares/genética , DNA de Neoplasias/análise , Meduloblastoma/genética , Adolescente , Criança , Pré-Escolar , Aberrações Cromossômicas , Transtornos Cromossômicos , Mapeamento Cromossômico , Feminino , Seguimentos , Amplificação de Genes , Genes myc/genética , Humanos , Hibridização in Situ Fluorescente , Masculino , Hibridização de Ácido Nucleico
8.
Fertil Steril ; 77(1): 68-75, 2002 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-11779593

RESUMO

OBJECTIVE(S): To determine the copy number and identity of the DAZ genes on the Y chromosomes of infertile patients. DESIGN: Prospective study. SETTING: University medical center. PATIENT(S): One hundred and thirty-nine patients with male factor infertility. INTERVENTION(S): The separate genes were detected by polymerase chain reaction (PCR) digestion assays of sequence family variants in leukocyte DNA and by fluorescence in situ hybridization of interphase nuclei and chromatin fibers. MAIN OUTCOME MEASURE(S): Number of DAZ genes present. RESULT(S): One hundred twenty-nine patients had four genes, 6 patients had two genes, and 4 patients had none. Three patients had a deletion of the two proximal DAZ genes, and three were missing both distal genes. Semen analysis showed a less severe phenotype in patients with only two DAZ genes compared with patients missing all four genes. CONCLUSION(S): In six patients, two different partial deletions were found that were not detected by PCR with conventional markers. One patient with an AZFb deletion appeared to also have a partial AZFc deletion that was not detected by routine PCR. Phenotypic differences between patients with different deletions suggest a dose effect of the DAZ genes.


Assuntos
Infertilidade Masculina/genética , Oligospermia/genética , Proteínas de Ligação a RNA/genética , Substituição de Aminoácidos , DNA/sangue , DNA/genética , Proteína 1 Suprimida em Azoospermia , Fertilidade , Variação Genética , Humanos , Hibridização in Situ Fluorescente , Leucócitos/fisiologia , Masculino , Família Multigênica , Reação em Cadeia da Polimerase , Proteínas/genética , Valores de Referência , Reprodutibilidade dos Testes , Deleção de Sequência , Contagem de Espermatozoides
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