RESUMO
OBJECTIVE: The aim of this study was to assess the prevalence of congenital defects observed in patients with Prader-Willi syndrome (PWS) and to compare this prevalence with that described in the general population. In addition, these findings were correlated with the different etiologic subtypes. METHODS: A total of 180 children with PWS followed for 13 years were included in this study. Diagnosis was confirmed by the methylation test, and genetic subtypes were established by using fluorescence in situ hybridization or multiplex ligation-dependent probe amplification and microsatellite analyses. The prevalence of congenital defects was compared with national and international registries of congenital defects in the general population (Estudio Colaborativo Latinoamericano de Malformaciones Congénitas, European Surveillance of Congenital Anomalies, and the New York Registry). RESULTS: Twenty-two percent of the patients presented congenital defects with a risk of 5.4 to 18.7 times higher than that of the general population. The most frequent congenital defects were heart defects, renoureteral malformations, vertebral anomalies, hip dysplasia, clubfoot, and agenesis/hypoplasia of the corpus callosum. Each of these congenital defects was significantly more frequent in the children with PWS than in the general population. The congenital heart defects were more frequent in girls than in boys with PWS. No significant differences were found when the defects were correlated with the different etiologic subtypes. CONCLUSIONS: An increased prevalence of congenital defects was found in our PWS patients. This finding suggests the need for further studies in PWS children that allow physicians to detect the congenital defects found in this series and, thus, to anticipate complications, with the ultimate aim of enhancing the management of PWS patients.
Assuntos
Anormalidades Congênitas/epidemiologia , Síndrome de Prader-Willi/epidemiologia , Adolescente , Criança , Deleção Cromossômica , Cromossomos Humanos Par 15/genética , Estudos de Coortes , Comorbidade , Anormalidades Congênitas/diagnóstico , Anormalidades Congênitas/genética , Estudos Transversais , Feminino , Seguimentos , Expressão Gênica/genética , Impressão Genômica/genética , Genótipo , Humanos , Masculino , Fenótipo , Síndrome de Prader-Willi/diagnóstico , Síndrome de Prader-Willi/genética , Estudos Retrospectivos , Fatores Sexuais , Dissomia Uniparental/genéticaRESUMO
Argentine population is highly heterogeneous for the cystic fibrosis (CF) transmembrane regulator (CFTR) gene mutations. The study of 14 more common mutations identified both mutated alleles in only 51% of patients. This study confirmed the diagnosis of cystic fibrosis in these patients and enabled the detection of asymptomatic carriers in their families. However, in the remaining patients the direct molecular assay did not provide the necessary information for genetic counselling. To establish the mutated allele transmission in the affected families, negative for the most common mutations, three microsatellites (IVS17bTA, IVS8CA and IVS17bCA) located in intronic regions of CFTR gene were studied. In the 40 CF families analyzed, different allelic variants were detected: 15 for IVS17bTA, 10 for IVS8CA and 4 for IVS17bCA. Polymorphism information content and heterozygosity were high, except for IVS17bCA. By the simultaneous analysis of the three microsatellites we could counsel 100% of the families. Ours results show that these microsatellites are an excellent group of markers for linkage studies in cystic fibrosis families of the Argentine population.
Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/genética , DNA Satélite/genética , Alelos , Argentina , Fibrose Cística/diagnóstico , Feminino , Ligação Genética , Marcadores Genéticos , Haplótipos , Humanos , Masculino , Repetições de Microssatélites , MutaçãoRESUMO
Argentine population is highly heterogeneous for the cystic fibrosis (CF) transmembrane regulator (CFTR) gene mutations. The study of 14 more common mutations identified both mutated alleles in only 51
of patients. This study confirmed the diagnosis of cystic fibrosis in these patients and enabled the detection of asymptomatic carriers in their families. However, in the remaining patients the direct molecular assay did not provide the necessary information for genetic counselling. To establish the mutated allele transmission in the affected families, negative for the most common mutations, three microsatellites (IVS17bTA, IVS8CA and IVS17bCA) located in intronic regions of CFTR gene were studied. In the 40 CF families analyzed, different allelic variants were detected: 15 for IVS17bTA, 10 for IVS8CA and 4 for IVS17bCA. Polymorphism information content and heterozygosity were high, except for IVS17bCA. By the simultaneous analysis of the three microsatellites we could counsel 100
of the families. Ours results show that these microsatellites are an excellent group of markers for linkage studies in cystic fibrosis families of the Argentine population.
RESUMO
The primary structure of an HLA class I genomic clone isolated from a homozygous HLA-B35 Caucasian individual of hispanic origin was determined. The nucleotide sequence of exons 1, 2, 4, 5, 6, and 7 is identical to that of the HLA-B35 allele of Oriental origin reported previously. Exon 3 differs in only three nucleotides present in a stretch of 23 bp. These changes introduce three amino acid substitutions in residues 109 (Leu----Phe), 114 (Asp----Asn), and 116 (Ser----Tyr), two of which (114 and 116) are located in one of the beta sheets at the bottom of the peptide binding site. The nature of these replacements in this HLA-B35 variant is likely to affect peptide binding and recognition by T lymphocytes. Introns 1, 2, 3, 4, 5, and 6 from this genomic clone are identical to those present in HLA-Bw58, further confirming the evolutionary origin of HLA-B35.
Assuntos
Genes MHC Classe I , Antígeno HLA-B35/genética , Sequência de Aminoácidos , Argentina , Sequência de Bases , Feminino , Variação Genética , Humanos , Íntrons , Dados de Sequência Molecular , Homologia de Sequência do Ácido Nucleico , Espanha/etnologia , População Branca/genéticaRESUMO
Peripheral blood leukocyte DNA from 31 donors, previously typed as HLA-B35, was digested with EcoRV and analyzed by Southern transfer and hybridization to an HLA class I probe. Out of 31 HLA-B35 positive (+) individuals, 24 showed a 4.6-kb band, previously associated with the B35 allele by Cohen et al. (Proc Natl Acad Sci USA 80:6289-6292). The HLA-B35 allele has a strong linkage disequilibrium (70%) with the Cw4 allele. All samples having the 4.6-kb band corresponded to HLA-B35+, Cw4+ cells, whereas those lacking the band came from HLA-B35+, Cw4-negative (-) cells. Five HLA-B35-, Cw4+ samples were also studied and none showed the band. An HLA-B locus-specific probe gave a strong hybridization signal to this fragment, whereas an HLA-C locus-specific probe revealed different bands. The results suggest that the 4.6-kb fragment contains the B35 gene. Digestion with other restriction enzymes, located the polymorphic site to the 3' end of the gene. Analysis of 18 additional individuals with other specificities of the "4c" antigenic cluster (HLA-B18, B51, B52 and B53) showed that the EcoRV/4.6 kb-band was also present in 5/5 B52 cells and 4/4 B53 samples.