RESUMO
INTRODUCTION: Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder characterised by degeneration of spinal cord anterior horn cells, leading to muscular atrophy. It is the second most frequent autosomal recessive disease among Caucasian populations with a prevalence of between 1 in 6000 and 1 in 10,000 live births, and a carrier frequency of about 1 in 50. The International SMA Consortium classification defines several types of SMA depending on the age of onset and clinical severity. In the past, the diagnosis of SMA was confirmed by muscle biopsy and, sometimes, electromyography. In 1990, SMA was linked to the 5q13 region of chromosome 5. In 1995, it was found that >95% of patients with SMA have homozygous deletions of exons 7 and 8 of the survival motor neurone 1 (SMN1) gene, one of the candidate genes identified within 5q13. The purpose of our study was to determine the frequency of SMN1 deletions in patients with known SMA and the impact of this on the diagnosis of SMA. MATERIALS AND METHODS: Molecular analysis was performed on stored DNA and case notes were reviewed retrospectively. RESULTS: Twenty-two (91.7%) out of 24 patients with all types of SMA were homozygously deleted for exons 7 and/or 8 of SMN1. We also report our experience with prenatal diagnosis of SMA. CONCLUSIONS: Molecular studies can replace conventional investigations for SMA and have made the option of prenatal diagnosis possible for couples at risk.
Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , DNA/análise , Deleção de Genes , Proteínas do Tecido Nervoso/genética , Proteínas de Ligação a RNA/genética , Atrofias Musculares Espinais da Infância/genética , Adulto , Idade de Início , Biópsia , Pré-Escolar , Eletromiografia , Éxons/genética , Feminino , Seguimentos , Homozigoto , Humanos , Lactente , Recém-Nascido , Masculino , Músculo Esquelético/patologia , Músculo Esquelético/fisiopatologia , Reação em Cadeia da Polimerase , Gravidez , Estudos Retrospectivos , Proteínas do Complexo SMN , Singapura/epidemiologia , Atrofias Musculares Espinais da Infância/diagnóstico , Atrofias Musculares Espinais da Infância/epidemiologia , Taxa de Sobrevida , Proteína 1 de Sobrevivência do Neurônio MotorAssuntos
Análise Mutacional de DNA/métodos , Síndrome do Cromossomo X Frágil/diagnóstico , Proteínas do Tecido Nervoso/genética , Reação em Cadeia da Polimerase/métodos , Proteínas de Ligação a RNA , Expansão das Repetições de Trinucleotídeos , Algoritmos , Metilação de DNA , Feminino , Proteína do X Frágil da Deficiência Intelectual , Síndrome do Cromossomo X Frágil/classificação , Síndrome do Cromossomo X Frágil/genética , Genótipo , Humanos , MasculinoRESUMO
Isolated oral clefts, including cleft lip with/without cleft palate (CL/P) and cleft palate (CP), have a complex and heterogeneous etiology. Case-parent trios from three populations were used to study genes spanning chromosome 2, where single nucleotide polymorphic (SNP) markers were analyzed individually and as haplotypes. Case-parent trios from three populations (74 from Maryland, 64 from Singapore and 95 from Taiwan) were genotyped for 962 SNPs in 104 genes on chromosome 2, including two well-recognized candidate genes: TGFA and SATB2. Individual SNPs and haplotypes (in sliding windows of 2-5 SNPs) were used to test for linkage and disequilibrium separately in CL/P and CP trios. A novel candidate gene (ZNF533) showed consistent evidence of linkage and disequilibrium in all three populations for both CL/P and CP. SNPs in key regions of ZNF533 showed considerable variability in estimated genotypic odds ratios and their significance, suggesting allelic heterogeneity. Haplotype frequencies for regions of ZNF533 were estimated and used to partition genetic variance into among-and within-population components. Wright's fixation index, a measure of genetic diversity, showed little difference between Singapore and Taiwan compared with Maryland. The tensin-1 gene (TNS1) also showed evidence of linkage and disequilibrium among both CL/P and CP trios in all three populations, albeit at a lower level of significance. Additional genes (VAX2, GLI2, ZHFX1B on 2p; WNT6-WNT10A and COL4A3-COL4A4 on 2q) showed consistent evidence of linkage and disequilibrium only among CL/P trios in all three populations, and TGFA showed significant evidence in two of three populations.
Assuntos
Cromossomos Humanos Par 2 , Fenda Labial/genética , Fissura Palatina/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Mapeamento Cromossômico , Saúde da Família , Feminino , Frequência do Gene , Ligação Genética , Genótipo , Haplótipos , Humanos , Desequilíbrio de Ligação , Masculino , Maryland , Análise Multivariada , Núcleo Familiar , Singapura , TaiwanRESUMO
OBJECTIVE: To compare the efficacy of routine haematological tests and molecular analysis in the diagnosis of double heterozygous alpha- and beta-thalassaemia. METHODS: Screening was carried out in extended family members from 125 families registered in the National Thalassaemia Registry, known to have both alpha- and beta-thalassaemia carriers. RESULTS: Eighty-three individuals from 59 families were identified to be double heterozygous for alpha- and beta-thalassaemia only upon molecular analyses. Among 40 married individuals, 1 was at 25% risk for having beta-thalassaemia major children and 6 for having Bart's hydrops pregnancies. CONCLUSION: Molecular analysis must be used for the accurate diagnosis of double heterozygous alpha- and beta-thalassaemia for proper risk ascertainment, especially in regions with a high prevalence of both types of thalassaemia.