RESUMO
A polymorphic variant in the human HEXA gene is described. This gene encodes the alpha-subunit of hexosaminidase A, the enzyme which is deficient in Tay-Sachs disease (TSD). In individuals carrying the polymorphism there is a T-->C transition at position -6 in intron 13. The substitution creates a site for the restriction endonuclease Pst1. This variant has an unusual ethnogeographic distribution. It occurs on 1.4% of non-TSD carrier chromosomes in Ashkenazi Jews. All individuals ascertained carrying the Pst+ allele have ancestry in Lithuania, Belarus and Ukraine. By contrast, no individuals carrying the Pst+ allele have been detected among non-Jewish Lithuanians, Jews of Sephardic origin or in several other ethnic groups. Two unrelated non-Jewish families have been identified in which the Pst+ variant occurs. In both cases the variant occurs on a chromosome carrying a novel TSD mutation (G772C) association with the B1 phenotype. The Pst+ G772C chromosomes are of Scots-Irish descent.
Assuntos
Doença de Tay-Sachs/genética , beta-N-Acetil-Hexosaminidases/genética , Alelos , Sequência de Bases , Desoxirribonucleases de Sítio Específico do Tipo II , Hexosaminidase A , Humanos , Dados de Sequência Molecular , Polimorfismo GenéticoRESUMO
OBJECTIVES: To provide an update of the international experience with carrier screening and prenatal diagnosis for Tay-Sachs disease (TSD), to assess the impact of these efforts, and to review the recent developments in DNA technology with application to TSD carrier detection and screening. DESIGN: Through the International TSD Testing, Quality Control, and Data Collection Center, all testing centers in the world were surveyed annually to assess overall experience with carrier testing and prenatal diagnosis. Quality control and laboratory surveillance of testing centers were performed through an annual assessment, using samples provided by the center. SETTING: Tay-Sachs disease testing centers around the world. PARTICIPANTS: Nearly 1 million young adults from both Jewish and non-Jewish populations. INTERVENTION: Gene product screening (enzyme testing) and DNA-based mutation analysis (in some populations). MAIN OUTCOME MEASURE: Impact of screening program on disease incidence. RESULTS: Data from all centers in the international TSD network on experience with TSD carrier testing and prenatal diagnosis since 1974 indicated that more than 36,000 heterozygotes were identified and 1056 couples found to be at risk for TSD in their offspring. A total of 2416 pregnancies at increased risk for TSD were monitored by amniocentesis or chorionic villus sampling. A dramatic decrease in the incidence of TSD in the Jewish populations was demonstrated. With both serum and leukocyte proficiency testing, there have been only 16 instances (of 845 cumulative laboratory evaluations) of one or more errors reported by a laboratory since 1983 resulting in nonaccreditation. CONCLUSIONS: This analysis represents a prototypic effort in coordinating adult education, carrier testing, and genetic counseling directed toward prospective prevention of a uniformly fatal childhood disease and demonstrates that such an effort can dramatically affect disease incidence.
Assuntos
Testes Genéticos , Doença de Tay-Sachs/genética , Ensaios Enzimáticos Clínicos , Feminino , Testes Genéticos/métodos , Testes Genéticos/normas , Saúde Global , Heterozigoto , Humanos , Incidência , Cooperação Internacional , Judeus , Masculino , Mutação , Gravidez , Diagnóstico Pré-Natal , Controle de Qualidade , Doença de Tay-Sachs/diagnóstico , Doença de Tay-Sachs/epidemiologia , beta-N-Acetil-Hexosaminidases/análiseRESUMO
In a previous study we found that a Tay-Sachs disease (TSD) causing mutation in the intron 9 donor splice site of the HEXA gene occurs at high frequency in non-Jewish patients and carriers from the British Isles. It was found more frequently in subjects of Irish, Scottish, and Welsh origin compared with English origin (63% and 31% respectively). We have now tested, in a blind study, 26 American TSD carriers and 28 non-carriers who have British ancestry for the intron 9 splice site mutation. Six of the carriers and none of the controls were positive for the mutation. All six had Irish ancestry, compared with nine of the 20 other (intron 9 mutation negative) TSD carriers (p < 0.05). These results confirm the previously found high frequency of the intron 9 mutation in non-Jewish TSD families of British Isles, particularly Irish, origin, and reinforce the need to screen such families for this mutation.