ISSN:1090-6576    

DOI:10.1089/gte.1997.1.1

年代:1997

数据来源: MAL

ISSN:1090-6576    

DOI:10.1089/gte.1997.1.3

年代:1997

数据来源: MAL

摘要:

ABSTRACTGaucher disease is the most prevalent lysosomal storage disease and has its highest incidence in the Ashkenazi Jewish population. Over 100 mutant alleles have been identified in affected patients, but four alleles, termed N370S, L444P, 84GG, and IVS2, have significant frequencies in this population. In affected patients, genotype data show that the presence of a single N370S allele is diagnostic of the type 1 or nonneuronopathic variant, whereas the L444P/L444P genotype is highly associated with neuronopathic variants in the Caucasian population. Large screening studies also indicate a significant underestimation (∼two-fold) of the prevalence of the N370S/N370S genotype in the affected Ashkenazi Jewish patient population. These results indicate that the N370S/N370S genotype provides a necessary but not sufficient condition for the development of the Gaucher disease phenotype. The genotype/phenotype correlations and gene frequencies have significant impact on genetic counseling of at-risk couples and the future need for therapy of affected patient

ISSN:1090-6576    

DOI:10.1089/gte.1997.1.5

年代:1997

数据来源: MAL

摘要:

ABSTRACTNiemann–Pick Disease (NPD) is an autosomal recessive lysosomal storage disorder caused by a deficiency of acid sphingomyelinase (ASM). NPD occurs in two forms, neuronopathic Type A and nonneuronopathic Type B. The incidence of Type A NPD is highest among Ashkenazi Jews. Type B NPD is more common in non-Jews but has been reported in Ashkenazi Jews. Different mutations in ASM are presumed to be responsible for the different NPD phenotypes. Three mutations are predicted to account for>95% of all Type A NPD chromosomes among Ashkenazi Jews (L302P, R496L, fsP330). Based on limited screens for these mutations among Ashkenazi Jews, a carrier frequency for Type A NPD of 1:90 is reported for this population. Less is known about mutations responsible for Type B NPD, although one mutation (ΔR608) has been identified in both Ashkenazi Jews and non-Jews. Screening of the Ashkenazi Jewish population to detect>95% of NPD carriers can be accomplished with a four-mutation panel that includes L302P, R496L, fsP330, and ΔAR608, the three predominant Type A mutations and one recurrent Type B mutat

ISSN:1090-6576    

DOI:10.1089/gte.1997.1.13

年代:1997

数据来源: MAL

摘要:

ABSTRACTCanavan disease, spongy degeneration of the brain, is an autosomal recessive disorder with increased prevalence among Ashkenazi Jews. The biochemical marker for this disease is increased levels of N-acetylaspartic acid, due to the defective enzyme, aspartoacylase. This discovery allowed for accurate diagnosis of the disease. The gene for aspartoacylase has been cloned and two mutations have been found to be responsible for Canavan disease among Ashkenazi Jewish patients in 98% of the cases. Molecular analysis of healthy Jewish individuals for these mutations has resulted in an unexpectedly high carrier frequency for Canavan disease among Jews. Therefore, carrier testing of the Jewish population is possible and indicated.

ISSN:1090-6576    

DOI:10.1089/gte.1997.1.21

年代:1997

数据来源: MAL

摘要:

ABSTRACTFanconi anemia (FA) is an autosomal recessive disorder characterized clinically by progressive pancytopenia, diverse congenital abnormalities, and a predisposition to malignancy, particularly acute myelogenous leukemia (AML). Hypersensitivity of FA cells to the clastogenic effect of crosslinking agents such as diepoxybutane (DEB) is used as a diagnostic criterion, because phenotypic heterogeneity makes clinical diagnosis difficult. Studies of genetic heterogeneity have shown that there are at least five different complementation groups, FA– A through FA–E. Overall, FA–A is the most prevalent group, accounting for 60%–65% of all FA. TheFAAgene, which maps to chromosome 16q24.3, was recently isolated and methods for molecular diagnosis of FA–A are currently being developed. The first FA gene to be isolated (FAC) maps to chromosome 9q22.3; FA–C accounts for 10%–15% of FA. A variety of mutations and polymorphisms have been described inFAC. The most common of these is IVS4 +4 A → T, which is the onlyFACmutation found in Ashkenazi Jewish FA patients and their families. This mutation has not been found in any affected individual of non-Jewish ancestry. The carrier frequency of the IVS4 mutation was found to be 1 in 89 (1.1%; 95% confidence interval 0.79% to 1.56%) in an Ashkenazi Jewish population, whereas no carriers were identified in an Iraqi Jewish population, which represents the original gene pool of the Jews. We have developed amplification refractory mutation system (ARMS) assays forFACmutations, which provide a means of rapid, nonradioactive genetic testing. These assays have been used to assign FA patients to Group C, to provide rapid carrier testing and prenatal diagnosis fo

ISSN:1090-6576    

DOI:10.1089/gte.1997.1.27

年代:1997

数据来源: MAL

摘要:

ABSTRACTThe incidence of cystic fibrosis and the frequency of disease causing mutations varies among different ethnic groups and geographical regions around the world. The Jewish population is comprised of two major ethnic groups. Ashkenazi and Non-Ashkenazi. The latter is further classified according to country of origin. An extreme variability in the disease frequency (from 1:2400–1:39,000) was found among the different Jewish ethnic groups. In the entire Jewish CF population, only 12 mutations were identified that altogether enable the identification of 91% of the CF chromosomes. However, in each Jewish ethnic group, the disease is caused by a different repertoire of a small number of mutations. In several ethnic groups, there is a major CFTR mutation that accounts for at least 48% of the CF chromosomes. High proportion of the CF chromosomes can be identified in Ashkenazi Jews (95%), Jews originating from Tunisia (100%), Libya (91%), Turkey (90%), and Georgia (88%). High frequencies of CFTR mutations were found among infertile males with CBAVD who might not have additional CF clinical characteristics. Of the Jewish males with CBAVD, 77% carried at least one CFTR mutation. The 5T mutation is the major mutation in Jewish CBAVD affecteds accounting for 32% of the chromosomes among Ashkenazi Jews and 36% among the non-Ashkenazi Jews. Five additional CFTR mutations, W1282X (12%), ΔF508 (9%), N1303K (3%), D1152H, (5%)), and R117H (1%) were identified among Ashkenazi Jews with CBAVD. Only two mutations, ΔF508 and R117H, were found among non-Ashkenazi males with CBAVD. An increased frequency of the 5T allele was also found among Jewish patients with atypical CF presentation, 18% in Ashkenazi, and 10% in non-Ashkenazi Jews. In summary, we present the required information for genetic counseling of Jewish families with typical and atypical CF and for carrier screening of healthy Jewish individu

ISSN:1090-6576    

DOI:10.1089/gte.1997.1.35

年代:1997

数据来源: MAL

摘要:

ABSTRACTThe strongest risk factors currently known for inherited predisposition to breast and ovarian cancer are mutations in BRCA1 and BRCA2. Two mutations in BRCA1 and one mutation in BRCA2 have been identified that are present to a particularly high degree in the Ashkenazi Jewish population due to ancient founder effects. To clarify the role of ancient and novel BRCA1 and BRCA2 mutations in the Ashkenazi Jewish population, families with a strong history of breast and ovarian cancer were examined. Seventeen Ashkenazi Jewish families with four or more breast or ovarian cancers were analyzed for ancient and novel mutations in BRCA1 and BRCA2. Ancient mutations existed in 9 families; 7 had the BRCA1 185 del AG mutation, 1 had BRCA1 5382 ins C, and 1 had BRCA2 6174 del T. A novel mutation, BRCA2 6425 del TT, was discovered in 1 of the remaining 8 families. Seven families with four or more cases of breast and ovarian cancer cannot be accounted for by either the ancient or novel mutations. Therefore, ancient mutations in BRCA1 and BRCA2 are present in approximately half of Ashkenazi Jewish families in this series, suggesting the possibility of novel mutations, either in BRCA1, BRCA2, or in currently unidentified gene(s), responsible for the remainder.

ISSN:1090-6576    

DOI:10.1089/gte.1997.1.41

年代:1997

数据来源: MAL

摘要:

ABSTRACTTheBRCA1mutations 185delAG and 5382insC and theBRCA2mutation 6174delT have been detected in a significant proportion of Ashkenazi Jewish women with early-onset breast cancer. A group of 236 Jewish women with breast cancer was screened for the presence of these alterations. Mutations were detected in 25.0% (59/236). Among women with breast cancer diagnosed at or before the age of 45, the prevalence of these mutations was 29.1% (42/144). Among women diagnosed with breast cancer after age 45, mutations were noted in 18.5% (17/92). Among women with a family history of breast or ovarian cancer, the likelihood of detecting a mutation was 32.1% (53/165).BRCA1185delAG was the most common mutation overall (40/236, 16.9%). The ratio ofBRCA1185delAG toBRCA26174delT was 4.0 in women with early-onset breast cancer and 1.3 in women with breast cancer diagnosed after age 45. Clinical features such as age at diagnosis, family history of breast or ovarian cancer, bilateral breast cancer, and personal history of breast and ovarian cancer increase the likelihood of detecting mutations among Ashkenazi women with breast cancer. The yield of testing is low in the absence of any of these features.

ISSN:1090-6576    

DOI:10.1089/gte.1997.1.47

年代:1997

数据来源: MAL

摘要:

ABSTRACTPopulation screening for cystic fibrosis (CF) carriers, now possible because of the cloning of the CFTR gene, merits evaluation because CF is common, serious, and without satisfactory treatment, and because prenatal diagnosis is available. Clinical trials of CF population carrier screening are reviewed. These trials have involved pregnant women, adults of both sexes of reproductive age, or adolescents. Schools, the usual setting for screening programs for adolescents, provide an excellent opportunity for a formal educational component and for comprehensive coverage of the population, but compared to a health-care setting, may entail subtle coercion and may compromise confidentiality. In the case of adults, many say they prefer screening before conception but do not see a physician for evaluation before conception and providers find screening more readily accomplished in the setting of a prenatal visit. Two large U.S. studies of prenatal screening with quite different subject populations and health-care settings encountered few of the adverse outcomes originally predicted for CF carrier population screening.

ISSN:1090-6576    

DOI:10.1089/gte.1997.1.53

年代:1997

数据来源: MAL