Carrier screening for Canavan disease in Australia.

This study reports, for the first time, the carrier frequency of Canavan disease in the Ashkenazi Jewish population in Australia, and the identification of a novel mutation in the ASPA gene.

Rapid mutation scanning of genes associated with familial cancer syndromes using denaturing high-performance liquid chromatography.

Germline mutations in tumor suppressor genes, or less frequently oncogenes, have been identified in up to 19 familial cancer syndromes including Li-Fraumeni syndrome, familial paraganglioma, familial adenomatous polyposis coli and breast and ovarian cancers. Multiple genes have been associated with some syndromes as approximately 26 genes have been linked to the development of these familial cancers. With this increased knowledge of the molecular determinants of familial cancer comes an equal expectation for efficient genetic screening programs. We have trialled denaturing high-performance liquid chromatography (dHPLC) as a tool for rapid germline mutation scanning of genes implicated in three familial cancer syndromes -- Cowden syndrome (PTEN mutation), multiple endocrine neoplasia type 2 (RET mutation) and von Hippel-Lindau disease (VHL mutation). Thirty-two mutations, including 21 in PTEN, 9 in RET plus a polymorphism, and 2 in VHL, were analyzed using the WAVE DNA fragment analysis system with 100% detection efficiency. In the case of the tumor suppressor gene PTEN, mutations were scattered along most of the gene. However, mutations in the RET proto-oncogene associated with multiple endocrine neoplasia type 2 were limited to specific clusters or "hot spots." The use of GC-clamped primers to scan for mutations scattered along PTEN exons was shown to greatly enhance the sensitivity of detection of mutant hetero- and homoduplex peaks at a single denaturation temperature compared to fragments generated using non--GC-clamped primers. Thus, when scanning tumor suppressor genes for germline mutation using dHPLC, the incorporation of appropriate GC-clamped primers will likely increase the efficiency of mutation detection.

The frequency of founder mutations in the BRCA1, BRCA2, and APC genes in Australian Ashkenazi Jews: implications for the generality of U.S. population data.

BACKGROUND: Several studies have shown that Ashkenazi Jews in the United States and Israel have a high prevalence of the founder mutations BRCA1 185delAG, BRCA1 5382insC, BRCA2 6174delT, and APC I1307K at frequencies of 1.0--1.1%, 0.2--0.3%, 0.6--1.4%, and 6.1--7.0%, respectively. The objective of this study was to compare the prevalence of these alleles in the Australian Jewish population with that of U.S. Jews. Australian Jews have a different history of migration, with less opportunity for changes in allele frequency due to conversion or intermarriage with non-Jewish Australians. The results obtained therefore can be used to assess whether U.S. data can be generalized to other Jewish populations. SUBJECTS AND METHODS. Subject samples were ascertained through a screening program for Tay-Sachs disease as part of a community-based screening program in New South Wales and Victoria. DNA extracted from 1200 deidentified blood samples was tested using amplification refractory mutation system polymerase chain reaction. RESULTS: The allele frequencies found were as follows: BRCA1 185delAG 1.25% (95% confidence interval [CI], 0.62--1.88%), BRCA1 5382insC 0.25% (95% CI, 0--0.53%), BRCA2 6174delT 1.08% (95% CI, 0.50--1.67%), and APC I1307K 8.67% (95% CI, 7.07--10.26%). The prevalence of breast carcinoma predisposition alleles therefore is greater than 2.5% in Australian Ashkenazim. CONCLUSIONS: There were no significant differences between the allele frequencies in Australian Ashkenazim and those identified in other studies with similar ascertainment strategies, despite the different migration patterns of Australian Jews. This suggests the broad applicability of the U.S. and Israeli data, not only to Australian Ashkenazim, but also to Ashkenazi communities throughout the world.

The Tay-Sachs disease prevention program in Australia: Sydney pilot study.

OBJECTIVES: To determine the frequency of heterozygous carriers of the Tay-Sachs disease gene in an asymptomatic Ashkenazi Jewish population and to compare the acceptability of different community testing strategies. DESIGN: Pilot survey of carrier rates and community attitudes. SETTING: Sydney, February 1993 to November 1994. PARTICIPANTS: 147 self- or medically referred people of Ashkenazi Jewish origin were tested. Jewish religious, medical and community organisations and leaders were consulted. OUTCOMES: Prevalence of HEXA mutations, client and community preference for different testing and reporting strategies. RESULTS: Frequency of heterozygous carriers was 1 in 18, with a relative frequency of the three major allelic variants similar to that in overseas studies. Most subjects were medically referred and preferred individual reporting of their carrier status. Community representatives had serious reservations about this strategy and few orthodox Jews participated in the study. An alternative strategy was developed for future testing. CONCLUSIONS: Frequency of heterozygous carriers of the Tay-Sachs disease gene was higher than found among Ashkenazi Jews in other countries, possibly because of ascertainment bias. A testing strategy with medical referral and individual reporting of carrier status may not be appropriate for all the community at risk and a modified strategy is necessary.

Taming the supplies and inventory process at Westmead Hospital.

UNLABELLED: In July 1991, a team within the Clinical Chemistry Department at Westmead Hospital used control charts and other statistical tools to analyze the supplies and inventory process. No single major problem was discovered. Instead, the team found many small problems causing delays and inefficiencies in the process. By developing and implementing multiple solutions, the team was able to streamline the process and reduce the number of principal suppliers. RESULTS: The number of principal suppliers was reduced by two-thirds. The average number of "urgent" orders, which add extra steps to the purchasing process, was reduced by three-quarters. The mean turnaround time for common clinical chemistry laboratory tests improved by 8%.

Familial hypobetalipoproteinaemia: a rare presentation to the lipid clinic.

OBJECTIVE: To report a case of familial hypobetalipoproteinaemia in a woman who presented after the incidental finding of marked hypocholesterolaemia during laboratory tests. CLINICAL FEATURES: An asymptomatic 37-year-old Lebanese woman presented to the lipid clinic with a serum total cholesterol concentration of 1.1 mmol/L, high density lipoprotein (HDL) cholesterol of 1.0 mmol/L, and triglycerides of 0.28 mmol/L. No secondary cause for the hypocholesterolaemia was established. INVESTIGATION AND OUTCOME: Her serum apolipoprotein B (apo B) levels were markedly reduced at 0.07 g/L. Except for one daughter (IV-4), all other family members including her husband (her first cousin) had apo B levels about 25% of normal. Daughter IV-4 had undetectable apo B levels. Family studies confirmed an autosomal dominant pattern of inheritance consistent with familial hypobetalipoproteinaemia. CONCLUSION: Familial hypobetalipoproteinaemia is a rare condition that should be considered in the differential diagnosis of hypocholesterolaemia. Absence of clinical features, autosomal dominant pattern of inheritance, and reduced apo B levels suggest the diagnosis.