Anne Proos

Mutations in the guanine nucleotide exchange factor gene IQSEC2 cause nonsyndromic intellectual disability

The first family identified as having a nonsyndromic intellectual disability was mapped in 1988. Here we show that a mutation of IQSEC2, encoding a guanine nucleotide exchange factor for the ADP-ribosylation factor family of small GTPases, caused this disorder. In addition to MRX1, IQSEC2 mutations were identified in three other families with X-linked intellectual disability. This discovery was made possible by systematic and unbiased X chromosome exome resequencing.

A genetic screening programme for Tay-Sachs disease and cystic fibrosis for Australian Jewish high school students

Australia has a Jewish population of about 90 000, mostly living in metropolitan Sydney or Melbourne and most are of Ashkenazi (northern and central Europe) Jewish origin.1 While community genetic carrier testing programmes for Tay-Sachs disease (TSD) have been established since 1970 and are now operating in various forms in 15 countries,2–4 before 1993 in Australia all TSD laboratory testing was only available through a medical consultation service. Following a two year pilot study,1 the Tay-Sachs Disease Programme (TSDP), organised by the Australasian Community Genetics Programme (ACGP), was established in 1995. Knowledge of genetic carrier status allows people an accurate assessment of their risks for having children with conditions such as TSD, enabling at risk couples the opportunity to explore their reproductive options, which may include prenatal testing, adoption, sperm or egg donation, and more recently preimplantation genetic diagnosis.2,5 While decision making in this area is optimally made before pregnancy, there are enormous difficulties in informing those of reproductive age of the availability of genetic carrier testing and its relevance.5 The ideal age for population screening for autosomal recessive diseases (such as TSD) is therefore early in adulthood, when young people can make mature decisions about testing6 based on information provided in a forum that enables discussion and debate. The high school environment provides that opportunity and it has been successfully shown in Montreal by Mitchell et al 7 that screening for genetic carriers for TSD (1973–1992) and β-thalassaemia (1980–1992) can be undertaken over a 20 year period without apparent psychological or sociological harm. As a result, in their study, practically all women in Montreal who were referred for prenatal diagnosis of β-thalassaemia major or TSD had undergone screening in high school. The benefits include enabling informed reproductive choices to be made …

The frequency of founder mutations in the BRCA1, BRCA2, and APC genes in australian Ashkenazi Jews

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.

Cost-effectiveness of a school-based Tay-Sachs and cystic fibrosis genetic carrier screening program

Purpose: To explore the cost-effectiveness of school-based multidisease genetic carrier screening.Method: Decision analysis of the cost-effectiveness of a school-based Tay-Sachs disease and cystic fibrosis genetic carrier screening program, relative to no screening. Data relating to ethnicity profile, test-accepting behavior, and screening program cost were sourced from an existing program in Sydney, Australia.Results: Compared to no screening, the incremental cost-effectiveness of the screening program is A

Ashkenazi Jewish population screening for Tay–Sachs disease: The International and Australian experience

5,834 per additional carrier detected. This cost-effectiveness ratio is most sensitive to changes in genetic test accuracy, and the cost of laboratory assays. The results imply a cost per affected birth avoided of approximately A

Tay-Sachs disease: current perspectives from Australia.

530,000 (≈ US

Tay Sachs disease in Australia: reduced disease incidence despite stable carrier frequency in Australian Jews.

371,000).Conclusions: This preconceptional genetic carrier screening program offers comparable cost-effectiveness to prenatal screening programs for cystic fibrosis.

Tay-Sachs disease preconception screening in Australia: self-knowledge of being an Ashkenazi Jew predicts carrier state better than does ancestral origin, although there is an increased risk for c.1421 + 1G > C mutation in individuals with South African heritage.

Internationally, Tay‐Sachs disease (TSD) preconception screening of Ashkenazi Jewish (AJ) individuals and couples has led to effective primary prevention of TSD. In Australia, adolescent preconception genetic screening programs operate mainly in Jewish community high schools. These existing programs offer an effective means of primary prevention of TSD, are cost effective and safe. However, in the broader Australian community TSD screening is not systematically performed and cases still occur in unscreened AJ individuals. In order to improve the effectiveness of Australian screening, there is a need for definitive guidelines for healthcare professionals to facilitate extension of the proven benefits of preconception TSD screening to all AJ individuals at risk. We performed a systematic review of the relevant literature relating to AJ pre‐conception and antenatal screening for TSD. The evidence was assessed using an established National Health and Medical Research Council evidence grading system. Evaluations of efficacy of TSD screening programs design and execution, cost‐benefit and cost‐utility health economic evaluation, and population outcomes were undertaken. The results have been used to propose a model for universal AJ TSD preconception and antenatal screening for the primary care setting.

Carrier screening for Canavan disease in Australia

Tay-Sachs disease (TSD) is a fatal, recessively inherited neurodegenerative condition of infancy and early childhood. Although rare in most other populations, the carrier frequency is one in 25 in Ashkenazi Jews. Australian high-school-based TSD preconception genetic screening programs aim to screen, educate, and optimize reproductive choice for participants. These programs have demonstrated high uptake, low psychological morbidity, and have been shown to result in fewer than expected Jewish TSD-affected births over 18 years of operation. The majority of Jewish individuals of reproductive age outside of the high school screening program setting in Australia have not accessed screening. Recent recommendations advocate supplementing the community high school screening programs with general practitioner- and obstetrician-led genetic screening of Ashkenazi Jewish individuals for TSD and other severe recessive diseases for which this group is at risk. Massively parallel DNA sequencing is expected to become the testing modality of choice over the coming years.

Validation of a HLA-B*15:02 screening method in the prevention of carbamazepine – Induced severe cutaneous adverse reactions

Objectives: To evaluate the outcomes of preconception screening of Jewish Australians for Tay Sachs disease (TSD) carrier status on Jewish TSD‐affected births.