Prevention is the Best Therapy: The Geneticist's Approach.

Abstract During the last two decades prenatal genetic screening and diagnosis has become the cornerstone of medical care for family planning to prevent genetic disease. Carrier screening programs for genetic disorders that are prevalent in various populations identify couples and pregnancies at risk of having an affected child. These couples can proceed with a choice of invasive prenatal diagnosis tests of the fetus (chorionic villous sampling and amniocentesis), or non-invasive prenatal testing of free fetal DNA circulation in the maternal blood which has emerged within the last few years and is currently available for fetal sexing for X Linked disorders. Despite the advances in prenatal diagnosis, couples found to have a fetus affected with a genetic disorder may need to face the dilemma of pregnancy termination. Preimplantation genetic diagnosis (PGD) is an alternative to preempt risk of having a child affected with a life-altering genetic disorder. This technique allows biopsy and genetic diagnosis of embryos obtained from in vitro fertilization by analysis of the genetic material from one or a few embryonic cells. Only unaffected embryos are returned to the mother to establish the pregnancy. We present our experience using PGD for four Lysosomal storage disorders: Tay Sachs, Gaucher type 1, Hunter and Fabry disease with some of the couples being carriers of more than one genetic disorder. PGD is applicable to most disorders for which the gene and the familial mutation are known and should be presented to couples as an alternative to invasive prenatal testing.

Population screening for reproductive risk for single gene disorders in Australia: now and the future.

Abstract As the results of the Human Genome Project are realized, it has become technically possible to identify carriers of numerous autosomal and X-linked recessive disorders. Couples at risk of having a child with one of these conditions have a number of reproductive options to avoid having a child with the condition should they wish. In Australia the haemoglobinopathies are the only group of conditions for which population screening is widely offered and which is government funded. In some Australian states there are also population screening programs for cystic fibrosis and autosomal recessive conditions more common in Ashkenazi Jewish individuals which are generally offered on a user pays basis. It is predicted that as consumer demand increases and testing becomes cheaper, that many people planning or in the early stages of pregnancy will have carrier screening for multiple genetic conditions. This will have significant implications for genetic counseling, laboratory and prenatal testing resources. In addition such screening raises a number of ethical issues including the value of lives of those born with genetic conditions for which screening is available.

Heterozygote carrier testing in high schools abroad: what are the lessons for the U.S.?

The main value of carrier detection in the general population is to determine reproductive risks. In this manuscript I examine the practice of providing carrier screening programs in the school setting. While the data show that high school screening programs can achieve high uptake, I argue that this may reflect a lack of full understanding about risks, benefits, and alternatives, and the right not to know. It may also reflect the inherent coercion in group testing, particularly for adolescents who are prone to peer pressure. The problem of carrier screening in the schools is compounded when the condition has a predilection for certain groups based on race, ethnicity or religion. I examine programs around the world that seek to test high school students for Tay Sachs and Cystic Fibrosis carrier status. I argue that carrier programs should be designed so as to minimize stigma and to allow individuals to refuse. The mandatory school environment cannot achieve this. Rather, I conclude that screening programs should be designed to attract young adults and not adolescents to participate in a more voluntary venue.

Assessing ethnicity in preconception counseling: genetics--what nurse practitioners need to know.

PURPOSE: To define and discuss five genetic disorders--Tay-Sachs, sickle cell anemia, Canavan's disease, thalassemia, and cystic fibrosis (CF)--and to explain the importance of the nurse practitioner's (NP's) assessment of clients' ethnicity during preconception counseling, which should address these genetic conditions. DATA SOURCES: Review of literature from professional journals, professional organizations' Web sites, guidelines from the American College of Obstetricians and Gynecologists, the National Institute of Health Consensus Statement, and the authors' professional clinical experience. CONCLUSIONS: The goal of preconception counseling is to identify potential or actual medical, psychological, or social conditions that may affect the mother or fetus. NPs are often the health care providers that initiate preconception counseling to women in varied primary care settings. NPs must be familiar with ethnicity-related inheritable conditions in order to provide appropriate client information and education and to implement testing and, when needed, referral for genetic counseling to individuals and families at risk for genetic disorders such as Tay-Sachs, Canavan's disease, CF, sickle cell anemia, and thalassemia. IMPLICATIONS FOR PRACTICE: NPs providing health care to women of child-bearing age should assess the client's use of contraception and intent for future pregnancy. Preconception counseling when indicated should be initiated to all women to increase their potential for healthy pregnancy outcomes. Although a comprehensive personal, family, medical, and psychosocial history and initiation of folic acid are the mainstays of preconception counseling, assessment for risk of ethnicity-related genetic conditions must also be included in prepregnancy health care.

Screening Jews and genes: a consideration of the ethics of genetic screening within the Jewish community: challenges and responses.

Screening for genetic disorders, particularly Tay-Sachs Disease, has been traditionally welcome by the Jewish community. I review the history of genetic screening among Jews and the views from the Jewish tradition on the subject, and then discuss ethical challenges of screening and the impact of historical memories upon future acceptance of screening programs. Some rational principles to guide future design of genetic screening programs among Jews are proposed.

Tay-Sachs disease carrier screening: a model for prevention of genetic disease.

Tay-Sachs disease (TSD) is an autosomal-recessive, progressive, and ultimately fatal neurodegenerative disorder. Within the last 30 years, the discovery of the enzymatic basis of the disease, namely deficiency of the enzyme hexosaminidase A, made possible both enzymatic diagnosis of TSD and heterozygote identification. In the last decade, the cloning of the HEXA gene and the identification of more than 80 associated TSD-causing mutations has permitted molecular diagnosis in many instances. TSD was the first genetic condition for which community-based screening for carrier detection was implemented. As such, the TSD experience can be viewed as a prototypic effort for public education, carrier testing, and reproductive counseling for avoiding fatal childhood disease. More importantly, the outcome of TSD screening over the last 28 years offers convincing evidence that such an effort can dramatically reduce incidence of the disease.

Discovery of children's carrier status for recessive genetic disease: some ethical issues.

Knowledge of one's carrier status for recessive genetic diseases is useful primarily in making marital and reproductive decisions. These decisions are peculiarly the private domain of the young adults who are dating, mating, and forming new families. The privacy of these decisions may be compromised when parents know the carrier status of their children. Thus, the practice of sharing that information with the parents of fetuses, babies, and minor children ought to be discouraged, out of respect for the autonomy and privacy of these children when they become adults.

Novel mutations and DNA-based screening in non-Jewish carriers of Tay-Sachs disease.

We have evaluated the feasibility of using PCR-based mutation screening for non-Jewish enzyme-defined carriers identified through Tay-Sachs disease-prevention programs. Although Tay-Sachs mutations are rare in the general population, non-Jewish individuals may be screened as spouses of Jewish carriers or as relatives of probands. In order to define a panel of alleles that might account for the majority of mutations in non-Jewish carriers, we investigated 26 independent alleles from 20 obligate carriers and 3 affected individuals. Eighteen alleles were represented by 12 previously identified mutations, 7 that were newly identified, and 1 that remains unidentified. We then investigated 46 enzyme-defined carrier alleles: 19 were pseudodeficiency alleles, and five mutations accounted for 15 other alleles. An eighth new mutation was detected among enzyme-defined carriers. Eleven alleles remain unidentified, despite the testing for 23 alleles. Some may represent false positives for the enzyme test. Our results indicate that predominant mutations, other than the two pseudodeficiency alleles (739C-->T and 745C-->T) and one disease allele (IVS9+1G-->A), do not occur in the general population. This suggests that it is not possible to define a collection of mutations that could identify an overwhelming majority of the alleles in non-Jews who may require Tay-Sachs carrier screening. We conclude that determination of carrier status by DNA analysis alone is inefficient because of the large proportion of rare alleles. Notwithstanding the possibility of false positives inherent to enzyme screening, this method remains an essential component of carrier screening in non-Jews. DNA screening can be best used as an adjunct to enzyme testing to exclude known HEXA pseudodeficiency alleles, the IVS9+1G-->A disease allele, and other mutations relevant to the subject's genetic heritage.

Polymerase chain reaction amplification specificity: incidence of allele dropout using different DNA preparation methods for heterozygous single cells.

PURPOSE: The purpose was to evaluate methods of DNA preparation in a single cell to determine the ability to amplify and correctly diagnose a targeted gene. METHODS: One- or two-cell lymphoblasts (n = 100/group), heterozygous for the normal and 4-base pair insertion on exon 11 of the beta-hexosaminidase A gene, were collected and prepared under the following conditions: (1) freeze-thaw liquid nitrogen, then boiling (LN2); (2) potassium hydroxide/dithiothreitol, heated to 65 degrees C, followed by acid neutralization (KOH); (3) boiling only (Bl); and (4) water only (H2O). Cells were analyzed by polymerase chain reaction using nested primers. RESULTS: The total number of cells amplifying [in brackets] and the cells with amplification for both alleles (heterozygous), the normal allele, or the mutant allele were as follows, respectively: LN2 [38], 11, 16, 11; KOH [97], 91, 5, 1; Bl [41], 17, 13, 11; and H2O [85], 41, 16, 28. With two cells per reaction tube the results were as follows: LN2 [85], 53, 14, 18; and KOH [97], 96, 1, 0. CONCLUSIONS: KOH lysis was significantly greater than with all other methods (P < 0.006) and should be used for single cells. This study also demonstrates the importance of using heterozygous cells to determine the ability to amplify both alleles as a method of quality control for single-cell analysis.

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.