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Experiences from a pilot program bringing BRCA1/2 genetic screening to theUS Ashkenazi Jewish population

Population screening of three common BRCA1/BRCA2 mutations in Ashkenazi Jews (AJ) apparently fulfills screening criteria. We compared streamlined BRCA screening via self-referral with proactive recruitment in medical settings. Unaffected AJ, age ≥25 years without known familial mutations, were either self-referred or recruiter-enrolled. Before testing, participants received written information and self-reported family history (FH). After testing, both non-carriers with significant FH and carriers received in-person genetic counseling. Psychosocial questionnaires were self-administered 1 week and 6 months after enrollment. Of 1,771 participants, 58% were recruiter-enrolled and 42% were self-referred. Screening uptake was 67%. Recruited enrollees were older (mean age 54 vs. 48, P 90%). At 6 months, carriers had significantly increased distress and anxiety, greater knowledge, and similar satisfaction; 90% of participants would recommend general AJ BRCA screening. Streamlined BRCA screening results in high uptake, very high satisfaction, and no excess psychosocial harm. Proactive recruitment captured older women less selected for FH. Further research is necessary to target younger women and assess other populations. Genet Med advance online publication 08 December 2016

Many recessive genetic disorders are found at a higher incidence in people of Ashkenazi Jewish (AJ) descent than in the general population. The American College of Medical Genetics and the American College of Obstetricians and Gynecologists have recommended that individuals of AJ descent undergo carrier screening for Tay Sachs disease, Canavan disease, familial dysautonomia, mucolipidosis IV, Niemann-Pick disease type A, Fanconi anemia type C, Bloom syndrome, and Gaucher disease. Although these recommendations have led to increased test volumes and number of laboratories offering AJ screening, well-characterized genomic reference materials are not publicly available. The Centers for Disease Control and Prevention-based Genetic Testing Reference Materials Coordination Program, in collaboration with members of the genetic testing community and Coriell Cell Repositories, have developed a panel of characterized genomic reference materials for AJ genetic testing. DNA from 31 cell lines, representing many of the common alleles for Tay Sachs disease, Canavan disease, familial dysautonomia, mucolipidosis IV, Niemann-Pick disease type A, Fanconi anemia type C, Bloom syndrome, Gaucher disease, and glycogen storage disease, was prepared by the Repository and tested in six clinical laboratories using three different PCR-based assay platforms. A total of 33 disease alleles was assayed and 25 different alleles were identified. These characterized materials are publicly available from Coriell and may be used for quality control, proficiency testing, test development, and research.

Tay-Sachs disease (TSD) carrier screening, initiated in the 1970s, has reduced the birth-rate of Ashkenazi Jews with TSD worldwide by 90%. Recently, several nationwide programs have been established that provide carrier screening for the updated panel of Jewish genetic diseases on college campuses and in Jewish community settings. The goals of this study were to determine the performance characteristics of clinical TSD testing in college- and community-based screening programs and to determine if molecular testing alone is adequate in those settings. Clinical data for TSD testing were retrospectively anonymized and subsequently analyzed for 1,036 individuals who participated in these programs. The performance characteristics of the serum and the platelet Hexosaminidase assays were compared, and also correlated with the results of targeted DNA analysis. The serum assay identified 29 carriers and the platelet assay identified 35 carriers for carrier rates of 1/36 and 1/29, respectively. One hundred sixty-nine samples (16.3%) were inconclusive by serum assay in marked contrast to four inconclusive samples (0.4%) by the platelet assay. Molecular analysis alone would have missed four of the 35 carriers detected by the platelet assay, yielding a false negative rate of 11.4% with a sensitivity of 88.6%. Based on the results of this study, platelet assay was superior to serum with a minimal inconclusive rate. Due to changing demographics of the Ashkenazi Jewish population, molecular testing alone in the setting of broad-based population screening programs is not sufficient, and biochemical analysis should be the assay of choice.

Patients with Gaucher disease (GD) are divided into three types based on the presence and rate of progression of the neurologic manifestations. While type 1 GD has a strong predilection in the Jewish Ashkenazi population, both other types lack such a propensity. We report the occurrence of type 2 GD (GD2) in four pregnancies in two Jewish families in Israel (in one case the mother was not Ashkenazi but was from a Sfaradi Jewish family) and also review seven additional cases of GD2 in Ashkenazi Jewish families reported in the literature. Phenotypically, GD2 in Ashkenazi Jews does not differ significantly from this form in other ethnic groups. Genotypic analysis of probands from the two Israeli families demonstrates that each carried two heterozygous glucocerebrosidase mutations. We could find no explanation why GD2 is so rare in the Jewish Ashkenazi population but we could hypothesize that homozygosity for certain Ashkenazi alleles might be lethal, leading to a lower than expected frequency of GD2 and noted that no cases of homozygous L444P has ever been described in Ashkenazi Jews

Background Multiple sclerosis (MS) is an autoimmune disease of the central nervous system, with a strong genetic component. Over 100 genetic loci have been implicated in susceptibility to MS in European populations, the most prominent being the 15:01 allele of the HLA-DRB1 gene. The prevalence of MS is high in European populations including those of Ashkenazi origin, and low in African and Asian populations including those of Jewish origin. Methods Here we identified and extracted a total of 213 Ashkenazi MS cases and 546 ethnically matched healthy control individuals from two previous genome-wide case-control association analyses, and 72 trios (affected proband and two unaffected parents) from a previous genome-wide transmission disequilibrium association study, using genetic data to define Ashkenazi. We compared the pattern of genetic risk between Ashkenazi and non-Ashkenazi Europeans. We also sought to identify novel Ashkenazi-specific risk loci by performing association tests on the subset of Ashkenazi cases, controls, probands, and parents from each study. Results The HLA-DRB1*15:01 allele and the non-HLA risk alleles were present at relatively low frequencies among Ashkenazi and explained a smaller fraction of the population-level risk when compared to non-Ashkenazi Europeans. Alternative HLA susceptibility alleles were identified in an Ashkenazi-only association study, including HLA-A*68:02 and one or both genes in the HLA-B*38:01-HLA-C*12:03 haplotype. The genome-wide screen in Ashkenazi did not reveal any loci associated with MS risk. Conclusion These results suggest that genetic susceptibility to MS in Ashkenazi Jews has not been as well established as that of non-Ashkenazi Europeans. This implies value in studying large well-characterized Ashkenazi populations to accelerate gene discovery in complex genetic diseases. Electronic supplementary material The online version of this article (doi:10.1186/s12881-015-0201-2) contains supplementary material, which is available to authorized users.

The Jews are an ancient and unique group of people linked by language, religion and customs in spite of their major geographical shifts, expulsions, forced conversions and massacres throughout their entire history. As a result of these historical events that led to repeated migration, the Jewish people became dispersed into various ethnic sub-groups. Between these ethnic groups exists heterogeneity, as well as some similarities, to the populations amongst whom they lived. Rare genetic diseases have been reported to be prevalent among the different groups of Jews, which for the most part can be explained by random genetic drift together with intra-familial marriages. In this publication, we will briefly discuss the origin of the various ethnic groups and some of the genetic diseases commonly found in them, with emphasis on the Ashkenazim, their prevalent genetic diseases and cancer susceptibility.

A founder effect can account for the presence of an allele at an unusually high frequency in an isolated population if the allele is selectively neutral and if all copies are identical by descent with a copy that either was carried by a founder individual or arose by mutation later. Here, a statistical test of both aspects of the founder-effect hypothesis is developed. The test is performed by a modified version of a program that implements the Slatkin-Bertorelle test of neutrality. The test is applied to several disease-associated alleles found predominantly in Ashkenazi Jews. Despite considerable uncertainty about the demographic history of Ashkenazi Jews and their ancestors, available genetic data are consistent with a founder effect resulting from a severe bottleneck in population size between a.d. 1100 and a.d. 1400 and an earlier bottleneck in a.d. 75, at the beginning of the Jewish Diaspora. The relatively high frequency of alleles causing four different lysosomal storage disorders, including Tay-Sachs disease and Gaucher disease, can be accounted for if the disease-associated alleles are recessive in their effects on reproductive fitness.

Several relatively rare genetic diseases are found at greater frequencies in Ashkenazi Jewish populations. Most of these conditions are untreatable and shorten life expectancy. Genetic screening using molecular detection of a few common mutations for each of these diseases facilitates their prevention by identification of carrier couples. Conversely, couples with negative results are reassured by reduced carrier risks. Using a standardized format, a brief overview for each of the nine genetic diseases is presented. Known mutations, a short clinical summary, clinical and laboratory diagnostic methods and information on supportive treatments is provided for each. Finally, a brief discussion of available DNA testing technologies and a review of platforms for expanded testing options for Ashkenazi Jewish diseases under development are presented.

The frequency of several genes responsible for 'single-gene' disorders and disease predispositions is higher among Ashkenazi Jews than among Sephardi Jews and non-Jews. The disparity is most likely the result of founder effect and genetic drift, rather than heterozygote advantage. The more common Mendelian Ashkenazi Jewish genetic disorders are summarized, and examples of variable expressivity and penetrance, inconsistent genotype-phenotype correlation, and potential modifiers are presented. The importance of genetic counseling in both the pre- and post-test phases of population screening is emphasized.

The aim of carrier testing is to identify carrier couples at risk of having offspring with a serious genetic (autosomal recessive) disorder. Carrier couples are offered genetic consultation where their reproductive options, including prenatal diagnosis, are explained. The Ashkenazi Jewish population is at increased risk for several recessively inherited disorders (Tay-Sachs disease, Cystic fibrosis, Canavan disease, Gaucher disease, Familial Dysautonomia, Niemann-Pick disease, Fanconi anemia, and Bloom syndrome). Unlike Tay-Sachs disease, there is no simple biochemical or enzymatic test to detect carriers for these other disorders. However, with the rapid identification of disease-causing genes in recent years, DNA-based assays are increasingly available for carrier detection. Approximately 5% of the world's population carries a mutation affecting the globin chains of the hemoglobin molecule. Among the most common of these disorders are the thalassemias. The global birth rate of affected infants is at least 2 per 1000 (in unscreened populations), with the greatest incidence in Southeast Asian, Indian, Mediterranean, and Middle Eastern ethnic groups. Carriers are detected by evaluation of red cell indices and morphology, followed by more sophisticated hematological testing and molecular analyses. The following issues need to be considered in the development of a carrier screening program: (1) test selection based on disease severity and test accuracy; (2) funding for testing and genetic counselling; (3) definition of the target population to be screened; (4) development of a public and professional education program; (5) informed consent for screening; and (6) awareness of community needs.

SummaryThe N370S mutation at the GBA locus on human chromosome 1q21, which causes Gaucher disease (GD), has a high frequency in the Ashkenazim and is the second-most-widespread GD mutation in the European non-Jewish population. A common ancient origin for the N370S mutation in the Ashkenazi Jewish and Spanish populations has been proposed on the basis of both a similar haplotype for associated markers and an age estimate that suggests that this mutation appeared several thousand years ago. However, a reappraisal of haplotype data, using the Risch formula properly along with a Luria-Delbrück setting of the genetic clock, allows identification of the likely origin of the N370S mutation in Ashkenazi Jews between the 11th and 13th centuries. This result is consistent with the estimated ages of other mutations that are frequent among Ashkenazim, with the exception of type II (Glu117Stop) factor XI deficiency, which is deemed to be >3000 years old, predating the separation of the Ashkenazi and Iraqi Jews. The present finding supports the hypothesis of a more recent origin for the N370S mutation and is consistent with both a founder chromosome transfer from Ashkenazim who assimilated in some European populations and a non-Jewish origin of the European N370S-bearing chromosomes.

The Roman Jewish community has been historically continuous in Rome since pre-Christian times and may have been progenitor to the Ashkenazi Jewish community. Despite a history of endogamy over the past 2000 yr, the historical record suggests that there was admixture with Ashkenazi and Sephardic Jews during the Middle Ages. To determine whether Roman and Ashkenazi Jews shared common signature mutations, we tested a group of 107 Roman Jews, representing 176 haploid sets of chromosomes. No mutations were found for Bloom syndrome, BRCA1, BRCA2, Canavan disease, Fanconi anemia complementation group C, or Tay-Sachs disease. Two unrelated individuals were positive for the 3849 + 10C->T cystic fibrosis mutation; one carried the N370S Gaucher disease mutation, and one carried the connexin 26 167delT mutation. Each of these was shown to be associated with the same haplotype of tightly linked microsatellite markers as that found among Ashkenazi Jews. In addition, 14 individuals had mutations in the familial Mediterranean fever gene and three unrelated individuals carried the factor XI type III mutation previously observed exclusively among Ashkenazi Jews. These findings suggest that the Gaucher, connexin 26, and familial Mediterranean fever mutations are over 2000 yr old, that the cystic fibrosis 3849 + 10kb C->T and factor XI type III mutations had a common origin in Ashkenazi and Roman Jews, and that other mutations prevalent among Ashkenazi Jews are of more recent origin.

Bloom's syndrome (BS) is a rare, autosomal recessive disease characterized by sun sensitivity, short stature, and predisposition to cancer. Although rare in the general population, BS is more common in the Ashkenazi Jewish population (German, 1993). The isolation of the gene for BS, known as BLM, has permitted the identification of mutations within the gene and the discovery that most BS individuals of Ashkenazi Jewish origin carry the identical 6-bp deletion/7-bp insertion at position 2,281 of BLM (blmAsh). We have developed a rapid method for detecting blmAsh based on restriction enzyme digestion of a PCR product containing the mutation. blmAsh creates a restriction site within the amplified fragment allowing distinction of normal and mutant DNAs. This method has been designed for use with genomic DNA or cDNA. Hum Mutat 11:175–178, 1998. © 1998 Wiley-Liss, Inc.

To the Editor: In a recent article, Risch et al. (2003) analyzed the frequencies of the various inherited disorders that are found in relatively high frequency among Ashkenazi Jews. By comparing three parameters—namely, the numbers of allelic mutations, allele frequency distribution, and estimated coalescence dates of mutations—Risch et al. (2003) demonstrated a similar pattern of these parameters between lysosomal storage disorders (LSDs) and 14 prevalent nonlysosomal disorders (NLSDs) that are prevalent among Ashkenazi Jews. Their conclusion, therefore, was that the LSDs are not unique in this population and the relatively high prevalence of LSDs stems from a genetic drift, rather than a selection process in favor of the LSDs in this population, as suggested elsewhere (Zlotogora et al. 1988). However, although we agree on the importance of the genetic drift to explain the high frequency of mutation in the Ashkenazi Jewish population, we still think that selective advantage for carriers of LSDs was apparently another important factor. Among >10,000 established gene loci (MIM Statistics, March 2003), >20 are responsible for disorders found with an increased prevalence among Ashkenazi Jews. As expected in a random process, there is no known relationship between most of the genes responsible for these disorders. The exceptions are the four prevalent LSDs among Ashkenazim—namely, Tay-Sachs disease (TSD [MIM 272800]), Gaucher disease (GD1 [MIM 230800]), Niemann-Pick disease (NPD [MIM 257200]), and mucolipidosis type IV (MLIV [MIM 252650])—in which the mutations are in genes that encode for enzymes from a common biochemical pathway. In all cases, the main storage substances are sphingolipids: GM2 ganglioside in TSD, glucosylceramide in GD, sphingomyelin in NPD, and various gangliosides in MLIV. A further indication of a nonrandom process is the number of mutations responsible for each disorder. As expected for random events, in almost all the NLSDs, one mutation is prevalent, and, if more than one mutation is found, its frequency is significantly 10% prevalent, when compared with the frequency of the major mutation. For instance, in NPD, three mutations are found in equal frequencies, and, in MLIV, there are two common mutations with a ratio of ∼2:1. In TSD, the ratio of the three common mutations is 73:18:3.5. In GD, the ratio between the two common mutations is 77:13 (Zlotogora et al. 2000). Furthermore, it should be noted that the data for allelic frequencies in the Risch et al. (2003) paper was partially based on the frequencies obtained by the Dor Yeshorim screening program, which uses mutation analysis. That program is aimed at the detection of heterozygotes for some eight prevalent severe disorders among Ashkenazim and is designed for a specific section of that population, the ultraorthodox community. We have shown elsewhere (Bach et al. 2001) that the frequency of TSD and allelic distribution of the three common mutations, in a sample of 32,000 individuals in the Dor Yeshorim program, is significantly different from the distribution found in the Ashkenazi population at large. We have seen a similar trend with other disorders as well, including familial dysautonomy (FD [MIM 223900]), MLIV, and others (G. Bach, unpublished data). Indeed, this community represents a relatively close section in which most individuals originated from specific locations in Europe. Thus, the data for allelic distribution in the Ashkenazi population, as reported in the article (Risch et al. 2003), does not fully represent the true picture. Risch et al. (2003) demonstrated a diverse geographic distribution of allelic mutations in some of the Ashkenazim with LSDs; certain mutations originated in Central Europe, whereas others originated in Eastern Europe. We suggest that this does not contradict a selection process, but that it may point to a secondary genetic drift. A well-known selection process by malaria in favor of heterozygotes has been demonstrated for sickle cell anemia (HBB [MIM 603903]) and is suspected for other blood disorders, such as thalassemia (HBB [MIM 141900]). If we focus on β thalassemia as an example, many mutations have been described in the populations that were exposed to malaria for centuries. Comparing the allelic distribution among Jews who originated from a relatively small geographic region, the mutations were significantly different in the Iranian, Turkish, and Iraqi parts of the Kurdistan Mountains (Rund et al. 1991). Nowadays, the high prevalence of thalassemia among the Kurdish Jews in Israel is due to several mutations, as a result of two processes: selection and genetic drift. Determining the forces that led to the present observations in the Ashkenazi Jews is complicated, and there is no clear data for the nature of the selection process in favor of the carriers of LSDs, if that process occurred. It was suggested that certain lung disorders (i.e., pneumonia and tuberculosis) conferred a heterozygous advantage for these disorders (Myrianthopoulos and Melnick 1977). If this is indeed the basis for the selection phenomenon or, in fact, any other similar environmental factor, the occurrence of different geographic origins of the various allelic mutations or different coalescence dates does not contradict a selection process but, rather, strengthens it. Regarding Ashkenazi Jews, although we have no clear evidence for the selection force, we can safely assume that the environmental factor lasted for centuries and that there is no reason to doubt that this selection force was effective in Central Europe as well as in the eastern part. Medical care for the Jewish people was not basically different in these regions. Thus, we would expect to find diverse distributions of allelic mutations for a selection process. Although the four LSDs are recessive, it can be postulated that, under extreme conditions, such as lung disorders, heterozygotes might undergo even a slight lysosomal storage of these substances, which might confer beneficial resistance to these conditions. To try to understand the past, one can look at the present and foresee the future. This can be done for genetic diseases found nowadays in populations whose living conditions are similar to those of the Ashkenazi Jews in Europe. One example is the Arab population living in the Middle East, in which the preference is for consanguineous marriages, as was the case for the Ashkenazi Jews. For the Jews who lived in Europe, like the Arabs living nowadays in Israel, further reasons to marry within the community were religious and geopolitical. In these populations, many genetic diseases are found with a high prevalence, and, although most are due to a single random mutation, others present a different distribution. For instance, among Arabs in Galilee, several diseases are found with an increased prevalence. On a molecular basis, in most cases, a single founder mutation explains the relatively high frequency for each disease. However, for other diseases—such as metachromatic leukodystrophy (MLD [MIM 250100]), Hurler syndrome (MPS1 [MIM 252800]), hyperoxaluria (HP1 [MIM 259900]), or ataxia telangiectasia (AT [MIM 208900])—many different mutations were found (Zlotogora 2002). In each case, all the patients were homozygous for a single mutation that was frequent, in general, in one village only. Another example is the high frequency of Mendelian disorders among the Bedouins of the Negev, owing to, in most cases, random founder mutations (Sheffield et al. 1998). However, Bardet-Biedl syndrome (BBS [MIM 209900]) is present among the Bedouins of the Negev in a very high prevalence, owing to mutations in three different genes. These observations, of either several mutations in the same gene or mutations in different genes responsible for the high prevalence of some genetic diseases in relatively small populations, cannot be explained as a random phenomenon. The possibility of a selective phenomenon must be raised, even though it has not yet been characterized. It may be expected that, in the future, with the expansion and mixing of the population, some of these mutations will be lost, whereas others will remain. Some mutations that are the result of genetic drift will be relatively prevalent in the general Arab population. One may wonder why the selection phenomenon was restricted primarily to the Ashkenazim and not to the non-Jewish people around them. Two, equally plausible, assumptions might explain this phenomenon. (a) The Jews in Europe, particularly in earlier periods (i.e., the 10th–17th centuries) lived for the most part in an extremely poor socioeconomic status with poor medical management. Thus, a selection force by heterozygous advantage might have been more effective for that population. (b) The genetic background of Jews was shown to be unique and different from that of other European people. It can be postulated that this particular genetic structure might have conferred a higher sensitivity or susceptibility to certain lung disorders, when compared with other people in the same region. We, therefore, conclude that the LSDs among Ashkenazim represent a unique group indicating a nonrandom phenomenon that might be explained by a selection process. This does not contradict a genetic drift, as was indicated by Risch et al. (2003)

Autosomal recessive nonsyndromic sensorineural hearing loss (ARNSHL) in Ashkenazi Jews, is mainly caused by mutations in the GJB2 and GJB6 genes. Here we describe a novel homozygous mutation of the LOXHD1 gene resulting in a premature stop codon (R1572X) in nine patients of Ashkenazi Jewish origin who had severe-profound congenital non-progressive ARNSHL and benefited from cochlear implants. Upon screening for the mutation among 719 anonymous Ashkenazi-Jews we detected four carriers, indicating a carrier rate of 1:180 Ashkenazi Jews. This is the second reported mutation in the LOXHD1 gene, and its homozygous presence in two of 39 Ashkenazi Jewish families with congenital ARNSHL suggest that it could account for some 5% of the familial cases in this community.

testing in the Ashkenazi Jewish population,aimed at reducing morbidity and mortality of breast/ovariancancer, is seemingly an obvious candidate for such a screeningprogram. In Ashkenazi Jews, three common, easily tested mu-tations account for the majority of deleterious alleles, effectivepreventive measures for

Yemenite Jews in Israel are a distinctive ethnic division of the Jewish diaspora. Clinical findings, disease course and genetic tests for the LRRK2 6055G > A (G2019S) mutation were compared between Ashkenazi and Yemenite Israeli patients with Parkinson's disease (PD). Age of onset was significantly younger in the Yemenites (P < 0.001). There were no differences in the distribution of initial symptoms, environmental risk factors or rate of motor/non-motor phenomena. The Yemenite group had a more severe disease (P < 0.001), and a more rapid disease course (P = 0.006). The frequency of Lrrk2 substitution was 12.7% in the Ashkenazi group and was not observed in the Yemenites. These results show that there are differences between Israeli Jewish ethnic groups in the severity and progression of PD, but not in clinical symptoms. The high frequency of Lrrk2 G2019S in the Ashkenazi and its absence in the Yemenite Jews suggests a specific ancestral pattern of inheritance in Ashkenazi Jews.

Disclaimer: This guideline is designed primarily as an educational resource for medical geneticists and other health care providers to help them provide quality medical genetic services. Adherence to this guideline does not necessarily assure a successful medical outcome. This guideline should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, the geneticist should apply his or her own professional judgment to the specific clinical circumstances presented by the individual patient or specimen. It may be prudent, however, to document in the patient's record the rationale for any significant deviation from this guideline.

Mucolipidosis type IV (MLIV) is a rare genetic disorder that primarily affects persons of Ashkenazi Jewish descent. Current information available about testing options and the Ashkenazi Jewish Screening panel, including the addition of screening for MLIV, is presented. The importance of genetic screening and counseling is emphasized.

Gaucher disease is the most common sphingolipid storage disease but genotype only broadly predicts phenotype. The 1604G→A (1604A;R496H) mutation has been described as having a low incidence among Ashkenazi Jews. The purpose of this study was to ascertain phenotypic expression and prevalence of this mutation among patients with Gaucher disease and among healthy Ashkenazi Jews. Patients in two Gaucher clinics (in the United States and Israel) and from an international Gaucher registry were assessed for frequency and phenotype expression; 200 healthy Ashkenazi Jews were screened as well. Molecular analysis was performed by standard methods. In the Gaucher clinic with mostly Jewish patients, the gene frequency was 1.68% compared with 0.38% in the international registry with mostly non-Jewish patients. Among Ashkenazi Jewish controls, no alleles with 1604A were identified. There was a marked overrepresentation of severe alleles in patients carrying the 1604A mutation, suggesting that many patients who are compound heterozygotes for 1604A are not diagnosed as having Gaucher disease because their disease is presumably so mild as to evade detection. In view of its rarity and mild expression, the inclusion of the 1604A mutation in the standard kit for screening for Gaucher disease is unnecessary.

In the Ashkenazi Jewish population there are at least nine severely debilitating autosomal recessive disorders that can be prevented by carrier screening and genetic counseling. There are common mutations that permit carrier identification with greater than 95% delectability. Simultaneous screening of both partners is recommended to avoid the anxiety associated with sequential screening when the first tested partner is found to be a carrier. Pretest and post-test genetic counseling should be provided, and screening of couples where only one member is Jewish is recommended. Experience with multiplex carrier screening in the Ashkenazi Jewish population has proved effective and provides a prototype for future mass carrier screening for genetic diseases in the general population.

In the community of the Orthodox Jews most of the marriages are arranged a screening program that is aimed at preventing the marriage of two carriers of autosomal recessive disorders is conducted by the Dor Yesharim organization. A random sample of 6,076 individuals of the Orthodox Jewish Ashkenazi community, were screened for the five mutations common in Ashkenazi patients (delta F508, W1282X, G542X, N1303K, 3849 + 10Kb C--T). Two hundred thirty-two carriers were identified, giving a heterozygote frequency of 1:26. The relative frequencies of the individual mutations in the general population were comparable to those in the patients.

This work was funded in part by a grant from the National Foundation for Jewish Genetic Diseases. We thank Dr. Robert Pergolizzi (North Shore University Hospital, Manhasset, NY), for the automated sequencing, and the NIGMS Human Genetic Mutant Cell Repository (Camden, NJ), for generously supplying the control cell lines used in this study.

Summary Several deleterious and lethal autosomal recessive genes appear to exist in equilibrium with their normal alleles at a variety of stable, or near stable frequencies of considerable antiquity. One person in 25 is, for instance, a carrier of the Tay-Sachs gene among Ashkenazi Jews, compared with 1 in 300 among Sephardic and Oriental Jews and non-Jews. The explanations offered for t his phenomenon have generally not been entirely satisfactory. It has been shown that parents replace fortuitous infant and childhood deaths with, on average, approximately two surviving sibs each. When mutation rates are low, this practice, which has also been shown to occur among other animals, can maintain considerable variations in the stable incidence of autosomal recessive disease, should such ethnic polymorphism arise through genetic drift, the founder effect or hitch-hiking. High mutation rates would appear to preclude ethnic variations in the stable incidence of genetic disease.

Hunter disease in Israel occurs among Ashkenazi, Oriental, and Sephardic Jews and is by far more frequent than Hurler disease. None of the other mucopolysaccharidoses has been diagnosed in Ashkenazi Jews. The possibility of Hunter disease being a “Jewish” disease is discussed.