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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.

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

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.

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.

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)

To the Editor: We read with interest and much concern the recent recommendation of the College regarding carrier screening in individuals of Ashkenazi Jewish (AJ) descent (Genet Med 2008;10: 54 –56). Specifically, we felt that Recommendation 4, “if only one member of a couple is of AJ background, testing should still be offered,” is quite problematic. As stated in the Guidelines, the cumulative probability of being a carrier for one of the conditions in the panel is between 20 and 25%. One in 4 or 1 in 5 couples where only one member is of AJ descent will be identified as at increased risk to have an affected child and offered testing for that specific condition for the non-AJ partner. The screening of the non-AJ partner for the mutations that occur in the AJ population is an exercise in unknown probabilities (Table 1). Since the frequency of those mutations that occur more often in the AJ population is unknown in non-AJ populations, there is no way to revise a couple’s risk after screening the non-AJ member for the AJ mutations. Counseling a couple that the non-AJ member does not carry any of the AJ mutations does not provide much solace (or information) regarding their risk for a child with one of the AJ genetic conditions. In the case of cystic fibrosis (where gene frequencies are known in various populations) and in the case of Tay-Sachs disease (where enzyme analysis is informative regardless of ethnicity) the Practice Guidelines do provide useful information that would aid a family in their decision-making process. Even without testing the non-AJ member, counselors can be reassuring to those couples where the AJ member is a carrier for Dysautonomia, Bloom syndrome, or Mucolipidosis IV, as these conditions are either extremely rare or unreported in non-AJ populations. So the question remaining (with the exception of cystic fibrosis and Tay-Sachs screening) is what do we accomplish by the implementation of these Guidelines in couples where only one member is of AJ descent? Michael L. Begleiter, MS, CGC Janda L. Buchholz, MS, CGC Andrea M. Atherton, MS, CGC Lee Z. Mays, MS, CGC Molly M. Lund, MS, CGC Meghan E. Strenk, MS Genetics, Dysmorphology and Metabolism, The Children’s Mercy Hospitals & Clinics, Kansas City, Missouri, The University of Missouri-Kansas City, School of Medicine, Kansas City, Missouri