non-Jewish Individuals Research Articles

Particulate Air Pollution Exposure and Stroke among Adults in Israel.

Stroke is the second most common cause of death and disability in the world. Many studies have found fine particulate matter (PM2.5) exposure to be associated with an increased risk of atherosclerotic cardiovascular disease, mostly focusing on ischemic heart disease and acute myocardial infarction. In a national analysis conducted in Israel-an area with unique climate conditions and high air pollution levels, we estimated the association between short-term PM2.5 exposure and ischemic stroke, intracerebral hemorrhage (ICH), or transient ischemic attacks (TIA). Using the Israeli National Stroke Registry, we obtained information on all stroke cases across Israel in 2014-2018. We obtained daily PM2.5 exposures from spatiotemporally resolved exposure models. We restricted the analytical data to days in which PM2.5 levels did not exceed the Israeli 24 h standard (37.5 µg/m3). We repeated the analysis with a stratification by sociodemographic characteristics and comorbidities. For all outcomes, the exposure-response curves were nonlinear. PM2.5 exposure was associated with a higher ischemic stroke risk, with larger effect estimates at higher exposure levels. Although nonsignificant, the exposure-response curve for TIA was similar. The associations with ICH were nonsignificant throughout the PM2.5 exposure distribution. The associations with ischemic stroke/TIA were larger among women, non-Jewish individuals, older adults, and individuals with diabetes, hypertension, and ischemic heart disease. In conclusion, short-term PM2.5 exposure is associated with a higher risk for ischemic stroke and possibly TIA, even when PM2.5 concentrations do not exceed the Israeli air quality guideline threshold. Vulnerability to the air pollution effects differed by age, sex, ethnicity, and comorbidities.

Materiality and Holocaust Memory: Activating and Theorizing Poland’s Unquiet Places

Materiality and Holocaust Memory: Activating and Theorizing Poland’s Unquiet Places Erica Lehrer (bio) In the summer of 1992, I participated in a new program at the budding Research Centre on the History and Culture of Jews in Poland at the Jagiellonian University in Kraków, on ul. Batorego (est. 1986, the first of its kind at a Polish university). Titled “Tracing the Jewish Heritage in Poland,” it gathered a cadre of established and emerging experts—among them site specialists Adam Bartosz, Eugeniusz Duda, Leszek Hońdo, Sławomir Kapralski, Monika Krajewska, and Andrzej Paluch—who presented the state of local scholarship, cultural production, and material heritage to a motley handful of foreign Jews, including two Holocaust survivors, a filmmaker, a Judaica librarian from UCLA, and a few students like myself, along with two or three local Polish “philosemites,” an emerging category of non-Jewish individuals ethically or emotionally motivated to engage with their country’s forgotten Jewish past. The challenges of language, knowledge, and cultural sensitivities on both sides made this a bumpy ride, but the most profound confrontation took place during the group’s minibus tour across the southeastern Polish countryside, visiting former Galician shtetls and listening to local inhabitants’ recollections of their Jewish neighbors. It was a deeply unsettling experience and exposed a vast array of assumptions I didn’t realize I had. The most central was that Poland was a Jewish void. Instead, I was met by a landscape littered with the physical traces of the country’s prewar Jewish community of 3,300,000 people. I was an aspiring photographer then, and the roofless synagogues that now served as forest floors (the biblical polychrome murals obscured by leafy canopies) and the farmer’s field cobbled with a path of matsevot (tombstones whose Hebrew letters faced up under the wooden wheels of a hay-laden cart) formed indelible images. [End Page 239] Such images and fragments would become increasingly meaningful to roots-seeking foreign Jews with Polish ancestry (like myself), as well as to local Jewish and non-Jewish Poles who began to rediscover this landscape in the following decades.1 My most moving encounter was meeting an elderly Catholic stonemason, one Jan Sasak, in the formerly half-Jewish town of Przeworsk, who had made with his own hands a monument to his murdered Jewish neighbors at the site of the local bus station, which the municipality had built by paving over the town’s former Jewish cemetery.2 Gnawing at the edges of this inspiring, humble gesture was the fact that Mr. Sasak took pains to ensure that his neighbors did not know we were visiting him to express appreciation for an act whose heroic interpretation they did not share. In Poland, the geographic epicenter of the Holocaust, relations with Jewishness are often mediated by material objects, which stand in for the missing, murdered, or exiled people to whom they once belonged. The war and its aftermath separated Poland’s Jewish community from most of its physical property, which fell into the hands of the surrounding Polish Catholic population. The existence of local, vernacular Polish meanings for the country’s wide variety of formerly Jewish objects and sites became a topic of interest to researchers beginning in the late 1980s and early 1990s. These “disinherited” objects, which have been incompletely rein-herited by non-Jewish Poles, carry the curious Polish name pożydowskie (“post-Jewish”). It is to the Polish scholars, artists, and activists fighting to retain the visibility of the country’s Jewish past (in the face of both oblivion and other Polish efforts to erase it) that I dedicate these brief reflections. Despite some deep hermeneutical (and perhaps political) disagreements and a diversity of approaches to inquiry and knowledge production,3 I treat these individuals here as an interdisciplinary intellectual-ethical community defined by a shared field of inquiry. Their engagement with these once-Jewish [End Page 240] sites and objects constitutes an important act of heritage custodianship, redefining both sides of that term and calling into being multiethnic communities of care and implication4 that contrast with the government’s abysmal record on Jewish property restitution. Intertwined with this grassroots activity...

The Politics of Defining Antisemitism

The Politics of Defining Antisemitism Joshua Shanes (bio) The editors of this new volume—following david engel's provocative essay "Away from a Definition of Antisemitism"—explicitly reject the idea that a single definition can capture the entire history of this phenomenon, doubting that it even constitutes a single phenomenon.1 "This volume is informed by the insight," they write, "that there is neither a single way to think about antisemitism, nor an unambiguous, universally accepted definition of the term itself."2 Instead, they approach it from twenty-one different, if at times overlapping, perspectives. They admit that this is "not merely a topic of 'academic' interest" and "recognize the importance of juridical efforts to define antisemitism for the purpose of curbing hate crimes," but remain skeptical of efforts to construct a single definition that covers all its history.3 This begs the question, however, of what definition should be used to curb those hate crimes and why there is such a contentious debate at this moment over the issue. Arguably, support for these "juridical efforts" contests Engel's essay and suggests antisemitism can be defined, despite their support for Engel's contextual approach. Toward this end, it would have helped to address popular efforts at definition, and yet not a single essay in this volume discusses the popular "working definition" of antisemitism by the International Holocaust Remembrance Alliance (IHRA) that has been so effectively weaponized in North America and Europe in debates over Israel and Zionism, nor the competing Jerusalem Declaration (JDA) composed and signed by hundreds of leading scholars of antisemitism around the world. The definitions are remarkable in both their similarities and differences. IHRA chooses a relatively open-ended definition of antisemitism, as follows: "Antisemitism is a certain perception of Jews, which may be expressed as hatred toward Jews. Rhetorical and physical manifestations of antisemitism are directed toward Jewish or non-Jewish individuals and/or their property, toward Jewish community institutions and religious facilities."4 It follows with eleven brief examples of antisemitism, seven of which focus on Israel. The Jerusalem Declaration opens with [End Page 188] a more concise definition—"Antisemitism is discrimination, prejudice, hostility or violence against Jews as Jews (or Jewish institutions as Jewish)"—and then develops examples more fully and methodically, with a clear intention of responding to potential overreach regarding IHRA, in some cases affirming but in others countering explicit or implicit assumptions of antisemitism in the earlier document.5 As a result, a vigorous and often personal public debate quickly broke out, as advocates of the earlier definition rallied to defend their preference. Why is this debate happening now—a question that surely speaks to the timing of this volume's release—and what divides these two definitions and their advocates? To answer these questions, let's first look at defenses of IHRA published in response to the release of the Jerusalem Declaration. "The Jerusalem Declaration on Antisemitism is itself antisemitic.… Their real objective is to use the fight against antisemitism as another weapon with which to vilify Israel."6 This was the title of the JDA analysis of Dr. Dana Barnett, from the Begin-Sadat Center for Strategic Studies, and it is the broad consensus of nearly every critique of the JDA in defense of IHRA this author could find. In other words, the scholars behind the JDA were allegedly not working to fight antisemitism but rather hoped to manipulate the definition in order to harm Israel. David Hirsh, author of Contemporary Leftwing Antisemitism, went even farther. He accused the authors of the JDA of composing the definition not to fight antisemitism but rather to "fight efforts to fight antisemitism" and to protect antisemites.7 A consortium of other English scholars went farther still, accusing the "smug Jewish academics and intellectuals" who signed the JDA of seeking to "incite Jew hatred," adding for good measure that they were motivated by the "desperate longing to be regarded as 'good Jews.'"8 Why the vitriol, and what exactly is the argument about? The irony is that scholars—as this new volume makes clear—mostly agree on the basic features of antisemitism, at least implicitly, even when reticent to define it explicitly...

"Examining Anti-Semitism on College Campuses" United States House of Representatives Committee on the Judiciary

"Examining Anti-Semitism on College Campuses" United States House of Representatives Committee on the Judiciary Pamela S. Nadell (bio) PREFACE On a chilly fall morning, I passed through security into the Rayburn Building, found the House Judiciary Committee hearing room, and took a seat—where I never thought I would be—at the witness table. How did I come to testify before the US House of Representatives Committee on the Judiciary? Three weeks before the committee convened the hearing, "Examining Anti-Semitism on College Campuses," Kenneth Stern, executive director of the Justus and Karin Rosenberg Foundation, called. During World War II, Danzig-born Justus Rosenberg, known as Gussie, was a courier for Varian Fry's Centre Américain de Secours, which had rescued 2,000 artists and intellectuals, among them Marc Chagall and Hannah Arendt, from Vichy France. After the war, Rosenberg came to America; became a professor of European history, literature, and culture; and, around 2014, established a foundation to fight antisemitism. Kenneth Stern, formerly of the American Jewish Committee, was its executive director.1 Stern was looking for a scholar who shared the foundation's concern about a bill then wending its way through Congress, the Anti-Semitism Awareness Act. The act proposed codifying the State Department's 2010 fact sheet "Working Definition of Anti-Semitism" and its examples which were adapted from the European Monitoring Center on Racism and Xenophobia. At the AJC, Stern had been the lead author on the working definition for the European Monitoring Center. There it provided guidance for gathering data on antisemitic incidents.2 [End Page 189] Turning the State Department's fact sheet into federal law would transform this rubric for compiling data into a statute used to investigate complaints under Title VI of the 1964 Civil Rights Act. Title VI prohibits discrimination on the basis of race, color, and national origin in programs and activities receiving federal funding, like those at colleges and universities.3 I knew little about the bill, but I know something about antisemitism. My regular Jewish history rotation at American University includes a survey where I introduce the tropes of medieval anti-Judaism and their consequences and a course on the Holocaust. For about a decade, I also taught the history of anti-Judaism and antisemitism to parochial Catholic school educators for the Anti-Defamation League's Bearing Witness summer institute on the Holocaust. Stern walked me through the bill's legislative tangle. The previous December, the Senate, without a committee hearing and without any meaningful debate, had passed the Anti-Semitism Awareness Act just hours after it was introduced. The House was then poised to follow suit. A parallel resolution had been introduced and was about to bypass committee deliberation. Then the American Civil Liberties Union sounded the alarm: The bill posed a "serious threat" to the First Amendment's guarantee of free speech.4 The ACLU called for careful consideration of the bill. Now more than ten months later, that was about to get underway in the House. Stern had spoken with colleagues I admire who shared the ACLU's and his concerns about the bill. But none was available to testify. My name had come up; I was conveniently located in Washington. Would I do it? In the following days, I spoke with colleagues who urged me to step forward. A former student with long experience on the Hill told me not to waste my time. The bill would fly through the House. I consulted with the Association for Jewish Studies Executive Committee because I was then AJS President. Meanwhile, I began thinking long and hard about the fact sheet and its addenda "Contemporary Examples of Anti-Semitism" and "What [End Page 190] is Anti-Semitism Relative to Israel?" Other than my preference for the spelling of antisemitism,5 I had no problem with the working definition: Anti-Semitism is a certain perception of Jews, which may be expressed as hatred toward Jews. Rhetorical and physical manifestations of anti-Semitism are directed toward Jewish or non-Jewish individuals and/or their property, toward Jewish community institutions and religious facilities. But I became increasingly uneasy about the examples and their implications for curbing free...

Comprehensive overview of the pharmacogenetic diversity in Ashkenazi Jews

BackgroundAdverse drug reactions are a major concern in drug development and clinical therapy. Genetic polymorphisms in genes involved in drug metabolism and transport are major determinants of treatment efficacy and...

Pathology update to the Manchester Scoring System based on testing in over 4000 families

BackgroundWhile the requirement for thresholds for testing for mutations in BRCA1/2 is being questioned, they are likely to remain for individuals unaffected by a relevant cancer. It is still useful...

The VKORC1 Asp36Tyr variant and VKORC1 haplotype diversity in Ashkenazi and Ethiopian populations

The vitamin K epoxide reductase (VKORC1) is a key enzyme in the vitamin K cycle impacting various biological processes. VKORC1 genetic variability has been extensively studied in the context of warfarin pharmacogenetics revealing different distributions of VKORC1 haplotypes in various populations. We previously identified the VKORC1 Asp36Tyr mutation that was associated with warfarin resistance and with distinctive ethnic distribution. In this study, we performed haplotype analysis using Asp36Tyr and seven other VKORC1 markers in Ashkenazi and Ethiopian-Jewish and non-Jewish individuals. The VKORC1 variability was represented by nine haplotypes (V1-V9) that could be grouped into two distinct clusters (V1-V3 and V4-V9) with intra-cluster difference limited to two nucleotide changes. Phylogeny analysis suggested that these haplotypes could have developed from an ancestral variant, the common V8 haplotype (40% in all population samples), after ten single mutation events. Asp36Tyr was exclusive to the V5 haplotype of the second cluster. Two haplotypes V5 and V4, distinguished only by Asp36Tyr, were prevalent in both Ethiopian population samples. The V2 haplotype, belonging to the first cluster, was the second most prevalent haplotype in the Ashkenazi population sample (15.8%) but relatively uncommon in the Ethiopian origin (4.5-4.7%). We discuss the genetic diversity among studied populations and its potential impact on warfarin-dose management in certain populations of African and European origin.

Tay-Sachs carrier screening in the genomics age: Gene sequencing versus enzyme analysis in non-Jewish individuals

Purpose: To compare the sensitivity of Hexosaminidase A (HexA) enzyme-based testing to gene sequencing for carrier detection in non-Jewish individuals. Methods: Blood samples were obtained from parents and relatives of affected patients at an annual Tay-Sachs and Allied Diseases Foundation meeting. A family history was taken for each individual. Samples were analyzed for leukocyte HexA activity, serum HexA activity and subjected to extensive gene sequencing. The results from these analyses were combined with our previously published data describing 34 obligate Tay-Sachs disease (TSD) carriers. Results: Twelve additional TSD carriers were detected in this study. Gene sequencing successfully identified all 12 carriers whereas enzyme analysis identified 11 of 12 carriers. This individual is a carrier of the B1 variant that is known to cause false negative results with enzyme testing. Combined data from 46 non-Jewish TSD carriers revealed that gene sequencing had a higher sensitivity rate than HexA enzyme-based testing (94% versus 87%) in non-Jewish TSD carriers. In our series, approximately 4% of non-Jewish TSD carriers have this mutation. Conclusions: HexA gene sequencing provides a higher sensitivity for TSD carrier detection than HexA based enzyme analysis in non-Jewish patients primarily due to the presence of individuals with the B1 variant.

"A Drama of Faith and Family": Familialism, Nationalism, and Ethnicity among Jews in Postwar France

"A Drama of Faith and Family": Familialism, Nationalism, and Ethnicity among Jews in Postwar France 1 Daniella Doron (bio) The Second World War presented postwar French Jews with an excruciating death toll as well as a devastating demographic landscape: large numbers of single parent households, nuclear families in economic and emotional distress, and approximately three thousand orphaned children. In the decade following the Liberation, debates over to whom these Jewish children "belonged" captivated French Jewish child welfare workers, Jewish and non-Jewish policymakers and the public, and above all else families occupied with the Herculean task of deciding the future lives of parentless youth. 2 Should children remain with those non-Jewish individuals who had hidden, saved, and often loved them even at risk to their own lives? Or should these young children be turned over to distant relatives or Jewish communal institutions in an effort to keep them as Jews? In short, who and what constituted these children's best interests? The heated issue of custody rights of orphaned Jewish children confronted social workers, families, and surely the children themselves with heart-wrenching dilemmas, but it also presented them with an opportunity to ruminate over the contours of ethnicity, nationalism, and familialism in postwar France. For Jewish activists anxious to reassert Jewish ethnicity in the aftermath of the Holocaust, the best interests of the child could only be served in a Jewish setting, be it familial or institutional. In contrast, dominant French policy and public opinion regarding the settlement of thousands of displaced Jewish youth generally favored universal and republican values. French non-Jewish families facing the prospect of an emotionally wrenching family separation generally maintained that any loving family—be it Christian or Jewish—ought to represent "the best interests of the child." Many French judges and bureaucrats concurred, viewing the custody disputes as a propitious opportunity to reassert secular republicanism after the unsettling experience of occupation and collaboration. Regardless of these youths' prior nationalities and ethnicities, they could become the citizens France desperately needed. In [End Page 1] these struggles over youth, malleable ideas about the family were utilized to articulate both contested ideas about Jewish identity after the Holocaust and republicanism after Vichy. By exploring a series of politically and emotionally charged custody disputes, this article complements recent scholarly efforts to revise older narratives that suggested that postwar Jews preferred to slip back into a "normal" life by denying particularism. 3 Instead, ensuring a Jewish identity and education for orphaned youth acquired particular urgency and poignancy for French Jewish organizations and individuals after the genocide. More generally, these case studies reveal how ideas about national identity and citizenship have informed the familialist strategies of Jews in the modern era. The debates about the Jewish family that erupted in the wake of the Liberation demonstrate the extent to which notions of family and nationhood were often intertwined and how quickly they could be destabilized in moments of crisis. "A Difference of Psychology": Familialism, Ethnicity, and Universalism The case of Jeannine G. shines a light on ideas about familialism, nationalism, and ethnicity that emerged as France's citizens—Jewish and non-Jewish—worked to rebuild children's lives and the French nation. 4 In 1946, assuming their parents dead, Mr. Goldstein of Paris approached the Bundist Jewish child welfare agency the School Colony (La colonie scolaire) to seek help in gaining custody of his young cousins. Jeannine and Simone G. had been hidden from the Nazis by the Lacostes of the Nièvre since 1942. Now that safety had arrived, however, the Lacostes hesitated to give up the two girls they had loved for years. Upon hearing of the case, the School Colony—in the words of one social worker—agreed that the "fight must be continued" and helped Mr. Goldstein organize a family court proceeding (conseille de famille), which named him guardian of the girls. Soon thereafter, the older daughter Simone, then fourteen years old, left the family that had sheltered and saved her for the home of the Feldmans, her parents' friends in Paris. Later that year, when Mrs. Lacoste now adamantly refused to return Jeannine, Mr. Goldstein, in the words of a social worker, "virtually...

A genome-wide genetic signature of Jewish ancestry perfectly separates individuals with and without full Jewish ancestry in a large random sample of European Americans

A principal components analysis of genomic information showed that individuals with full Jewish ancestry formed a clearly distinct cluster from those individuals with no Jewish ancestry.

The Y152X MC1R gene mutation: occurrence in ethnically diverse Jewish malignant melanoma patients

MC1R sequence variants are associated with malignant melanoma risk, and most commonly are missense mutations. Few (n=9) truncating mutations have been described in this gene as predisposing to malignant melanoma. In this study, three Jewish individuals were found to harbor an identical truncating MC1R mutation--Y152X: an Ashkenazi patient with two malignant melanomas, a non-Ashkenazi malignant melanoma patient with familial malignant melanoma and her asymptomatic mother. Both malignant melanoma patients carried additional, seemingly pathogenic MC1R variants. Haplotype analysis revealed that all three mutation carriers shared the same haplotype. This sequence variant was previously described in ethnically diverse, non-Jewish individuals and in all likelihood represents an error-prone domain that, in conjunction with other genetic and environmental factors, increases malignant melanoma risk.

Refined genomic localization and ethnic differences observed for the IBD5 association with Crohn's disease

Although the general association of the inflammatory bowel disease (IBD) 5 region on chromosome 5q31 to Crohn's disease (CD) has been replicated repeatedly, the identity of the precise causal variant within the region remains unknown. A recent report proposed polymorphisms in solute carrier family 22, member 4 (SLC22A4) organic cation transporter 1(OCTN1) and solute carrier family 22, member 5 (SLC22A5) (OCTN2) as responsible for the IBD5 association, but definitive, large-sample comparison of those polymorphisms with others known to be in strong linkage disequilibrium was not performed. We evaluated 1879 affected offspring and parents ascertained by a North American IBD Genetics Consortium for six IBD5 tag single nucleotide polymorphisms (SNPs) to evaluate association localization and ethnic and subphenotypic specificity. We confirm association to the IBD5 region (best SNP IGR2096a_1/rs12521868, P<0.0005) and show this association to be exclusive to the non-Jewish (NJ) population (P=0.00005) (risk allele undertransmitted in Ashkenazi Jews). Using Phase II HapMap data, we demonstrate that there are a set of polymorphisms, spanning genes from prolyl 4-hydroxylase (P4HA2) through interferon regulatory factor 1 (IRF1) with equivalent statistical evidence of association to the reported SLC22A4 variant and that each, by itself, could entirely explain the IBD5 association to CD. Additionally, the previously reported SLC22A5 SNP is rejected as the potential causal variant. No specificity of association was seen with respect to disease type and location, and a modest association to ulcerative colitis is also observed. We confirm the importance of IBD5 to CD susceptibility, demonstrate that the locus may play a role in NJ individuals only, and establish that IRF1, PDLIM, and P4HA2 may be equally as likely to contain the IBD5 causal variant as the OCTN genes.

The Tyr978X BRCA1 mutation: occurrence in non-Jewish Iranians and haplotype in French-Canadian and non-Ashkenazi Jews

The Tyr978X BRCA1 mutation is a founder mutation detected in high-risk Iraqi-Iranian Jewish families as well as in the general non-Ashkenazi population. The same mutation was also reported in non-Jewish high-risk women from Canada. Its occurrence in non-Jewish individuals from Iran has never been tested. Assess the occurrence rate of Tyr978X BRCA1 germline mutation in the general population of Iranian non- Jewish individuals and compare the BRCA1-linked haplotype of Jewish and non-Jewish mutation carriers. PCR amplification of the relevant fragment of the BRCA1 gene, followed by restriction enzyme digestion that differentiates wild type from mutant allele. For haplotyping, 7 BRCA1-linked markers were used. The tested population included 442 apparently healthy Iranian non-Jewish individuals, and 17 mutation carriers from Israel and Canada. The Tyr978X BRCA1 mutation was not detected in any Iranian non-Jewish individual. The intragenic haplotype of all Jewish Israeli mutation carriers was identical, but differed from that of Canadian non-Jews in two intragenic markers. The Tyr978X BRCA1 mutation which is a founder mutation in Jews, may be a hot spot in non-Jewish high risk women, and probably does not represent a rare sequence variant in Iranian non-Jews.

Novel splice site mutation of aspartoacylase gene in a Turkish patient with Canavan disease

Canavan disease is a severe, progressive autosomal recessive neurodegenerative leukodystrophy. Canavan disease occurs more frequently among Ashkenazi Jewish individuals with two predominant mutations in the aspartoacylase (ASPA) gene. The disease is less frequent in non-Jewish individuals and the mutations randomly reside on the ASPA gene, with one mutation seen more frequently among patients of European extraction. In the present study we report a novel homozygous donor splice site mutation of intron 4 in a child with first-cousin parents of Turkish extraction.

Two novel polymorphic sequences in the glucocerebrosidase gene region enhance mutational screening and founder effect studies of patients with Gaucher disease.

Gaucher disease, an inherited glycolipid storage disorder, is caused by a deficiency of the catabolic enzyme glucocerebrosidase (EC 3.2.1.45). The gene for human glucocerebrosidase is located on chromosome 1q21 and has a highly homologous pseudogene situated 16 kb downstream. We report two novel polymorphic sequences in the glucocerebrosidase gene region: the first consists of a variable number of dinucleotide (CT) repeats located 3.2 kb upstream from the glucocerebrosidase gene, and the second is a tetranucleotide (AAAT) repeat found between the glucocerebrosidase gene and its pseudogene, 9.8 kb downstream from the functional gene. These polymorphic sequences, along with a previously reported PvuII polymorphism in intron 6 of the glucocerebrosidase gene, were analyzed in patients with Gaucher disease (n=106) and in two normal control populations, one of Ashkenazi Jewish ancestry (n=72) and the second comprising non-Jewish individuals (n=46). In these samples, strong linkage disequilibrium was found between mutations N370S, c.84-85insG, and R463C and specific haplotypes; no significant linkage disequilibrium was found when examining haplotypes of patients with the L444P mutation. Studies of these polymorphic sites in several instances also led to the recognition of genotyping errors and the identification of unusual recombinant alleles. These new polymorphic sites provide additional tools for mutational screening and founder effect studies of Gaucher disease.

Ashkenazi Jewish population frequency of the Bloom syndrome gene 2281 delta 6ins7 mutation.

Bloom syndrome is an autosomal recessive disorder characterized clinically by small size, sun-sensitive facial erythema, and immunodeficiency, and cytogenetically by increased chromosome breakage and sister chromatid exchange. Genomic instability renders Bloom syndrome patients at elevated risk for multiple cancers. Bloom syndrome occurs most commonly in the Ashkenazi Jewish population due to an apparent founder effect. The BLM gene on chromosome 15q26.1 was identified to encode a RecQ DNA helicase. Multiple mutations were identified, with Ashkenazi Jewish Bloom syndrome patients almost exclusively homozygous for a complex frameshift mutation (6-bp deletion/7-bp insertion at BLM nucleotide 2,281). This molecular genetic study seeks to verify the Ashkenazi Jewish carrier frequency of the BLM 2281 delta 6ins7 allele using semiautomated allele-specific oligonucleotide (ASO) analysis. Anonymized DNA samples from 1,016 Ashkenazi Jewish individuals and 307 non-Jewish individuals were screened. Ten Ashkenazi heterozygote carriers for the 2281 delta 6ins7 mutation were identified, giving a carrier frequency estimate of 0.98%, or approximately 1 carrier out of 102 individuals in the Ashkenazi Jewish population. These results are consistent with previous estimates, and combining our findings with the published molecular data collectively yields an Ashkenazi Jewish carrier frequency of approximately 1 in 104. Given its high population frequency and detection rate among Ashkenazi Jewish patients, the blmAsh mutation constitutes an appropriate addition to screening panels for Ashkenazi Jewish disease testing.

Analysis of Two Novel Polymorphic Sites in the Glucocerebrosidase Gene Region in Patients with Gaucher Disease 739

Gaucher disease is caused by the inherited deficiency of the enzyme glucocerebrosidase (EC 3.2.1.45). The gene for glucocerebrosidase is located on chromosome 1q21 and a highly homologous pseudogene is situated 16kb downstream. Two novel polymorphisms were identified in the glucocerebrosidase gene region: the first consists of a variable number of tetranucleotide (AAAT) repeats located upstream of the glucocerebrosidase gene, and the second is a series of dinucleotide (CT) repeats found in the intergenic region between the glucocerebrosidase gene and its pseudogene. These two polymorphisms, along with the previously reported PvuII polymorphism in intron 6 of the glucocerebrosidase gene, were analyzed in an affected population (n=102) and in two normal control populations, one consisting of non-Jewish individuals of mixed ethnic background (n=46) and the second of Ashkenazi Jewish individuals(n=72). Strong linkage disequilibrium was found between mutations N370S, 84GG, and R463C and specific haplotypes; no significant linkage disequilibrium was found in patients carrying mutation L444P. Unexpected haplotypes lead to the recognition of several genotyping errors and complex alleles. These two novel polymorphic sites provide a new tool for the identification of mutant alleles in patients and for the study of founder effects in populations with Gaucher disease.

Gaucher disease type 1: cloning and characterization of a cDNA encoding acid beta-glucosidase from an Ashkenazi Jewish patient.

Gaucher disease (GD) type 1 is the most prevalent lysosomal storage disease and the most prevalent genetic disease among the Ashkenazi Jews. The defective activity of acid beta-glucosidase is the enzymatic basis of GD and is inherited as an autosomal recessive trait. To investigate the genetic basis of Ashkenazi Jewish GD type 1, a cDNA encoding acid beta-glucosidase was isolated from a cDNA library constructed using splenic poly(A)+RNA from a patient. The cDNA was sequenced to identify mutations, and the presence of a single missense mutation in the patients' genome was confirmed by selective oligonucleotide hybridization and by restriction endonuclease digestion analyses of amplified genomic sequences. This G----A transition (Arg-119 to Gln-119) was present heterozygously in the index patient and his affected third cousin but was not present in normal non-Jewish individuals. This mutation is the second single base mutation found in Ashkenazi Jewish GD type 1 patients. Furthermore, results obtained with the affected third cousin suggest that at least three mutant alleles may be present in this GD subpopulation.