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"The Jewish 'East' and its Restricted Agencies" is an article that examines the historical relationship between Jews and Muslims in Israel and the MENA region. It challenges the simplistic portrayal of Israel as a Western oppressor and Islamic entities as oppressed Easterners, arguing that this oversimplifies the complex dynamics at play. The article also discusses the treatment of Mizrahi Jews in Israel and their integration into a predominantly European-oriented Zionist society. It emphasizes the need to reclaim Jewish agencies and challenges the perception of Israel as a white-Ashkenazi presence in the Middle East. The article calls for a more nuanced exploration of Jewish history in Islamic contexts to give voice to Mizrahi Jewish experiences. [Extracted from the article]

"The Jewish 'East' and its Restricted Agencies" is an article that examines the historical relationship between Jews and Muslims in Israel and the MENA region. It challenges the simplistic portrayal of Israel as a Western oppressor and Islamic entities as oppressed Easterners, arguing that this oversimplifies the complex dynamics at play. The article also discusses the treatment of Mizrahi Jews in Israel and their integration into a predominantly European-oriented Zionist society. It emphasizes the need to reclaim Jewish agencies and challenges the perception of Israel as a white-Ashkenazi presence in the Middle East. The article calls for a more nuanced exploration of Jewish history in Islamic contexts to give voice to Mizrahi Jewish experiences. [Extracted from the article]

INTRODUCTION: Most Alzheimer's disease (AD) loci have been discovered in individuals with European ancestry (EA). METHODS: We applied principal component analysis using Gaussian mixture models and an Ashkenazi Jewish (AJ) reference genome‐wide association study (GWAS) data set to identify Ashkenazi Jews ascertained in GWAS (n = 42,682), whole genome sequencing (WGS, n = 16,815), and whole exome sequencing (WES, n = 20,504) data sets. The association of AD was tested genome wide (GW) in the GWAS and WGS data sets and exome wide (EW) in all three data sets (EW). Gene‐based analyses were performed using aggregated rare variants. RESULTS: In addition to apolipoprotein E (APOE), GW analyses (1355 cases and 1661 controls) revealed associations with TREM2 R47H (p = 9.66 × 10−9), rs541586606 near RAB3B (p = 5.01 × 10−8), and rs760573036 between SPOCK3 and ANXA10 (p = 6.32 × 10−8). In EW analyses (1504 cases and 2047 controls), study‐wide significant association was observed with rs1003710 near SMAP2 (p = 1.91 × 10−7). A significant gene‐based association was identified with GIPR (p = 7.34 × 10−7). DISCUSSION: Our results highlight the efficacy of founder populations for AD genetic studies. [ABSTRACT FROM AUTHOR]

In this paper, archaeo- and ethnoastronomical methods are used to investigate the orientation of synagogues, graves and prayer among Ashkenazi Jewish communities in the centralnorthern part of the Argentinian Province of Santa Fe, in the southern Gran Chaco region of South America. These communities have their origin in Jewish agricultural colonies, which were established by immigrants from central and eastern Europe who arrived during the late nineteenth and early twentieth centuries. The study shows the complexity of the logics involved in the construction of the meaning of spatial orientations in local Jewish religious practices, and also the necessity of ethnographic surveys as a complement to quantitative studies of orientations. [ABSTRACT FROM AUTHOR]

Background: Individuals of Ashkenazi Jewish ancestry have been identified as having higher prevalence of specific pathogenic variants associated with susceptibility to specific rare and chronic diseases. In Mexico, the prevalence and composition of rare cancer predisposing germline variants in Ashkenazi Jewish individuals has not been evaluated. Aim and methods: We aimed to evaluate the prevalence of pathogenic variants by massive parallel sequencing in a panel of 143 cancer-predisposing genes in 341 women from the Ashkenazi Jewish community of Mexico, who were contacted and invited to participate in the study through the ALMA Foundation for Cancer Reconstruction. Pre- and posttest genetic counseling was given and a questionnaire on personal, gyneco-obstetric, demographic and lifestyle variables was conducted. From peripheral blood DNA, the complete coding region, and splicing sites of a panel of 143 cancer susceptibility genes, including 21 clinically relevant genes, were sequenced. The Mexican founder mutation BRCA1 ex9-12del [NC_000017.10(NM_007294):c. (825+1–826-1)_(4,589+1–4,590-1)del] was also evaluated. Results: Among study participants (mean age ±standard deviation: 47 ± 14) 15% reported a personal history of cancer (50/341). Fourteen percent of participants (48/ 341) were carriers of pathogenic and likely pathogenic variants distributed among seven high-risk genes (APC, CHEK2, MSH2, BMPR1A, MEN1, MLH1, and MSH6), whereas 18.2% (62/341) had variants of uncertain clinical significance in genes associated with breast and ovarian cancer susceptibility (list of genes with VUS). Pathogenic and likely pathogenic variants in 16 susceptibility genes with ambiguous or non-well-established risk association for cancer were detected in 17.6% (60/341) of participants. Sixty four percent of participants reported current alcohol consumption compared with the 39 percent prevalence of alcohol consumption in Mexican women. None of the participants carried the recurrent Ashkenazi and Mexican founder mutations in BRCA1 or BRCA2, but 2% (7/341) had pathogenic Ashkenazi Jewish founder variants in BLM. Conclusion: Our findings show a diverse pathogenic variant composition among the recruited individuals of Ashkenazi Jewish ancestry in Mexico consistent with being a high-risk population for genetic diseases, which warrants further investigation to adequately assess the burden of hereditary breast cancer in this group and implement appropriate preventative programs. [ABSTRACT FROM AUTHOR]

Background: Individuals of Ashkenazi Jewish ancestry have been identified as having higher prevalence of specific pathogenic variants associated with susceptibility to specific rare and chronic diseases. In Mexico, the prevalence and composition of rare cancer predisposing germline variants in Ashkenazi Jewish individuals has not been evaluated.Aim and methods: We aimed to evaluate the prevalence of pathogenic variants by massive parallel sequencing in a panel of 143 cancer-predisposing genes in 341 women from the Ashkenazi Jewish community of Mexico, who were contacted and invited to participate in the study through the ALMA Foundation for Cancer Reconstruction. Pre- and posttest genetic counseling was given and a questionnaire on personal, gyneco-obstetric, demographic and lifestyle variables was conducted. From peripheral blood DNA, the complete coding region, and splicing sites of a panel of 143 cancer susceptibility genes, including 21 clinically relevant genes, were sequenced. The Mexican founder mutation BRCA1 ex9-12del [NC_000017.10(NM_007294):c. (825+1–826-1)_(4,589+1–4,590-1)del] was also evaluated.Results: Among study participants (mean age ±standard deviation: 47 ± 14) 15% reported a personal history of cancer (50/341). Fourteen percent of participants (48/341) were carriers of pathogenic and likely pathogenic variants distributed among seven high-risk genes (APC, CHEK2, MSH2, BMPR1A, MEN1, MLH1, and MSH6), whereas 18.2% (62/341) had variants of uncertain clinical significance in genes associated with breast and ovarian cancer susceptibility (list of genes with VUS). Pathogenic and likely pathogenic variants in 16 susceptibility genes with ambiguous or non-well-established risk association for cancer were detected in 17.6% (60/341) of participants. Sixty four percent of participants reported current alcohol consumption compared with the 39 percent prevalence of alcohol consumption in Mexican women. None of the participants carried the recurrent Ashkenazi and Mexican founder mutations in BRCA1 or BRCA2, but 2% (7/341) had pathogenic Ashkenazi Jewish founder variants in BLM.Conclusion: Our findings show a diverse pathogenic variant composition among the recruited individuals of Ashkenazi Jewish ancestry in Mexico consistent with being a high-risk population for genetic diseases, which warrants further investigation to adequately assess the burden of hereditary breast cancer in this group and implement appropriate preventative programs.

Simple Summary: APC I1307K has a two-fold increased risk for colorectal cancer in Ashkenazi Jews (AJ) compared to non-Jewish populations. The study aims to demonstrate the prevalence of the APC I1307K variant in the largest cohort of AJ and non-AJ white (NAW) descents described so far. In addition, we assessed the prevalence of CRC and extracolonic malignancies among I1307K carriers. We found that NAW I1307K carriers had a higher risk of any cancer, such as CRC, melanoma, breast, and prostate cancer. Among AJ, the variant increased the risk for CRC and renal cancer, and AJ men had a higher risk for any cancer and melanoma. We believe these findings are significant and may suggest the necessity for cancer screening in this population. Purpose: APC I1307K has a higher prevalence among Ashkenazi Jews (AJ), and a two-fold increased risk for colorectal cancer (CRC) compared to non-Jewish populations. We assessed CRC and extracolonic malignancies among I1307K carriers from AJ and non-AJ whites (NAW). Methods: We compared the rate of I1307K in cancer patients who underwent germline genetic testing via a multi-gene panel with healthy subjects retrieved from the gnomAD database. Cases undergoing testing were not selected and testing was undertaken through a commercial laboratory. Results: Overall, 586/7624 (7.6%) AJ with cancer carried I1307K compared to 342/4918 (6.9%) in the AJ control group (p = NS). In the NAW, 318/141,673 (0.2%) cancer patients and 73/58,918 (0.1%) controls carried the variant [OR = 1.8, (95% CI 1.41–2.35), p < 0.001]. I1307K in NAW was associated with an increased risk of CRC [OR = 1.95, (95% CI 1.39–2.73), p < 0.01], melanoma [OR = 2.54, (95% CI 1.57–3.98)], breast [females, OR = 1.73, (95% CI 1.18–2.65), p < 0.01], and prostate cancer [males, OR = 2.42, (95% CI 1.45–3.94), p < 0.01]. Among AJ, the variant increased the risk for CRC [OR = 1.67, (95% CI 1.36–2.05), p < 0.001] and renal cancer [OR = 1.64, (95% CI 1.04–2.47)]. AJ men had a higher risk for any cancer [OR = 1.32, (95% CI 1.05–1.66), p < 0.05] and melanoma [OR = 2.04, (95% CI 1.24–3.22); p < 0.05]. Conclusions: This is the most extensive study to date conducted on I1307K carriers, although it is amenable to selection bias. NAW carrying I1307K had a higher risk of any cancer and several specific cancer types, whereas AJ carrying the variant had a risk for only a few select cancers. Our data add to the research base on I1307 carriers concerning future risk management. [ABSTRACT FROM AUTHOR]

Objective: Ashkenazi‐Jewish (AJ) population‐based BRCA testing is acceptable, cost‐effective and amplifies primary prevention for breast & ovarian cancer. However, data describing lifestyle impact are lacking. We report long‐term results of population‐based BRCA testing on lifestyle behaviour and cancer risk perception. Design: Two‐arm randomised controlled trials (ISRCTN73338115, GCaPPS): (a) population‐screening (PS); (b) family history (FH)/clinical criteria testing. Setting North London AJ‐population. Population/Sample: AJ women/men >18 years. Exclusions: prior BRCA testing or first‐degree relatives of BRCA‐carriers. Methods: Participants were recruited through self‐referral. All participants received informed pre‐test genetic counselling. The intervention included genetic testing for three AJ BRCA‐mutations: 185delAG(c.68_69delAG), 5382insC(c.5266dupC) and 6174delT(c.5946delT). This was undertaken for all participants in the PS arm and participants fulfilling FH/clinical criteria in the FH arm. Patients filled out customised/validated questionnaires at baseline/1‐year/2‐year/3‐year follow‐ups. Generalised linear‐mixed models adjusted for covariates and appropriate contrast tests were used for between‐group/within‐group analysis of lifestyle and behavioural outcomes along with evaluating factors associated with these outcomes. Outcomes are adjusted for multiple testing (Bonferroni method), with P < 0.0039 considered significant. Outcome measures: Lifestyle/behavioural outcomes at baseline/1‐year/2‐year/3‐year follow‐ups. Results: 1034 participants were randomised to PS (n = 530) or FH (n = 504) arms. No significant difference was identified between PS‐ and FH‐based BRCA testing approaches in terms of dietary fruit/vegetable/meat consumption, vitamin intake, alcohol quantity/ frequency, smoking behaviour (frequency/cessation), physical activity/exercise or routine breast mammogram screening behaviour, with outcomes not affected by BRCA test result. Cancer risk perception decreased with time following BRCA testing, with no difference between FH/PS approaches, and the perception of risk was lowest in BRCA‐negative participants. Men consumed fewer fruits/vegetables/vitamins and more meat/alcohol than women (P < 0.001). Conclusion: Population‐based and FH‐based AJ BRCA testing have similar long‐term lifestyle impacts on smoking, alcohol, dietary fruit/vegetable/meat/vitamin, exercise, breast screening participation and reduced cancer risk perception. Jewish Pop BRCA testing increases vitamin use and has similar lifestyle impact as FH testing on diet, exercise, alcohol, breast screening. [ABSTRACT FROM AUTHOR]

During the late 1970s and early 1980s, population geneticists sought computational solutions to integrate greater numbers of genetic traits into their debates about the ancestral relationships of human groups. At the same time, geneticists' longstanding assumptions about Jewish communities, especially Ashkenazim, were challenged by a series of social, political, and intellectual developments. In Israel, the entrenched cultural and political dominance of Ashkenazi Jews faced major social upheaval. Meanwhile, to counteract lingering anti-Semitism in Europe and the United States, Arthur Koestler's The Thirteenth Tribe and Raphael Patai and Jennifer Patai Wing's The Myth of the Jewish Race argued that Jewish identity was not connected to biological ancestry from the ancient Israelites. Drawing on scientific publications and archived correspondence, this article reconstructs a transnational social history showing how geneticists responded to these shifting claims about Ashkenazi identity and ancestry. Many argued that these claims could be tested using new statistical models, which provided allegedly more "objective" estimates of ancestral gene frequencies and histories of population admixture. However, they simultaneously engaged in heated debates over the relative superiority of competing statistical approaches. These debates reveal how the transnational reverberations of Israeli ethnic politics and Euro-American anti-Semitism affected the development of new calculations for genetic admixture, permanently shifting the assumptions of population genetic research on Jewish populations as well as other human groups. [ABSTRACT FROM AUTHOR]

The aim of this paper is to investigate the existing Judeo-Spanish ethnonyms with the original meaning of 'Polish' and the semantic changes that they have undergone. We focus especially on the lexeme lehli (etymologically derived from Lehistan, that is, the denomination of Poland in Ottoman Turkish), which now is used mainly to designate Ashkenazi Jew. We contrast the lexicographical information with real usage examples and opinions of Ladino native speakers. [ABSTRACT FROM AUTHOR]

A missense variant (p.Ser428Phe [S428F]) in the CHEK2 gene is reportedly associated with a 2–3 fold increase in breast cancer risk in Ashkenazi Jews. This study aimed to re-evaluate cancer risks conferred by the CHEK2 S428F variant in Ashkenazi Jews. De-identified data from CHEK2 S428F variant carriers sequenced with multigene panels were analyzed. Overall, 486/341,531 (0.14%) cases of all ethnicities diagnosed with any cancer type were CHEK2 S428F carriers, of whom 243/9980 self-identified as Ashkenazi Jews and carried this risk variant only. Compared with ethnically matched non-cancer controls, across all cancer cases, this variant was not more prevalent (p = 0.271). Specifically, variant prevalence was not different in breast cancer cases compared with controls. Though the variant was shown to be enriched in pancreatic cancer cases (p = 0.008), sample size was small. The CHEK2 S428F variant was not overrepresented in Ashkenazi Jews with breast cancer and most other cancer types analyzed, except for pancreatic cancer, compared with ethnically matched non- cancer controls. These findings should prompt reevaluating ethnic-specific CHEK2 S428F cancer attributable risk. [ABSTRACT FROM AUTHOR]

In Ashkenazi Jews (AJ) three recurring pathogenic sequence variants (PSVs) are detected in ~2.5% of the general population in the BRCA1 (c.68_69del = 185delAG, c.5266dup = 5382insC), and BRCA2 (c.5946del = 6174delT). Population‐based screening for these PSVs in AJ women is part of the health basket in Israel. To assess the feasibility and outcome of BRCA genotyping in the Jewish population of Uruguay, AJ in the greater Montevideo area were recruited using ethically approved protocol and without pretest counseling were genotyped for the three predominant AJ PSVs in the BRCA genes. Independently confirmed PSV carriers were counseled, and genetic testing was offered to additional family members. Overall, 327 participants were enrolled: 312 (95%) female, 261 (80%) had all four grandparents AJ, and 14 (4%) women were breast cancer survivors with a mean age ± standard deviation (SD) 50 ± 11.5 years. The BRCA1 c.68_69del PSV was detected in three cancer free participants (0.92%, CI 95% 0.31–2.6), all with a suggestive family history. No carriers of the other two recurrent PSVs were detected. Online oncogenetic counseling was provided for all carriers. In conclusion, the rate of the BRCA1 c.68_69del PSV was similar with the rate in other AJ communities. AJ population BRCA genotyping screens in Uruguay seem feasible and should be promoted. [ABSTRACT FROM AUTHOR]

Abstract In Ashkenazi Jews (AJ) three recurring pathogenic sequence variants (PSVs) are detected in ~2.5% of the general population in the BRCA1 (c.68_69del = 185delAG, c.5266dup = 5382insC), and BRCA2 (c.5946del = 6174delT). Population‐based screening for these PSVs in AJ women is part of the health basket in Israel. To assess the feasibility and outcome of BRCA genotyping in the Jewish population of Uruguay, AJ in the greater Montevideo area were recruited using ethically approved protocol and without pretest counseling were genotyped for the three predominant AJ PSVs in the BRCA genes. Independently confirmed PSV carriers were counseled, and genetic testing was offered to additional family members. Overall, 327 participants were enrolled: 312 (95%) female, 261 (80%) had all four grandparents AJ, and 14 (4%) women were breast cancer survivors with a mean age ± standard deviation (SD) 50 ± 11.5 years. The BRCA1 c.68_69del PSV was detected in three cancer free participants (0.92%, CI 95% 0.31–2.6), all with a suggestive family history. No carriers of the other two recurrent PSVs were detected. Online oncogenetic counseling was provided for all carriers. In conclusion, the rate of the BRCA1 c.68_69del PSV was similar with the rate in other AJ communities. AJ population BRCA genotyping screens in Uruguay seem feasible and should be promoted.

The average early modern family of Ashkenazi Jews is often portrayed in literature in static terms as a nuclear household that is similar in many regards to the other European urban families of premodern Europe. The main goal of this study is to verify this image and to analyze the political and economic factors influencing the size and structure of Jewish households. This study uses three registers of Jewish communities – the 1578 register of Lviv, the 1610 register of Worms, and the 1619 register of Poznan – to conduct a comparative analysis of Ashkenazi Jewish households and their living conditions at the turn of 16th and 17th centuries. The study demonstrates that the existence of significantly different models of Jewish households and indicates a strong relation between the higher status and wealth of families and their larger size and more complex household structure. At the same time, the results also suggest that contextual factors played a significant role in the structure and living conditions of those households. In cities where the economic costs, and legal and political constraints of settling were smaller, there were significantly greater numbers of small households created by the poorer members of the community. On the other hand, in cities where living was associated with greater prestige, prosperity and security, but also required greater wealth and overcoming the difficulties posed by the Christian majority, households were often larger, multi-generational, and included servants and guests. [ABSTRACT FROM AUTHOR]

Exome and genome sequencing were used to identify the genetic etiology of a severe neurodevelopmental disorder in two unrelated Ashkenazi Jewish families with three affected individuals. The clinical findings included a prenatal presentation of microcephaly, polyhydramnios and clenched hands while postnatal findings included microcephaly, severe developmental delay, dysmorphism, neurologic deficits, and death in infancy. A shared rare homozygous, missense variant (c.274A > G; p.Ser92Gly, NM_024516.4) was identified in PAGR1, a gene currently not associated with a Mendelian disease. PAGR1 encodes a component of the histone methyltransferase MLL2/MLL3 complex and may function in the DNA damage response pathway. Complete knockout of the murine Pagr1a is embryonic‐lethal. Given the available evidence, PAGR1 is a strong candidate gene for a novel autosomal recessive severe syndromic neurodevelopmental disorder. [ABSTRACT FROM AUTHOR]

Objective: To assess whether or not the current American College of Obstetricians and Gynecologists (ACOG) recommendations regarding carrier screening are sufficiently robust in detecting mutations in the Ashkenazi Jewish (AJ) population. Design: Cross-sectional study. Setting: Outreach program at university community center. Patient(s): Self-identified Jewish students, 18–24 years of age, interested in genetic carrier testing. Intervention(s): Expanded carrier screening (ECS) with the use of a commercially available targeted genotyping panel including >700 mutations in 180 genes. Main Outcome Measure(s): Gene mutations found in this population were grouped into three categories based on ACOG’s 2017 committee opinion regarding carrier screening: category 1: the four commonly recommended genetic conditions known to be a risk for this population; category 2: 14 genetic disorders that should be considered for more comprehensive screening, including those of category 1; and category 3: the ECS panel, which includes category 2. Result(s): A total of 81 students underwent screening and 36 (44.4%) were ascertained to be carriers of at least one mutation. A total of 45 mutations were identified, as 8 students were carriers for more than one condition. If testing were limited to category 1, 84% of the mutations would not have been identified, and if limited to category 2, 55% of mutations would have gone undetected. Conclusion(s): Individuals of Ashkenazi Jewish descent are at significant risk for carrying a variety of single-gene mutations and therefore they should be offered panethnic ECS to increase the likelihood of detecting preventable disorders.

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.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.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.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.

In post-Soviet Central Asia, Jewish educational frameworks were shaped by unique forces introduced by various Jewish organizations. This article describes and explains the unique formation of Jewish education in post-Soviet Central Asian republics, how it was revived and which organizations shaped it. The article presents and analyses various educational initiatives introduced by Jewish organizations and educational frameworks: formal and informal, local and foreign, state and privately sponsored, religious and civic–national. It claims that all were unique. [ABSTRACT FROM AUTHOR]

Background: Hereditary breast and ovarian cancer syndrome (HBOC) and Lynch syndrome (LS), the most common inherited cancer syndromes, are attributed to a single heterozygous pathogenic variant (PV) in BRCA1/2 or in a DNA MMR gene, respectively. Little is known about the phenotype in double heterozygotes who carry PVs in both genes. Methods: Carriers of double-PVs in any DNA MMR gene and BRCA1/2 attending one of three tertiary oncogenetic clinics between 1/2005 and 1/2020 were identified by database search, and their relevant data were retrieved and analyzed. Results: Eleven double carriers from four seemingly unrelated Ashkenazi Jewish families were evaluated. All carried an Ashkenazi Jewish founder BRCA PV, BRCA2 c.5946delT/c.6174delT (n = 10) or BRCA1 c.185delAG (n = 1). Four carried the MSH2 c.1906G > C founder PV, and 3, the MSH6 c.3984_3987dupGTCA founder PV; 3 patients had the MSH6 c.3956_3957dup PV. Eight double carriers (73%) had cancer: breast cancer (5 cases, 2 bilateral), melanoma (2 cases), urothelial cancer (2 cases), and colon, endometrial, prostate, cutaneous squamous cell cancer, glioblastoma, gastric stromal tumor, and lymphoma (1 case each). Six carriers had 1–2 tumors, one had 3 tumors, and one had 5 primary tumors. Age at diagnosis of the first tumor was 36–76 years. All carriers met NCCN BRCA1/2 testing criteria, and 3 met the revised Bethesda guidelines. Conclusions: This case series, supported by the literature, suggests that the phenotype of double MSH2/6 and BRCA1/2 carriers is not associated with early disease onset or a more severe phenotype. The findings have implications for improved genetic testing guidelines and treatment strategies. [ABSTRACT FROM AUTHOR]

ObjectiveStatins stimulate transcription of proprotein convertase subtilisin/kexin type 9 (PCSK9), a negative regulator of the low-density lipoprotein receptor, thus blunting the cholesterol-lowering effects of statin treatment. Although there is interindividual variation in PCSK9 statin response, little is known about ancestral and other genetic factors that could contribute to this variation.MethodsWe measured plasma PCSK9 levels before and after 6 weeks of treatment with 40 mg/day simvastatin in 901 participants of the Cholesterol and Pharmacogenetics clinical trial and tested phenotypic and genetic factors for correlation with PCSK9 statin response.ResultsStatin-induced changes in plasma low-density lipoprotein cholesterol, total cholesterol, and apolipoprotein B were all significantly correlated with statin-induced changes in PCSK9. A detailed examination of the associations of genetic ancestry with PCSK9 statin response revealed that Ashkenazi Jews had smaller statin-induced increases in PCSK9 levels than other self-reported Caucasians (P=0.016). Using genomewide association analysis, we found that the 'G' minor allele of rs13064411 in the WD repeat domain 52 (WDR52) gene was significantly associated with greater statin-induced increases in plasma PCSK9 in Caucasians (P=8.2 × 10(-8)) in the Cholesterol and Pharmacogenetics trial.ConclusionOverall, these results suggest that genetic ancestry and the rs13064411 genotype contribute to interindividual variation in PCSK9 statin response in Caucasians.

Purpose: The co-occurrence or double heterozygosity of pathogenic/likely pathogenic sequence variants (P/LPSVs) in major cancer susceptibility genes has rarely been reported. Such co-occurrence raises the issues of accurate genetic counseling, preferred recommended surveillance scheme, and the use of preimplantation genetic diagnosis (PGD). Methods: A clinical report of an Ashkenazi Jewish (AJ) family with co occurrence of two PSVs in BRCA1 and TP53 and a literature search. Results: In an AJ family with a substantial history of cancer limited to the maternal side, two siblings co-harbored TP53 (c.733C>A; p.G245S) and the predominant 5266dup BRCA1 mutation, originating from the mother and the father, respectively. PGD is ongoing. Four families were thus far reported as double heterozygotes for both BRCA1/BRCA2 and TP53. Based on the limited available data, it seems that the phenotype in double PSV heterozygotes is not more severe than in single PSV carrier in either gene. Conclusions: This family highlights the need to genotype both parents, especially in populations with founder mutations, when a BRCA1 mutation is detected in an offspring, regardless of family history. The combination of mutations in these two genes presents a challenge for PGD since both genes are located on chromosome 17. [ABSTRACT FROM AUTHOR]

The article is devoted to the important scientific problem of Jews’ adaptation in Turkestan. Its comprehension makes it possible to consider a specific example of the interaction of representatives of the two main religions in Russia - the Christian and the Muslim ones. The relevance of this topic is also determined by the persisting confrontation between Israel and the Arab world, Jews and Muslims. Moreover, Jews’ resettlement during the colonization of Central Asia allows understanding the contradictions of the national and migration policy of the tsarist Russia at the turn of the 20th century. Through the use of a wide range of sources, the author reveals the peculiarities of the life of Jews in the Russian Empire, various aspects of which were silenced or distorted in the Soviet historiography for a long time. The article contains data on the localization, number and social composition of the Jewish population on the territory of the Russian Empire. It is noted that the vast majority of the first European Jews were former military - privates and non-commissioned officers. The Ashkenazi Jews played an important role in the construction of railways in Russia and, above all, the Tashkent-Orenburg railway. The author concludes that the construction of railways in Europe was an important field of activity for Jewish bankers. In this area, it is the personal ties of the Jewish capitalists with the governments which played an important role, since railways were built mostly on the basis of special concessions and under the official control. Over a relatively short historical period, the Jews demonstrated their high social activity and made a significant contribution to the development of Central Asia territory.

The discovery of genes underlying inherited predisposition to breast and ovarian cancer has revolutionized the ability to identify women at high risk for these diseases before they become affected. Women who are carriers of deleterious variants in these genes can undertake surveillance and prevention measures that have been shown to reduce morbidity and mortality. However, under current strategies, the vast majority of women carriers remain undetected until they become affected. In this review, we show that universal testing, particularly of the BRCA1 and BRCA2 genes, fulfills classical disease screening criteria. This is especially true for BRCA1 and BRCA2 in Ashkenazi Jews but is translatable to all populations and may include additional genes. Utilizing genetic information for large-scale precision prevention requires a paradigmatic shift in health-care delivery. To address this need, we propose a direct-to-patient model, which is increasingly pertinent for fulfilling the promise of utilizing personal genomic information for disease prevention. [ABSTRACT FROM AUTHOR]

Objective: Unselected population-based BRCA testing provides the opportunity to apply genomics on a population-scale to maximise primary prevention for breast-and-ovarian cancer. We compare long-term outcomes of population-based and family-history (FH)/clinical-criteria-based BRCA testing on psychological health and quality of life.Design: Randomised controlled trial (RCT) (ISRCTN73338115) GCaPPS, with two-arms: (i) population-screening (PS); (ii) FH/clinical-criteria-based testing.Setting: North London Ashkenazi-Jewish (AJ) population.Population/sample: AJ women/men.Methods: Population-based RCT (1:1). Participants were recruited through self-referral, following pre-test genetic counselling from the North London AJ population.Inclusion Criteria: AJ women/men >18 years old; exclusion-criteria: prior BRCA testing or first-degree relatives of BRCA-carriers.Interventions: Genetic testing for three Jewish BRCA founder-mutations: 185delAG (c.68_69delAG), 5382insC (c.5266dupC) and 6174delT (c.5946delT), for (i) all participants in PS arm; (ii) those fulfilling FH/clinical criteria in FH arm. Linear mixed models and appropriate contrast tests were used to analyse the impact of BRCA testing on psychological and quality-of-life outcomes over 3 years.Main Outcome Measures: Validated questionnaires (HADS/MICRA/HAI/SF12) used to analyse psychological wellbeing/quality-of-life outcomes at baseline/1-year/2-year/3-year follow up.Results: In all, 1034 individuals (691 women, 343 men) were randomised to PS (n = 530) or FH (n = 504) arms. There was a statistically significant decrease in anxiety (P = 0.046) and total anxiety-&-depression scores (P = 0.0.012) in the PS arm compared with the FH arm over 3 years. No significant difference was observed between the FH and PS arms for depression, health-anxiety, distress, uncertainty, quality-of-life or experience scores associated with BRCA testing. Contrast tests showed a decrease in anxiety (P = 0.018), health-anxiety (P < 0.0005) and quality-of-life (P = 0.004) scores in both PS and FH groups over time. Eighteen of 30 (60%) BRCA carriers identified did not fulfil clinical criteria for BRCA testing. Total BRCA prevalence was 2.9% (95% CI 1.97-4.12%), BRCA1 prevalence was 1.55% (95% CI 0.89-2.5%) and BRCA2 prevalence was 1.35% (95% CI 0.74-2.26%).Conclusion: Population-based AJ BRCA testing does not adversely affect long-term psychological wellbeing or quality-of-life, decreases anxiety and could identify up to 150% additional BRCA carriers.Tweetable Abstract: Population BRCA testing in Ashkenazi Jews reduces anxiety and does not adversely affect psychological health or quality of life. [ABSTRACT FROM AUTHOR]

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Background: Mutations in CACNA1F have been mainly associated with X-linked incomplete congenital stationary night blindness (icCSNB). Variable phenotypic expression in females was reported in some families. We report here three non-related Ashkenazi Jewish families originating in Eastern Europe, that included males and a many affected females, initially diagnosed with variable retinal phenotypes. Materials and Methods: Whole exome sequencing (WES), Sanger sequencing and microsatellite haplotyping were used for genetic analysis. Complete ophthalmologic examination was performed including visual acuity, refraction, colour vision, slit-lamp, fundoscopy and electroretinography (ERG). Results: We identified four affected males, showing moderate visual impairment, and seven female carriers, six of them presenting mild to moderate visual impairment. Infantile nystagmus was found in all affected males and in 5/7 females. Nyctalopia and myopia were common in both males and females. Initial clinical differential diagnosis included cone-dystrophy, cone-rod dystrophy, cone-dystrophy with supernormal rod response or CSNB based on ERG results. WES and Sanger sequencing revealed a previously described missense mutation c.2225T>G; p.(F742C) in CACNA1F (NM_001256789.2) in all three families, encompassed by a shared haplotype Conclusions: Our data suggests that p.(F742C) in CACNA1F is an X-linked founder mutation in Ashkenazi Jews originating in Eastern Europe. This mutation causes a mild-to-moderate icCSNB phenotype, expressed in most female carriers. A targeted test for this variant in suspected patients may initiate diagnostic analysis. Our results highlight the relevance of WES in the clinic, allowing fast and accurate diagnosis for unclear and variable clinical phenotype and in pedigrees with multiple possible inheritance patterns. [ABSTRACT FROM AUTHOR]

Objective: To evaluate factors affecting unselected population-based BRCA testing in Ashkenazi Jews (AJ).Design: Cohort-study set within recruitment to the GCaPPS trial (ISRCTN73338115).Setting: North London AJ population.Population or Sample: Ashkenazi Jews women/men >18 years, recruited through self-referral.Methods: Ashkenazi Jews women/men underwent pre-test counselling for BRCA testing through recruitment clinics (clusters). Consenting individuals provided blood samples for BRCA testing. Data were collected on socio-demographic/family history/knowledge/psychological well-being along with benefits/risks/cultural influences (18-item questionnaire measuring 'attitude'). Four-item Likert-scales analysed initial 'interest' and 'intention-to-test' pre-counselling. Uni- and multivariable logistic regression models evaluated factors affecting uptake/interest/intention to undergo BRCA testing. Statistical inference was based on cluster robust standard errors and joint Wald tests for significance. Item-Response Theory and graded-response models modelled responses to 18-item questionnaire.Main Outcome Measures: Interest, intention, uptake, attitude towards BRCA testing.Results: A total of 935 individuals (women = 67%/men = 33%; mean age = 53.8 (SD = 15.02) years) underwent pre-test genetic-counselling. During the pre-counselling, 96% expressed interest in and 60% indicated a clear intention to undergo BRCA testing. Subsequently, 88% opted for BRCA testing. BRCA-related knowledge (P = 0.013) and degree-level education (P = 0.01) were positively and negatively (respectively) associated with intention-to-test. Being married/cohabiting had four-fold higher odds for BRCA testing uptake (P = 0.009). Perceived benefits were associated with higher pre-counselling odds for interest in and intention to undergo BRCA testing. Reduced uncertainty/reassurance were the most important factors contributing to decision-making. Increased importance/concern towards risks/limitations (confidentiality/insurance/emotional impact/inability to prevent cancer/marriage ability/ethnic focus/stigmatisation) were significantly associated with lower odds of uptake of BRCA testing, and discriminated between acceptors and decliners. Male gender/degree-level education (P = 0.001) had weaker correlations, whereas having children showed stronger (P = 0.005) associations with attitudes towards BRCA testing.Conclusions: BRCA testing in the AJ population has high acceptability. Pre-test counselling increases awareness of disadvantages/limitations of BRCA testing, influencing final cost-benefit perception and decision-making on undergoing testing.Tweetable Abstract: BRCA testing in Ashkenazi Jews has high acceptability and uptake. Pre-test counselling facilitates informed decision-making. [ABSTRACT FROM AUTHOR]

Most survey research treats the refusal to embrace any ethnic/racial label as "missing information" or includes such responses in a general "other ethnicity/race" category. This article discusses the conceptual and theoretical problems involved in dismissing the refusal to embrace an ethnic/racial identity, and raises the possibility that in some contexts such a refusal actually represents a discursive challenge to the established system of classification and domination. The article then proposes a detailed approach to conceptualizing, measuring, and interpreting this type of claim, and illustrates this approach through an investigation of the link between ethnic/racial identity and attitudes among a sample Jewish Israelis. The results show that compared to Jewish Israelis who claim an ethnic label, Jewish Israelis who refuse to claim an ethnic label have more positive and inclusive views of Arab/Palestinians in Israel. More broadly, these findings highlight the need to treat refusals to choose an ethnic/racial label as a meaningful form of self-identification and to evaluate the social and political implications of the refusal to claim an ethnic label. [ABSTRACT FROM AUTHOR]

Background: Whether breast cancer (BC) should be considered within the spectrum of tumors in Lynch syndrome (LS) is unsettled. Recently, MSH6 and PMS2 germline mutations have reportedly been associated with an increased BC risk and with hereditary breast and ovarian cancer (HBOC) phenotype. We assessed the rates of the recurring Ashkenazi Jewish (AJ) mutations in the MSH6 gene (c.3984_3987dupGTCA and c.3959_3962delCAAG) in AJ cases with seemingly sporadic BC or HBOC phenotype, who were negative for the founder AJ BRCA1/2 mutations.Methods: All AJ individuals, affected with BC ≤ 70 years and/or ovarian cancer at any age who were counseled, genotyped and tested negative for the BRCA1/2 founder mutations between January 2010 and February 2018 at the Oncogenetics unit, Sheba Medical Center, were genotyped for the AJ mutations in MSH6.Results: Of 1016 genotyped participants (815 BC cases, 132 ovarian cancer cases, and 69 with more than one cancer), five carriers (0.49%) of the recurring AJ mutations in MSH6 were identified. All had BC, and two had personal history of additional cancers (pancreatic, endometrial, colorectal). The rate of MSH6 mutations was 0.93% (4/429) when considering only cases with a personal or first-degree relative with LS-related cancer, and 0.17% (1/587) of cases with second-degree relative or no family history of LS-related cancers (p = 0.087).Conclusions: Our data suggest the spectrum of genotyped mutations in AJ BC patients with a personal or family history of LS-related cancers should be expanded. These data should be validated in other populations with a similar phenotype. [ABSTRACT FROM AUTHOR]

The article examines the various presentations of Ashkenazi Jews in Israeli fiction. Ashkenazi identity in Israel is controversial both in everyday life and in fiction. However, the literary and artistic manifestations of Ashkenazi Jews are quite different from their political and social image. Ashkenazi Jews are usually portrayed as the intellectual, economic and professional elite, and also as those who were responsible for the inequality between Jews who immigrated to Israel from Europe and Jews from Arabic countries. They are depicted by the Israeli media as those who forced the oriental Jews to settle in remote towns in Israel, thus denying them the ability to move up the social ladder. The arrogant, upper-middle-class Ashkenazi is often absent from Israeli literature. Israeli artists of Ashkenazi origin present themselves in autobiographical literature as "weak" or "problematic" and they add a "fragile" aspect to the Ashkenazi identity. The Ashkenazi Jew is depicted as an insecure figure who agonizes over fears and childhood traumas. The image of the "fragile Ashkenazi," appears in some of the most prominent Israeli writing: Amos Oz's A Tale of Love and Darkness, David Grossman's A Horse Walks into a Bar, and Gila Almagor's book and film Avia's Summer. [ABSTRACT FROM AUTHOR]

Introduction: Most Alzheimer's disease (AD) loci have been discovered in individuals with European ancestry (EA)., Methods: We applied principal component analysis using Gaussian mixture models and an Ashkenazi Jewish (AJ) reference genome-wide association study (GWAS) data set to identify Ashkenazi Jews ascertained in GWAS (n = 42,682), whole genome sequencing (WGS, n = 16,815), and whole exome sequencing (WES, n = 20,504) data sets. The association of AD was tested genome wide (GW) in the GWAS and WGS data sets and exome wide (EW) in all three data sets (EW). Gene-based analyses were performed using aggregated rare variants., Results: In addition to apolipoprotein E (APOE), GW analyses (1355 cases and 1661 controls) revealed associations with TREM2 R47H (p = 9.66 × 10 -9 ), rs541586606 near RAB3B (p = 5.01 × 10 -8 ), and rs760573036 between SPOCK3 and ANXA10 (p = 6.32 × 10 -8 ). In EW analyses (1504 cases and 2047 controls), study-wide significant association was observed with rs1003710 near SMAP2 (p = 1.91 × 10 -7 ). A significant gene-based association was identified with GIPR (p = 7.34 × 10 -7 )., Discussion: Our results highlight the efficacy of founder populations for AD genetic studies., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Charcot-Marie-Tooth (CMT) disease refers to a heterogeneous group of axonal and demyelinating polyneuropathies, characterized by chronic motor and sensory dysfunction. CMT is the most common genetic cause of neuropathy. The present study aimed to identify the gene mutation responsible for CMT in Ashkenazi Jew (AJ) patient. Genomic DNA was extracted from whole blood leukocytes of affected family and normal subject. Whole-exome sequencing was performed using the Illumina HiSeq2500. The DNA region containing the identified mutation was amplified by PCR and sequenced using dye-terminator chemistry and the forward primer. Physical examination of the patient revealed weakness and atrophy of the lower extremity muscles and Pes cavus foot deformity. Whole-exome sequencing indicated that the patient is homozygous for a novel frameshift mutation (c.1877_1878insAGAG, p.Arg630fs) in the myotubularin-related protein-2 gene (MTMR2), which resulted in an erroneous C-terminal sequence and extension by 15 amino acids. Patients’ parents are healthy, and DNA sequencing analysis indicated that both are heterozygotes to the described mutation. The clinical feature of the patient may indicate a complete co-segregation of the p.Arg630fs mutation in MTMR2 gene with the CMT type 4B1 phenotype. Further studies are needed in order to estimate the prevalence of this mutation among AJ. [ABSTRACT FROM AUTHOR]