Ashkenazi Research Articles

Familial communication and cascade testing among relatives of BRCA population screening participants

PurposePopulation BRCA1/BRCA2 screening identifies carriers irrespective of family history, yet this information is actionable for relatives. We examined familial communication rates and cascade testing in the screening setting and assessed sociodemographic and psychosocial predictors. MethodsParticipants in a BRCA1/BRCA2 screening study of healthy Ashkenazi Jews self-administered a family communication questionnaire. Intent to communicate was determined before genetic status was known, along with result communication (carriers and noncarriers) 6 months and 2 years after enrollment. Carriers underwent in-depth interviews and provided cascade testing information. ResultsIn total, 88% (524/595) of questionnaire responders and 97% (30/32) of carriers informed at least one relative. In multivariate analysis, family history (P = 0.005) and greater Satisfaction With Health Decision scores (P < 0.001) predicted communication of results. Among carriers’ adult first- and second-degree relatives, 71 (48%) had cascade testing, more commonly performed in first- (58%) than in second-degree relatives (26%, P = 0.0002), and in females (56%) vs. males (36%, P = 0.02). At least 11% remained uninformed. ConclusionFamilial communication rates and characteristics in a screening setting parallel those reported by Cancer Genetics clinics. Universal screening circumvents dependence on familial disclosure. However, our finding that satisfaction—a potentially modifiable factor—predicts communication, raises the hypothesis that improving the testing experience could facilitate familial communication.

Survival rates among Parkinson's disease patients who carry mutations in the LRRK2 and GBA genes

The G2019S mutation in the LRRK2 gene generates a milder PD phenotype compared with GBA-PD; however, genetic based survival studies are lacking. To compare mortality rates between LRRK2-PD, GBA-PD, and idiopathic PD patients (iPD). Patients were screened for the G2019S mutation in the LRRK2 gene and the seven common GBA mutations among Ashkenazi Jews, classified as mild and severe (mGBA, sGBA). Motor symptoms onset and date of death were ascertained, with mortality rates calculated for each group of patients. Overall, 380 of 1,086 idiopathic PD patients, 49 of 159 LRRK2-PD, 56 of 148 mGBA-PD, and 13 of 49 sGBA-PD participants died by the time of analysis. LRRK2-PD tended to have longer survival compared to idiopathic PD whereas GBA status did not affect mortality. Genetic status did not predict mortality in a multivariate analysis. Survival of patients with PD does not seem to be related to GBA status, whereas LRRK2 might confer higher survival rates.

Provider's Perceptions of Barriers and Facilitators for Latinas to Participate in Genetic Cancer Risk Assessment for Hereditary Breast and Ovarian Cancer.

The Comprehensive Cancer Network (NCCN) recommends genetic cancer risk assessment (GCRA) referral to women at high risk of hereditary breast and ovarian cancer. Latinas affected by breast cancer have the second highest prevalence of BRCA1/2 mutations after Ashkenazi Jews. Compared to non-Hispanic Whites, Latinas have lower GCRA uptake. While some studies have identified barriers for GCRA use in this population, few studies have focused on health care providers’ perspectives. The purpose of the study was to examine providers’ perceptions of barriers and facilitators for at-risk Latina women to participate in GCRA and their experiences providing services to this population. We conducted semi-structured interviews with 20 healthcare providers (e.g., genetic counselors, patient navigators) recruited nationally through snowballing. Interviews were transcribed. Two coders independently coded each interview and then met to reconcile the codes using Consensual Qualitative Research guidelines. Providers identified several facilitators for GCRA uptake (e.g., family, treatment/prevention decisions) and barriers (e.g., cost, referrals, awareness, stigma). Genetic counselors described important aspects to consider when working with at-risk Latina including language barriers, obtaining accurate family histories, family communication, and testing relatives who live outside the US. Findings from this study can inform future interventions to enhance uptake and quality of GCRA in at-risk Latina women to reduce disparities.

Recent Selection on a Class I ADH Locus Distinguishes Southwest Asian Populations Including Ashkenazi Jews.

The derived human alcohol dehydrogenase (ADH)1B*48His allele of the ADH1B Arg48His polymorphism (rs1229984) has been identified as one component of an East Asian specific core haplotype that underwent recent positive selection. Our study has been extended to Southwest Asia and additional markers in East Asia. Fst values (Sewall Wright’s fixation index) and long-range haplotype analyses identify a strong signature of selection not only in East Asian but also in Southwest Asian populations. However, except for the ADH2B*48His allele, different core haplotypes occur in Southwest Asia compared to East Asia and the extended haplotypes also differ. Thus, the ADH1B*48His allele, as part of a core haplotype of 10 kb, has undergone recent rapid increases in frequency independently in the two regions after divergence of the respective populations. Emergence of agriculture may be the common factor underlying the evident selection.

A New Look at Familial Risk of Inflammatory Bowel Disease in the Ashkenazi Jewish Population

Background and AimsThe inflammatory bowel diseases (IBD) are particularly common among the Ashkenazi Jewish (AJ) population. Population-specific estimates of familial risk are important for counseling; however, relatively small cohorts of AJ IBD patients have been analyzed for familial risk to date. This study aimed to recruit a new cohort of AJ IBD patients, mainly from the UK, to determine the familial occurrence of disease.MethodsA total of 864 AJ IBD patients were recruited through advertisements, hospital clinics, and primary care. Participants were interviewed about their Jewish ancestry, disease phenotype, age of diagnosis, and family history of disease. Case notes were reviewed.ResultsThe 864 probands comprised 506 sporadic and 358 familial cases, the latter with a total of 625 affected relatives. Of the UK cases, 40% had a positive family history with 25% having at least one affected first-degree relative. These percentages were lower among those recruited through hospital clinics and primary care (33% for all relatives and 22% among first-degree relatives). Examining all probands, the relative risk of IBD for offspring, siblings, and parents was 10.5, 7.4, and 4, respectively. Age of diagnosis was significantly lower in familial versus sporadic patients with Crohn’s disease.ConclusionsThis study reports familial risk estimates for a significant proportion of the AJ IBD population in the UK. The high rate of a positive family history in this cohort may reflect the greater genetic burden for IBD among AJs. These data are of value in predicting the likelihood of future recurrence of IBD in AJ families.

Interethnic Variability in CYP2D6, CYP2C9, and CYP2C19 Genes and Predicted Drug Metabolism Phenotypes Among 6060 Ibero- and Native Americans: RIBEF-CEIBA Consortium Report on Population Pharmacogenomics.

Pharmacogenetic variation in Latin Americans is understudied, which sets a barrier for the goal of global precision medicine. The RIBEF-CEIBA Network Consortium was established to characterize interindividual and between population variations in CYP2D6, CYP2C9, and CYP2C19 drug metabolizing enzyme genotypes, which were subsequently utilized to catalog their "predicted drug metabolism phenotypes" across Native American and Ibero American populations. Importantly, we report in this study, a total of 6060 healthy individuals from Ibero-America who were classified according to their self-reported ancestry: 1395 Native Americans, 2571 Admixed Latin Americans, 96 Afro-Latin Americans, 287 white Latin Americans (from Cuba), 1537 Iberians, and 174 Argentinean Ashkenazi Jews. Moreover, Native Americans were grouped into North-, Central-, and South Amerindians (from Mexico, Costa Rica, and Peru, respectively). All subjects were studied for the most common and functional CYP2D6, CYP2C9, and CYP2C19 allelic variants, and grouped as genotype-predicted poor or ultrarapid metabolizer phenotypes (gPMs and gUMs, respectively). Native Americans showed differences from each ethnic group in at least two alleles of CYP2D6, CYP2C9, and CYP2C19. Native Americans had higher frequencies of wild-type alleles for all genes, and lower frequency of CYP2D6*41, CYP2C9*2, and CYP2C19*17 (p < 0.05). Native Americans also showed less CYP2C19 gUMs than the rest of the population sample. In addition, differences within Native Americans (mostly North vs. South) were also found. The interethnic differences described supports the need for population-specific personalized and precision medicine programs for Native Americans. To the best of our knowledge, this is the largest study carried out in Native Americans and other Ibero-American populations analyzing CYP2D6, CYP2C9, and CYP2C19 genetic polymorphisms. Population pharmacogenomics is a nascent field of global health and warrants further research and education.

POLD1 and POLE Gene Mutations in Jewish Cohorts of Early-Onset Colorectal Cancer and of Multiple Colorectal Adenomas.

Germline mutations in the DNA polymerase genes POLD1 and POLE confer high risk for multiple colorectal adenomas and colorectal cancer. However, prevalence and the clinical phenotype of mutation carriers are still not fully characterized. The purpose of this study was to assess the prevalence of germline mutations and to describe the genotype-phenotype correlation in POLD1 and POLE genes in Jewish subjects with multiple colorectal adenomas and/or early-onset mismatch repair proficient colorectal cancers. This study is a comparison of genetic and clinical data from affected and control groups. The study was conducted at a high-volume tertiary referral center. The study cohort included 132 subjects: 68 with multiple colorectal adenomas and 64 with early-onset mismatch repair proficient colorectal cancers. The control group included 5685 individuals having no colorectal cancer or colorectal adenomas. Study and control subjects were tested for POLD1 and POLE mutations and a clinical correlation was assessed. Eleven of the 132 study subjects (8.3%) carried either a POLD1 or a POLE mutation: 7 of 68 (10.3%) subjects with multiple colorectal adenomas and 4 of 64 (6.2%) subjects with early-onset mismatch repair proficient colorectal cancer. Three mutations were detected, showing statistical significance in frequency between study and control groups (p < 0.001). Eight of the 11 mutation carriers were Ashkenazi Jews carrying the same POLD1 mutation (V759I), implicating it as a possible low-to-moderate risk founder mutation. Phenotype of mutation carriers was notable for age under 50 at diagnosis, a propensity toward left-sided colorectal cancer, and extracolonic tumors (64%, 100%, and 27% of cases). The study cohort was limited by its relatively small size. Germline mutations in POLD1 and POLE were found to be relatively frequent in our Jewish cohorts. Further studies are needed to clarify the importance of POLD1 and POLE mutations and to define the most suitable surveillance program for Jewish and other POLD1 and POLE mutation carriers. See Video Abstract at http://links.lww.com/DCR/A658.

Correction: The effect of CAG repeats length on differences in hirsutism among healthy Israeli women of different ethnicities.

[This corrects the article DOI: 10.1371/journal.pone.0195046.].

From “Jews in China” to “Jews and China”

When Kathryn Hellerstein of the University of Pennsylvania suggested that we launch a joint research project on China and Ashkenazi Jewry two years ago, I gladly accepted the idea, as I saw in it a...

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...

Rare coding variant analysis in a large cohort of Ashkenazi Jewish families with inflammatory bowel disease

Rare variants are thought to contribute to the genetics of inflammatory bowel disease (IBD), which is more common amongst the Ashkenazi Jewish (AJ) population. A family-based approach using exome sequencing of AJ individuals with IBD was employed with a view to identify novel rare genetic variants for this disease. Exome sequencing was performed on 960 Jewish individuals including 513 from 199 multiplex families with up to eight cases. Rare, damaging variants in loci prioritized by linkage analysis and those shared by multiple affected individuals within the same family were identified. Independent evidence of association of each variant with disease was assessed. A number of candidate variants were identified, including in genes involved in the immune system. The ability to achieve statistical significance in independent case/control replication data was limited by power and was only achieved for variants in the well-established Crohn’s disease gene, NOD2. This work demonstrates the challenges of identifying disease-associated rare damaging variants from exome data, even amongst a favorable cohort of familial cases from a genetic isolate. Further research of the prioritized rare candidate variants is required to confirm their association with the disease.

BRCA1 and BRCA2 Mutations Other Than the Founder Alleles Among Ashkenazi Jewish in the Population of Argentina

In Ashkenazi Jewish (AJ) high risk families 3 mutations [2 in BRCA1 (c. 68_69del and c.5266dup) and 1 in BRCA2 (c.5946del)] account for the majority of high risk breast and ovarian cancer cases in that ethnic group. Few studies with limited number of genotyped individuals have expanded the spectrum of mutations in both BRCA genes beyond the 3 mutation panel. In this study, 279 high risk individual AJ were counseled at CEMIC (Centro de Educación Médica e Investigaciones Clínicas), and were genotyped first for the 3 recurrent mutation panel followed by Next Generation Sequencing (NGS) of BRCA1 BRCA2 in 76 individuals who tested negative for the first genotyping step. Of 279 probands (259 women), 55 (50 women) harbored one of the 3 mutations (19.7%); Of 76 fully sequenced cases (73 women), 6 (5 women) (7.9%) carried a pathogenic mutation: in BRCA1, c.2728C>T - p.(Gln910*); c.5407-?_(*1_?)del and c.5445G>A - p.(Trp1815*); in BRCA2, c.5351dup - p.(Asn1784Lysfs*3); c.7308del - p.(Asn2436Lysfs*33) and c.9026_9030del - p.(Tyr3009Serfs*7). Of 61 mutation carriers the distribution was as follows: 11 cancer free at the time of genotyping, 34 female breast cancer cases with age range 28–72 years (41.6 ± 9.3), 3 male breast cancer cases with age range 59–75 years (65 ± 7.3), 6 breast and ovarian cancer cases with age range 35–60 years (breast 40.4 ± 5.2; ovary 47.8 ± 7.2) and 7 ovarian cancer cases with age range 41–77 years (60.6 ± 13.3). This information proved highly useful for counseling, treatment, and prevention for the patient and the family. In conclusion comprehensive BRCA1/2 testing in AJ high risk breast ovarian cancer cases adds valuable clinically relevant information in a subset of cases estimated up to 7% and is therefore recommended.

A study of Kibbutzim in Israel reveals risk factors for cardiometabolic traits and subtle population structure.

Genetic studies in isolated populations often increase power for identifying loci associated with complex diseases and traits. We present here the Kibbutzim Family Study (KFS), aimed at investigating the genetic basis of cardiometabolic traits in extended Israeli families characterized by long-term social stability and a homogeneous environment. Extensive information on cardiometabolic traits, as well as genome-wide genotypes, were collected on 901 individuals. We observed that most KFS participants were of Ashkenazi Jewish (AJ) genetic origin, confirmed a recent severe bottleneck in the AJ recent history, and detected a subtle within-AJ population structure. Focusing on genetic variants relatively common in the KFS but very rare in Europeans, we observed that AJ-enriched variants appear in cancer-related pathways more than expected by chance. We conducted an association study of the AJ-enriched variants against 16 cardiometabolic traits, and found seven loci (24 variants) to be significantly associated. The strongest association, which we also replicated in an independent study, was between a variant upstream of MSRA (frequency ≈1% in the KFS and nearly absent in Europeans) and weight (P = 3.6∙10-8). In conclusion, the KFS is a valuable resource for the study of the population genetics of Israel as well as the genetics of cardiometabolic traits.

The yield of full BRCA1/2 genotyping in Israeli high-risk breast/ovarian cancer patients who do not carry the predominant mutations.

BRCA1 and BRCA2 genotyping results have clinical implications for cancer risk assessment and targeted therapy. Current practice in Israel is to genotype for the predominant BRCA1/2 mutations first, followed by full gene analysis in eligible mutation-negative individuals. This work assessed the rate of non-predominant mutations in BRCA1/2 in ethnically diverse high-risk cases. Breast and/or ovarian cancer patients who tested negative for the predominant BRCA1/2 mutations were referred for comprehensive BRCA1/2 genotyping if calculated risk for carrying a BRCA mutation was ≥10%. Of 1258 eligible patients, 41 (3.3%) carried one of 38 mutations: 3% of Ashkenazi Jews and 3.4% of mixed ethnicities. Detection rate was < 5% among patients diagnosed with cancer younger than 40 or with bilateral breast cancer, and was 5.5% of ovarian cancer patients. Three of the carriers (7.3%) carried gene rearrangements. Three mutations were reported in more than one case. The overall yield of comprehensive BRCA1/2 testing in ethnically diverse high-risk Israeli individuals is 3.3%. This is lower than expected by probability models. A slightly higher rate of BRCA1/2 carriers was seen among ovarian cancer cases. These data should guide BRCA1/2 optimal testing strategy in Israel.

MPZL2 is a novel gene associated with autosomal recessive nonsyndromic moderate hearing loss.

While recent studies have revealed a substantial portion of the genes underlying human hearing loss, the extensive genetic landscape has not been completely explored. Here, we report a loss-of-function variant (c.72delA) in MPZL2 in three unrelated multiplex families from Turkey and Iran with autosomal recessive nonsyndromic hearing loss. The variant co-segregates with moderate sensorineural hearing loss in all three families. We show a shared haplotype flanking the variant in our families implicating a single founder. While rare in other populations, the allele frequency of the variant is ~ 0.004 in Ashkenazi Jews, suggesting that it may be an important cause of moderate hearing loss in that population. We show that Mpzl2 is expressed in mouse inner ear, and the protein localizes in the auditory inner and outer hair cells, with an asymmetric subcellular localization. We thus present MPZL2 as a novel gene associated with sensorineural hearing loss.

Cancer Susceptibility Genetic Testing in a High-Risk Cohort of Urban Ashkenazi Jewish Individuals.

Prior to 2013, genetic testing for Ashkenazi Jewish (AJ) individuals primarily consisted of the three-site BRCA1/BRCA2 AJ panel, full sequencing of BRCA1/2, or the Lynch syndrome mismatch repair genes. Multigene panel testing became more widely available in 2013, but limited data are available regarding the impact of multigene panel testing for AJ individuals. Here, we report the frequency of cancer susceptibility gene mutations in a cohort of 427 AJ individuals seen in the Cancer Risk Clinic at The University of Chicago. We found that 29% of affected and 37% of unaffected individuals carried a pathogenic mutation (32% of overall cohort), primarily known familial mutations in BRCA1/2. A minority of mutations were identified in non-BRCA1/2 genes and consisted mainly of AJ founder mutations in CHEK2, APC, and the mismatch repair genes. A panel of AJ founder mutations would have identified the majority (94%) of mutations in clinically actionable genes in both affected and unaffected patients. Based on recent cost-effectiveness studies, offering all AJ individuals a founder mutation panel may be a cost-effective cancer prevention strategy.

Una aculturación plural indirecta: la herencia sefardita y española en la obra del escritor judío-argentino Alberto Gerchunoff

Aunque de origen askenazí, el escritor argentino Alberto Gerchunoff se convirtió en infatigable propagador de la cultura española, especialmente de su herencia tricultural. Hasta hoy, el denominado Nestor de la literatura judía en Argentina es el representante más conocido en toda hispanoamérica de lo que se ha llamado «sefardización secundaria» de los judíos askenazíes.

Read Yourself!

AbstractCentered on the opening scene of reading staged by Giorgio Agamben in his study of reading machines, The Open: Man and Animal, this article considers how Agamben’s own messianic reading of an illuminated page from a medieval Ashkenazi Bible (Biblioteca Ambrosiana MSS B 30–32) erases the entangled biopolitical histories of medieval Ashkenazi Jews and their Christian sovereigns. What happens if we read the distinctive animal-headed Jews peopling medieval Ashkenazi manuscripts of Bibles and Haggadot dated to the thirteenth and early fourteenth centuries, not in a messianic mode but in the temporal mode of biopolitical bare life? What is the temporal structure of precarious life? Furthermore, how does this Ashkenazi figural tradition of animal-headed Jews point to forms of resistance to the biopolitics of medieval Christendom? How is messianic theory now unconsciously entangled in modes of temporality of precarious life, then?

Increased yield of full GBA sequencing in Ashkenazi Jews with Parkinson's disease

BackgroundVariants in GBA are the most common genetic risk factor for Parkinson's disease (PD), and are especially prevalent in the Ashkenazi Jewish (AJ) population. However, most studies on GBA in AJ genotype only seven selected Gaucher-associated pathogenic variants rather than sequencing the whole gene, which may leave carriers of PD-associated GBA variants undiscovered. MethodsGBA was fully sequenced using molecular inversion probes (MIPs) and Sanger sequencing in 735 AJ PD patients and 662 AJ controls, from Israel and New York. Additional AJ control data (n = 3044) from the Inflammatory Bowel Disease Exome Portal was used. ResultsFull GBA sequencing increased the number of variants discovered by 17.4%, compared to targeted genotyping. An additional 17 PD patients were identified with GBA-associated PD. The p.E326K variant was found in 1.6% of AJ PD patients, making it the second most common PD-associated GBA variant in AJ. GBA variants were found in 18% of PD patients and 7.5% of controls (OR = 2.7, 95%CI = 1.9–3.8, p < 0.0001). ConclusionWithout full sequencing of GBA, or at minimum including p.E326K in the genotyping panel, a significant proportion of variant carriers go undiscovered and may be incorrectly assigned as non-carriers in studies or clinical trials.

Multi-ethnic SULT1A1 copy number profiling with multiplex ligation-dependent probe amplification.

To develop a SULT1A1 multiplex ligation-dependent probe amplification assay and to investigate multi-ethnic copy number variant frequencies. A novel multiplex ligation-dependent probe amplification assay was developed and tested on 472 African-American, Asian, Caucasian, Hispanic and Ashkenazi Jewish individuals. The frequencies of atypical total copy number (i.e., greater or less than two) were 38.7% for Hispanics, 38.9% for Ashkenazi Jewish, 43.2% for Caucasians, 53.6% for Asians and 64.1% for African-Americans. Heterozygous SULT1A1 deletion carriers (slow sulfators) were most common among Caucasians (8.4%), whereas African-Americans had the highest frequencies of three or more copies (rapid sulfators; 60.9%). Different ethnic and racial populations have varying degrees of SULT1A1-mediated sulfation activity, which warrants further research and that may have utility for drug response prediction among SULT1A1-metabolized medications.