Ashkenazi Research Articles

OSMANLI DÖNEMİNDE MUSEVİ MATBAACILIĞININ TEMEL GELİŞİMİ

The first Jewish printing activities in the Ottoman period started with the initiatives of the Sephardic Jews who had to leave Spain due to the exile. Sephardic Jews and Ashkenazi Jews, who were forced to immigrate from Poland and the surrounding areas, wanted to create works of their own religion and culture by continuing their printing activities in Thessaloniki, Edirne, Izmir and Istanbul. Even though the first Jewish printing house was established in 1493 during the Ottoman period, intensive publication of works only occurred during the 19th and 20th centuries. The first Jewish journalistic activities came to the fore in Izmir in 1842. After that, they spread to Istanbul and intensified in both cities. This study aims to deal with Jewish printing activities, which existed in the Ottoman period, within the scope of political and social processes. In the article covering the period between 1493 and 1922, the printing activities of the Jews were examined using the document analysis method. As a result, in spite of intermittent pauses in printing activities during the Ottoman period, it still experienced a successful growth over time. The Ottoman government’s permission for the Jews, as a non-Muslim nation, to conduct printing activities was a socially and commercially important move, especially when Muslims in the region were not using the printing press. The constant presence of religious themes in Jewish works can be attributed to the attempt to preserve their religious identities due to their exile from Spain, being a minority in the places they migrated to, and the fear of annihilation. The fact that they turned to literature and science in the works they published in the following process can be expressed as both the decrease in their sense of threat over time and an effort to assess and utilize the deep-rooted culture they received from Spain.

Xenpozyme: a revelation for Neiman-Pick disease

Nieman-Pick disease (NPD) also known as acid sphingomyelinase deficiency (ASMD) is a rare autosomal recessive disorder of lysosomal storage which affects 1 in 250,000 individuals mainly belonging to the Ashkenazi Jew population. The prevalence varies across the three main subtypes where type A and B affects 1 in 40,000 and type C affects 1 in 150,000 individuals, being more prevalent in the French-Acadian descent in the region of Nova Scotia.

Emerging insights into ethnic-specific TP53 germline variants.

The recent expansion of human genomics repositories has facilitated the discovery of novel TP53 variants in populations of different ethnic origins. Interpreting TP53 variants is a major clinical challenge because they are functionally diverse, confer highly variable predisposition to cancer (including elusive low-penetrance alleles), and interact with genetic modifiers that alter tumor susceptibility. Here, we discuss how a cancer risk continuum may relate to germline TP53 mutations on the basis of our current review of genotype-phenotype studies and an integrative analysis combining functional and sequencing datasets. Our study reveals that each ancestry contains a distinct TP53 variant landscape defined by enriched ethnic-specific alleles. In particular, the discovery and characterization of suspected low-penetrance ethnic-specific variants with unique functional consequences, including P47S (African), G334R (Ashkenazi Jewish), and rs78378222 (Icelandic), may provide new insights in terms of managing cancer risk and the efficacy of therapy. Additionally, our analysis highlights infrequent variants linked to milder cancer phenotypes in various published reports that may be underdiagnosed and require further investigation, including D49H in East Asians and R181H in Europeans. Overall, the sequencing and projected functions of TP53 variants arising within ethnic populations and their interplay with modifiers, as well as the emergence of CRISPR screens and AI tools, are now rapidly improving our understanding of the cancer susceptibility spectrum, leading toward more accurate and personalized cancer risk assessments.

P-746 Carrier Screening analysis in more than 20.000 patients. Is complete analysis important vs genotyping analysis?

Abstract Study question How comprehensive gene sequencing analysis impacts on carrier screening (CS) results and couple risk reduction? Summary answer Comprehensive genetic sequencing analysis facilitates more accurate carrier rates and provides better information for final panel design and partner risk reduction. What is known already Since CS began in the 1970s, it has helped millions of couples at risk of affected offspring affected by genetic diseases.From the first panels for Ashkenazi Jewish to today’s pan-ethnic CS panels, genetic testing has improved from analysis of a few known pathogenic variants to full sequence analysis. The American College of Medical Genetics and Genomics (ACMG) published Standards and Guidelines for the Interpretation of Sequence Variants in 2015, providing an important tool for full sequence analysis for CS. CS analyses can report only already known mutations (genotyping) or screen for all variants with ACMG-guidelines and laboratory experience (full sequencing). Study design, size, duration This study includes 20774 patients screened with an expanded carrier screening panel of 301 genes, including autosomal recessive (AR) and X-linked (XL) disorders by next-generation sequencing (NGS). ACMG guidelines for variant interpretation were followed in 13954 patients and only pathogenic and likely pathogenic variants were reported. 6820 patients were analyzed with genotyping analysis. 15758 matching analyses were performed for couples and gamete donors. The study has been conducted between August 2018 and December 2022. Participants/materials, setting, methods DNA was extracted from saliva and blood samples and sequenced. The data obtained were processed by means of computer tools. The carrier frequency (CFR) was obtained from the full sequencing analyses. The observed CFRs was compared with the expected CFRs obtained from databases and literature.To define its similarity a range of +-25% was accepted as similar CFR. For matching analyses, high at-risk couples were divided for autosomal recessive diseases(both carriers) and X-linked diseases (female carriers). Main results and the role of chance For the 301 genes analyzed, 34%(103) had a similar CF than the expected one and, more importantly, 65%(198) showed different CFR. In some cases this difference is due to the lack of complete information on the CFR on bibliography and databases like the CFR associated a diseases with more than one gene associated or genes related with more than one disease, some of which with low clinical implications, usually underdiagnosed. One of the genes on which the CFR was not similar to the expected was SMN1. For this well-known gene, related to spinal muscular atrophy, the CFR was higher than expected, probably due to the analysis of the variants c.*3 + 80T>G(p.?),c.*211_*212del(p.?) that indicate a higher risk of 0 + 2 configuration. The patients with these variants and 2 SMN1-exon8 copies are at higher risk to be silent carriers, but they may not be carriers. For the 15758 performed, if one or both patients were analyzed by genotyping analysis, 3,6% (432/12055 matchings) identified had high risk of affected offspring for autosomal or X-Linked recessive diseases. When both patients were analyzed by sequencing, 6% (223/3703 matchings) were identified at high risk of affected offspring of the diseases analyzed allowing a higher identification of couples at risk. Limitations, reasons for caution The analysis was performed on 301 genes, in order to have a better understanding of CFR for panel designs or patients genetic counseling, a larger cohort of genes should be taken into account, these results show the importance of complete analysis to assess the carrier risks. Wider implications of the findings It is important to have wider genetic databases for CFR but also for variant pathogenicity in order to have better results on CFR analyses and panel designs, in order to provide proper genetic counseling to patients looking to improve the chances of healthy offspring. Trial registration number Not applicable

Clinical Multigene Panel Testing Identifies Racial and Ethnic Differences in Germline Pathogenic Variants Among Patients With Early-Onset Colorectal Cancer.

The early-onset colorectal cancer (EOCRC) burden differs across racial/ethnic groups, yet the role of germline genetic predisposition in EOCRC disparities remains uncharacterized. We defined the prevalence and spectrum of inherited colorectal cancer (CRC) susceptibility gene variations among patients with EOCRC by race and ethnicity. We included individuals diagnosed with a first primary CRC between age 15 and 49 years who identified as Ashkenazi Jewish, Asian, Black, Hispanic, or White and underwent germline genetic testing of 14 CRC susceptibility genes performed by a clinical testing laboratory. Variant comparisons by racial and ethnic groups were evaluated using chi-square tests and multivariable logistic regression adjusted for sex, age, CRC site, and number of primary colorectal tumors. Among 3,980 patients with EOCRC, a total of 530 germline pathogenic or likely pathogenic variants were identified in 485 individuals (12.2%). By race/ethnicity, 12.7% of Ashkenazim patients, 9.5% of Asian patients, 10.3% of Black patients, 14.0% of Hispanic patients, and 12.4% of White patients carried a germline variant. The prevalence of Lynch syndrome (P = .037), as well as APC, CHEK2, MLH1, monoallelic MUTYH, and PTEN variants, varied by race/ethnicity among patients with EOCRC (all P < .026). Ashkenazim and Hispanic patients had significantly higher odds of presenting with a pathogenic APC variant, which included p.I1307K (odds ratio [OR], 2.67; 95% CI, 1.30 to 5.49; P = .007) and MLH1 variant (OR, 8.69; 95% CI, 2.68 to 28.20; P = .0003), respectively, versus White patients in adjusted models. Germline genetic features differed by race/ethnicity in young patients with CRC, suggesting that current multigene panel tests may not be representative of EOCRC risk in diverse populations. Further study is needed to optimize genes selected for genetic testing in EOCRC via ancestry-specific gene and variant discovery to yield equitable clinical benefits for all patients and to mitigate inequities in disease burden.

Variant Tyr 394Ser in the GCM2 Gene Is Rare in a Cohort of Ashkenazi Jews With Primary Hyperparathyroidism.

Various genes have been associated with familial and sporadic primary hyperparathyroidism (PHPT), including activating mutations of the glial cells missing transcription factor 2 (GCM2) gene. The aim of this study was to assess the prevalence of the GCM2 p.Tyr394Ser variant in the Jerusalem Ashkenazi Jewish (AJ) population with PHPT, and to conclude whether routine genetic testing is justified. The blood of 40 self-reported AJ patients with PHPT and 200 AJ controls was tested for the GCM2 p.Tyr394Ser variant. Demographic and medical information was extracted from the patients' charts and evaluated accordingly. Two (5%) PHPT patients and 3 (1.5%) controls were heterozygotes for the tested variant. Our patients were mostly (87.5%) sporadic cases. One of the heterozygote patients had familial PHPT; the other had 2 parathyroid adenomas, and the levels of his blood and urinary calcium were extremely high. Our results suggest that in AJ patients with sporadic, single-gland PHPT, the likelihood of the tested variant is low and genetic testing should be limited to those with familial PHPT or multiglandular disease.

Pathogenic germline variants in patients with endometrial cancer across diverse ancestries.

5596 Background: Racial/ethnic disparities in outcomes exist in endometrial cancer (EC), particularly amongst self-reported Black compared to Non-Hispanic White (NH-White) patients. However, the contribution of differences in germline pathogenic variants (gPV) and genetics care to disparities is unknown. We seek to describe the spectrum of gPV in unselected patients with EC by ancestry to characterize variations and describe any differences in subsequent genetic counseling follow-up. Methods: Germline assessment of ≥76 cancer predisposition genes was performed in patients with EC undergoing clinical tumor-normal MSK-IMPACT sequencing from 1/1/15-6/30/21. Self-reported data on race/ethnicity and Ashkenazi Jewish (AJ) ancestry were used to classify patients into mutually exclusive ancestry groups: AJ, Asian, Black, Hispanic, NH-White, or Unknown. Genetic ancestry was inferred from MSK-IMPACT, and those with single population ancestral fraction &gt;0.8 were assigned to African (AFR), European (EUR), East Asian (EAS), Native American (NAM), South Asian (SAS), and AJ (ASJ) ancestry populations or considered admixed (Mixed). Clinicopathologic variables were reported using summary statistics and compared by ancestry using non-parametric tests. Results: Among 1,625 patients with EC, self-reported ancestry [202 AJ (12.4%), 124 (7.6%) Asian, 171 Black (10.5%), 124 Hispanic (7.6%), 927 NH-White (57.1%), and 77 missing (4.7%)] correlated with genetic ancestry. In those identifying as Black, 122 (71%) had &gt;80% African ancestry, 45 (26%) were considered Mixed, and 4 (3%) had missing data. We observed gPV in 216 (13.3%) patients (73 high, 36 moderate and 107 low/uncertain penetrance), with 15 patients having &gt;1 gPV. Rates of gPV varied significantly by self-reported ancestry [AJ: 40 (19.8%), Asian: 15 (12.1%), Black: 12 (7.0%), Hispanic: 15 (12.1%), NH-White: 129 (13.9%), Missing: 5; p=0.009] and genetic ancestry [AFR: 9 (6.4%), AJ: 53 (19.3%), EAS: 9 (11.0%), EUR: 112 (13.3%), NAM: 2 (40%), SAS: 7(20%), Mixed: 17 (8.6%), Missing: 7; p&lt;0.001]. Self-reported Black patients had the lowest rate with 13 gPV observed in 12 patients (7.0%); 5 gPV had biallelic inactivation within the tumor (2 MSH2, 1 MSH6, 1 BRCA2 and 1 FANCA). Biallelic inactivation was observed in 70 (32%) patients overall with highest rates in Black (42%), Asian (40%), AFR (67%) and SAS (71%) populations. In those with new gPV (n=114), 102 (89%) overall were seen in genetics clinic for follow-up care, with the lowest rates in patients identifying as Black (75%) and of AFR ancestry (67%). Conclusions: Although rates of gPV varied by ancestry, they are drivers of disease in all populations, emphasizing the importance of germline assessment in EC. Differences in gPV and subsequent genetics care may contribute to racial/ethnic disparities in outcomes in EC by affecting treatment and cancer prevention and should be studied further.

Novel loci for Alzheimer's disease identified by a genome-wide association study in Ashkenazi Jews.

Most Alzheimer's disease (AD) loci have been discovered in individuals with European ancestry (EA). 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. 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 ). Our results highlight the efficacy of founder populations for AD genetic studies.

Polygenic risk score calibration and association with breast cancer in diverse ancestries.

10505 Background: Polygenic risk scores (PRS) have been shown to substantially improve breast cancer (BC) risk prediction when incorporated into traditional risk assessment models. However, PRS developed primarily in women of European ancestry have shown poor performance when applied to non-European populations. We previously described development and validation of a multiple-ancestry PRS (MA-PRS) that is based on individual ancestral genetic composition. MA-PRS has been incorporated into the Tyrer-Cuzick model for use in clinical practice and has been shown to provide independent value to the model. Here, we describe performance of the MA-PRS in a large cohort of women from diverse ancestral backgrounds. Methods: The study cohort included 203,586 patients who were referred for hereditary cancer testing and negative for pathogenic variants in genes associated with BC. MA-PRS was calculated as previously described based on 149 SNPs (93 BC and 56 ancestry-informative). Association of MA-PRS with invasive BC status (affected vs unaffected) was analyzed using logistic regression adjusted for personal and family cancer history, age, and ancestry. Calibration was assessed by examining the MA-PRS distribution within unaffected patients, and through goodness-of-fit tests. All analyses were conducted within the full cohort and within ancestral subpopulations. Odds ratios (ORs) are reported per standard deviation. Results: One-fifth (43,782/203,586, 21.5%) of patients were diagnosed with invasive BC, and 60,657 (29.8%) of patients reported BC in a first degree relative. The MA-PRS distribution was centered around zero among unaffected patients overall and within each subpopulation. MA-PRS significantly improved BC risk prediction over clinical factors in the full cohort (OR = 1.43, 95% CI:1.41-1.44) and within each ancestral subpopulation (Table). The strongest associations were observed in Ashkenazi Jewish (OR = 1.56, 95% CI:1.39-1.76) and South Asian (OR = 1.49,95% CI: 1.23-1.81) populations. The top decile of the MA-PRS consistently identified patients with two-fold increased risk of developing BC. Goodness-of-fit tests showed that the MA-PRS was well calibrated and predicted BC risk accurately in the tails of the distribution for both European and non-European women. Conclusions: The breast cancer MA-PRS based on genetic ancestral composition is well-calibrated and strongly associated with BC in all tested ancestral populations. Incorporation of PRS adds independent information to risk models and supports equitable access to personalized BC risk management. [Table: see text]

Prospective prevalence estimation of BRCA1, BRCA2, and other germline mutations associated with hereditary pancreatic cancer (HPC) using a comprehensive gene panel in an unselected cohort of Mexican patients with pancreatic ductal adenocarcinoma (PDAC).

10609 Background: Prevalence of pathogenic or likely pathogenic germline variants (PGVs) in patients with PDAC varies across populations. There is limited information on the prevalence of PGVs among Mexican patients with PDAC. We prospectively tested an unselected cohort of newly diagnosed PDAC patients using a comprehensive gene panel in order to estimate the prevalence of BRCA1/2, and other germline mutations associated with HPC. Methods: The protocol was approved by the ethics committee at each institution: INCMNSZ, INCAN, and CM ABC Observatorio. Key inclusion criteria: age &gt; 18 years and PDAC diagnosed within 6 months of inclusion. Patients were enrolled consecutively, regardless of age, personal or family history of cancer, known hereditary cancer syndrome, or stage of the disease. Written informed consent was obtained before any procedure. Clinical variables including family history of cancer were collected. We used the 84-gene Invitae Multi-Cancer Panel. Genetic testing had no cost for patients. Patient characteristics and family history were summarized using descriptive statistics (IBM SPSS Statistics Version 25). The trial was registered on Clinical Trials (NCT05305001). Results: From August 2020 to June 2022, 119 patients with newly diagnosed PDAC were identified. Of these, 107 patients were included: 58% women, median age was 63 y/o, clinical stages at diagnosis were: I (24%), II (22%), III (6%), and IV (48%). All patients had Hispanic ancestry except one (Ashkenazi Jewish). Only 7.5% (n = 8) had a personal history of other cancer, mainly breast cancer (N = 3); 62% had a family history of any cancer, while 47.6% had a first-degree relative (FDR) with any cancer. 11% (n = 12) had family history of pancreatic cancer (PC), and 9% (n = 10) had an FDR with PC. Five patients met clinical criteria for hereditary cancer syndrome: familial pancreatic cancer (4) and Lynch syndrome (1). PGVs were identified in 17.8% (n = 19) of patients. The prevalence of PGVs in genes associated with autosomal dominant risk of PC was 11.2%: CDKN2A(5.6%), ATM (3.7%), BRCA2 (0.93%), and MSH6 (0.93%). Two patients had a PGV associated with autosomal dominant predisposition to other cancers ( CHECK2 and NF1). Six patients (5.6%) had PGVs associated with autosomal recessive predisposition to rare syndromes with increased cancer risk other than PDAC (MUTYH, RECQL4, FH and WRN). Variants of uncertain significance were present in 42% of patients. Conclusions: In Mexican patients with PDAC, the prevalence of PGVs on BRCA1/2 is &lt; 1%. The prevalence of PGVs in other susceptibility genes is 11%. Our results support the role of universal germline testing in Mexican patients with PDAC using a comprehensive gene panel. Selective testing for BRCA1/2 is discouraged.

Novel variants in genes related to vesicle-mediated-transport modify Parkinson's disease risk.

VPS35 and VPS13 have been associated with Parkinson's disease (PD), and their shared phenotype in yeast when reduced in function is abnormal vacuolar transport. We aim to test if additional potentially deleterious variants in other genes that share this phenotype can modify the risk for PD. 77 VPS and VPS-related genes were analyzed using whole-genome-sequencing data from 202 PD patients of Ashkenazi Jewish (AJ) ancestry. Filtering was done based on quality and functionality scores. Ten variants in nine genes were further genotyped in 1200 consecutively recruited unrelated AJ-PD patients, and allele frequencies and odds ratio calculated compared to gnomAD-AJ-non-neuro database, in un-stratified (n=1200) and stratified manner (LRRK2-G2019S-PD patients (n=145), GBA-PD patients (n=235), and non-carriers of these mutations (NC, n=787)). Five variants in PIK3C3, VPS11, AP1G2, HGS and VPS13D were significantly associated with PD-risk. PIK3C3-R768W showed a significant association in an un-stratified (all PDs) analysis, as well as in stratified (LRRK2, GBA, and NC) analyses (Odds ratios=2.71, 5.32, 3.26. and 2.19 with p=0.0015, 0.002, 0.0287, and 0.0447, respectively). AP1G2-R563W was significantly associated in LRRK2-carriers (OR=3.69, p=0.006) while VPS13D-D2932N was significantly associated in GBA-carriers (OR=5.45, p=0.0027). VPS11-C846G and HGS-S243Y were significantly associated in NC (OR=2.48 and 2.06, with p=0.022 and 0.0163, respectively). Variants in genes involved in vesicle-mediated protein transport and recycling pathways, including autophagy and mitophagy, may differentially modify PD-risk in LRRK2-carriers, GBA carriers, or NC. Specifically, PIK3C3-R768W is a PD-risk allele, with the highest effect size in LRRK2-G2019S carriers. These results suggest oligogenic effect that may depends on the genetic background of the patient. An unbiased burden of mutations approach in these genes should be evaluated in additional PD and control groups. The mechanisms by which these novel variants interact and increase PD-risk should be researched in depth for better tailoring therapeutic intervention for PD prevention or slowing disease progression.

The Names of the Georgian Jews

&nbsp;Historical documents, literary works and recorded materials provide direct evidence that until the 1970s the Jews were mostly given biblical names and, in particular, the ones found in the Torah. It should be noted that one of the manifestations of the identity of Georgian Jews was their names. In some cases, both non-Jews and Jews were given biblical names in Georgia. In such cases, Georgians preferred the Greek forms, while Jews would use the Hebrew variant for self-identification purposes. Ashkenazi and Mizrahi Jews also lived in Georgia. They had different names. From the 1970s, in order to avoid being ridiculed, most of the Jews chose common Georgian names for their new-born babies. Despite the fact that some Jews changed their names for various reasons, almost none of them was less Jewish.After repatriation to Israel, the Georgian Jews choose different kinds of names for their infants. The names can be divided into categories according to their origin (biblical and modern Hebrew, Yiddish and other languages) and popularity in the Jewish (Israeli) community.&nbsp;&nbsp

Familial dysautonomia.

Familial dysautonomia (FD) is an autosomal recessive hereditary sensory and autonomic neuropathy (HSAN, type 3) expressed at birth with profound sensory loss and early death. The FD founder mutation in the ELP1 gene arose within the Ashkenazi Jews in the sixteenth century and is present in 1:30 Jews of European ancestry. The mutation yield a tissue-specific skipping of exon 20 and a loss of function of the elongator-1 protein (ELP1), which is essential for the development and survival of neurons. Patients with FD produce variable amounts of ELP1 in different tissues, with the brain producing mostly mutant transcripts. Patients have excessive blood pressure variability due to the failure of the IXth and Xth cranial nerves to carry baroreceptor signals. Neurogenic dysphagia causes frequent aspiration leading to chronic pulmonary disease. Characteristic hyperadrenergic "autonomic crises" consisting of brisk episodes of severe hypertension, tachycardia, skin blotching, retching, and vomiting occur in all patients. Progressive features of the disease include retinal nerve fiber loss and blindness, and proprioceptive ataxia with severe gait impairment. Chemoreflex failure may explain the high frequency of sudden death in sleep. Although 99.5% of patients are homozygous for the founder mutation, phenotypic severity varies, suggesting that modifier genes impact expression. Medical management is currently symptomatic and preventive. Disease-modifying therapies are close to clinical testing. Endpoints to measure efficacy have been developed, and the ELP1 levels are a good surrogate endpoint for target engagement. Early intervention may be critical for treatment to be successful.

The Racial Ambiguities of American Sephardic and Ashkenazi Jews

This paper analyzes the racial ambiguities of Sephardic and Ashkenazi Jews in American law by examining three Supreme Court cases: DeFunis v. Odegaard, Shaare Tefila Congregation v. Cobb, and Bennun v. Rutgers State University. Despite being classified as a religious group, Jews have also been subjected to racial categorization, with Sephardic and Ashkenazi Jews often occupying different racial spaces. Through a close reading of these cases, the paper explores how the Supreme Court has grappled with the complexity of Jewish identity in America, and how these cases have shaped the legal understanding of Jewishness as both a religious and a racial identity. Ultimately, the paper argues that these cases highlight the need for a more nuanced and inclusive approach to understanding race and ethnicity in American law, particularly in how it relates to the Jewish community.

Identifying high-impact variants and genes in exomes of Ashkenazi Jewish inflammatory bowel disease patients

Inflammatory bowel disease (IBD) is a group of chronic digestive tract inflammatory conditions whose genetic etiology is still poorly understood. The incidence of IBD is particularly high among Ashkenazi Jews. Here, we identify 8 novel and plausible IBD-causing genes from the exomes of 4453 genetically identified Ashkenazi Jewish IBD cases (1734) and controls (2719). Various biological pathway analyses are performed, along with bulk and single-cell RNA sequencing, to demonstrate the likely physiological relatedness of the novel genes to IBD. Importantly, we demonstrate that the rare and high impact genetic architecture of Ashkenazi Jewish adult IBD displays significant overlap with very early onset-IBD genetics. Moreover, by performing biobank phenome-wide analyses, we find that IBD genes have pleiotropic effects that involve other immune responses. Finally, we show that polygenic risk score analyses based on genome-wide high impact variants have high power to predict IBD susceptibility.

Variants in PSMB9 and FGR differentially affect Parkinson's disease risk in GBA and LRRK2 mutation carriers

IntroductionRecent studies found an association between Parkinson's disease (PD) and alterations in the innate immune system. However, whether the involvement of this system in two of the known genetic forms of PD, GBA-PD and LRRK2-PD, and in patients who do not carry these mutations is different, is yet to be determined. We aimed to test if genetic variations in the innate immune genes are differentially associated with PD in these subgroups. MethodsInnate immune genes were identified and classified into sub-lists according to Reactome pathways. Whole-genome-sequencing (WGS) was performed on 201 unrelated Ashkenazi-Jewish (AJ) PD patients including 104 GBA-PD, 32 LRRK2-PD, and 65 non-carriers-PD (NC-PD). To identify genes with different burden between these subgroups of PD, gene-based Sequence kernel association optimal unified test (SKAT-O) analysis was performed on innate immune pathways. Candidate variants within the significant genes were further genotyped in a cohort of 1200 unrelated, consecutively recruited, AJ-PD patients, and to evaluate their association with PD-risk their allele frequencies were compared to AJ-non-neuro cases in gnomAD database, in a stratified and un-stratified manner. ResultsSKAT-O analysis showed significantly different burden for PSMB9 (GBA-PD versus NC-PD) and FGR (GBA-PD versus LRRK2-PD). Two candidate variants in PSMB9 showed an association with GBA-PD-risk and NC-PD-risk while one FGR variant showed an association with LRRK2-PD-risk. ConclusionOur data supports differential involvement of innate immunity risk alleles in PD and emphasizes the differences between the GBA- and LRRK2-PD subgroups.

Breast cancer polygenic risk scores derived in White European populations are not calibrated for women of Ashkenazi Jewish descent

PurposePolygenic risk scores (PRSs) are a major component of accurate breast cancer (BC) risk prediction but require ethnicity-specific calibration. Ashkenazi Jewish (AJ) population is assumed to be of White European (WE) origin in some commercially available PRSs despite differing effect allele frequencies (EAFs). We conducted a case-control study of WE and AJ women from the Predicting Risk of Cancer at Screening Study. The Breast Cancer in Northern Israel Study provided a separate AJ population–based case-control validation series. MethodsAll women underwent Illumina OncoArray single-nucleotide variation (SNV; formerly single-nucleotide polymorphism [SNP]) analysis. Two PRSs were assessed, SNV142 and SNV78. A total of 221 of 2243 WE women (discovery: cases = 111; controls = 110; validation: cases = 651; controls = 1772) and 221 AJ women (cases = 121; controls = 110) were included from the UK study; the Israeli series consisted of 2045 AJ women (cases = 1331; controls = 714). EAFs were obtained from the Genome Aggregation Database. ResultsIn the UK study, the mean SNV142 PRS demonstrated good calibration and discrimination in WE population, with mean PRS of 1.33 (95% CI 1.18-1.48) in cases and 1.01 (95% CI 0.89-1.13) in controls. In AJ women from Manchester, the mean PRS of 1.54 (1.38-1.70) in cases and 1.20 (1.08-1.32) in controls demonstrated good discrimination but overestimation of BC relative risk. After adjusting for EAFs for the AJ population, mean risk was corrected (mean SNV142 PRS cases = 1.30 [95% CI 1.16-1.44] and controls = 1.02 [95% CI 0.92-1.12]). This was recapitulated in the larger Israeli data set with good discrimination (area under the curve = 0.632 [95% CI 0.607-0.657] for SNV142). ConclusionAJ women should not be given BC relative risk predictions based on PRSs calibrated to EAFs from the WE population. PRSs need to be recalibrated using AJ-derived EAFs. A simple recalibration using the mean PRS adjustment ratio likely performs well.

Explanations for the discrepancy between variant frequency and homozygous disease occurrence: Lessons from Ashkenazi Jewish data

Ample data on recessive disorders among Ashkenazi Jews has been gathered and published through the years. The opportunity to integrate molecular records analyzed in actual affected individuals with data derived from population-documented frequencies enables to compare these figures.We reviewed assumed pathogenic variants reported among patients in the Israeli medical genetic database (IMGD) with a carrier frequency of 1% or more among Ashkenazi Jews in gnomAD. Among the 60 assumed pathogenic variants recorded in IMGD, 15 (25%) had either a disease incidence considerably lower than expected by the calculated carrier frequency (12 variants), or the variant was not characterized in Ashkenazi Jewish patients (three variants).Possible explanations for the rarity or absence of affected individuals despite high carrier frequency include embryonic lethality, clinical variability, and incomplete and age-related penetrance, in addition to the existence of additional assumed pathogenic variants on the founder haplotype, hypomorphic variants or digenic inheritance.The discrepancy in actual versus expected number of patients calls for caution upon designing and choosing targeted genes and recessive mutations for carrier screening.

On Practical Uses of Ten Sefirot: Material Readings in an Early Modern Kabbalistic Collectaneum (MS Michael 473)

AbstractBy the end of the sixteenth century, textual manifestations of kabbalah—a variety of Jewish mysticism that first emerged in medieval Provence and Catalonia—achieved the status of elite but authoritative lore in Eastern and Central Europe, even if at times they stirred religious opposition. At the same time, and especially in the seventeenth century, the so-called practical kabbalah, associated with magic and a talismanic approach to religious ritual, gained substantial popularity among Ashkenazi (i.e., Eastern and Central European) Jews. This study centers on a multiple-text and composite codex, Oxford-Bodleian MS Michael 473, and throws into relief the dynamics of circulation of various kabbalistic traditions in early modern Eastern and Central Europe. By zooming in on a single codex, this article foregrounds the hermeneutic potential of contextual reading of texts in complex manuscripts and of interpreting material choices taken by their cocreators. It does so with a methodological agenda that goes beyond tracing of authorial genealogies, and beyond the sociology of texts and their producers, toward exploring the interpretive relations of literary and material form in early modern handwritten kabbalistic texts. The article showcases a single textual unit, Qabbalat ‘Eser Sefirot, that MS Michael 473 contains, in order to focus on the position of practical kabbalistic texts and practices within the spectrum of kabbalistic traditions of seventeenth- and early eighteenth-century Eastern and Central Europe, ushered in by the contemporary modes of reading and transcription of texts.

Community data-driven approach to identify pathogenic founder variants for pan-ethnic carrier screening panels

BackgroundThe American College of Medical Genetics and Genomics (ACMG) recently published new tier-based carrier screening recommendations. While many pan-ethnic genetic disorders are well established, some genes carry pathogenic founder variants (PFVs) that are unique to specific ethnic groups. We aimed to demonstrate a community data-driven approach to creating a pan-ethnic carrier screening panel that meets the ACMG recommendations.MethodsExome sequencing data from 3061 Israeli individuals were analyzed. Machine learning determined ancestries. Frequencies of candidate pathogenic/likely pathogenic (P/LP) variants based on ClinVar and Franklin were calculated for each subpopulation based on the Franklin community platform and compared with existing screening panels. Candidate PFVs were manually curated through community members and the literature.ResultsThe samples were automatically assigned to 13 ancestries. The largest number of samples was classified as Ashkenazi Jewish (n = 1011), followed by Muslim Arabs (n = 613). We detected one tier-2 and seven tier-3 variants that were not included in existing carrier screening panels for Ashkenazi Jewish or Muslim Arab ancestries. Five of these P/LP variants were supported by evidence from the Franklin community. Twenty additional variants were detected that are potentially pathogenic tier-2 or tier-3.ConclusionsThe community data-driven and sharing approaches facilitate generating inclusive and equitable ethnically based carrier screening panels. This approach identified new PFVs missing from currently available panels and highlighted variants that may require reclassification.