Ashkenazi Research Articles

Reduction in Filamin C transcript is associated with arrhythmogenic cardiomyopathy in Ashkenazi Jews

BackgroundFilamin C is a cytoskeletal protein expressed in cardiac cells. Nonsense variations in the filamin C gene (FLNC) were associated with dilated and arrhythmogenic cardiomyopathies. Methods and resultsWe identified an intronic variation in FLNC gene (c.3791-1G > C) in three unrelated Ashkenazi Jewish families with variable expression of arrhythmia and cardiomyopathy. cDNA was prepared from a mutation carrier's cultured skin fibroblasts. Quantitative PCR demonstrated a reduction in total FLNC transcript, and no other FLNC splice variants were found. Single-nucleotide polymorphism (SNP) analysis revealed heterozygous variations in the genomic DNA that were not expressed in the messenger RNA. Immunohistochemical analysis of cardiac sections detected a normal distribution of filamin C protein in the heart ventricles. ConclusionThe transcript that included the FLNC variant was degraded. Haploinsufficiency in filamin C underlies arrhythmogenic cardiomyopathy with variable symptoms.

Ancestry-specific hereditary cancer panel yields: Moving toward more personalized risk assessment.

Healthcare disparities in genomic medicine are well described. Despite some improvements, we continue to see fewer individuals of African American, Asian, and Hispanic ancestry undergo genetic counseling and testing compared to those of European ancestry. It is well established that variant of uncertain significance (VUS) rates are higher among non-European ancestral groups undergoing multi-gene hereditary cancer panel testing. However, pathogenic variant (PV) yields, and genomic data in general, are often reported in aggregate and derived from cohorts largely comprised of individuals of European ancestry. We performed a retrospective review of clinical and ancestral data for individuals undergoing multi-gene hereditary cancer panel testing to determine ancestry-specific PV and VUS rates. An ancestry other than European was reported in 29,042/104,851 (27.7%) of individuals. Compared to Europeans (9.4%), individuals of Middle Eastern ancestry were more likely to test positive for one or more pathogenic variants (12.1%, p=.0025), while African Americans were less likely (7.9%, p<.0001). Asian and Middle Eastern individuals were most likely (34.8% and 33.2%, respectively) to receive a report with an overall classification of VUS, while individuals of Ashkenazi Jewish and European ancestry were least likely (17.1% and 20.4%, respectively). These data suggest that in addition to higher VUS rates, there may be ancestry-specific PV yields. Providing aggregate data derived from cohorts saturated with European individuals does not adequately reflect genetic testing outcomes in minority groups, and interrogation of ancestry-specific data is a step toward a more personalized risk assessment.

Ethnic disparities in the frequency of cancer reported in family histories.

This study was designed to observe whether disparities exist between ethnicities in reporting a family history of cancer in a cancer genetic counseling clinic. Four hundred sixty-nine pedigrees collected between2015 to 2017 from a cancer clinic at the University of California, Irvine, were analyzed. Pedigrees were separated by ethnicity into the following categories: non-Hispanic White, Hispanic, Asian, or Ashkenazi Jewish. The number of first- and second-degree relatives was calculated for each pedigree, and the total number of relatives reported with cancer. The total reported with cancer was divided by total number of relatives to derive a percentage of cancer reporting for each pedigree. The percentages of cancer reporting were analyzed using column proportions, nonparametric tests, and a Poisson regression. Cancer reporting in first- and second-degree relatives was highest among non-Hispanic Whites and Ashkenazi Jewish individuals, with median percentages of 22% and 27%, respectively. The median percentage of cancer reporting in first- and second-degree relatives in both Hispanics and Asians was 10%. Cancer reporting medians were significantly lower in Hispanics and Asians when compared to non-Hispanic Whites and Ashkenazi Jewish individuals (p<.001). Ethnicity was a significant factor for predicting the number of relatives reported to have cancer when analyzed with a Poisson regression. This study concluded that cancer is reported less frequently in families when the proband and their families are Hispanic or Asian. Hispanics and Asians have lower cancer incidence rates; however, incidence rates alone may not explain the reporting disparity observed. Hence, family cancer histories in minority populations may be truncated. Healthcare professionals should be aware of this disparity when assessing cancer risks so appropriate modifications can be made accordingly for recommended cancer screening and/or cancer genetic testing. Further efforts are warranted to disseminate information to minority populations about the value of family health history regarding cancer risk assessment.

Inflammatory Bowel Disease Clusters Within Affected Sibships in Ashkenazi Jewish Multiplex Families

Inflammatory bowel disease (IBD) has a long-established familial incidence, 1 Kirsner J.B. et al. Ann Intern Med. 1963; 59: 133-144 Crossref PubMed Scopus (101) Google Scholar ,2 Hislop I.G. et al. Gut. 1969; 10: 994-995 Crossref PubMed Scopus (15) Google Scholar with an ever-increasing number of genetic risk alleles discovered, tolling more than 300 with current genome-wide association studies. 3 Liu J.Z. et al. Nat Genet. 2015; 47: 979-986 Crossref PubMed Scopus (1153) Google Scholar The Ashkenazi Jewish (AJ) population is enriched for mutations associated with rare Mendelian and common complex diseases 4 Kenny E.E. et al. PLoS Genet. 2012; 8e1002559 Crossref PubMed Scopus (104) Google Scholar and has an approximately 4-fold increased prevalence of IBD 5 Bernstein C.N. et al. Am J Gastroenterol. 2006; 101: 1559-1568 Crossref PubMed Scopus (442) Google Scholar and frequent familial aggregation. 6 Schiff E.R. et al. Dig Dis Sci. 2018; 63: 3049-3057 Crossref PubMed Scopus (6) Google Scholar However, familial aggregation does not necessarily imply an underlying, exclusively genetic etiology and has also been proposed to be caused by environmental factors. We aimed to determine the contribution of an underlying shared environment to familial aggregation by studying large AJ IBD sibships from a restricted geographic area. We hypothesized that, in a purely genetically inherited disease, affected siblings are expected to be randomly distributed within sibships. On the other hand, if there is an environmental contribution to the disease, it is expected that siblings in closer proximity due to birth order will share more environmental factors and will, thus, be more often concordant for disease than siblings substantially different in birth order.

Global Assessment of Mendelian Stroke Genetic Prevalence in 101 635 Individuals From 7 Ethnic Groups.

Background and Purpose- Mendelian stroke confers a high lifetime risk for mutation carriers; however, ethnicity-specific prevalence estimates have been difficult to establish. Methods- Eighteen genes responsible for Mendelian stroke were investigated using the Genome Aggregation Database. Genome Aggregation Database participants belonged to 1 of 7 populations: African/African-American, Latino/Admixed American, Ashkenazi Jewish, East Asian, Finnish European, non-Finnish European, and South Asian. Rare nonsynonymous variants from 101 635 participants free of neurological disease were examined for each ethnicity. Mutations were categorized according to 3 nested classes: pathogenic clinical variants, likely damaging variants based on in silico prediction, and all nonsynonymous variants. Results- ABCC6, KRIT1, CECR1, COL3A1, COL4A1, COL4A2, COLGALT1, GLA, HTRA1, NOTCH3, RNF213, and TREX1 harbored pathogenic clinical variants in Genome Aggregation Database. Across all 18 genes, total nonsynonymous carrier frequency was found to be high in 5 ethnicities (African/African-American, Latino/Admixed American, East Asian, non-Finnish European, and South Asian; 28.5%-37.5%) while lower total frequencies were estimated for in silico-predicted likely damaging variants (14.9%-19.7%) and pathogenic clinical variants (0.7%-2.8%). Overall, East Asian exhibited the highest total pathogenic clinical mutation carrier frequency (2.8%). ABCC6 pathogenic clinical variants were most prevalent among East Asian (0.8%). Pathogenic NOTCH3 variants, causal for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, were most frequent among East Asian (1.1%) and South Asian (1.2%). East Asian also demonstrated the highest carrier rate for RNF213 (0.8%). Finnish European exhibited the greatest HTRA1 frequency (0.2%), while COL4A1 pathogenic variants were most prevalent in African/African-American (0.3%). Conclusions- Especially, among pathogenic clinical variants, Mendelian stroke genetic prevalence differed significantly between populations. These prevalence estimates may serve as guides for screening and risk profiling in patients worldwide, particularly for understudied non-European populations.

A110 DGAT1 MUTATION OF LIPID TRAFFICKING ASSOCIATED WITH A RARE CASE OF CONGENITAL DIARRHEA

Abstract Background Congenital diarrheas and enteropathies (CODEs) are rare and cause severe chronic diarrhea in children under 2 years of age.1 Current genomic research has identified several monogenic defects resulting in epithelial disorders of nutrient and electrolyte transport, enzymes function, metabolism and trafficking. Aims To discuss a rare case of congential diarrhea. Methods Case Report. Results A 10-month-old Ashkenazi Jewish boy was referred to Pediatric Gastroenterology for loose stools and failure to thrive. Born at 27 weeks, he was a NICU inpatient for his first 3 months of life. Explosive loose stools were first noticed after discharge and treated as cow’s milk protein allergy. At aged 10 months he was admitted to his local hospital with irritability, abdominal distension, foul smelling loose stools and developmental delay. Despite an intake of 130kcal/kg/day he failed to gain weight (weight and length &amp;lt; 3rd centile). His abdomen was distended but there was no organomegaly on examination. On transfer to Sick Kids he underwent extensive work up with low albumin 24 g/L but normal CBC, amylase, lipase and IgA and anti-TTG negative. The lipid profile showed hypertriglyceridemia 2.98 mmol/L (normal &amp;lt;0.85), low HDL 0.81 mmol/L but normal total cholesterol. Low apoliprotein A1 0.79 g/L (0.92 - 1.96), low apoliprotein B 0.54 g (0.59 - 1.46) and vitamin E deficiency 9.6 umol/L (14.5 - 33.0). Normal fecal elastase (&amp;gt; 500 ug/g stool). Upper GI endoscopy showed duodenal villi blunting with non-specific chronic inactive duodenitis on histopathology. Due to ongoing poor weight gain he commenced TPN. A repeat endoscopy four weeks after admission revealed patchy villous blunting, crypt hyperplasia and enterocyte vacuolization. However, ultrastructural electron microscopy examination showed normal enterocyte brush border with well-formed microvilli with no inclusions or vesicular bodies. With a differential diagnosis of chylomicron retention disorder, abetalipoproteinemia or hypolipoproteinemia he was commenced on a low-fat diet with MCT feeds. A 72-hour fecal fat collection on this diet was within normal range 5.4 mmol/day (2–7). One year later his weight is now on 3rd centile and his albumin levels have normalized. However, triglycerides remain elevated. Whole exome sequencing identified two pathogenic variants in the DGAT1 gene; c.629_631delCCT, pSer210del and c751 + 2T&amp;gt;C, IVSB+2T&amp;gt;C. Conclusions Diacylglycerol acyltransferase (DGAT)1 catalyzes triglyceride biosynthesis.2 Loss of function DGAT1 gene mutations are described in several cases studies3,4 characterized by electrolyte transport–related diarrhea, protein-losing enteropathy and growth failure. Our cases adds to the understanding of the phenotypic and histological spectrum of DGAT1 mutations. Management strategies currently focus on growth with dietary lipid restriction, while substituting fat-soluble vitamins and essential fatty acids. Funding Agencies CAG

Practices in synagogues regarding Jewish genetic disease education.

Approximately one in three Ashkenazi Jews are carriers for an autosomal recessive Jewish genetic disease (JGD). However, studies indicate that most Jews are uneducated on this topic and obstetricians do not routinely offer carrier screening to Jewish patients. Both the Reform and Conservative movements of Judaism call for JGD education to take place within the synagogue; however, little is known about the extent of this education occurring today. An online survey was created for Reform and Conservative rabbis to assess the types of JGD education taking place within the synagogue. Additionally, the survey included questions to assess JGD knowledge and possible factors that could predict counseling activity and knowledge level. Of the 94 participants, 91% had provided education about JGDs to congregants, with 98.8% providing this education during premarital counseling sessions. For most respondents, explaining recessive inheritance pattern and carrier screening was the extent of the discussion. Additionally, the majority of rabbis scored below 50% on the knowledge portion of the survey, with an average score of 1.9/4. There were no statistically significant differences between JGD education in Reform vs. Conservative synagogues, and there were no statistically significant predictors of knowledge score or JGD education frequency. In conclusion, while the number of rabbis discussing this topic is encouraging, discussion topics were found to be limited and their knowledge of JGDs was found to be poor.

Geographic and Ethnic Heterogeneity of Germline BRCA1 or BRCA2 Mutation Prevalence Among Patients With Metastatic Pancreatic Cancer Screened for Entry Into the POLO Trial

Germline BRCA1 and/or BRCA2 mutations (gBRCAms) are risk factors for pancreatic cancer. The extent to which demographic and geographic factors affect the uptake of gBRCAm testing in pancreatic cancer (PC) is unknown. We conducted a retrospective, descriptive analysis of demographic/geographic data from the first 2,206 patients with metastatic PC (mPC) screened for eligibility to enter the phase III POLO trial of maintenance olaparib. No formal statistical tests were performed. Of 2,167 patients with previously unknown gBRCAm status, 128 (5.9%) had a newly identified gBRCAm; rates were highest in the United States, France, and Israel (9.5%, 7.6%, and 7.4%, respectively). When including patients with a previously known gBRCAm, prevalence rose to 7.2% (or 5.8% after excluding populations enriched in Ashkenazi Jews, who are known to have a high rate of BRCA1 and BRCA2 founder mutations). Patients with a gBRCAm were slightly younger (57.9 v 61.1 years) and more likely to have early-onset mPC than those without. Higher newly identified gBRCAm prevalence was observed among African American (n = 28) versus white (n = 1,808), Asian (n = 218), and other (n = 61) patients (10.7% v 6.1%, 5.0%, and 1.6%, respectively). Of 139 white patients with a gBRCAm, 110 were newly identified during screening; the majority of gBRCAms in African American, Asian, and Hispanic patients (n = 3, n = 11, and n = 5, respectively) were newly identified. We identified substantial geographic and some racial variability in gBRCAm prevalence among patients with mPC, an important consideration given the increased use of familial screening and possible future use of targeted therapies in this setting. Although our study included small numbers of nonwhite patients, prior knowledge of their gBRCAm status was limited compared with their white counterparts, which suggests disparities in genetic testing uptake.

Abstract P6-08-15: Racial and ethnic variation in BRCA1 and BRCA2 genetic test results among individuals referred for genetic counseling at a large urban comprehensive cancer center

Abstract Background It is estimated that up to 10% of women diagnosed with breast cancer in the United States have a BRCA1 or BRCA2 inherited susceptibility, which accounts for approximately 125,000 women. There are racial and ethnic differences in the prevalence and types of pathogenic mutations and variants of uncertain significance (VUS) in BRCA1 and BRCA2. To better understand the prevalence of recurring pathogenic mutations and/or uncover novel mutations in specific racial and ethnic groups, we evaluated the mutational profile of individuals who had genetic counseling and testing at a large urban NCI designated Comprehensive Cancer Center. Methods Data was extracted from the Karmanos Cancer Institute (KCI) Cancer Genetic Counseling Service database over a 19 year period through 12/31/18. The cohort consisted of 5,929 individuals evaluated for high-risk of hereditary disease at 6 sites across Michigan including Detroit. We estimated the prevalence of BRCA1/2 pathogenic mutations and variants of uncertain significance (VUS) by race and ethnicity. Odds Ratios (OR) and 95% confidence intervals (CI) were calculated to compare the rate of pathogenic and VUS mutations in race and ethnic groups with non-Hispanic whites (NHW) indicated as the reference group. Results There were 3,114 (52.5%) unrelated individuals who underwent clinical BRCA1/2 testing. The racial/ethnic breakdown of the cohort included: 68.4% NHW, 21% African American (AA), 2.7% Ashkenazi Jewish (AJ), 2.2% Arab, 0.9% Hispanic (H), and 4.8% other. There were 290 individuals with pathogenic mutations (137 BRCA1 and 153 BRCA2) and 186 with VUS (61 BRCA1 and 125 BRCA2). For BRCA1, there were no differences by race and ethnicity in pathogenic mutations, however AA and Arab individuals were more likely to have VUS compared to NHW (OR &amp; 95% CI, 2.63, 1.53-4.54 and 3.39, 1.01-11.41) respectively. For BRCA2, AJ individuals were more likely to have pathogenic mutations compared to NHW (OR &amp; 95% CI, 2.51, 1.22-5.17) and both AA and AJ individuals were more likely to have VUS (OR &amp; 95% CI, 1.55, 1.02-2.35 and 3.15, 95% CI 1.46-6.79) respectively. The table lists the most common pathogenic mutations seen in BRCA1 and BRCA2 by race and ethnicity. All mutations are unique and seen in more than one person unless indicated. Conclusions AA, Arab and AJ individuals were more likely to have VUS in BRCA1&amp;BRCA2 than NHW suggesting the importance of variant reclassification in understanding cancer risk in racial and ethnic minority groups. Understanding the prevalence of BRCA1/2 mutations in specific racial and ethnic groups can potentially lead to customization of genetic testing and possible classification of new founder mutations. The most common pathogenic mutations by race and ethnicityRace/EthnicityBRCA1 (n)BRCA2 (n)% of Total MutationsNHWp.Glu1756Pro (14)p.Ile605Asn (7)p.Cys61Glu (5)p.Arg645Glu (2)p.Ser1253Arg (4)p.Ala938Pro (2)BRCA1: 28/102=27.5%p.Lys894Thr (3)p.Glu2198Asn (2)BRCA2: 17/103=16.5%p.Asp825Glu (2)2)p.Gln1886Ter (2)p.Asn312Ile (2)AA5296del4 (2)p.Gly1013Glu (2)IVS16+6T&amp;gt;C (2)p.Lys2496Ter (2)BRCA1: 6/23=26.1%p.Thr276Ala (2)p.Lys936Asn (2)BRCA2: 8/32=25%p.Lys1872Asn (2)AJp.Glu23Val (1)p.Ser1982Arg (5)BRCA1: 1/1=100%BRCA2: 5/9=55.6%Arabp.Gln12X(1)p.Ile1859Lys (2)BRCA1: 1/5=20%BRCA2: 2/3 = 66.7%Hispanicp.Arg71Gly (1)p.Glu1308Ter (1)BRCA1: 1/1=100%BRCA2: 1/1=100% Citation Format: Michael Steven Simon, Nadline Abdallah, Hadeel Assad, Rachel Reagle, Nancie Petrucelli, Kristen Purrington. Racial and ethnic variation in BRCA1 and BRCA2 genetic test results among individuals referred for genetic counseling at a large urban comprehensive cancer center [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-08-15.

Abstract P6-08-22: Racial and ethnic variation in multi-gene panel genetic test results among individuals referred for genetic counseling at a large urban comprehensive cancer center

Abstract Background There are racial and ethnic differences in the prevalence and types of pathogenic mutations and variants of uncertain significance (VUS) in BRCA1 and BRCA2. Since the landmark May 13, 2013 Supreme Court Ruling invalidating the patent for BRCA1 and BRCA2 genetic testing, numerous gene panels have been utilized to identify individuals at high risk for hereditary disease due to mutations in other cancer predisposing genes. To better understand the prevalence of recurring pathogenic mutations and/or uncover novel mutations in specific racial and ethnic groups, we evaluated the mutational profile of individuals who had genetic counseling and testing at a large urban NCI designated Comprehensive Cancer Center. Methods Data was extracted from the Karmanos Cancer Institute (KCI) Cancer Genetic Counseling Service data base from May 13, 2013 through December, 31, 2018. The cohort consisted of 3,544 unrelated individuals evaluated for high-risk of hereditary disease and 1,868 who had panel testing at 6 sites across Michigan including Detroit. We estimated the prevalence of pathogenic mutations and VUS from multigene panels by race and ethnicity. Odds Ratios (OR) and 95% confidence intervals (CI) were calculated to compare the rate of pathogenic mutations and VUS in race and ethnic groups with non-Hispanic whites (NHW) indicated as the reference group. Results There were 1,868 (52.7%) individuals who had panel testing which included 67.4% NHW, 24.1% African American (AA), 2.2% Arab, 1.9% Ashkenazi Jewish (AJ), 1.0% Hispanic (H), and 3.4% other. There were 174 individuals with pathogenic mutations and 312 with VUS. Compared to NHW, AA individuals were less likely to have pathogenic mutations on multi-panel testing (OR, 95% CI, 0.20, 0.10-0.37) and more likely to have VUS (OR, 95% CI, 1.41, 1.07-1.85). There were no differences in pathogenic mutations or VUS for other race or ethnic groups. Within a common 18 gene panel (excluding BRCA1 and BRCA2), the five most common genes with a pathogenic mutation were ATM (23), CHEK2 (21), PALB2 (13) and MSH6 (11). The three most common genes and number of pathogenic mutations identified by race and ethnicity were NHW (ATM -21, CHEK2-21&amp;MSH6 -8), AA (MSH6-1, RAD51C-1&amp;TP53-1), and Arab (PALB2-2, RAD50-1 and BARD1-1). For AJ individuals there were 2 pathogenic mutations identified in the MSH6 gene. There were no pathogenic mutations seen in Hispanics. Conclusions Understanding the prevalence of mutations in multi-gene panels in specific racial and ethnic groups can lead to better identification of individuals at risk for hereditary cancer who can benefit from enhanced surveillance and risk reducing management. Citation Format: Michael Steven Simon, Nadine Abdallah, Hadeel Assad, Malini Surapaneni, Rachel Reagle, Nancie Petrucelli, Kristen Purrington. Racial and ethnic variation in multi-gene panel genetic test results among individuals referred for genetic counseling at a large urban comprehensive cancer center [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-08-22.

Abstract P6-08-16: Evaluation of a decision aid on BRCA1/2 genetic testing in Orthodox Jewish women

Abstract Background: Ashkenazi Jews have a 1 in 40 chance of carrying a BRCA1 or BRCA2 (BRCA1/2) pathogenic variant. Our prior research has shown that Orthodox Jewish women face unique social, cultural, and religious factors that may influence uptake of BRCA1/2 genetic testing. The aim of our study was to examine the impact of a web-based decision aid (DA) on BRCA1/2 genetic testing intention/uptake in Orthodox Jewish women. Methods: We conducted a pilot study among 50 Orthodox Jewish women in the New York/New Jersey area who were given access to the RealRisks DA and completed surveys at baseline prior to exposure to RealRisks and at 1 and 6 months after exposure to RealRisks. RealRisks is a patient-centered DA that includes family history intake, calculation of personalized breast cancer risk according to the BRCAPRO model, education about the pros and cons of genetic testing, and preference elicitation. The surveys collected information on participant demographics, health literacy, subjective numeracy, perceived breast cancer risk and BRCA1/2 mutation risk, breast cancer worry, stigma, hereditary breast and ovarian cancer (HBOC) genetic testing knowledge, autonomy, decision self-efficacy, decisional conflict, decision regret, and genetic testing intention/uptake. Descriptive statistics and paired t-tests and Chi-squared tests were conducted to assess changes in the study measures from baseline to follow-up. Results: Fifty women completed the baseline survey, 43 (86%) the 1-month survey, and 38 (74%) the 6-month survey. Mean age was 43.9 years (standard deviation [SD] 14.6); 94% had adequate health literacy and mean numeracy score was 4.25 (SD 0.83; range, 1-6). At baseline, 74% of women had adequate HBOC genetic testing knowledge and 52% thought it was likely that they carried an altered BRCA1/2 gene. Compared to baseline, there was a significant increase in HBOC genetic testing knowledge and decrease in decisional conflict at 1 month and 6 months. There was no significant change in decision self-efficacy, autonomy, stigma, or breast cancer worry after exposure to RealRisks at 1-month or 6-month follow-up. The percentage of women who intended to complete or already completed BRCA1/2 genetic testing decreased from 54% at baseline to 30% at 1 month. At 6 months, 21% reported they had completed or intended to complete BRCA1/2 genetic testing at that time. Conclusions: The RealRisks DA was effective at improving HBOC genetic testing knowledge and reducing decisional conflict about HBOC genetic testing; however, genetic testing intention decreased after exposure to the DA. An intervention that directly addresses the religious and cultural issues regarding genetic testing in the Orthodox Jewish community may improve BRCA1/2 genetic testing uptake and adoption of cancer prevention strategies in this population. Such an intervention will likely have to include religious, community, and medical leaders within the Orthodox Jewish community. Changes in study measures over 3 time pointsOutcome MeasuresBaseline Mean (SD)1 month Mean (SD)p-value compared to baseline6 months Mean (SD)p-value compared to baselineHBOC geneting testing knowledge [range, 0-11]6.60 (2.18)7.74 (1.94)&amp;lt;0.0017.24 (2.07)0.050Decision self-efficacy [range, 0-100]56.26 (15.63)55.39 (16.91)0.869Not Assessed (NA)Decisional conflict [range, 0-100]52.45 (28.43)33.93 (28.74)&amp;lt;0.00128.29 (27.64)&amp;lt;0.001Autonomy [range, 0-7]4.21 (1.43)4.36 (1.38)0.680NAStigma [range, 1-7]3.51 (1.15)3.25 (0.98)0.477NABreast cancer worry [range, 1-7]2.23 (1.03)2.27 (0.98)0.7672.26 (1.00)0.889HBOC genetic testing completion or intention to complete (%)54%30%0.02021%0.002 Citation Format: Meghna S Trivedi, Haley Manley, Haeseung Yi, Thomas Silverman, Wendy K Chung, Paul S Appelbaum, Rebecca Starck, Isaac Schechter, Rita Kukafka, Katherine D Crew. Evaluation of a decision aid on BRCA1/2 genetic testing in Orthodox Jewish women [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-08-16.

Smith-Lemli-Opitz syndrome: what is the actual risk for couples carriers of the DHCR7:c.964-1G>C variant?

The founder variant DHCR7:c.964-1G>C causing autosomal recessive Smith-Lemli-Opitz (SLOS) was introduced into the Israeli preconception carrier program for Ashkenazi Jews in 2017 because of the high carrier frequency in this population (2.3%). Other disease-causing variants in DHCR7 are relatively rare in Israeli population. Discrepancy between the carrier frequency and disease prevalence raises the question of the actual risks for affected offspring for couples detected by the screening program. We performed a literature review of all relevant publications regarding homozygous DHCR7:c.964-1G>C fetuses/patients. We also collected clinical data about couples identified in the national screening program, including reproductive history. Out of 32 homozygous fetuses, six died in utero, 11 pregnancies were terminated during second trimester, and 15 children were born. All died between first days of life till 3 months of age. Reproductive history of SLOS-at-risk couples showed that after correction for ascertainment bias, out of 61 pregnancies, there was an absence of affected fetuses/children and an excess of miscarriages even if assumed that all the homozygous fetuses were miscarried. Out of these, eight families were Israelis, they had a total of one sick child, 21 healthy children, and 21 miscarriages. Our observations support the previous knowledge that homozygosity for c.964-1G>C in DHCR7 leads to a severe phenotype or early miscarriage. An unexpected observation was the excess of early miscarriages. This phenomenon is unclear and awaits further studies.

Congenital factor XI deficiency caused by a novel F11 missense variant: a case report

Hereditary factor XI (FXI) deficiency is a mild bleeding disorder, rare in the general population but relatively common among Ashkenazi Jews. The human F11 gene comprises 15 exons, spanning over 23 kb of the long arm of chromosome 4 (4q35). Homozygotes or compound heterozygotes typically show severe FXI deficiency, whereas heterozygotes show partial or mild deficiency. However, the genotype-phenotype relationship is difficult to establish, even among individuals within the same family. We report on a female patient with a heterozygous variant in F11 and FXI deficiency (49 IU/dL), who suffers from menorrhagia since menarche and easy bruising. She experienced excessive bleeding during thyroidectomy and after a cesarean section. Her younger sister, who carries the same heterozygous variant in F11 and has mild FXI deficiency (47 IU/dL), has menorrhagia without other bleeding difficulties although she has undergone several surgeries. Their father, who carries the same missense variant, has not experienced any bleeding difficulties (but he has not undergone any surgeries either). The family study revealed that the A428C mutation was inherited from the father. This variant has not previously been described in the literature and is the first F11 variant described in the Croatian population. Our study showed that even when family members have the same germline F11 variant, they still may experience phenotypic variability, making disease prognosis more complex.

Allele frequencies of two dihydropyrimidine dehydrogenase (DPYD) risk variants, c.1905+1G&gt;A (*2A) and c.2846A&gt;T (D949V), in a direct-to-consumer genetic database.

2 Background: Pharmacogenetic (PGt) testing holds great potential for supporting clinical decision making and optimizing medication outcomes for cancer patients. Genetic variants in the DPYD gene are associated with reduced dihydropyrimidine dehydrogenase enzyme activity, and can cause severe fluoropyrimidine-related toxicity. However, the clinical uptake of PGt testing has been slow. Recent FDA authorization for a direct-to-consumer (DTC) PGt test will improve access to PGt testing. This study assessed the frequency of two DPYD variants, c.1905+1G &gt; A (*2A) and c.2846A &gt; T (D949V), in a generally unselected group of genotyped individuals who have used DTC genetic testing (23andMe, Inc. Sunnyvale, CA). Methods: Study participants were genotyped using Illumina genotyping arrays that included the DPYD c.1905+1G &gt; A and c.2846A &gt; T variants. Eligible subjects were 23andMe U.S. customers who were at least 18 years of age and consented to participate in research. IRB approval was obtained from Ethical &amp; Independent Review Services. Results: Out of approximately 6.4 million eligible participants included in this analysis, the overall allele frequencies of DPYD c.1905+1G &gt; A and c.2846A &gt; T were 0.42% and 0.47%, respectively. People of Ashkenazi Jewish, South Asian, and European descent had the highest frequencies (0.56%, 0.56%, and 0.47%, respectively) for the DPYD c.1905+1G &gt; A variant, and people of European and Hispanic/Latino descent had the highest frequencies (0.55% and 0.43%, respectively) for the DPYD c.2846A &gt; T variant. Conclusions: This is the first description of an unselected cohort of individuals with DPYD c.1905+1G &gt; A and c.2846A &gt; T variants identified through DTC genetic testing. Preemptive DTC PGt testing can help disseminate potentially clinically useful information to a large number of consumers.

Allele frequencies of two MUTYH variants, Y179C, and G396D, in a direct-to-consumer genetic database.

63 Background: MUTYH-associated polyposis (MAP) is an autosomal recessive condition that accounts for about 0.3-0.7% of all colorectal cancer (CRC) cases. The two most common variants among people of Northern European descent are MUTYH Y179C (rs34612342) and G396D (rs36053993), with a carrier frequency of 1-2%. However, understanding the frequency of these variants in other populations can better inform population health approaches for CRC screening and prevention. This study assessed the frequency of these two variants in a generally unselected group of genotyped individuals who have used direct-to-consumer (DTC) genetic testing (23andMe, Inc. Sunnyvale, CA). Methods: Study participants were genotyped on Illumina genotyping arrays, which included the Y179C and G396D variants. Eligible subjects were 23andMe customers who were at least 18 years of age and who consented to participate in research. IRB approval was obtained from Ethical and Independent Review Services. Results: Out of the 3,617,279 eligible participants included in this study, the overall allele frequencies of Y179C and G396D were 0.18% and 0.51%, respectively. People of European descent had the highest frequencies (0.22% and 0.59%), while people of Ashkenazi Jewish, East Asian, and South Asian descent had the lowest frequencies ( &lt; 0.015% for both variants). The allele frequencies for people of Hispanic/Latino descent were 0.15% and 0.51%. Conclusions: This is the first description of an unselected cohort of individuals with MUTYH Y179C and G396D variants identified through DTC genetic testing. While these two variants were most common among people of European descent, they were also observed at relatively high frequency among people of Hispanic/Latino descent. These results may help guide CRC screening and prevention strategies in different ethnicities.

БОЛЕЗНИ ОБМЕНА ЛИПИДОВ НА ПРИМЕРЕ GM2 ГАНГЛИОЗИДОЗА И ПРЕДРАСПОЛОЖЕННОСТЬ К НИМ ОПРЕДЕЛЕННЫХ ЭТНИЧЕСКИХ ГРУПП ЛЮДЕЙ

The relevance of the study is due to the fact that the scientific literature does not have sufficient data on the predisposition of certain ethnic groups of people to metabolic diseases on the example of GM2 gangliosidosis, so the purpose of the work is to clarify and analyze this predisposition of some ethnic groups of people to Tey — Sachs disease (GM2 gangliosidosis, amaurotic idiocy). The research materials and methods are a scientific and analytical review of modern publications on this topic. Research result: a review of the scientific literature has shown that the Jewish population of Eastern European origin (Ashkenazi Jews) has a higher incidence of TaySachs disease and other lipid accumulation diseases. Conclusions: the frequency of hereditary metabolic diseases ranges from 1: 2000 newborns to 1:1000000, and many of these diseases are characterized by differences in the frequency of occurrence in different ethnic groups and populations. In relation to GM2 gangliosidosis, it is shown that 1 in 27-30 Ashkenazi Jews in the United States is a recessive carrier of this disease. BTS affects 1 in 3,600 newborn Jews. One in 20 Jews have a hereditary predisposition to the disease.

Breast cancer-associated gene 1/2 mutations are not associated with risk of exudative age-related macular degeneration in Ashkenazi Jews

Breast cancer-associated gene 1/2 mutations are not associated with risk of exudative age-related macular degeneration in Ashkenazi Jews

Mode and Tense in Yiddish

The historical dialect area of Eastern Yiddish in Central and Eastern Europe is widely detached from the Germanic languages and mainly surrounded by Balto-Slavic (but also Romanic and Uralic) languages. The geographical location of Eastern Yiddish lead to looking at language contact with mostly Slavic languages. But this perspective simplifies the real language situation in two ways: on the one hand, the contact to Germanic languages (especially to German) was not completely broken off even in predominantly Slavic-speaking areas, for example via administrative languages or German-speaking settlements (language islands), and on the other hand, much more decisively, Yiddish has not suddenly ceased to be a Germanic language in the Slavic language area, so it still follows the internal rules of a continental West Germanic language. The following article examines the European Yiddish dialects, as they were collected in the 1960 s within the survey of the “Language and Culture Archive of Ashkenazic Jewry” (LCAAJ), in the mirror of a West Germanic dialect continuum. Looking at just one random area of morphosyntax as an example, we can see how analytical tendencies of Yiddish dialects fit into this continuum. A distinctive Germanic tendency is the decline of the synthetic subjunctive form in favour of analytical formations as a result of a structural remodelling of the TAM-system. Besides the analyses of the subjunctive additional evaluations of the analytic formations of the pluperfect and future are considered.

The Music Traditions of the Ashkenazi Jews and Radical Jewish Culture: A Brief Outline of the Definitions and Content of Jewish Music in the Past and Nowadays

The main purpose of this paper is to describe John Zorn’s approach to klezmer music and Jewish music tradition in general. The text has been divided into shorter sections. The first part of the article is dedicated to providing an overview of problems concerning the definition of Jewish music. The second part focuses on analysing klezmer motifs in John Zorn’s selected works and Jewish symbols present in the visual component of his recording projects. The last section contains a summary and conclusions.

The Ballad in Eastern European Jewish Folklore: Origins, Poetics, Music

Analysis of the poetics and music of Yiddish folk ballads reveals that the Ashkenazi Jews of Eastern Europe did not preserve German songs,widely popular among them up to the beginning of their gradual migration to the east, but instead developed a ballad repertoire of their own.The group of songs, designated as “medieval” by Sophia Magid, the author of a monumental study on the Yiddish ballad, includes both old ballads and those borrowed from the Germans towards the end of the 18th century and later. While the borrowed songs carried a similarity to the German originals as shown in their melodic contours, vocabulary, and plots, the old Yiddish ballads, though generally echoing both Slavic and Western European balladry, differed significantly. The article attempts to identify and characterize this older layer. It apparently first came into being in Central and Eastern Europe in the 15th 16th centuries and continued to develop until the new“urban” ballad emerged in the mid 1800s.The poetics and music of the Yiddish ballad reflect the genre’s hallmark – ballad-singing as a form of communication – which distinguished it from the Yiddish lyric song, performed “for oneself”. The ballad melodies lack melismatic embellishments and dramatic shifts; their tempo is usually moderate; some of them frequently feature the “Ionic minor” rhythmic pattern; many others resemble Klezmer dance music. These features reflect Yiddish ballad aesthetics: music is an ostensibly neutral frame for revealing a narrative that evokes emotions without referring to them directly.Two features of the international ballad canon – readiness to draw material from diverse sources, and a focus on the collective emotional response to key moments of everyday life–stimulated the formation of the indigenous Yiddish tradition. Its character also reflected the remoteness of Eastern Ashkenazi folk culture from rural Slavic folklore, and the lack of a permanent social function of balladsinging in the Ashkenazi tradition.