Ashkenazi Jewish Patients Research Articles

TMEM16F regulates pathologic α-synuclein secretion and spread in cellular and mouse models of Parkinson's disease.

One of the main hallmarks of Parkinson's disease (PD) pathology is the spread of the aggregate-prone protein α-synuclein (α-syn), which can be detected in the plasma and cerebrospinal fluid of patients as well as in the extracellular environment of neuronal cells. The secreted α-syn can exhibit "prion-like" behavior and transmission to naïve cells can promote conformational changes and pathology. The precise role of plasma membrane proteins in the pathologic process of α-syn is yet to be fully resolved. The TMEM16 family of lipid scramblases and ion channels has been recently associated with cancer and infectious diseases but is less known for its role in aging-related diseases. To elucidate the role of TMEM16F in α-syn spread, we transduced neurons derived from TMEM16F knockout mice with a reporter system that enables the distinction between donor and recipient neurons of pathologic α-synA53T. We found that the spread of α-synA53T was reduced in neurons derived from TMEM16F-knockout mice. These findings were recapitulated invivo in a mouse model of PD, where attenuated α-synA53T spread was observed when TMEM16F was ablated. Moreover, we identified a single nucleotide polymorphism in TMEM16F of Ashkenazi Jewish PD patients resulting in a missense Ala703Ser mutation with enhanced lipid scramblase activity. This mutation is associated with altered regulation of α-synA53T extracellular secretion in cellular models of PD. Our study highlights TMEM16F as a novel regulator of α-syn spread and as a potential therapeutic target in synucleinopathies.

A Leaky Deep Intronic Splice Variant in CLRN1 Is Associated with Non-Syndromic Retinitis Pigmentosa

Background: Inherited retinal diseases (IRDs) are clinically complex and genetically heterogeneous visual impairment disorders with varying penetrance and severity. Disease-causing variants in at least 289 nuclear and mitochondrial genes have been implicated in their pathogenesis. Methods: Whole exome sequencing results were analyzed using established pipelines and the results were further confirmed by Sanger sequencing and minigene splicing assay. Results: Exome sequencing in a 51-year-old Ashkenazi Jewish patient with non-syndromic retinitis pigmentosa (RP) identified compound heterozygous variants in the CLRN1 gene: a known pathogenic missense [p.(N48K)] and a novel deep intronic variant c.254-643G>T. A minigene splicing assay that was performed aiming to study the effect of the c.254-643G>T variant on CLRN1 pre-mRNA splicing revealed the inclusion of a pseudo-exon that was also reported to be included in the transcript due to an adjacent variant, c.254-649T>G. However, unlike the reported c.254-649T>G variant, c.254-643G>T showed aberrant splicing in a leaky manner, implying that the identified variant is not totally penetrant. Conclusion: We report on a novel deep intronic variant in CLRN1 causing non-syndromic RP. The non-syndromic phenotype observed in this index case may be attributed to the leaky nature of this variant, which is causing some normal transcripts to be produced.

Abstract PO5-08-11: Genetic Landscape of Early Breast Cancer in an Ashkenazi Jewish Cohort

Abstract Background: The Ashkenazi Jewish (AJ) population exhibits a distinctive mutation profile in BRCA1 and BRCA2 (BRCA1/2), characterized by 3 common founder mutations: BRCA1 185delAG, BRCA1 5382insC, and BRCA2 6174delT. These 3 mutations are associated with 10% of invasive breast cancer (BC) cases among AJ women. However, the frequency of non-founder pathogenic variants in BRCA1/2 and other BC-related genes in AJ women with BC remains unclear. Methods: This retrospective study included AJ patients diagnosed with stage I-II human epidermal receptor growth factor 2 negative BC between 2004-2022 at the Weill Cornell Breast Center. We collected clinicopathological characteristics and genetic information to determine the frequency of predisposing mutations in BC and non-BC related genes in AJ patients with early BC. We also analyzed the clinicopathological characteristics and outcomes of patients with and without germline mutations in these genes. Results: The study included 232 self-identified AJ patients, with 98% being females. The median age at BC diagnosis was 62 years (IQR: 50-70). Stage I and II cancers accounted for 68% and 32% of cases, respectively. Hormone receptor positivity (HR+) was observed in 71% of patients, while 29% had triple-negative tumors. Genetic testing was performed on 88% (n=203) of the patients, while 5% of patients declined to undergo genetic testing. Among the tested patients, 12% (n=25/203) had pathogenic variants in BRCA1 or BRCA2, with 44% and 16% of these corresponding to the BRCA1 and BRCA2 founder mutations, respectively. Testing beyond BRCA1/2 genes was conducted on 154 patients, and only 6% (n=9/154) were found to have pathogenic variants in CHEK2, while no mutations were detected in other prevalent BC-related genes, including PALB2 and ATM. Fourteen-percent of patients had pathogenic mutations in other genes including APC, CFTR, FH, DIS3L2, FANCC, MUTYH, NF1 and VHL. The frequency of pathogenic BRCA1/2 variants was inversely proportional to the age at BC diagnosis: 50% (n=8/16), 21% (n=8/39), 15% (n=6/40), and 3% (n=3/108) of patients diagnosed at age < 40, 40-49, 50-59, and >60 years, respectively, had a pathogenic variant in either BRCA1 or BRCA2. The frequency of founder mutations varied according to age at diagnosis: 63%, 75%, 17%, and 100% for patients aged < 40, 40-49, 50-59, and >60 years, respectively. Patients with BRCA1/2 mutations exhibited higher-risk clinicopathological features compared to those without mutations, including a higher proportion of high histological grade (88%), and triple-negative tumors (76%). Mastectomy was the primary surgical treatment for 56% and 23% of patients with and without BRCA1/2 mutations, respectively. No difference in disease-free survival was found between patients with and without BRCA1/2 mutations with a median follow up of 3 years (IQR: 1-4). Conclusions: In our cohort, 17% of AJ patients with early BC carried a pathogenic variant in a BC-related gene, with BRCA1/2 being the most commonly affected genes. The proportion of pathogenic variants in BRCA1/2 showed an inverse correlation with the age at BC diagnosis, reaching up to 50% in patients diagnosed under the age of 40. These findings contrast with the lower prevalence of pathogenic variants in BRCA1/2 (38%) reported in the existing literature for this age group. Additionally, 8% of patients had pathogenic variants in other tested cancer genes carrying a genetic predisposition to colorectal cancer (CRC). These findings contribute to our understanding of the genetic landscape of early BC in the AJ population and emphasize the importance of comprehensive genetic testing, particularly among young patients. These results also suggest the need for earlier and more frequent CRC screening in a population of BC patients that may not be adhering to recommended guidelines. Furthermore, our study provides insight into how this genetic landscape may vary when analyzing late-stage BC in women of AJ heritage. Citation Format: Laura Munoz Arcos, Eleonora Nicolò, Maira Pires, Letizia Pontolillo, Leticia Varella, Tessa Cigler, Eleni Andreopolu, Anne Moore, Ashley Schreier, Carlos Munoz-Zuluaga, Lisa Newman, Georgia Syrnioti, Massimo Cristofanilli. Genetic Landscape of Early Breast Cancer in an Ashkenazi Jewish Cohort [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-08-11.

Genetic diagnosis and detection rates using C9orf72 repeat expansion and a multi-gene panel in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder. It is mostly sporadic, with the C9orf72 repeat expansion being the most common genetic cause. While the prevalence of C9orf72-ALS in patients from different populations has been studied, data regarding the yield of C9orf72 compared to an ALS gene panel testing is limited.We aimed to explore the application of C9orf72 versus a gene panel in the general Israeli population. A total of 140 ALS patients attended our Neurogenetics Clinic throughout 2018-2023. Disease onset was between ages 60 and 69years for most patients (34%); however, a quarter had an early-onset disease (< 50years). Overall, 119 patients (85%) were genetically evaluated: 116 (97%) were tested for the C9orf72 repeat expansion and 64 (54%) underwent gene panel testing. The C9orf72 repeat expansion had a prevalence of 21% among Ashkenazi Jewish patients compared to 5.7% in non-Ashkenazi patients, while the gene panel had a higher yield in non-Ashkenazi patients with 14% disease-causing variants compared to 5.7% in Ashkenazi Jews. Among early-onset ALS patients, panel testing was positive in 12% compared to 2.9% for C9orf72.We suggest a testing strategy for the Israeli ALS patients: C9orf72 should be the first-tier test in Ashkenazi Jewish patients, while a gene panel should be considered as the first step in non-Ashkenazi and early-onset patients. Tiered testing has important implications for patient management, including prognosis, ongoing clinical trials, and prevention in future generations. Similar studies should be implemented worldwide to uncover the diverse ALS genetic architecture and facilitate tailored care.

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.

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.

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.

Decreased delta-band event-related power in dementia with Lewy bodies with a mutation in the glucocerebrosidase gene

ObjectiveTo compare event-related oscillations in patients with dementia with Lewy bodies (DLB) who are carriers and non-carriers of glucocerebrosidase (GBA) mutations. MethodsEEG was recorded during a visual oddball task in eight Ashkenazi Jewish DLB patients with the N370S mutation in theGBAgene (GBA-DLB) and eleven DLB non-carriers. The time–frequency power and inter-trial phase clustering were calculated from the Morlet wavelet convolution for the midline electrodes. ResultsTask performance and cognitive assessments were comparable between groups. While the within-non-GBA-DLB group analysis revealed delta-band power synchronization relative to the baseline (p = 0.01, Cohen's d = 1.0), the within-GBA-DLB-group analysis detected no event-related changes in power. Both groups showed an increase relative to the baseline in the delta and theta bands inter-trial phase clustering (all p < 0.03, d > 1.3). The between-group analysis revealed that event-related power – but not clustering – was lower in GBA-DLB compared to non-carriers in the delta band at Fz and Cz (p = 0.04, d = -0.9). ConclusionsGBA-DLB patients showed decreased delta-band power compared to non-carriers despite the similar cognitive performance, whereas inter-trial phase clustering was comparable in both groups. SignificancePreserved inter-trial phase clustering possibly compensates for the impaired power by eliciting the appropriate functional configuration needed for stimulus processing and task performance.

Differences in MS clinical and epidemiological characteristics between Ashkenazi and non-Ashkenazi Jewish patients in Israel: a retrospective single center study

The prevalence and severity of Multiple Sclerosis (MS) varies across different ethnicities, with a tendency to a more severe phenotype in non-Caucasian populations. Our objective was to evaluate the differences in disease phenotype between Ashkenazi Jewish and Non-Ashkenazi Jewish patients in Israel. We conducted a single center retrospective cohort study in which subjects were assigned to Ashkenazi or Non-Ashkenazi groups according to self-reported ancestry and disease severity was assessed using the expanded disability status (EDSS), MS severity score (MSSS), progression index (PI) and MRI metrics. 330 Ashkenazi Jewish (AJ) and 207 Non-Ashkenazi Jewish patients (Non-AJ) were included. Non-AJ had a younger age of disease onset (32.7 years vs. 35.7 years, p = 0.05), with a lower proportion of females (62.3% vs. 73.3%, p = 0.01). These differences were maintained within the subgroup of Israeli native patients. Ethnicity was a significant predictor of MSSS (β = 0.601, p = 0.003), with a higher estimate than that of other epidemiological factors. To conclude, Non-AJ patients had an earlier age of onset and a more disabling disease as well as having a more balanced female to male ratio compared to AJ patients. These findings demonstrate variability of disease phenotype within Caucasian patient's dependent on their ethnicity despite equivalent access to healthcare services.

Vision and sensorimotor defects associated with loss of Vps11 function in a zebrafish model of genetic leukoencephalopathy

Genetic Leukoencephalopathies (gLEs) are heritable white matter disorders that cause progressive neurological abnormalities. A founder mutation in the human endolysosomal trafficking protein VPS11 has been identified in Ashkenazi Jewish patients manifesting classic gLE symptoms of hypomyelination, developmental delay, motor and systemic deficits. In this study, we characterized the visual and sensorimotor function of two zebrafish vps11 mutant lines: the previously reported vps11(plt), and a new vps11(−/−) null mutant line, using behavioral analysis to track larval motor responses to visual and acoustic stimuli. We found that mutant larvae from both vps11(plt) and vps11(−/−) lines were able to visually distinguish light and dark, but showed a progressive loss of a normal sensorimotor response to visual stimuli from 5 days post fertilization (dpf) to 7dpf. Additionally, optokinetic response analysis performed at 5dpf indicated that the mutants were significantly visually impaired. Both mutant lines also displayed a progressively lower sensorimotor response to a singular acoustic stimulus from 5-7dpf. Next, we tested the habituation response of the mutant lines to series of acoustic taps. We found both mutant lines habituated faster than their siblings, and that vps11(plt) mutants habituated faster than the vps11(−/−) mutants. Together, these data suggest that loss of Vps11 function results in progressive visual and sensorimotor abnormalities in the zebrafish vps11(plt) and vps11(−/−) mutant lines. This is the first study to characterize behavioral deficits in a vertebrate model of Vps11-dependent gLE. The mutants and behavioral assays described here could be a valuable model system in which to test potential pharmacological interventions for gLE.

Identification of Novel and Recurrent Variants in MYO15A in Ashkenazi Jewish Patients With Autosomal Recessive Nonsyndromic Hearing Loss.

Hearing loss is a genetically and phenotypically heterogeneous disorder. The purpose of this study was to determine the genetic cause underlying hearing loss in four Ashkenazi Jewish families. We screened probands from each family using a combination of targeted mutation screening and exome sequencing to identifiy the genetic cause of hearing loss in each family. We identified four variants in MYO15A, two novel variants never previously linked to deafness (c.7212+5G>A and p.Leu2532ArgfsTer37) and two recurrent variants (p.Tyr2684His and p.Gly3287Gly). One family showed locus heterogeneity, segregrating two genetic forms of hearing loss. Mini-gene assays revealed the c.7212+5G>A variant results in abnormal splicing and is most likely a null allele. We show that families segregrating the p.Gly3287Gly variant show both inter and intra-familial phenotypic differences. These results add to the list of MYO15A deafness-causing variants, further confirm the pathogenicity of the p.Gly3287Gly variant and shed further light on the genetic etiology of hearing loss in the Ashkenazi Jewish population.

Differences in MS clinical and epidemiological characteristics in Ashkenazi and Non Ashkenazi Jewish patients in Israel – A retrospective single center study

The prevalence and severity of Multiple Sclerosis (MS) are diverse across different ethnicities, with a tendency to a more severe phenotype in Non-Caucasian populations.

The Effect of GBA Mutations and APOE Polymorphisms on Dementia with Lewy Bodies in Ashkenazi Jews

Background:Glucocerebrosidase (GBA) gene mutations and APOE polymorphisms are common in dementia with Lewy bodies (DLB), however their clinical impact is only partially elucidated.Objective:To explore the clinical impact of mutations in the GBA gene and APOE polymorphisms separately and in combination, in a cohort of Ashkenazi Jewish (AJ) patients with DLB.Methods:One hundred consecutively recruited AJ patients with clinically diagnosed DLB underwent genotyping for GBA mutations and APOE polymorphisms, and performed cognitive and motor clinical assessments.Results:Thirty-two (32%) patients with DLB were carriers of GBA mutations and 33 (33%) carried an APOE ɛ4 allele. GBA mutation carriers had a younger age of onset (mean [SD] age, 67.2 years [8.9] versus 71.97 [5.91]; p = 0.03), poorer cognition as assessed by the Mini-Mental State Examination (21.41 [6.9] versus 23.97 [5.18]; p < 0.005), and more severe parkinsonism as assessed with the Unified Parkinson’s Disease Rating Scale motor part III (34.41 [13.49] versus 28.38 [11.21]; p = 0.01) compared to non-carriers. There were statistically significant interactions between the two genetic factors, so that patients who carried both a mild GBA mutation and the APOE ɛ4 allele (n = 9) had more severe cognitive (p = 0.048) and motor dysfunction (p = 0.037).Conclusion:We found a high frequency of both GBA mutations and the APOE ɛ4 allele among AJ patients with DLB, both of which have distinct effects on the clinical disease phenotype, separately and in combination.

Racial and Ethnic Disparities in Genetic Testing at a Hereditary Breast and Ovarian Cancer Center.

Prior studies suggest that referral to genetic counseling and completion of genetic testing vary by race/ethnicity; however, the data are limited. We sought to evaluate patterns of genetic testing and clinical outcomes across race/ethnicity at a hereditary breast and ovarian cancer center. The medical records for all patients undergoing genetic assessment at a hereditary breast and ovarian cancer center were reviewed and stratified by self-reported race/ethnicity (non-Hispanic White, Hispanic, non-Hispanic Black, and Asian). A total of 1666 patients met inclusion criteria (non-Hispanic Whites, 1367; Hispanics, 85, non-Hispanic Blacks, 101; Asians, 113). Demographics, patient characteristics, and referral patterns for patients who underwent genetic testing were analyzed using Kruskal-Wallis tests, chi-square test, or Fisher's exact tests, stratifying by self-reported race/ethnicity. Pathogenic mutations and variants of unknown significance (VUS) were reviewed. Outcomes of patients with genetic mutations and personal history of breast and/or gynecologic malignancies were compared. Non-Hispanic Whites were more likely to be referred due to family cancer history compared to all other ethnicities while Non-Hispanic Blacks, Hispanics, and Asians were more likely to be referred due to personal history of cancer (p < 0.001). Non-Hispanic Blacks and Hispanics were more likely to have advanced-stage cancer at the time of genetic testing (p < 0.02). Rates of mutations did not differ by race/ethnicity when Ashkenazi Jewish patients were excluded (p = 0.08). Among patients found to have a BRCA1/2 mutation, Non-Hispanic Whites were more likely to undergo cancer screening and risk-reducing surgery compared with all other ethnicities (p = 0.04). Minority patients were more likely to utilize genetic services following a cancer diagnosis and less likely due to family cancer history, suggesting a missed opportunity for mutation detection and cancer prevention in this population. Efforts to eradicate racial/ethnic disparities in early access to genetic testing and guided cancer prevention strategies are essential.

An RTEL1 Mutation Links to Infantile-Onset Ulcerative Colitis and Severe Immunodeficiency.

More than 50 different monogenic disorders causing inflammatory bowel disease (IBD) have been identified. Our goal was to characterize the clinical phenotype, genetic workup, and immunologic alterations in an Ashkenazi Jewish patient that presented during infancy with ulcerative colitis and unique clinical manifestations. Immune workup and whole-exome sequencing were performed, along with Sanger sequencing for confirmation. Next-generation sequencing of the TCRB and IgH was conducted for immune repertoire analysis. Telomere length was evaluated by in-gel hybridization assay. Mass cytometry was performed on patient's peripheral blood mononuclear cells, and compared with control subjects and patients with UC. The patient presented in infancy with failure to thrive and dysmorphic features, consistent with a diagnosis of dyskeratosis congenita and Hoyeraal-Hreidarsson syndrome. Severe ulcerativecolitis manifested in the first year of life and proceeded to the development of a primary immunodeficiency, presenting as Pneumocystis jiroveci pneumonia and hypogammaglobulinemia. Genetic studies identified a deleterious homozygous C.3791G>A missense mutation in the helicase regulator of telomere elongation 1 (RTEL1), leading to short telomeres in the index patient. Immune repertoire studies showed polyclonal T and B cell receptor distribution, while mass cytometry analysis demonstrated marked immunological alterations, including a predominance of naïve T cells, paucity of B cells, and a decrease in various innate immune subsets. RTEL1 mutations are associated with significant alterations in immune landscape and can manifest with infantile-onset IBD. A high index of suspicion is required in Ashkenazi Jewish families where the carriage rate of the C.3791G>A variant is high.

Abstract C043: Ethnic disparities among pancreatic cancer patients undergoing germline testing

Abstract Background: New NCCN guidelines recommend germline testing for all patients with confirmed pancreatic cancer (PC) regardless of stage, family history, or ethnicity. PC is linked to inherited cancer susceptibility syndromes, with approximately 10% of cases occurring in the presence of family history. Per SEER statistics, African-Americans (AA) have the highest incidence rate (67% higher) of PC of all ethnic groups and the worse prognosis. Current data links this risk to social and access issues rather than biology. We aim to determine whether the prevalence of germline mutations associated with increased PC susceptibility varies by ethnicity. Methods: We retrospectively examined publicly-available, de-identified, germline and clinical data of patients with a diagnosis of pancreatic cancer (PC) referred to Color Genomics by a healthcare provider for testing of 30 genes associated with hereditary cancer risk. Clinical data included age at diagnosis, sex, self-reported ethnicity, family history of cancer, and personal history of cancer. Ashkenazi Jewish (AJ) ancestry was classified as an ethnic group. Germline genetic variants were classified as pathogenic (P), likely pathogenic (LP), variant of uncertain significance (VUS), likely benign, or benign. Prevalence of P/LP and VUS variants was compared among subgroups classified by age at diagnosis (£ 65 or &amp;gt; 65 years-old), sex, self-reported ethnicity, family history of PC, and personal history of other cancer using chi-square tests. Results: We identified 167 patients with PC of any stage who underwent germline testing. Among these, 47.9% were female and 52.1% male. Ethnic composition was 73.1% Caucasian, 8.4% AJ, 3.6% Hispanic, 3.6% AA, 4.2% Asian, and 7.2% of other or unknown ethnicity. Twenty-four (14.4%) patients carried a P/LP variant, and 45 (26.9%) patients carried a VUS. The most prevalent P/LP variants were BRCA2 (29.6%), ATM (22.2%), and MUTYH (14.8%). APC (18.4%), BRCA2 (14.3%), and ATM (12.2%) were the most prevalent VUS variants. AJ patients had an increased prevalence of P/LP BRCA2 variants (83%, n=5). Ethnicity was significantly associated with risk of carrying any P/LP variant (p = 0.049) but not with a VUS; this association was lost when excluding those of AJ ancestry. Age, sex, family history of PC, and personal history of a second cancer were not associated with risk of carrying any P/LP or VUS variants. Conclusions: Germline mutations are prevalent among PC patients and highest among those of AJ ancestry. Although the prevalence of germline variants is not associated with other ethnic groups, our study highlights the underrepresentation of minorities in germline testing databases, particularly AA. The prevalence of germline variants in minority ethnic groups with PC remains an understudied area and is an example of how barriers to access can limit our understanding of diseases. Further studies are needed to address this critical unmet need. Citation Format: Ana I Velazquez, Carolina Bernabe Ramirez, Daniel H Kwon, Ryan Leibrandt, Narjust Duma. Ethnic disparities among pancreatic cancer patients undergoing germline testing [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr C043.

Cover

The cover image is based on the Original Article Lessons learned from expanded reproductive carrier screening in self-reported Ashkenazi, Sephardi, and Mizrahi Jewish patients by Gidon Akler et al., https://doi.org/10.1002/mgg3.1053.

Differences in performance on English and Hebrew versions of the MoCA in Parkinson's patients

IntroductionThe Montreal Cognitive Assessment (MoCA), an instrument widely used for cognitive screening in Parkinson's disease (PD), is validated in Hebrew and English. However, it remains unknown whether the scores are comparable. MethodsThe MoCA was analyzed in 483 Ashkenazi Jewish PD patients in Tel-Aviv and New York who had MoCA ≥21. Each section of the MoCA was compared between English and Hebrew. Linear regression models were used to test the association between MoCA performance and language. ResultsTotal MoCA scores were lower in Hebrew than in English (25.4 versus 26.1; P = 0.007), even after adjustment for age, sex, PD duration, genotype, levodopa equivalent dose, the Unified Parkinson's Disease Rating Scale (UPDRS-III), and Geriatric Depression Scale score in a linear model (P < 0.001). However, when language sections were removed from the total, scores were similar between the languages (Hebrew 23.7 versus English 23.4, P = 0.111). ConclusionThe language section of the MoCA may be more difficult in Hebrew. The comparability of MoCA in different languages requires further evaluation.

Lessons learned from expanded reproductive carrier screening in self-reported Ashkenazi, Sephardi, and Mizrahi Jewish patients.

BackgroundNext‐generation sequencing (NGS)‐based panels have gained traction as a strategy for reproductive carrier screening. Their value for screening Ashkenazi Jewish (AJ) individuals, who have benefited greatly from population‐wide targeted testing, as well as Sephardi/Mizrahi Jewish (SMJ) individuals (an underserved population), has not been fully explored.MethodsThe clinical utilization by 6,805 self‐reported Jewish individuals of an expanded NGS panel, along with several ancillary assays, was assessed retrospectively. Data were extracted for a subset of 96 diseases that, during the panel design phase, were classified as being AJ‐, SMJ‐, or pan‐Jewish/pan‐ethnic‐relevant.Results64.6% of individuals were identified as carriers of one or more of these 96 diseases. Over 80% of the reported variants would have been missed by following recommended AJ screening guidelines. 10.7% of variants reported for AJs were in “SMJ‐relevant genes,” and 31.2% reported for SMJs were in “AJ‐relevant genes.” Roughly 2.5% of individuals carried a novel, likely pathogenic variant. One in 16 linked cohort couples was identified as a carrier couple for at least one of these 96 diseases.ConclusionFor maximal carrier identification, this study supports using expanded NGS panels for individuals of all Jewish backgrounds. This approach can better empower at‐risk couples for reproductive decision making.

Screening of the glucocerebrosidase (GBA) gene in South Africans of African ancestry with Parkinson's disease

Sequence variants in glucocerebrosidase (GBA) are a major genetic risk factor for Parkinson's disease (PD), and display ethnic-dependent frequencies, for example, variants such as p.N370S and 84insGG are common in Ashkenazi Jewish patients. Notably, there are limited studies on black patients from the African continent; hence, we conducted a study on 30 South African black PD patients. All 11 exons of GBA were screened using a nested PCR approach to avoid pseudogene contamination. We identified previously described Gaucher's disease–associated variants, p.R120W in one patient [age at onset (AAO) of 35 years], and p.R131L in another patient (AAO 30 years) and in her affected sibling (AAO 45 years). In addition, we found 3 previously identified [p.K(-27)R, p.T36del, and p.Q497*] and 2 novel (p.F216L and p.G478R) variants. Screening of ethnic-matched controls for the novel variants revealed that the allele frequency of p.F216L was 9.9%, whereas p.G478R was not found in the controls. Studies such as these are important and necessary to reveal the genetic architecture underlying PD in the understudied patients of African ancestry.