Jewish genes

PURPOSE: Several recurring pathogenic variants (PVs) in BRCA1/BRCA2 and additional cancer susceptibility genes are described in the ethnically diverse Israeli population. Since 2019, testing for these recurring PVs is reimbursed unselectively for all patients with breast cancer (BC) in Israel. The aim was to evaluate the yield of genotyping for these PVs in non-Ashkenazi Jewish (AJ) patients with BC diagnosed ≥age 50 years. METHODS: Clinical and genotyping data of all patients with BC undergoing oncogenetic counseling at the Oncology Institute at Sheba Medical Center from June 2017 to December 2023 were reviewed...

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...

Pathogenic germline variants (PGVs) may be under-detected as causative etiologies in patients with non-small cell lung cancer (NSCLC). The prevalence of PGVs has been reported between 1 and 15% of patients, depending on the patient population. The rate within Hispanic/Latinx populations remains unknown. We retrospectively analyzed the genomic results (Guardant360, Redwood City, CA, USA) of 878 patients with advanced or metastatic NSCLC at five centers in South Florida, USA, from 2019 to 2022 to analyze the rate of incidental PGVs (iPGVs) identified via circulating cell-free tumor DNA (ctDNA)...

The global obesity pandemic presents a pressing health challenge, with an increasing prevalence shaped by an intricate interplay of genetics and environment. Brain-derived neurotrophic factor (BDNF) plays a pivotal role in regulating feeding behavior and energy expenditure. BDNF single nucleotide polymorphisms have been linked to obesity risk. We hypothesized that BDNF rs925946 is positively associated with obesity susceptibility in the Israeli population. We aimed to study BDNF rs925946 association with obesity susceptibility and its interaction with environmental factors, including eating habits, sugar-sweetened beverages, and physical activity...

Advanced sequencing technologies enable rapid detection of sequence variants, aiming to uncover the molecular foundations of human genetic disorders. The challenge lies in interpreting the influence of new exome variants that lead to diverse phenotypes. Our study introduces a detailed, multi-tiered method for assessing the impact of novel variants, particularly focusing on the zinc finger protein 1 (ZPR1) gene. Herein, we employed a combination of variant effect predictors, protein stability analyses, and the American College of Medical Genetics and Association of Molecular Pathology (ACMG/AMP) guidelines...

American College of Medical Genetics and Genomics (ACMG) recommends offering Tier 3 carrier screening to pregnant patients and those planning a pregnancy for conditions with a carrier frequency of ≥1/200 (96 genes for autosomal recessive [AR] conditions). Certain AR conditions referred to as Finnish disease heritage (FINDIS) have a higher prevalence in Finland than elsewhere. Data from gnomAD v2.1 were extracted to assess carrier frequencies for ACMG-recommended AR and FINDIS AR and X-linked genes in Finnish, non-Finnish European, and Ashkenazi Jewish populations...

BACKGROUND: Adult Polyglucosan Body Disease (APBD) is an ultra-rare, genetic neurodegenerative disorder caused by autosomal recessive mutations in the glycogen branching enzyme gene. Knowledge of the demographic and clinical characteristics of APBD patients and the natural history of the disease is lacking. We report here initial results from a patient-reported registry of APBD patients. OBJECTIVES: (1) Maximize the quality of the APBD Registry survey data; (2) provide an initial report on APBD disease progression and natural history using these data; and (3) specify next steps in the process for testing potential new therapies...

The lysine methyltransferase 2B (KMT2B) gene product is important for epigenetic modifications associated with active gene transcription in normal development and in maintaining proper neural function. Pathogenic variants in KMT2B have been associated with childhood-onset Dystonia-28 and Intellectual developmental disorder, autosomal dominant 68 (MRD 68) for cases of neurodevelopmental impairment without dystonia (DYT28; OMIM 617284 and MRD68; OMIM 619934, respectively). Since its first description in 2016, approximately one hundred KMT2B genetic variants have been reported with heterogeneous phenotypes, including atypical patterns of dystonia evolution and non-dystonic neurodevelopmental phenotypes...

INTRODUCTION: Although the prevalence of a pathogenic variant in the BRCA1 and BRCA2 genes is about 1:400 (0.25%) in the general population, the prevalence is as high as 1:40 (2.5%) among the Ashkenazi Jewish population. Despite cost-effective preventive measures for mutation carriers, Orthodox Jews constitute a cultural and religious group that requires different approaches to BRCA1 and BRCA2 genetic testing relative to other groups. This study analyzed a dialogue of key stakeholders and community members to explore factors that influence decision-making about BRCA1 and BRCA2 genetic testing in the New York Orthodox Jewish community...

Genetic neuromuscular diseases are clinically and genetically heterogeneous genetic disorders that primarily affect the peripheral nerves, muscles, and neuromuscular junctions. This study aimed to identify pathogenic variants, calculate carrier frequency, and predict the genetic prevalence of autosomal recessive neuromuscular diseases (AR-NMDs). We selected 268 AR-NMD genes and analyzed their genetic variants sourced from the gnomAD database. After identifying the pathogenic variants using an algorithm, we calculated the carrier frequency and predicted the genetic prevalence of AR-NMDs...

Tay-Sachs disease (TSD) is a rare, fatal neurodegenerative disorder characterized by the deficiency of the enzyme hexosaminidase-A (Hex A), which results in the accumulation of monosialoganglioside2 (GM2) ganglioside within nerve cells, predominantly affecting individuals of Ashkenazi Jewish descent. We report a remarkable case of a three-year-old South Asian male with infantile GM2 gangliosidosis, compounded by bronchopneumonia, a rarely documented complication in Tay-Sachs patients. The patient presented with recurrent seizures, fever, cough, and developmental delay...

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Parkinson's disease (PD) is a neurodegenerative disorder with significant genetic influence. The LRRK2 gene is a major genetic contributor, particularly the Gly2019Ser mutation. This focused review investigates the global distribution of LRRK2 mutations, with emphasis on Gly2019Ser and other pathogenic variants. Prevalence rates of Gly2019Ser are highest in North Africa and the Ashkenazi-Jewish population, indicating a potential common ancestor and founder effect. Other LRRK2 mutations, including Asn1437His, Arg1441Gly/Cys/His, Tyr1699Cys and Ile2020Thr, exhibit varying global prevalences...

Introduction : MAPT locus is associated with Parkinson's disease (PD), which is located within a large inversion region of high linkage disequilibrium (LD). We aimed to determine whether the H2-haplotype protective effect and its effect size depends on the GBA1 or LRRK2 risk allele carrier status, and to further characterize genetic alterations that might contribute to its effect. Methods : LD analysis was performed using whole-genome sequencing data of 202 unrelated Ashkenazi Jewish (AJ) PDs. A haplotype-divergent variant was genotyped in a cohort of 1200 consecutively recruited AJ-PDs...

OBJECTIVE: Accumulative evidence indicates a critical role of mitochondrial function in autism spectrum disorders (ASD), implying that ASD risk may be linked to mitochondrial dysfunction due to DNA (mtDNA) variations. Although a few studies have explored the association between mtDNA variations and ASD, the role of mtDNA in ASD is still unclear. Here, we aimed to investigate whether mitochondrial DNA haplogroups are associated with the risk of ASD. METHOD: Two European cohorts and an Ashkenazi Jewish (AJ) cohort were analyzed, including 2,062 ASD patients in comparison with 4,632 healthy controls...

INTRODUCTION: Glutamate is a representative taste molecule with an umami flavor and is a major nutrient found abundantly in nature. Furthermore, it plays a significant role in the human body as a key metabolic intermediate and neurotransmitter. Therefore, the divergence of glutamate functions among populations during their evolution is of particular interest with a hypothesis that the genetic variation can lead to understanding divergence in taste perception. To elucidate variation in glutamate applications and to deepen our understanding of taste perception, we examined the nucleotide diversity of genes associated with glutamate sensing and metabolism among human populations...

Background: The LIPA gene encodes for lysosomal acid lipase (LAL), which catalyzes the hydrolysis of cholesterol esters and triglycerides. Variations in the LIPA gene impair LAL activity, predisposing patients to a rare metabolic disorder called LAL deficiency (LAL-D). The lack of functioning LAL promotes lipid accumulation and subsequent dyslipidemia, which can increase the likelihood of complications in both infants and adults. Although the worldwide prevalence is 1:500,000 births, the frequency in Mizrahi Jewish populations is projected to be as high as 1 in every 4200 births (Valles-Ayoub et al...

BACKGROUND: Alport syndrome is a hereditary disorder caused by pathogenic variants in the COL4A gene, which can be inherited in an autosomal recessive, dominant, or X-linked pattern. In the Bukharian Jewish population, no founder pathogenic variant has been reported in COL4A4. METHODS: The cohort included 38 patients from 22 Bukharian Jewish families with suspected Alport syndrome who were referred the nephrogenetics clinic between 2012 and 2022. The study collected demographic, clinical, and genetic data from electronic medical records, which were used to evaluate the molecular basis of the disease using Sanger sequencing, and next-generation sequencing...

Hereditary breast cancer is most commonly attributed to germline BRCA1 and BRCA2 gene variants. The vast majority of BRCA1 and BRCA2 mutation carriers are single heterozygotes, and double heterozygosity (DH) is a very rare finding. Here, we describe the case of a BRCA1 / BRCA2 double heterozygous female proband diagnosed with breast cancer. Genetic testing for hereditary breast and ovarian cancer revealed two pathogenic variants in the BRCA1 (c.5095C>T, p.(Arg1699Trp)) and in BRCA2 genes (c.658_659delGT, p...

BACKGROUND: Racial disparities in outcomes exist in endometrial cancer (EC). The contribution of ancestry-based variations in germline pathogenic variants (gPVs) is unknown. METHODS: Germline assessment of ≥76 cancer predisposition genes was performed in patients with EC undergoing tumor-normal Memorial Sloan Kettering Cancer Center Integrated Mutation Profiling of Actionable Cancer Targets sequencing from January 1, 2015 through June 30, 2021. Self-reported race/ethnicity and Ashkenazi Jewish ancestry data classified patients into groups...