Ashkenazi Research Articles

Breast cancer incidence in BRCA mutation carriers with ovarian cancer: A longitudal observational study

ObjectivesWe evaluated the incidence of breast cancer and overall survival in a multi-center cohort of ovarian cancer patients carrying BRCA1/2 mutations in order to assess risks and formulate optimal preventive interventions and/or surveillance. MethodsMedical records of 502 BRCA1/2 mutation carriers diagnosed with ovarian cancer between 2000 and 2018 at 7 medical centers in Israel and one in New York were retrospectively analyzed for breast cancer diagnosis. Data included demographics, type of BRCA mutations, surveillance methods, timing of breast cancer diagnosis, and family history of cancer. ResultsThe median age at diagnosis of ovarian cancer was 55.8 years (range, 23.9–90.1). A third (31.5%) had a family history of breast cancer and 17.1% of ovarian cancer. Most patients (67.3%) were Ashkenazi Jews, 72.9% were BRCA1 carriers. Breast cancer preceded ovarian cancer in 17.5% and was diagnosed after ovarian cancer in 6.2%; an additional 2.2% had a synchronous presentation. Median time to breast cancer diagnosis after ovarian cancer was 46.0 months (range, 11–168). Of those diagnosed with both breast cancer and ovarian cancer (n = 31), 83.9% and 16.1% harbored BRCA1 and BRCA2 mutations, respectively. No deaths from breast cancer were recorded. Overall survival did not differ statistically between patients with an ovarian cancer diagnosis only and those diagnosed with breast cancer after ovarian cancer. ConclusionThe low incidence of breast cancer after ovarian cancer in women carrying BRCA1/2 mutations suggests that routine breast surveillance, rather than risk-reducing surgical interventions, may be sufficient in ovarian cancer survivors.

Yield of targeted genotyping for the recurring pathogenic variants in cancer susceptibility genes in a healthy, multiethnic Israeli population.

Several recurring pathogenic variants in BRCA1/BRCA2 and other cancer susceptibility genes are encountered in ethnically diverse Jewish populations. The yield of genotyping for these recurring pathogenic variants in healthy Israeli individuals unselected for ethnicity, sex, or a family history of cancer has not been previously reported. Individuals voluntarily participating in annual medical surveillance at the Institute of Medical Screening of Sheba Medical Center were offered genotyping for predominant pathogenic variants in BRCA1/BRCA2 and recurring variants in CHEK2, MUTYH, APC, and the Lynch syndrome genes via a chip-based assay at the oncogenetic service of Sheba Medical Center from May 15, 2018, to December 15, 2020. All study participants were unrelated to one another. The study was approved by the Sheba ethics committee. Overall, 1764 individuals, including 1008 females (57%), with a mean age of 54.2 years (range, 25-86 years) were genotyped. The yield of the testing was 4% (71 of 1764), and it was higher in Ashkenazi Jews (AJs) and mixed AJ-non-AJ participants (4.75% [58 of 1222]; 1.8% for BRCA1/BRCA2 pathogenic variants) than non-AJ patients (2.2% [9 of 401]; 1% for BRCA1 pathogenic variants). When BRCA1/BRCA2 pathogenic variants were excluded, 2.44% carried low-penetrance variants, including CHEK2 c.1283C>T (n = 3), APC c.3920T>A (n = 36), and heterozygous MUTYH c.1187G>A (n = 4). A family history of cancer was not associated with a higher yield of pathogenic variant detection. The observed rates of positive genotyping in a healthy, unselected, multiethnic Israeli population warrant consideration of the inclusion of targeted genotyping of selected pathogenic variants in high-penetrance and perhaps lower penetrance cancer susceptibility genes for all Jewish individuals in Israel, regardless of their ethnicity or family history of cancer.

Impact of Pan-Ethnic Expanded Carrier Screening in Improving Population Health Outcomes: Proceedings from a Multi-Stakeholder Virtual Roundtable Summit, June 25, 2020.

Impact of Pan-Ethnic Expanded Carrier Screening in Improving Population Health Outcomes: Proceedings from a Multi-Stakeholder Virtual Roundtable Summit, June 25, 2020.

Analysis of Worldwide Carrier Frequency and Predicted Genetic Prevalence of Autosomal Recessive Congenital Hypothyroidism Based on a General Population Database.

To assess how genomic information of the general population reflects probabilities of developing diseases and the differences in those probabilities among ethnic groups, a general population database was analyzed with an example of congenital hypothyroidism. Twelve candidate genes that follow an autosomal recessive inheritance pattern in congenital hypothyroidism (SLC5A5, TPO, TG, IYD, DUOXA2, DUOX2, TSHR, SLC26A7, GLIS3, FOXE1, TSHB, TRHR) in the gnomAD database (v2.1.1) were analyzed. The carrier frequency (CF) and predicted genetic prevalence (pGP) were estimated. The total CF in the overall population was 3.6%. DUOX2 showed the highest CF (1.8%), followed by TG (0.46%), TPO (0.44%), TSHR (0.31%), SLC26A7 (0.144%), DUOXA2 (0.141%), IYD (0.08%), SLC5A5 (0.06%), TRHR (0.059%), GLIS3 (0.059%), TSHB (0.04%), and FOXE1 (0%). The pGP in the overall population was 10.01 individuals per 100,000 births (1:9992). The highest pGP was in the East Asian population at 52.48 per 100,000 births (1:1905), followed by Finnish (35.96), Non-Finnish European (9.56), African/African American (4.0), Latino/Admixed American (3.89), South Asian (3.56), and Ashkenazi Jewish (1.81) groups. Comparing the pGP with the real incidence of congenital hypothyroidism, the pGP in East Asian populations was highly consistent with the real incidence.

Investigating DYT1 in a Taiwanese dystonia cohort

A heterozygous three-nucleotide (GAG) in-frame deletion in the TOR1A gene causes the rare disease, dystonia (DYT1), which typically presents as focal limb dystonia during adolescence, then spreads to other limbs. This study investigated the frequency and clinical features of DYT1 in a Taiwanese dystonia cohort. We performed targeted next generation sequencing in 318 patients with primary dystonia. We identified one DYT1 family with various types of dystonia, and we described the clinical presentations observed in this family during a 30-year follow-up. We compared the clinical characteristics to those reported in previous studies on DYT1 from 2000 to 2020. Among 318 patients, we identified only one DYT1 patient (0.3%) with an autosomal dominant family history of dystonia. The proband was a 43-year-old man that experienced progressive onset of focal lower limb dystonia from age 11 years. The disease spread caudal-rostrally to the upper limbs and cervical muscles. Prominent cervical dystonia was noted during follow-up, which was an atypical presentation of DYT1. Clinical assessments of other family members showed intrafamily variability. The proband's father and an affected sibling demonstrated only mild right-hand writer's cramp. A systematic review of previously reported DTY1 cases showed that Asian patients had a higher frequency of cervical dystonia (44.8%) than groups of Ashkenazi Jews (35%) and Non-Jewish Caucasians (30.5%) (P=0.04). Our findings revealed that DYT1 is rare in a Taiwanese dystonia cohort. The presentation of marked cervical dystonia could be the main feature of Asian patients with DYT1.

A Feeling for the Human Subject: Margaret Lasker and the Genetic Puzzle of Pentosuria.

In 1933 Margaret Lasker, a biochemist who worked at the labs of Montefiore Hospital in New York, developed an accurate method for the differentiation between pentosuria and diabetes. Research into pentosuria, and mostly its genetic aspects, became Lasker's lifelong passion. Since research was not part of her job description, she conducted the chief part of her study in her home kitchen. Lasker's extensive and personal correspondence with her patients and their families may be the secret key for her success in maintaining a prolonged research career against all odds. Laker's last article was published in 1955 in Human Biology, presenting data on 72 cases of pentosuria, which occurs almost exclusively in Ashkenazi Jews. More than half a century later, and long after Lasker was gone, her well kept data and family records allowed the discovery of two mutations in the DCXR gene, by Mary-Claire King and her team.

Evaluation of two population screening programmes for BRCA1/2 founder mutations in the Australian Jewish community: a protocol paper

IntroductionPeople of Ashkenazi Jewish (AJ) ancestry are more likely than unselected populations to have a BRCA1/2 pathogenic variant, which cause a significantly increased risk of breast, ovarian and prostate cancer....

MHC Haplotyping of SARS-CoV-2 Patients: HLA Subtypes Are Not Associated with the Presence and Severity of COVID-19 in the Israeli Population.

HLA haplotypes were found to be associated with increased risk for viral infections or disease severity in various diseases, including SARS. Several genetic variants are associated with COVID-19 severity. Studies have proposed associations, based on a very small sample and a large number of tested HLA alleles, but no clear association between HLA and COVID-19 incidence or severity has been reported. We conducted a large-scale HLA analysis of Israeli individuals who tested positive for SARS-CoV-2 infection by PCR. Overall, 72,912 individuals with known HLA haplotypes were included in the study, of whom 6413 (8.8%) were found to have SARS-CoV-2 by PCR. A total of 20,937 subjects were of Ashkenazi origin (at least 2/4 grandparents). One hundred eighty-one patients (2.8% of the infected) were hospitalized due to the disease. None of the 66 most common HLA loci (within the five HLA subgroups: A, B, C, DQB1, DRB1) was found to be associated with SARS-CoV-2 infection or hospitalization in the general Israeli population. Similarly, no association was detected in the Ashkenazi Jewish subset. Moreover, no association was found between heterozygosity in any of the HLA loci and either infection or hospitalization. We conclude that HLA haplotypes are not a major risk/protecting factor among the Israeli population for SARS-CoV-2 infection or severity. Our results suggest that if any HLA association exists with the disease it is very weak, and of limited effect on the pandemic.Supplementary InformationThe online version contains supplementary material available at 10.1007/s10875-021-01071-x.

Disparities in pan-cancer patients undergoing germline cancer risk assessment by self-reported race/ethnicity and ancestry.

10508 Background: Disparities in access to germline testing for cancer patients (pts) have been demonstrated; however, disparities in post-testing care are unknown. We sought to evaluate germline findings and subsequent genetic counseling/care in cancer pts undergoing tumor-germline sequencing to explore differences by self-reported ancestry. Methods: Pan-cancer pts were prospectively consented to tumor-normal sequencing via a custom NGS panel (MSK-IMPACT) from 1/2015-12/2019 inclusive of germline analysis up to 88 genes. Germline analysis was performed as a research non-billable test in 97.5% of cases. Referral to clinical genetics service (CGS) was recommended for all pts with a new positive (likely pathogenic/pathogenic) germline variant (PV). Ancestry was defined using self-reported Federal definitions of race/ethnicity and designations of Ashkenazi Jewish (AJ) ancestry. Pts were categorized into mutually exclusive groups: AJ, White, Non-White (Asian, Black/African American, Hispanic, Other), and unknown. All pts self-identifying as Hispanic were classified as such, regardless of race. Abstracted data on germline findings and downstream CGS follow-up were compared across groups using non-parametric statistical tests. Results: Among the 15,775 pts in this cohort (59.6% White, 15.7% AJ, 20.5% Non-White [6.9% Asian, 6.8% Black, 6.7% Hispanic, 0.1% Other], and 4.2% unknown), 2663 (17%) had a PV. AJ pts had the highest rates of PV (n = 683, 27.6%), and Non-White pts had a lower proportion of PV (n = 433, 13.6%) compared to Whites (n = 1451, 15.5%), p < 0.01, with differences mostly due to increased prevalence of moderate/low penetrance variants in White and AJ pts . These findings were consistent across multiple tumor types. Prior knowledge of the PV (424/2663, 16%) was more common in Non-White (19.9%) and AJ (19.2%) than White pts (13.4%), p < 0.01. Among 2239 pts with new PV, all were referred to CGS, and 1652 (73.8%) pts were seen. Non-White pts had lower rates of completing visits (67.7%) than White (73.7%) and AJ pts (78.8%), p < 0.01, with the lowest rates occurring in Black (63%) and Hispanic (68.1%) pts. All pts without a visit (n = 587) received a close out letter including 139 pts (6.2% of pts with new PV) who had no documentation of receipt of results in the medical record. Higher rates of non-disclosure were observed in Non-White (6.7%) compared to White (5.4%) and AJ (3.4%) pts with new PV, p = 0.032; non-disclosure did not vary by gene penetrance. There was a non-significant trend towards lower rates of cascade testing at CGS in Asian and Black pts with ongoing analysis. Conclusions: Even when traditional barriers to genetic testing were minimized, Non-White pts were less likely to receive recommended cancer genetics follow-up for subsequent cancer risk counseling, with potential implications for oncological care, cancer risk reduction, and at-risk family members.

Limitations of direct-to-consumer (DTC) genetic testing for hereditary breast and ovarian cancer.

10515 Background: With the advent of DTC genetic testing, individuals have access to genetic testing without input from a healthcare professional. DTC testing now exists for the 3 Ashkenazi Jewish (AJ) BRCA1/2 founder variants. DTC testing may provide false reassurance to individuals that they do not carry a pathogenic or likely pathogenic variant (PLPV) in BRCA1/2 or other cancer-risk genes. Methods: Multi-panel genetic testing was performed in 348,692 individuals for a clinical indication of hereditary breast/ovarian cancer (Clinical cohort) and 7,636 self-referred ostensibly healthy individuals (Healthy cohort) by a clinical testing laboratory. The primary analysis evaluated PLPVs for Group 1 genes: BRCA1/2 AJ founder variants and Group 2: full sequence BRCA1/2. Secondary analyses assessed PLPVs in Group 3: high-risk breast cancer genes ( BRCA1/2, CDH1, PALB2, PTEN, STK11, TP53), Group 4: all breast or ovarian cancer-risk genes (Group 3 genes plus ATM, BARD1, BRIP1, truncating CHEK2, EPCAM, MLH1, MSH2/6, NF1, PMS2, RAD51C/D) and Group 5: 41 cancer-risk genes; these analyses were limited to participants who tested for all 41 genes. Potentially mosaic variants were excluded. Results: Table illustrates PLPVs found in both cohorts. The BRCA1/2 AJ founder variants account for only ̃11% (1513/13,987) and ̃30% (19/64) of the BRCA PLPVs in the Clinical and Healthy cohorts, respectively. Even among AJ individuals, testing only for the 3 founder variants will miss ̃10% (52/513) of all BRCA1/2 PLPVs. Evaluating only the BRCA AJ founder variants missed a higher percentage of PLPVs in other cancer-risk genes. Conclusions: The 3 BRCA1/2 AJ founder variants analyzed by DTC testing account for a small fraction of PLPVs in cancer-risk genes in the general population, and miss 10% of BRCA PLPVs even among AJ individuals. Greater public education is needed to dispel the misconception that DTC tests are equivalent to clinical assessment and comprehensive genetic testing. PLPVs identified in Clinical and Healthy Cohorts.[Table: see text]

Evaluation of cohort diversity in development and validation studies of hereditary cancer genetic risk assessment models.

10600 Background: Multiple models estimate a person’s chance of harboring a pathogenic variant increasing cancer risk. Some pathogenic variants are more common in individuals from specific ancestries, such as the BRCA1 and BRCA2 founder variants in Ashkenazi Jews. Yet data remains limited on the larger variant spectrum seen among people of different ancestral backgrounds and whether or not the pathogenic variant frequency differs in many populations. Due to this, it is important that genetic risk assessment models be validated in a diverse cohort including Black, Indigenous, People of Color (BIPOC). Methods: A literature search was conducted to identify published development and validation studies for the following genetic risk assessment models: BRCAPRO, MMRPRO, CanRisk/BOADICEA, Tyrer-Cuzick, and PREMM. Validation studies that only evaluated the cancer risk prediction capabilities of the models (and not the genetic variant risk prediction) were excluded. The following participant information was abstracted from each study: total number of participants, gender, race, and ethnicity. Authors were contacted to obtain missing information (if available). Results: 12 development and 12 validation studies of the genetic risk assessment models BRCAPRO, MMRPRO, CanRisk/BOADICEA, Tyrer-Cuzick, and PREMM were abstracted. Of the validation studies, five were internal validation studies conducted by the model developers, and seven were external validation studies. Four external validation studies compared multiple models. 75% (18/24) of papers did not include reporting of participant race or ethnicity information in their published reports. External validation studies (4/7, 57%) more often reported participant race/ethnicity than development (0/12, 0%) or internal validation (2/5, 40%) studies. The external validation studies for BRCAPRO reporting race/ethnicity information involved cohorts that ranged from 50-51% non-Ashkenazi Jewish white, 28% African American, 1% Asian, 2-49% Hispanic, and 19-42% Ashkenazi Jewish. The external validation studies for MMRPRO and PREMM reporting race/ethnicity information involved cohort that ranged from 0-82% white, 4-100% Asian, 7% Black, and 7% Hispanic. Conclusions: Increased reporting of participant ancestry and ethnicity is needed in the development and validation studies of genetic risk assessment models. BRCAPRO’s validation cohorts have included a higher percentage of Hispanic and Black/African American participants, while MMRPRO and PREMM have been validated in a higher percentage of Asian participants. As debate continues about the utility of currently used racial categories in genetics research, it will be important to determine how best to report on participant diversity. These findings highlight the continued need for genetics researchers to engage BIPOC and identify ways to diversify their participant cohorts.

Hereditary cancer testing in an ethnically diverse U.S. population.

10579 Background: The clinical utility of hereditary cancer multigene testing is well-established. Most testing has been performed in the White European population, with a relative shortage of data in other ethnic groups. Evaluation of hereditary cancer variants within diverse ethnic populations is important to drive accurate variant interpretation. This study aims to review the outcomes of hereditary cancer testing in an ethnically diverse U.S. population. Methods: We conducted a retrospective analysis of 8,888 test results from a 31-gene hereditary cancer test using next-generation sequencing with copy number variant analysis. Results were separated into seven categories based on the ethnicity selected on the test requisition: African American (AA), Asian (A), Ashkenazi Jewish (AJ), Hispanic (H), White (W), Other (O), and Unknown (U). O was used for any handwritten ethnicity or if multiple ethnicities were selected and U if no ethnicity was chosen. We quantified the number of negative, positive (pathogenic or likely pathogenic (P/LP) variant) and variant of uncertain significant (VUS) results for each ethnic group. We tallied the gene and variant for each result with a positive, negative or VUS. We used a Fisher's Exact test and Bonferroni-adjusted p-values to account for multiple hypothesis testing. Results: Of the 8,888 orders reviewed, 45% were non-White ethnic groups. The P/LP variant rate was lower for AA (4%, p=2e-04) compared to W (9%). The VUS rate was higher for O, AA and A (48%, 56%, and 57%; p=0.0045, 3.1e-17 and 4.8e-06, respectively), compared to 38% in W. Lower negative rates were found in A and AA (37% and 40%; p=0.00024 and 9.4e-10, respectively), and trending lower in O (46%, p=0.0097), compared to 58% for W. The VUS rate for H is 41% (p value = 0.095). Conclusions: Our results suggest that non-Whites may be at a disadvantage when it comes to hereditary cancer multigene testing due to the higher rate of VUS results. The inverse correlation between the overall rates of VUS and negative results when comparing these populations suggests there may be limited variant information for the non-White population in medical literature and available databases. This underrepresentation may make it more difficult to accurately characterize a variant. Despite the small sample size, these findings are consistent with previous publications; however, gene specific outcomes could not be evaluated. This finding suggests that providers could give these patients uninformative results more often, which has potential to impact screening protocols for these families. More research is needed to understand the impact of variant classification across ethnicities to decrease health disparities.

Mutations in GBA and LRRK2 Are Not Associated with Increased Inflammatory Markers.

Background:Inflammation is an integral part of neurodegeneration including in Parkinson’s disease (PD). Ashkenazi Jews have high rates of genetic PD with divergent phenotypes among GBA-PD and LRRK2-PD. The role of inflammation in the prodromal phase of PD and the association with disease phenotype has yet to be elucidated.Objective:To assess central and peripheral cytokines among PD patients with mutations in the LRRK2 and GBA genes and among non-manifesting carriers (NMC) of these mutations in order to determine the role of inflammation in genetic PD.Methods:The following cytokines were assessed from peripheral blood and cerebrospinal fluid (CSF): TNF-α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10 and INF- γ. A comprehensive intake including general medical conditions, use of anti-inflammatory treatments, motor and cognitive assessments and additional laboratory measures were recorded, enabling the construction of the MDS probable prodromal score.Results:Data from 362 participants was collected: 31 idiopathic PD (iPD), 30 LRRK2-PD, 77 GBA-PD, 3 homozygote GBA-PD, 3 GBA-LRRK2-PD, 67 LRRK2-NMC, 105 GBA-NMC, 14 LRRK2-GBA-NMC, and 32 healthy controls. No between-group differences in peripheral or CSF cytokines were detected. No correlation between disease characteristics or risk for prodromal PD could be associated with any inflammatory measure.Conclusion:In this study, we could not detect any evidence on dysregulated immune response among GBA and LRRK2 PD patients and non-manifesting mutation carriers.

Clinical, neuroimaging, and molecular spectrum of TECPR2-associated hereditary sensory and autonomic neuropathy with intellectual disability.

Bi-allelic TECPR2 variants have been associated with a complex syndrome with features of both a neurodevelopmental and neurodegenerative disorder. Here, we provide a comprehensive clinical description and variant interpretation framework for this genetic locus. Through international collaboration, we identified 17 individuals from 15 families with bi-allelic TECPR2-variants. We systemically reviewed clinical and molecular data from this cohort and 11 cases previously reported. Phenotypes were standardized using Human Phenotype Ontology terms. A cross-sectional analysis revealed global developmental delay/intellectual disability, muscular hypotonia, ataxia, hyporeflexia, respiratory infections, and central/nocturnal hypopnea as core manifestations. A review of brain magnetic resonance imaging scans demonstrated a thin corpus callosum in 52%. We evaluated 17 distinct variants. Missense variants in TECPR2 are predominantly located in the N- and C-terminal regions containing β-propeller repeats. Despite constituting nearly half of disease-associated TECPR2 variants, classifying missense variants as (likely) pathogenic according to ACMG criteria remains challenging. We estimate a pathogenic variant carrier frequency of 1/1221 in the general and 1/155 in the Jewish Ashkenazi populations. Based on clinical, neuroimaging, and genetic data, we provide recommendations for variant reporting, clinical assessment, and surveillance/treatment of individuals with TECPR2-associated disorder. This sets the stage for future prospective natural history studies.

The Hypothalamic-Pituitary-Testicular Axis in Exceptionally Old Men

Introduction: As life expectancy continues to increase and more men reach the extremes of age, it is important to understand the physiology of the aging hypothalamic-pituitary-testicular (HPT) axis and its role in health. While prior studies primarily focused on men younger than age ninety, we studied a unique cohort enriched for men with exceptional longevity to characterize the age-related trends in male sex-hormones, the etiology of the observed changes in the HPT axis, and its relationship with metabolic dysfunction and survival at the extremes of age. Methods: This is a cross-sectional study of community-dwelling Ashkenazi Jewish men (n = 427), age range 50-106 years. Longitudinal follow-up for vital status was conducted for men age ≥ 88 at enrollment (n = 86). Measurements included serum total testosterone (TT) by LC/MS, LH, SHBG, lipids, glucose and BMI. Free testosterone (FT) was calculated according to Vermeulen et. al. A change-point linear regression model was applied to describe the age trend of TT. Multivariable linear regression adjusted for comorbidities tested the associations between metabolic parameters and TT. The association between survival and TT was evaluated with the age-adjusted Cox proportional hazards model. Age-specific cutoffs for TT and LH were used to define primary and secondary hypogonadism. Results: The change point model was a significantly better fit for the data compared to the straight-line model (p = 0.004), indicating that TT significantly declines after age 88 years. Men age < 88 years had higher average TT (401 ± 162 vs. 278 ± 178 ng/dL, p < 0.001), FT (6.3 ± 2.0 vs. 3.3± 2.1 pg/mL, p < 0.001), and lower LH (4.3 [3.0 - 6.1] vs. 14.6 [7.2 - 25.5] mIU/mL, p < 0.001), compared to men age ≥ 88 years. The prevalence of primary and secondary hypogonadism was 2% and 11%, respectively, in men age < 88 years, and 30% and 11%, among men age ≥ 88 years (p < 0.001). A multivariable linear regression analysis revealed interactions between age, dichotomized at the change-point of 88 years, and metabolic parameters. Models stratified at age 88 demonstrated an inverse association between TT and BMI (p = 0.02), serum triglycerides (p = 0.007), and random glucose levels (p = 0.02) among men age < 88; whereas a positive association was noted between TT and HDL cholesterol (p = 0.009) in this group. In men age ≥ 88 years, TT was not associated with any of the metabolic parameters or overall survival. Conclusions: Low testosterone in men with exceptional longevity is largely a result of primary testicular failure that occurs around age 88 and is accompanied by preserved hypothalamic-pituitary response with no associated metabolic dysfunction or effect on survival. This is in contrast to younger men, whose low T typically results from hypothalamic-pituitary dysfunction and is associated with metabolic derangements.

Jewish branch of cultural text of the Crimean ethnic ornament

The subject of this research is the continuum of ethnic symbols of the ornament of the Crimean Jews. The object is the traditional decorative and applied art of the peoples of Crimea following Judaism: Ashkenazi Jews, Karaite and Krymchaks. The symbolism of ethnic art is viewed based on the analysis of traditional decor. The article employs the methods of comparative analysis, analysis of previous research, method of synthesis in conclusions pertinent to connotations of symbols. The author explores the morphology and semantics of visual symbols in decorative and applied art of the aforementioned people, as well as connotations of symbols. Special attention is given to aspects that characterize polyethnic cultural landscape of Crimea in the context of phylogenesis. The main conclusions are as follows: &amp;nbsp; 1. Crimea is a polyethnic region with various cultural processes &amp;ndash; from reception to inculturation and integration of ethnoses, which ultimately formed the Crimean cultural landscape. Its peculiarities are represented by ethnic ornament, such as decorated household items and ritual attributes &amp;nbsp; 2. Symbolism of the elements of traditional art of Ashkenazi Crimean Jews, Karaite and Krymchaks has common connotations due to the Torah that underlies the religious confession of all three ethnoses, as well as similar morphology. The art of Karaite and Krymchaks are more identical to each other than to Jewish. The author&amp;rsquo;s special contribution lies in systematization of the morphology of visual symbols in the art of the three ethnoses. The scientific novelty consists in carrying out a comparative analysis of the art of three Crimean ethnoses, revealing foundations of the genesis and continuum of its elements, their similarities and differences.

Ultra-Rare Exonic Variants Identified in a Founder Population Implicate Cadherins and Protocadherins in Schizophrenia

Identification of rare genetic variants associated with schizophrenia has proven challenging due to multiple sources of heterogeneity, which may be reduced in founder populations, such as the Ashkenazi Jewish (AJ) population.

The right of emphyteusis in the history of the Russian state (the late 15th – early 20th century)

The subject. The law of emphyteusis was studied in the Russian Empire in the middle of 19th – beginning of 20th century due to practical significance. The interest in this subject began to revive at the beginning of the 21st century, the first few publications appeared, but they were mostly replicas of Imperial period studies. The law of emphyteusis in Russia before the middle of the 19th century is not researched sufficiently. The purpose of the study is to confirm or disprove hypothesis that the law of emphyteusis was initially implemented in the system of Russian law as a legislative institution, but since the middle of the 19th century it has acquired the status of a local legal custom. The Russian state, having preserved the former system of civil law (the Lithuanian Statute) in the Western lands annexed from Lithuania and Poland, created the basis for the formation of a different system of legal awareness among a part of the population, thereby consolidating the dichotomy of the Empire and the Western provinces. Since the issue of land ownership is a key issue for feudal society, the law of emphyteusis is the most striking example of the split in the unity of the legal system of the Russian state. The methodology. The study is based on a combination of formal-legal and historical-legal methods: the methods of historicism, synchronous and diachronic comparison allow us to get an idea of the socio-political conditions in which the law of emphyteusis was formed and functioned. The main results, scope of application. The institute of emphyteusis (Latin – сensus, German – zins, Polish – czynsz) was formed on the basis of the reception of Roman and Byzantine law in the feudal law of a number of European States. Emphyteusis comes to the PolishLithuanian lands as an element of German law. The article describes the socio-political processes in the territories annexed by Russia from the Polish-Lithuanian Commonwealth, where the right of emphyteusis was preserved in the middle of 17th - first half of the 19th century as a local civil law under the Lithuanian Statute system. After the abolition of the Statute of Lithuania (1840) an emphyteusis preserved as a regional legal custom. The analysis of legislation and law enforcement practice on the issue of emphyteusis on the borderlands of the Russian state is carried out. The ineffectiveness of the state policy on the elimination of emphyteusis is noted. Conclusions. The revealed specifics of the development of emphyteusis in the Russian Empire are extremely poorly studied, although they indicate far-reaching consequences in the system of forming the legal consciousness of Russian, Ukrainian, Belarusian, Jewish (Ashkenazi) and other peoples.

A New Insight for the Identification of Oncogenic Variants in Breast and Prostate Cancers in Diverse Human Populations, With a Focus on Latinos.

Background: Breast cancer (BRCA) and prostate cancer (PRCA) are the most commonly diagnosed cancer types in Latin American women and men, respectively. Although in recent years large-scale efforts from international consortia have focused on improving precision oncology, a better understanding of genomic features of BRCA and PRCA in developing regions and racial/ethnic minority populations is still required. Methods: To fill in this gap, we performed integrated in silico analyses to elucidate oncogenic variants from BRCA and PRCA driver genes; to calculate their deleteriousness scores and allele frequencies from seven human populations worldwide, including Latinos; and to propose the most effective therapeutic strategies based on precision oncology. Results: We analyzed 339,100 variants belonging to 99 BRCA and 82 PRCA driver genes and identified 18,512 and 15,648 known/predicted oncogenic variants, respectively. Regarding known oncogenic variants, we prioritized the most frequent and deleterious variants of BRCA (n = 230) and PRCA (n = 167) from Latino, African, Ashkenazi Jewish, East Asian, South Asian, European Finnish, and European non-Finnish populations, to incorporate them into pharmacogenomics testing. Lastly, we identified which oncogenic variants may shape the response to anti-cancer therapies, detailing the current status of pharmacogenomics guidelines and clinical trials involved in BRCA and PRCA cancer driver proteins. Conclusion: It is imperative to unify efforts where developing countries might invest in obtaining databases of genomic profiles of their populations, and developed countries might incorporate racial/ethnic minority populations in future clinical trials and cancer researches with the overall objective of fomenting pharmacogenomics in clinical practice and public health policies.

Possible ethnic associations in primary hyperoxaluria type-III-associated HOGA1 sequence variants.

Primary hyperoxaluria type-III is a disorder of glyoxylate metabolism, caused by pathogenic variants in the HOGA1 gene. To date more than 50 disease-associated pathogenic sequence variants are identified in the gene. A few of the variants are population specific and are considered to have a founder effect in respective populations. The most prevalent variant, c.700+5G>T, identified frequently in Caucasian (allele frequency 0.63) and European (0.35) populations. Two variants, c.860G>T (p.Gly287Val) and c.944_946delAGG (p.Glu315del), account for 95% of the allele count in patients of Ashkenazi Jews ancestry. A possible mutational hot-spot at c.834 position is frequently found mutated in Chinese patients. This observed ethnic associations of HOGA1 alleles span a spectrum ranging from recurrence limited to an ethnic group to a possible founder-effect.