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2.
Health Soc Work ; 45(2): 101-109, 2020 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-32390055

RESUMO

Authors examined differences in assessment method (structured diagnostic interview versus self-report questionnaire) between ethnic groups in the prevalence of mood and anxiety disorders among women with breast cancer. A convenience sample of 88 Mizrahi (Jews of Middle Eastern/North African descent, n = 42) and Ashkenazi (Jews of European/American descent, n = 46) women with breast cancer from oncology units in three health centers across Israel participated in the study. Participants were within eight months of diagnosis. Participants completed the Hospital Anxiety and Depression Scale (HADS) and a structured diagnostic interview, the Mini-International Neuropsychiatric Interview (MINI). Approximately one-third (31.8 percent, n = 28) of participants were diagnosed with at least one mood or anxiety disorder based on the MINI. Significantly more Mizrahi participants (42.9 percent) were diagnosed with at least one mood or anxiety disorder, compared with their Ashkenazi counterparts (21.7 percent). Mean score on HADS was below the optimal cutoff score (≥13) among all participants, with no significant difference in mean score for emotional distress based on HADS between the two ethnic groups. The findings highlight the role of measurement variance in assessing mental health distress among women with breast cancer in general and among ethnic and racial minorities in particular.


Assuntos
Transtornos de Ansiedade/epidemiologia , Neoplasias da Mama/terapia , Judeus/psicologia , Transtornos do Humor/epidemiologia , Escalas de Graduação Psiquiátrica , Adulto , Neoplasias da Mama/genética , Feminino , Humanos , Entrevistas como Assunto , Israel/epidemiologia , Judeus/genética , Pessoa de Meia-Idade , Autorrelato , Inquéritos e Questionários
3.
Sci Rep ; 10(1): 7669, 2020 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-32376921

RESUMO

Current guidelines recommend BRCA1 and BRCA2 genetic testing for individuals with a personal or family history of certain cancers. Three BRCA1/2 founder variants - 185delAG (c.68_69delAG), 5382insC (c.5266dupC), and 6174delT (c.5946delT) - are common in the Ashkenazi Jewish population. We characterized a cohort of more than 2,800 research participants in the 23andMe database who carry one or more of the three Ashkenazi Jewish founder variants, evaluating two characteristics that are typically used to recommend individuals for BRCA testing: self-reported Jewish ancestry and family history of breast, ovarian, prostate, or pancreatic cancer. Of the 1,967 carriers who provided self-reported ancestry information, 21% did not self-report Jewish ancestry; of these individuals, more than half (62%) do have detectable Ashkenazi Jewish genetic ancestry. In addition, of the 343 carriers who provided both ancestry and family history information, 44% did not have a first-degree family history of a BRCA-related cancer and, in the absence of a personal history of cancer, would therefore be unlikely to qualify for clinical genetic testing. These findings may help inform the discussion around broader access to BRCA genetic testing.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Efeito Fundador , Variação Genética , Judeus/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Testes Genéticos , Síndrome Hereditária de Câncer de Mama e Ovário/epidemiologia , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Síndrome Hereditária de Câncer de Mama e Ovário/prevenção & controle , Humanos , Masculino , Pessoa de Meia-Idade , Autorrelato , Adulto Jovem
4.
Nat Commun ; 11(1): 2220, 2020 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-32393777

RESUMO

Few germline mutations are known to affect lung cancer risk. We performed analyses of rare variants from 39,146 individuals of European ancestry and investigated gene expression levels in 7,773 samples. We find a large-effect association with an ATM L2307F (rs56009889) mutation in adenocarcinoma for discovery (adjusted Odds Ratio = 8.82, P = 1.18 × 10-15) and replication (adjusted OR = 2.93, P = 2.22 × 10-3) that is more pronounced in females (adjusted OR = 6.81 and 3.19 and for discovery and replication). We observe an excess loss of heterozygosity in lung tumors among ATM L2307F allele carriers. L2307F is more frequent (4%) among Ashkenazi Jewish populations. We also observe an association in discovery (adjusted OR = 2.61, P = 7.98 × 10-22) and replication datasets (adjusted OR = 1.55, P = 0.06) with a loss-of-function mutation, Q4X (rs150665432) of an uncharacterized gene, KIAA0930. Our findings implicate germline genetic variants in ATM with lung cancer susceptibility and suggest KIAA0930 as a novel candidate gene for lung cancer risk.


Assuntos
Adenocarcinoma/genética , Proteínas Mutadas de Ataxia Telangiectasia/genética , Neoplasias Pulmonares/genética , Idoso , Alelos , Bases de Dados Genéticas , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Predisposição Genética para Doença , Técnicas de Genotipagem , Mutação em Linhagem Germinativa , Heterozigoto , Humanos , Judeus/genética , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Razão de Chances , Análise de Sequência com Séries de Oligonucleotídeos , Linhagem , RNA-Seq , Fatores de Risco
5.
Am J Hum Genet ; 106(5): 623-631, 2020 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-32275884

RESUMO

Nucleoporins (NUPs) are an essential component of the nuclear-pore complex, which regulates nucleocytoplasmic transport of macromolecules. Pathogenic variants in NUP genes have been linked to several inherited human diseases, including a number with progressive neurological degeneration. We present six affected individuals with bi-allelic truncating variants in NUP188 and strikingly similar phenotypes and clinical courses, representing a recognizable genetic syndrome; the individuals are from four unrelated families. Key clinical features include congenital cataracts, hypotonia, prenatal-onset ventriculomegaly, white-matter abnormalities, hypoplastic corpus callosum, congenital heart defects, and central hypoventilation. Characteristic dysmorphic features include small palpebral fissures, a wide nasal bridge and nose, micrognathia, and digital anomalies. All affected individuals died as a result of respiratory failure, and five of them died within the first year of life. Nuclear import of proteins was decreased in affected individuals' fibroblasts, supporting a possible disease mechanism. CRISPR-mediated knockout of NUP188 in Drosophila revealed motor deficits and seizure susceptibility, partially recapitulating the neurological phenotype seen in affected individuals. Removal of NUP188 also resulted in aberrant dendrite tiling, suggesting a potential role of NUP188 in dendritic development. Two of the NUP188 pathogenic variants are enriched in the Ashkenazi Jewish population in gnomAD, a finding we confirmed with a separate targeted population screen of an international sampling of 3,225 healthy Ashkenazi Jewish individuals. Taken together, our results implicate bi-allelic loss-of-function NUP188 variants in a recessive syndrome characterized by a distinct neurologic, ophthalmologic, and facial phenotype.


Assuntos
Alelos , Encéfalo/anormalidades , Proteínas de Drosophila/genética , Anormalidades do Olho/genética , Cardiopatias Congênitas/genética , Mutação com Perda de Função/genética , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Transporte Ativo do Núcleo Celular , Animais , Núcleo Celular/metabolismo , Pré-Escolar , Dendritos/metabolismo , Dendritos/patologia , Drosophila melanogaster , Anormalidades do Olho/mortalidade , Feminino , Fibroblastos , Genes Recessivos , Cardiopatias Congênitas/mortalidade , Humanos , Lactente , Recém-Nascido , Judeus/genética , Masculino , Complexo de Proteínas Formadoras de Poros Nucleares/deficiência , Convulsões/metabolismo , Síndrome , beta Carioferinas/metabolismo
6.
BJOG ; 127(3): 364-375, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31507061

RESUMO

OBJECTIVE: Unselected population-based BRCA testing provides the opportunity to apply genomics on a population-scale to maximise primary prevention for breast-and-ovarian cancer. We compare long-term outcomes of population-based and family-history (FH)/clinical-criteria-based BRCA testing on psychological health and quality of life. DESIGN: Randomised controlled trial (RCT) (ISRCTN73338115) GCaPPS, with two-arms: (i) population-screening (PS); (ii) FH/clinical-criteria-based testing. SETTING: North London Ashkenazi-Jewish (AJ) population. POPULATION/SAMPLE: AJ women/men. METHODS: Population-based RCT (1:1). Participants were recruited through self-referral, following pre-test genetic counselling from the North London AJ population. INCLUSION CRITERIA: AJ women/men >18 years old; exclusion-criteria: prior BRCA testing or first-degree relatives of BRCA-carriers. INTERVENTIONS: Genetic testing for three Jewish BRCA founder-mutations: 185delAG (c.68_69delAG), 5382insC (c.5266dupC) and 6174delT (c.5946delT), for (i) all participants in PS arm; (ii) those fulfilling FH/clinical criteria in FH arm. Linear mixed models and appropriate contrast tests were used to analyse the impact of BRCA testing on psychological and quality-of-life outcomes over 3 years. MAIN OUTCOME MEASURES: Validated questionnaires (HADS/MICRA/HAI/SF12) used to analyse psychological wellbeing/quality-of-life outcomes at baseline/1-year/2-year/3-year follow up. RESULTS: In all, 1034 individuals (691 women, 343 men) were randomised to PS (n = 530) or FH (n = 504) arms. There was a statistically significant decrease in anxiety (P = 0.046) and total anxiety-&-depression scores (P = 0.0.012) in the PS arm compared with the FH arm over 3 years. No significant difference was observed between the FH and PS arms for depression, health-anxiety, distress, uncertainty, quality-of-life or experience scores associated with BRCA testing. Contrast tests showed a decrease in anxiety (P = 0.018), health-anxiety (P < 0.0005) and quality-of-life (P = 0.004) scores in both PS and FH groups over time. Eighteen of 30 (60%) BRCA carriers identified did not fulfil clinical criteria for BRCA testing. Total BRCA prevalence was 2.9% (95% CI 1.97-4.12%), BRCA1 prevalence was 1.55% (95% CI 0.89-2.5%) and BRCA2 prevalence was 1.35% (95% CI 0.74-2.26%). CONCLUSION: Population-based AJ BRCA testing does not adversely affect long-term psychological wellbeing or quality-of-life, decreases anxiety and could identify up to 150% additional BRCA carriers. TWEETABLE ABSTRACT: Population BRCA testing in Ashkenazi Jews reduces anxiety and does not adversely affect psychological health or quality of life.


Assuntos
Ansiedade , Detecção Precoce de Câncer , Genes BRCA1 , Genes BRCA2 , Síndrome Hereditária de Câncer de Mama e Ovário , Qualidade de Vida , Adulto , Ansiedade/fisiopatologia , Ansiedade/prevenção & controle , Detecção Precoce de Câncer/métodos , Detecção Precoce de Câncer/psicologia , Feminino , Predisposição Genética para Doença/psicologia , Testes Genéticos/métodos , Testes Genéticos/estatística & dados numéricos , Síndrome Hereditária de Câncer de Mama e Ovário/diagnóstico , Síndrome Hereditária de Câncer de Mama e Ovário/etnologia , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Síndrome Hereditária de Câncer de Mama e Ovário/psicologia , Humanos , Judeus/genética , Judeus/estatística & dados numéricos , Londres/epidemiologia , Masculino , Anamnese/estatística & dados numéricos , Incerteza
7.
J Genet Couns ; 29(1): 56-66, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31663226

RESUMO

The intent of carrier screening is to identify individuals at risk for having a child with a genetic disorder. American College of Medical Genetics and Genomics (ACMG) guidelines currently recommend that individuals of Ashkenazi Jewish (AJ) descent be screened for carrier status for nine disorders. However, a joint statement from five professional organizations acknowledges benefits of expanded carrier screening and this is becoming common practice. To better understand the impact of expanded carrier screening for the AJ population, we performed a retrospective analysis comparing detection rates for AJ individuals screened by two targeted panels: a pan-ethnic panel comprising 87 disorders and an AJ panel comprising an 18-disorder subset of the pan-ethnic panel. We also extrapolated the detection rates for the 18 AJ disorders from the pan-ethnic panel data and for the nine ACMG-recommended disorders using data from both panels. We found that with the pan-ethnic panel 431/1150 (37.5%) individuals were carriers of at least one disorder, compared to 319/1248 (25.6%) individuals with the AJ panel. If the pan-ethnic panel cohort were tested in the AJ panel or for the nine ACMG-recommended disorders, the detection rates would have been 280/1150 (24.3%) and 207/1150 (18.0%) respectively. Therefore, the pan-ethnic expanded carrier screening panel of 87 disorders increased the carrier detection rate in AJ individuals by approximately 50% and 100%, respectively, compared with a panel of 18 disorders considered relevant to the AJ population and the ACMG-recommended disorders. Twenty disorders accounted for the difference in carrier detection rates between the pan-ethnic and AJ panels. Of these, three were among the 10 most commonly identified disorders. Our findings reinforce published data that targeted AJ panels are less effective than a pan-ethnic panel in carrier detection among AJ individuals and provide metrics to address the impact of expanded carrier screening in this population.


Assuntos
Triagem de Portadores Genéticos , Judeus/genética , Estudos de Coortes , Feminino , Humanos , Masculino , Estudos Retrospectivos
8.
Ophthalmic Genet ; 40(5): 443-448, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31651202

RESUMO

Background: Mutations in CACNA1F have been mainly associated with X-linked incomplete congenital stationary night blindness (icCSNB). Variable phenotypic expression in females was reported in some families. We report here three non-related Ashkenazi Jewish families originating in Eastern Europe, that included males and a many affected females, initially diagnosed with variable retinal phenotypes.Materials and Methods: Whole exome sequencing (WES), Sanger sequencing and microsatellite haplotyping were used for genetic analysis. Complete ophthalmologic examination was performed including visual acuity, refraction, colour vision, slit-lamp, fundoscopy and electroretinography (ERG).Results: We identified four affected males, showing moderate visual impairment, and seven female carriers, six of them presenting mild to moderate visual impairment. Infantile nystagmus was found in all affected males and in 5/7 females. Nyctalopia and myopia were common in both males and females. Initial clinical differential diagnosis included cone-dystrophy, cone-rod dystrophy, cone-dystrophy with supernormal rod response or CSNB based on ERG results. WES and Sanger sequencing revealed a previously described missense mutation c.2225T>G; p.(F742C) in CACNA1F (NM_001256789.2) in all three families, encompassed by a shared haplotypeConclusions: Our data suggests that p.(F742C) in CACNA1F is an X-linked founder mutation in Ashkenazi Jews originating in Eastern Europe. This mutation causes a mild-to-moderate icCSNB phenotype, expressed in most female carriers. A targeted test for this variant in suspected patients may initiate diagnostic analysis. Our results highlight the relevance of WES in the clinic, allowing fast and accurate diagnosis for unclear and variable clinical phenotype and in pedigrees with multiple possible inheritance patterns.


Assuntos
Artrite/genética , Canais de Cálcio Tipo L/genética , Surdez/genética , Oftalmopatias Hereditárias/etiologia , Doenças Genéticas Ligadas ao Cromossomo X/etiologia , Hemizigoto , Heterozigoto , Judeus/genética , Mutação de Sentido Incorreto , Miopia/etiologia , Cegueira Noturna/etiologia , Policondrite Recidivante/genética , Doenças Retinianas/etiologia , Adulto , Idoso , Oftalmopatias Hereditárias/patologia , Feminino , Seguimentos , Efeito Fundador , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Testes Genéticos , Humanos , Masculino , Pessoa de Meia-Idade , Miopia/patologia , Cegueira Noturna/patologia , Linhagem , Fenótipo , Prognóstico , Doenças Retinianas/patologia , Sequenciamento Completo do Exoma
9.
Genes (Basel) ; 10(10)2019 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-31635417

RESUMO

PURPOSE: To identify rare genetic variants in early age-related macular degeneration (AMD) utilizing whole-exome sequencing (WES). METHODS: Eight non-related early-AMD families of different Jewish ethnicities were ascertained. Initial mutation screening (phase-1) included common complement factor-H (CFH) p.Y402H; and age related maculopathy susceptibility 2 (ARMS2) p.A69S; and rare variants complement factor-I (CFI) p.V412M; and hemicentin1 (HMCN1) c.4163delC identified previously in our population. Four families, whose initial screening for the aforementioned variants was negative, underwent WES (phase-2). Bioinformatics filtering was based on functionality (from a panel of 234 genes with proven or presumed association to AMD); predicted severity; and frequency (rare variants with minor allele frequency <1%). When applicable, further screening for specific rare variants was carried out on additional cases of similar ethnicities and phenotypes (phase-3). RESULTS: Phase-1 identified three families carrying CFI p.V412M mutation. WES analysis detected probable disease-related variants in three out of the remaining families. These included: a family with a variant in PLEKHA1 gene p.S177N; a family with previously reported variant p.R1210C in CFH gene; and two families with the C3 p.R735W variant. CONCLUSIONS: Rare, high-penetrance variants have a profound contribution to early-AMD pathogenesis. Utilization of WES in genetic research of multifactorial diseases as AMD, allows a thorough comprehensive analysis with the identification of previously unreported rare variants.


Assuntos
Degeneração Macular/genética , Mutação , Idoso , Fator H do Complemento/genética , Fator I do Complemento/genética , Feminino , Heterozigoto , Humanos , Imunoglobulinas/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Judeus/genética , Degeneração Macular/etnologia , Degeneração Macular/patologia , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Linhagem , Penetrância , Proteínas/genética
10.
Nature ; 574(7779): 553-558, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31645721

RESUMO

Age-associated chronic inflammation (inflammageing) is a central hallmark of ageing1, but its influence on specific cells remains largely unknown. Fibroblasts are present in most tissues and contribute to wound healing2,3. They are also the most widely used cell type for reprogramming to induced pluripotent stem (iPS) cells, a process that has implications for regenerative medicine and rejuvenation strategies4. Here we show that fibroblast cultures from old mice secrete inflammatory cytokines and exhibit increased variability in the efficiency of iPS cell reprogramming between mice. Variability between individuals is emerging as a feature of old age5-8, but the underlying mechanisms remain unknown. To identify drivers of this variability, we performed multi-omics profiling of fibroblast cultures from young and old mice that have different reprogramming efficiencies. This approach revealed that fibroblast cultures from old mice contain 'activated fibroblasts' that secrete inflammatory cytokines, and that the proportion of activated fibroblasts in a culture correlates with the reprogramming efficiency of that culture. Experiments in which conditioned medium was swapped between cultures showed that extrinsic factors secreted by activated fibroblasts underlie part of the variability between mice in reprogramming efficiency, and we have identified inflammatory cytokines, including TNF, as key contributors. Notably, old mice also exhibited variability in wound healing rate in vivo. Single-cell RNA-sequencing analysis identified distinct subpopulations of fibroblasts with different cytokine expression and signalling in the wounds of old mice with slow versus fast healing rates. Hence, a shift in fibroblast composition, and the ratio of inflammatory cytokines that they secrete, may drive the variability between mice in reprogramming in vitro and influence wound healing rate in vivo. This variability may reflect distinct stochastic ageing trajectories between individuals, and could help in developing personalized strategies to improve iPS cell generation and wound healing in elderly individuals.


Assuntos
Envelhecimento/metabolismo , Reprogramação Celular , Senescência Celular/fisiologia , Fibroblastos/metabolismo , Cicatrização , Animais , Linhagem Celular , Reprogramação Celular/efeitos dos fármacos , Meios de Cultivo Condicionados/farmacologia , Citocinas/metabolismo , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/metabolismo , Mediadores da Inflamação/metabolismo , Judeus/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Análise de Sequência de RNA , Transdução de Sinais/efeitos dos fármacos , Análise de Célula Única , Processos Estocásticos , Fatores de Tempo , Cicatrização/efeitos dos fármacos
11.
Mol Genet Metab ; 128(4): 470-475, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31662221

RESUMO

BACKGROUND: GBA variants are the most common genetic risk factors for Parkinson's disease (PD) world-wide, and can be found in up to 20% of Ashkenazi PD patients. The E326K variant, which is not considered a Gaucher's disease causing mutation, was recently shown to increase the risk for PD. Since E326K is a common variant among Europeans, Finnish and Ashkenazi (2.4, 8.6 and 1.2% carrier rate, respectively), we aimed to refine its involvement in PD. METHODS: 1200 consecutively recruited PD patients of a full Ashkenazi origin were genotyped for 10 GBA variants, the LRRK2-G2019S and the SMPD1-L302P. Alleles' frequencies were compared to controls, composed of 378 elderly healthy individuals and the non-neuro gnomAD Ashkenazi database. Odds-Ratio (OR) and age-at-motor-symptom-onset (AAO) were also calculated for all genotypes. RESULTS: All allelic variations tested had significant allelic ORs, demonstrating a wide range (1.86-12.84). The lowest allelic OR was observed for E326K (p = .013). Forty-five patients (of 1200, 3.75%) had at least two mutations (of the 12 tested), compared to 2 (0.53%) among 378 controls (p = .0013). Of the E326K carrier patients, 37% (10/27) carried additional mutations and the genotypic OR for individuals who carried only the E326K variant was 1.07. It did not reach statistical significance even when simulating the expected carrier frequency of E326K in 100,000 Ashkenazi controls (p = .39). In addition, an additive effect was demonstrated for risk in carriers of two mutations, the LRRK2-G2019S and a mild-GBA mutation (N370S or R496H), compared to carriers of only one mutation in one of these genes (simulated OR 11.79 compared to 7.58 and 2.49, respectively). An additive effect was also suggested for earlier AAO (5.0 years earlier than in non-carriers, compared to 3.1 and 2.2 years, respectively). CONCLUSIONS: Compared to previous studies, we demonstrate here a higher frequency of PD patients that carry two mutations. The GBA-E326K is more likely to affect PD risk when accompanied by another mutation, and an additive effect on risk and earlier AAO was proposed for carriers of LRRK2/mild-GBA double mutations. Altogether, these data support an oligogenic approach to PD genetics.


Assuntos
Alelos , Substituição de Aminoácidos , Predisposição Genética para Doença , Glucosilceramidase/genética , Doença de Parkinson/epidemiologia , Doença de Parkinson/genética , Idade de Início , Feminino , Frequência do Gene , Estudos de Associação Genética , Genótipo , Humanos , Judeus/genética , Masculino , Mutação , Razão de Chances , Medição de Risco , Fatores de Risco
12.
J Biosci ; 44(3)2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31389361

RESUMO

The South Asian populations have a mosaic of ancestries likely due to the interactions of long-term populations of the landmass and those of East andWest Eurasia. Apart from prehistoric dispersals, there are some known population movements to India. In this study,we focussed on the migration of Jewish and Parsi populations on temporal and spatial scales. The existence of Jewish and Parsi communities in India are recorded since ancient times. However, due to the lack of high-resolution genetic data, their origin and affiliation with other Indian and non-Indian populations remains shrouded in legends. Earlier genetic studies on populations of Indian Jews have found evidence for a minor shared ancestry of Indian Jews with Middle Eastern (Jews) populations, whereas for Parsis, the Iranian link was proposed. Recently, in our high-resolution study, we were able to quantify the admixture dynamics of these groups, which has suggested a male-biased admixture. Here, we added the newly available ancient samples and revisited the interplay of genes and cultures. Thus, in this study we reconstructed a broad genetic profile of Indian Jews and Parsis to paint a fine-grained picture of these ethnic groups.


Assuntos
Grupo com Ancestrais do Continente Asiático/história , DNA Antigo/análise , Grupo com Ancestrais do Continente Europeu/história , Genética Populacional , Migração Humana/tendências , Judeus/história , Aculturação , Antropologia/métodos , Grupos Étnicos , Feminino , Variação Genética , História Antiga , Humanos , Índia/etnologia , Irã (Geográfico)/etnologia , Judeus/genética , Masculino
13.
Parkinsonism Relat Disord ; 66: 158-165, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31422003

RESUMO

OBJECTIVE: To determine the frequency of mutations known to cause autosomal dominant Parkinson disease (PD) in a series with more than 10% of Sweden's estimated number of PD patients. METHODS: The Swedish Parkinson Disease Genetics Network was formed as a national multicenter consortium of clinical researchers who together have access to DNA from a total of 2,206 PD patients; 85.4% were from population-based studies. Samples were analyzed centrally for known pathogenic mutations in SNCA (duplications/triplications, p.Ala30Pro, p.Ala53Thr) and LRRK2 (p.Asn1437His, p.Arg1441His, p.Tyr1699Cys, p.Gly2019Ser, p.Ile2020Thr). We compared the frequency of these mutations in Swedish patients with published PD series and the gnomAD database. RESULTS: A family history of PD in first- and/or second-degree relatives was reported by 21.6% of participants. Twelve patients (0.54%) carried LRRK2 p.(Gly2019Ser) mutations, one patient (0.045%) an SNCA duplication. The frequency of LRRK2 p.(Gly2019Ser) carriers was 0.11% in a matched Swedish control cohort and a similar 0.098% in total gnomAD, but there was a marked difference between ethnicities in gnomAD, with 42-fold higher frequency among Ashkenazi Jews than all others combined. CONCLUSIONS: In relative terms, the LRRK2 p.(Gly2019Ser) variant is the most frequent mutation among Swedish or international PD patients, and in gnomAD. SNCA duplications were the second most common of the mutations examined. In absolute terms, however, these known pathogenic variants in dominant PD genes are generally very rare and can only explain a minute fraction of familial aggregation of PD. Additional genetic and environmental mechanisms may explain the frequent co-occurrence of PD in close relatives.


Assuntos
Predisposição Genética para Doença/genética , Doença de Parkinson/genética , Variações do Número de Cópias de DNA , Bases de Dados Genéticas , Humanos , Judeus/genética , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Mutação , Doença de Parkinson/etnologia , Suécia/etnologia , alfa-Sinucleína/genética
14.
Am J Med Genet A ; 179(10): 2144-2151, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31287223

RESUMO

Warsaw breakage syndrome (WABS), caused by bi-allelic variants in the DDX11 gene, is a rare cohesinopathy characterized by pre- and postnatal growth retardation, microcephaly, intellectual disability, facial dysmorphia, and sensorineural hearing loss due to cochlear hypoplasia. The DDX11 gene codes for an iron-sulfur DNA helicase in the Superfamily 2 helicases and plays an important role in genomic stability and maintenance. Fourteen individuals with WABS have been previously reported in the medical literature. Affected individuals have been of various ethnic backgrounds with different pathogenic variants. We report two unrelated individuals of Ashkenazi Jewish descent affected with WABS, who are homozygous for the c.1763-1G>C variant in the DDX11 gene. Their phenotype is consistent with previously reported individuals. RNA studies showed that this variant causes an alternative splice acceptor site leading to a frameshift in the open reading frame. Carrier screening of the c.1763-1G>C variant in the Jewish population revealed a high carrier frequency of 1 in 68 in the Ashkenazi Jewish population. Due to the high carrier frequency and the low number of affected individuals, we hypothesize a high rate of miscarriage of homozygous fetuses and/or subfertility for carrier couples. If the carrier frequency is reproducible in additional Ashkenazi Jewish populations, we suggest including DDX11 to Ashkenazi Jewish carrier screening panels.


Assuntos
Anormalidades Múltiplas/genética , Judeus/genética , Adolescente , Sequência de Bases , Criança , Pré-Escolar , Feminino , Testes Genéticos , Heterozigoto , Humanos , Lactente , Recém-Nascido , Masculino , Fenótipo , Processamento de RNA/genética , Síndrome , Adulto Jovem
15.
PLoS Genet ; 15(7): e1008082, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31283753

RESUMO

Despite intensive study, most of the specific genetic factors that contribute to variation in human height remain undiscovered. We conducted a family-based linkage study of height in a unique cohort of very large nuclear families from a founder (Jewish) population. This design allowed for increased power to detect linkage, compared to previous family-based studies. Loci we identified in discovery families could explain an estimated lower bound of 6% of the variance in height in validation families. We showed that these loci are not tagging known common variants associated with height. Rather, we suggest that the observed signals arise from variants with large effects that are rare globally but elevated in frequency in the Jewish population.


Assuntos
Estatura/genética , Mapeamento Cromossômico/métodos , Judeus/genética , Locos de Características Quantitativas , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Frequência do Gene , Ligação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Adulto Jovem
16.
Clin Transl Gastroenterol ; 10(7): e00054, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31259752

RESUMO

OBJECTIVES: Loss-of-function mutations of BMPR1A cause juvenile polyposis syndrome (JPS), but large genomic deletions in BMPR1A are rare, reported in few families only, and data regarding the associated phenotype are limited. METHODS: We investigated clinical features and genomic data of 7 extended seemingly unrelated families with a genomic deletion of the entire coding region of BMPR1A. We defined mutation size, mutation prevalence, and tumor pathogenesis using whole-genome sequencing, targeted genotyping, and haplotype analysis. RESULTS: Patients with JPS from 7 families of Bukharin Jewish ancestry carried a deletion of 429 kb, encompassing the BMPR1A coding sequence and 8 downstream genes. Haplotype analysis and testing controls identified this as a common founder mutation occurring in 1/124 individuals of Bukharin origin. Tumor testing did not demonstrate loss of heterozygosity. Among carriers, JPS was almost fully penetrant, but clinical features varied widely, ranging from mild to very severe, including pan-enteric polyps, gastritis, and colorectal, esophageal, and testicular cancer, and carriers with phenotypes, which would not have raised suspicion of JPS. DISCUSSION: The phenotype in this large cohort was extremely variable, although all carriers shared the same variant and the same genetic background. New observations include a preponderance of adenomatous rather than juvenile polyps, possible association with testicular cancer, and unexpected upper gastrointestinal involvement.


Assuntos
Receptores de Proteínas Morfogenéticas Ósseas Tipo I/genética , Gastrite/complicações , Polipose Intestinal/congênito , Síndromes Neoplásicas Hereditárias/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Pré-Escolar , Neoplasias Colorretais/complicações , Neoplasias Colorretais/etnologia , Neoplasias Colorretais/genética , Neoplasias Esofágicas/complicações , Neoplasias Esofágicas/etnologia , Neoplasias Esofágicas/genética , Feminino , Gastrite/etnologia , Gastrite/genética , Genoma , Heterozigoto , Humanos , Polipose Intestinal/genética , Pólipos Intestinais/complicações , Pólipos Intestinais/etnologia , Pólipos Intestinais/genética , Pólipos Intestinais/patologia , Israel/etnologia , Judeus/genética , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Deleção de Sequência/genética , Neoplasias Testiculares/complicações , Neoplasias Testiculares/etnologia , Neoplasias Testiculares/genética , Adulto Jovem
18.
Cornea ; 38(8): 1033-1039, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31107761

RESUMO

PURPOSE: To report a case of bilateral and repetitive corneal perforations after corneal cross-linking (CXL) for keratoconus in a woman harboring potentially pathogenic variants in the ZNF469 gene and to characterize the keratoconus phenotype in this woman and her daughter who shared the same ZNF469 mutations. METHODS: Clinical characterization of the proband and her daughter followed by sequencing of the genes associated with brittle cornea syndrome, ZNF469 and PRDM5, in both individuals. RESULTS: An Ashkenazi Jewish woman in her sixth decade presented with diffuse corneal thinning and progressive steepening consistent with keratoconus. After CXL, epithelium-off in the first eye and epithelium-on in the second, she developed spontaneous corneal perforations in each eye. Her daughter in her fourth decade demonstrated a similar pattern of diffuse corneal thinning and progressive corneal steepening but did not undergo CXL and did not develop corneal perforation. Screening of the ZNF469 and PRDM5 genes revealed 3 missense ZNF469 variants (c.2035G>A, c.10244G>C, and c.11119A>G) in cis arrangement on 1 allele of ZNF469 in both proband and her daughter. Although the 3 variants share low (<0.01) global minor allele frequencies, each has significantly higher minor allele frequencies (0.01-0.03) in the Ashkenazi Jewish population, leading to uncertainty regarding a pathogenic role for the identified variants. CONCLUSIONS: CXL may be associated with the development of corneal perforation in particular at-risk individuals with keratoconus. Identifying clinical and genetic risk factors, including screening of ZNF469 and PRDM5, may be useful in the prevention of significant complications after CXL.


Assuntos
Perfuração da Córnea/etiologia , Reagentes para Ligações Cruzadas/efeitos adversos , Ceratocone/genética , Mutação de Sentido Incorreto , Fotoquimioterapia/efeitos adversos , Fatores de Transcrição/genética , Adulto , Colágeno/metabolismo , Perfuração da Córnea/diagnóstico , Substância Própria/metabolismo , Topografia da Córnea , Proteínas de Ligação a DNA/genética , Feminino , Humanos , Judeus/genética , Ceratocone/tratamento farmacológico , Ceratocone/metabolismo , Pessoa de Meia-Idade , Fármacos Fotossensibilizantes/efeitos adversos , Reação em Cadeia da Polimerase , Raios Ultravioleta
19.
Genet Med ; 21(9): 1940-1947, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30846881

RESUMO

PURPOSE: Prenatal genetic carrier screening can identify parents at risk of having a child affected by a recessive condition. However, the conditions/genes most appropriate for screening remain a matter of debate. Estimates of carrier rates across genes are needed to guide construction of carrier screening panels. METHOD: We leveraged an exome sequencing database (n = 123,136) to estimate carrier rates across six major ancestries for 415 genes associated with severe recessive conditions. RESULTS: We found that 32.6% (East Asian) to 62.9% (Ashkenazi Jewish) of individuals are variant carriers in at least one of the 415 genes. For couples, screening all 415 genes would identify 0.17-2.52% of couples as being at risk for having a child affected by one of these conditions. Screening just the 40 genes with carrier rate >1.0% would identify more than 76% of these at-risk couples. An ancestry-specific panel designed to capture genes with carrier rates >1.0% would include 5 to 28 genes, while a comparable panethnic panel would include 40 genes. CONCLUSION: Our work guides the design of carrier screening panels and provides data to assist in counseling prospective parents. Our results highlight a high cumulative carrier rate across genes, underscoring the need for careful selection of genes for screening.


Assuntos
Triagem de Portadores Genéticos , Doenças Genéticas Inatas/diagnóstico , Judeus/genética , Diagnóstico Pré-Natal , Grupo com Ancestrais do Continente Asiático/genética , Feminino , Aconselhamento Genético , Doenças Genéticas Inatas/genética , Heterozigoto , Humanos , Gravidez , Sequenciamento Completo do Exoma/métodos
20.
Ned Tijdschr Geneeskd ; 1632019 03 01.
Artigo em Holandês | MEDLINE | ID: mdl-30875152

RESUMO

Three BRCA1/BRCA2 mutations occur more frequently in the Jewish population than in the general population. In Jewish patients with breast cancer about 10% of cases are caused by one of these mutations; consequently, all patients with breast cancer and who are of Jewish ancestry, or their healthy family members, are eligible for genetic testing.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/genética , Judeus/genética , Mutação , Neoplasias Ovarianas/genética , Adulto , Proteína BRCA1/metabolismo , Proteína BRCA2/metabolismo , Feminino , Testes Genéticos , Humanos , Pessoa de Meia-Idade
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