RESUMO
Studies of long-lived individuals have revealed few genetic mechanisms for protection against age-associated disease. Therefore, we pursued genome sequencing of a related phenotype-healthy aging-to understand the genetics of disease-free aging without medical intervention. In contrast with studies of exceptional longevity, usually focused on centenarians, healthy aging is not associated with known longevity variants, but is associated with reduced genetic susceptibility to Alzheimer and coronary artery disease. Additionally, healthy aging is not associated with a decreased rate of rare pathogenic variants, potentially indicating the presence of disease-resistance factors. In keeping with this possibility, we identify suggestive common and rare variant genetic associations implying that protection against cognitive decline is a genetic component of healthy aging. These findings, based on a relatively small cohort, require independent replication. Overall, our results suggest healthy aging is an overlapping but distinct phenotype from exceptional longevity that may be enriched with disease-protective genetic factors. VIDEO ABSTRACT.
Assuntos
Envelhecimento/genética , Estudo de Associação Genômica Ampla , Longevidade , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/genética , Envelhecimento Cognitivo , Estudos de Coortes , Doença da Artéria Coronariana/genética , Feminino , Predisposição Genética para Doença , Humanos , MasculinoRESUMO
Preterm birth (PTB) complications are the leading cause of long-term morbidity and mortality in children. By using whole blood samples, we integrated whole-genome sequencing (WGS), RNA sequencing (RNA-seq), and DNA methylation data for 270 PTB and 521 control families. We analyzed this combined dataset to identify genomic variants associated with PTB and secondary analyses to identify variants associated with very early PTB (VEPTB) as well as other subcategories of disease that may contribute to PTB. We identified differentially expressed genes (DEGs) and methylated genomic loci and performed expression and methylation quantitative trait loci analyses to link genomic variants to these expression and methylation changes. We performed enrichment tests to identify overlaps between new and known PTB candidate gene systems. We identified 160 significant genomic variants associated with PTB-related phenotypes. The most significant variants, DEGs, and differentially methylated loci were associated with VEPTB. Integration of all data types identified a set of 72 candidate biomarker genes for VEPTB, encompassing genes and those previously associated with PTB. Notably, PTB-associated genes RAB31 and RBPJ were identified by all three data types (WGS, RNA-seq, and methylation). Pathways associated with VEPTB include EGFR and prolactin signaling pathways, inflammation- and immunity-related pathways, chemokine signaling, IFN-γ signaling, and Notch1 signaling. Progress in identifying molecular components of a complex disease is aided by integrated analyses of multiple molecular data types and clinical data. With these data, and by stratifying PTB by subphenotype, we have identified associations between VEPTB and the underlying biology.
Assuntos
Predisposição Genética para Doença/genética , Nascimento Prematuro/genética , Metilação de DNA/genética , Feminino , Genômica/métodos , Humanos , Recém-Nascido , Masculino , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Transdução de Sinais/genética , Sequenciamento Completo do Genoma/métodosRESUMO
The study objective was to test the hypothesis that having histocompatible children increases the risk of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), possibly by contributing to the persistence of fetal cells acquired during pregnancy. We conducted a case control study using data from the UC San Francisco Mother Child Immunogenetic Study and studies at the Inova Translational Medicine Institute. We imputed human leukocyte antigen (HLA) alleles and minor histocompatibility antigens (mHags). We created a variable of exposure to histocompatible children. We estimated an average sequence similarity matching (SSM) score for each mother based on discordant mother-child alleles as a measure of histocompatibility. We used logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals. A total of 138 RA, 117 SLE, and 913 control mothers were analyzed. Increased risk of RA was associated with having any child compatible at HLA-B (OR 1.9; 1.2-3.1), DPB1 (OR 1.8; 1.2-2.6) or DQB1 (OR 1.8; 1.2-2.7). Compatibility at mHag ZAPHIR was associated with reduced risk of SLE among mothers carrying the HLA-restriction allele B*07:02 (n = 262; OR 0.4; 0.2-0.8). Our findings support the hypothesis that mother-child histocompatibility is associated with risk of RA and SLE.
Assuntos
Artrite Reumatoide/etiologia , Histocompatibilidade/imunologia , Lúpus Eritematoso Sistêmico/etiologia , Adulto , Alelos , Artrite Reumatoide/genética , Estudos de Casos e Controles , Criança , Feminino , Frequência do Gene/genética , Predisposição Genética para Doença , Antígenos HLA-B/genética , Antígenos HLA-B/metabolismo , Cadeias beta de HLA-DQ/genética , Cadeias beta de HLA-DQ/metabolismo , Histocompatibilidade/genética , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Lúpus Eritematoso Sistêmico/genética , Masculino , Mães , Razão de Chances , GravidezRESUMO
Parenteral nutrition-associated cholestasis (PNAC) causes serious morbidity in the neonatal intensive care unit. Infection with gut-associated bacteria is associated with cholestasis, but the role of intestinal microbiota in PNAC is poorly understood. We examined the composition of stool microbiota from premature twins discordant for PNAC as a strategy to reduce confounding from variables associated with both microbiota and cholestasis. Eighty-four serial stool samples were included from 4 twin sets discordant for PNAC. Random Forests was utilized to determine genera most discriminatory in classifying samples from infants with and without PNAC. In infants with PNAC, we detected a significant increase in the relative abundance of Klebsiella, Veillonella, Enterobacter, and Enterococcus (Pâ<â0.05). Bray-Curtis dissimilarities in infants with PNAC were significantly different (Pâ<â0.05) from infants without PNAC. Our findings warrant further exploration in larger cohorts and experimental models of PNAC to determine if a microbiota signature predicts PNAC, as a basis for future interventions to mitigate liver injury.
Assuntos
Colestase , Microbiota , Colestase/etiologia , Colestase/terapia , Idade Gestacional , Humanos , Lactente , Recém-Nascido , Recém-Nascido Prematuro , Nutrição Parenteral/efeitos adversosRESUMO
BACKGROUND: Preliminary data suggest that the urinary microbiome may play a role in bladder cancer. Information regarding the most suitable method of collecting urine specimens is needed for the large population studies needed to address this. To compare microbiome metrics resulting from 16S ribosomal RNA gene sequencing between midstream, voided specimens and those obtained at cystoscopy. METHODS: Adults, with a history of superficial urothelial cell carcinoma (non-muscle invasive bladder cancer) being followed with periodic surveillance cystoscopy had a urine sample collected by a mid-stream, voided technique and then from the bladder at cystoscopy. Urine samples underwent 16S ribosomal RNA gene sequencing on the Illumina MiSeq platform. RESULTS: 22 subjects (8 female, 14 male) were included. There was no significant difference in beta diversity (diversity between samples) in all samples between collection methods. However, analysis by sex revealed a difference between voided and cystoscopy samples from the same individual in males (p = 0.006, Adonis test) but not in females (p = 0.317, Adonis test). No differences were seen by collection method in any alpha diversity (diversity within a sample) measurement or differential abundance of taxa. CONCLUSIONS: Beta diversity of the urine microbiome did differ by collection method for males only. This suggests that the urinary microbiomes of the two collection methods are not equivalent to each other, at least in males, which is the sex that bladder cancer occurs most frequently in. Therefore, the same collection method within a given study should be used.
Assuntos
Cistoscopia/métodos , Microbiota/fisiologia , Neoplasias da Bexiga Urinária/urina , Coleta de Urina/métodos , Urina/microbiologia , Urina/fisiologia , Idoso , Idoso de 80 Anos ou mais , Cistoscopia/normas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sequência de RNA/métodos , Neoplasias da Bexiga Urinária/diagnóstico , Coleta de Urina/normasRESUMO
BACKGROUND: Hispanic children are disproportionately affected by obesity, with this disparity starting at a young age, and there is a paucity of data comparing factors associated with excess weight in the first year of life in Hispanic vs. non-Hispanic populations. METHODS: Excess weight was defined as weight-for-length ≥95th percentile. The associations of potential risk factors were compared by ethnicity stratification. RESULTS: Of the 1009 children, 302 (30.0%) were Hispanic and 707 (70.0%) were non-Hispanic White. The rate of excess weight was 30.1% and 13.6% among Hispanic and non-Hispanic White children, respectively. Factors associated with excess weight for non-Hispanic White children were higher than recommended weight gain during pregnancy (odds ratio (OR) 1.8 (1.2-3.1)), higher paternal body mass index (BMI) (OR 1.1 (1.02-1.15)), higher birth weight (OR 1.001 (1.001-1.002)), and lower breast milk feedings at 6 months (OR 0.98 (0.96-0.98)). Factors associated with excess weight for Hispanic children were lower maternal education (OR 2.37 (1.1-4.5)) and lower breast milk feedings at 6 months (OR 0.98 (0.96-0.99)). CONCLUSION: There are differential risk factors associated with excess weight at 12 months between Hispanic and non-Hispanic White children. Identification of differential factors in different ethnicities may allow for more targeted anticipatory guidance reduce obesity in at-risk populations.
Assuntos
Peso Corporal , Obesidade Infantil/etnologia , Obesidade Infantil/genética , Aumento de Peso , Peso ao Nascer , Índice de Massa Corporal , Aleitamento Materno , Pai , Feminino , Hispânico ou Latino/estatística & dados numéricos , Humanos , Lactente , Recém-Nascido , Masculino , Mães , Razão de Chances , Gravidez , Fatores de Risco , Determinantes Sociais da Saúde , Estados Unidos/epidemiologia , População Branca/estatística & dados numéricosRESUMO
Congenital disorders of autophagy are multisystem disorders with significant neurological involvement. Ectopic p-granules protein 5 (EPG5)-associated Vici syndrome is a prototypical congenital disorder of autophagy and presents with the cardinal features of agenesis of the corpus callosum, cataracts, cardiomyopathy, immunodeficiency, and oculocutaneous hypopigmentation. The majority of EPG5 variants leading to Vici syndrome are null alleles with only a few missense variants published to date. Here we report a 3.5-year-old male with compound heterozygous EPG5 variants [NM_020964.2: c.772G > T/c.5943-9_5943-5del]. His clinical presentation deviates notably from classic Vici syndrome with a lack of hypopigmentation, cataracts, immunodeficiency, cardiomyopathy, or failure to thrive. Neurological manifestations within the known disease spectrum include early-onset global developmental delay, hypotonia, and postnatal microcephaly. Seizures, hearing loss, or optic nerve atrophy are absent, however. Magnetic resonance imaging demonstrates a thin but fully formed corpus callosum. Based on the ameliorated and primarily neurological phenotype, we hypothesized that the functional impact of the EPG5 variants present would be milder with a higher amount of residual EPG5 expression. Analyses of EPG5 messenger ribonucleic acid (mRNA) in the patient and his parents were performed to examine expression level and splicing; mRNA from a healthy control and a patient with classic Vici syndrome was also included. Aberrant splicing due to the intronic mutation was detected, but no loss of expression. In contrast, we observed a 50% reduction in mRNA expression in classic Vici syndrome patient fibroblasts. These results support a model of disease severity, which correlates to the dosage of EPG5 expression.
Assuntos
Agenesia do Corpo Caloso/genética , Proteínas Relacionadas à Autofagia/genética , Catarata/genética , Corpo Caloso/diagnóstico por imagem , Mutação , Fenótipo , Proteínas de Transporte Vesicular/genética , Agenesia do Corpo Caloso/diagnóstico por imagem , Catarata/diagnóstico por imagem , Pré-Escolar , Humanos , Imageamento por Ressonância Magnética , Masculino , Índice de Gravidade de DoençaRESUMO
Here, we applied targeted capture to examine 153 genes representative of all the major vertebrate developmental pathways among 333 probands to rank their relative significance as causes for holoprosencephaly (HPE). We now show that comparisons of variant transmission versus nontransmission among 136 HPE Trios indicates some reported genes now lack confirmation, while novel genes are implicated. Furthermore, we demonstrate that variation of modest intrinsic effect can synergize with these driver mutations as gene modifiers.
Assuntos
Fatores de Crescimento de Fibroblastos/metabolismo , Predisposição Genética para Doença , Proteínas Hedgehog/metabolismo , Holoprosencefalia/genética , Holoprosencefalia/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo , Fatores de Crescimento de Fibroblastos/genética , Frequência do Gene , Estudos de Associação Genética , Genótipo , Proteínas Hedgehog/genética , Holoprosencefalia/diagnóstico , Humanos , Padrões de Herança , Mutação , Fenótipo , Síndrome , Fator de Crescimento Transformador beta/genéticaRESUMO
Primary coenzyme Q10 (CoQ10 ; MIM# 607426) deficiencies are an emerging group of inherited mitochondrial disorders with heterogonous clinical phenotypes. Over a dozen genes are involved in the biosynthesis of CoQ10 , and mutations in several of these are associated with human disease. However, mutations in COQ5 (MIM# 616359), catalyzing the only C-methylation in the CoQ10 synthetic pathway, have not been implicated in human disease. Here, we report three female siblings of Iraqi-Jewish descent, who had varying degrees of cerebellar ataxia, encephalopathy, generalized tonic-clonic seizures, and cognitive disability. Whole-exome and subsequent whole-genome sequencing identified biallelic duplications in the COQ5 gene, leading to reduced levels of CoQ10 in peripheral white blood cells of all affected individuals and reduced CoQ10 levels in the only muscle tissue available from one affected proband. CoQ10 supplementation led to clinical improvement and increased the concentrations of CoQ10 in blood. This is the first report of primary CoQ10 deficiency caused by loss of function of COQ5, with delineation of the clinical, laboratory, histological, and molecular features, and insights regarding targeted treatment with CoQ10 supplementation.
Assuntos
Vias Biossintéticas/genética , Ataxia Cerebelar/diagnóstico , Ataxia Cerebelar/genética , Metiltransferases/deficiência , Encefalomiopatias Mitocondriais/diagnóstico , Encefalomiopatias Mitocondriais/genética , Proteínas Mitocondriais/deficiência , Ubiquinona/análogos & derivados , Biópsia , Ataxia Cerebelar/dietoterapia , Ataxia Cerebelar/metabolismo , Variações do Número de Cópias de DNA , Suplementos Nutricionais , Transporte de Elétrons , Feminino , Fibroblastos/metabolismo , Estudos de Associação Genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Leucócitos/metabolismo , Metiltransferases/genética , Encefalomiopatias Mitocondriais/dietoterapia , Encefalomiopatias Mitocondriais/metabolismo , Proteínas Mitocondriais/genética , Músculos/patologia , Consumo de Oxigênio , Linhagem , Polimorfismo de Nucleotídeo Único , Irmãos , Ubiquinona/biossínteseRESUMO
Notch signaling determines and reinforces cell fate in bilaterally symmetric multicellular eukaryotes. Despite the involvement of Notch in many key developmental systems, human mutations in Notch signaling components have mainly been described in disorders with vascular and bone effects. Here, we report five heterozygous NOTCH1 variants in unrelated individuals with Adams-Oliver syndrome (AOS), a rare disease with major features of aplasia cutis of the scalp and terminal transverse limb defects. Using whole-genome sequencing in a cohort of 11 families lacking mutations in the four genes with known roles in AOS pathology (ARHGAP31, RBPJ, DOCK6, and EOGT), we found a heterozygous de novo 85 kb deletion spanning the NOTCH1 5' region and three coding variants (c.1285T>C [p.Cys429Arg], c.4487G>A [p.Cys1496Tyr], and c.5965G>A [p.Asp1989Asn]), two of which are de novo, in four unrelated probands. In a fifth family, we identified a heterozygous canonical splice-site variant (c.743-1 G>T) in an affected father and daughter. These variants were not present in 5,077 in-house control genomes or in public databases. In keeping with the prominent developmental role described for Notch1 in mouse vasculature, we observed cardiac and multiple vascular defects in four of the five families. We propose that the limb and scalp defects might also be due to a vasculopathy in NOTCH1-related AOS. Our results suggest that mutations in NOTCH1 are the most common cause of AOS and add to a growing list of human diseases that have a vascular and/or bony component and are caused by alterations in the Notch signaling pathway.
Assuntos
Anormalidades Múltiplas/genética , Displasia Ectodérmica/genética , Displasia Ectodérmica/patologia , Deformidades Congênitas dos Membros/genética , Deformidades Congênitas dos Membros/patologia , Mutação/genética , Receptor Notch1/genética , Dermatoses do Couro Cabeludo/congênito , Adolescente , Adulto , Animais , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Camundongos , Linhagem , Dermatoses do Couro Cabeludo/genética , Dermatoses do Couro Cabeludo/patologia , Adulto JovemRESUMO
OBJECTIVE: To investigate whether a child's genotype affects a mother's risk of rheumatoid arthritis (RA) beyond the risk associated with her genotype and to test whether exposure to fetal alleles inherited from the father increases risk of RA among mothers without risk alleles. METHODS: A case-control study was conducted among 1165 mothers (170 cases/995 controls) and their respective 1482 children. We tested the association between having any child with alleles encoding amino acids (AAs) associated with RA including the 'shared epitope' (SE) and DERAA AA sequences at positions 70-74; AA valine, lysine and alanine at positions 11, 71 and 74 of HLA-DRB1; aspartic acid at position 9 of HLA-B and phenylalanine at position 9 of DPB1. We used logistic regression models to estimate OR and 95% CI for each group of alleles, adjusting for maternal genotype and number of live births. RESULTS: We found increased risk of RA among mothers who had any child with SE (OR 3.0; 95% CI 2.0 to 4.6); DERAA (OR 1.7; 95% CI 1.1 to 2.6); or valine (OR 2.3; 95% CI 1.6 to 3.5), lysine (OR 2.3; 95% CI 1.5 to 3.4) and alanine (OR 2.8; 95% CI 1.2 to 6.4) at DRB1 positions 11, 71 and 74, respectively. Among non-carrier mothers, increased risk of RA was associated with having children who carried DERAA (OR 1.7; 95% CI 1.0 to 2.7) and alleles encoding lysine at DRB1 position 71 (OR 2.3; 95% CI 1.5 to 4.8). CONCLUSION: Findings support the hypothesis that a child's genotype can contribute independently to risk of RA among mothers.
Assuntos
Artrite Reumatoide/epidemiologia , Antígenos HLA-B/genética , Cadeias beta de HLA-DP/genética , Cadeias HLA-DRB1/genética , Exposição Materna/estatística & dados numéricos , Mães/estatística & dados numéricos , Adulto , Idoso , Alelos , Artrite Reumatoide/genética , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Modelos Logísticos , Pessoa de Meia-Idade , Análise Multivariada , Razão de ChancesRESUMO
PurposeImmunodeficiency screening has been added to many state-directed newborn screening programs. The current methodology is limited to screening for severe T-cell lymphopenia disorders. We evaluated the potential of genomic sequencing to augment current newborn screening for immunodeficiency, including identification of non-T cell disorders.MethodsWe analyzed whole-genome sequencing (WGS) and clinical data from a cohort of 1,349 newborn-parent trios by genotype-first and phenotype-first approaches. For the genotype-first approach, we analyzed predicted protein-impacting variants in 329 immunodeficiency-related genes in the WGS data. As a phenotype-first approach, electronic health records were used to identify children with clinical features suggestive of immunodeficiency. Genomes of these children and their parents were analyzed using a separate pipeline for identification of candidate pathogenic variants for rare Mendelian disorders.ResultsWGS provides adequate coverage for most known immunodeficiency-related genes. 13,476 distinct variants and 8,502 distinct predicted protein-impacting variants were identified in this cohort; five individuals carried potentially pathogenic variants requiring expert clinical correlation. One clinically asymptomatic individual was found genomically to have complement component 9 deficiency. Of the symptomatic children, one was molecularly identified as having an immunodeficiency condition and two were found to have other molecular diagnoses.ConclusionNeonatal genomic sequencing can potentially augment newborn screening for immunodeficiency.
Assuntos
Síndromes de Imunodeficiência/epidemiologia , Síndromes de Imunodeficiência/genética , Triagem Neonatal , Sequenciamento Completo do Genoma , Biologia Computacional/métodos , Curadoria de Dados , Feminino , Testes Genéticos , Genótipo , Humanos , Síndromes de Imunodeficiência/diagnóstico , Recém-Nascido , Masculino , Triagem Neonatal/métodos , FenótipoRESUMO
In most human cancers the Myc proto-oncogene is highly activated. Dysregulation of Myc oncoprotein contributes to tumorigenesis in numerous tissues and organs. Thus, targeting Myc stability could be a crucial step for cancer therapy. Here we report Smad7 as a key molecule regulating Myc stability and activity by recruiting the F-box protein, Skp2. Ectopic expression of Smad7 downregulated the protein level of Myc without affecting the transcription level, and significantly repressed its transcriptional activity, leading to inhibition of cell proliferation and tumorigenic activity. Furthermore, Smad7 enhanced ubiquitylation of Myc through direct interaction with Myc and recruitment of Skp2. Ablation of Smad7 resulted in less sensitivity to the growth inhibitory effect of TGF-ß by inducing stable Myc expression. In conclusion, these findings that Smad7 functions in Myc oncoprotein degradation and enhances the cytostatic effect of TGF-ß signaling provide a possible new therapeutic approach for cancer treatment.
Assuntos
Citostáticos/farmacologia , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteínas Quinases Associadas a Fase S/metabolismo , Proteína Smad7/metabolismo , Fator de Crescimento Transformador beta/farmacologia , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Humanos , Proteínas Inibidoras de Diferenciação/genética , Proteínas Inibidoras de Diferenciação/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Ligação Proteica/efeitos dos fármacos , Domínios e Motivos de Interação entre Proteínas , Mapeamento de Interação de Proteínas , Estabilidade Proteica/efeitos dos fármacos , Proteólise/efeitos dos fármacos , Proto-Oncogene Mas , Transcrição Gênica/efeitos dos fármacos , Ubiquitina/metabolismoRESUMO
PURPOSE: To assess the potential of whole-genome sequencing (WGS) to replicate and augment results from conventional blood-based newborn screening (NBS). METHODS: Research-generated WGS data from an ancestrally diverse cohort of 1,696 infants and both parents of each infant were analyzed for variants in 163 genes involved in disorders included or under discussion for inclusion in US NBS programs. WGS results were compared with results from state NBS and related follow-up testing. RESULTS: NBS genes are generally well covered by WGS. There is a median of one (range: 0-6) database-annotated pathogenic variant in the NBS genes per infant. Results of WGS and NBS in detecting 28 state-screened disorders and four hemoglobin traits were concordant for 88.6% of true positives (n = 35) and 98.9% of true negatives (n = 45,757). Of the five infants affected with a state-screened disorder, WGS identified two whereas NBS detected four. WGS yielded fewer false positives than NBS (0.037 vs. 0.17%) but more results of uncertain significance (0.90 vs. 0.013%). CONCLUSION: WGS may help rule in and rule out NBS disorders, pinpoint molecular diagnoses, and detect conditions not amenable to current NBS assays.
Assuntos
Predisposição Genética para Doença , Genoma Humano , Triagem Neonatal/métodos , Análise de Sequência de DNA/métodos , Estudos de Coortes , Feminino , Variação Genética , Humanos , Recém-Nascido , Masculino , Sensibilidade e EspecificidadeRESUMO
Systemic lupus erythematosus (SLE) disproportionately affects women of reproductive age. During pregnancy, women are exposed to various sources of fetal material possibly constituting a significant immunologic exposure relevant to the development of SLE. The objective of this study was to investigate whether having any children who carry DRB1 alleles associated with SLE increase the risk of maternal SLE. This case-control study is based on the University of California, San Francisco Mother-Child Immunogenetic Study and from studies at the Inova Translational Medicine Institute. Analyses were conducted using data for 1304 mothers (219 cases/1085 controls) and their respective 1664 children. We selected alleles based on their known association with risk of SLE (DRB1*03:01, *15:01, or *08:01) or Epstein-Barr virus (EBV) glycoproteins (*04:01) due to the established EBV association with SLE risk. We used logistic regression models to estimate odds ratios (OR) and 95% confidence intervals (CI) for each allele of interest, taking into account maternal genotype and number of live births. We found an increase in risk of maternal SLE associated with exposure to children who inherited DRB1*04:01 from their father (OR 1.9; 95% CI, 1.1-3.2), among *04:01 allele-negative mothers. Increased risk was only present among mothers who were positive for one or more SLE risk-associated alleles (*03:01, *15:01 and/or *08:01). We did not find increased risk of maternal SLE associated with any other tested allele. These findings support the hypothesis that a child's alleles inherited from the father influence a mother's subsequent risk of SLE.
Assuntos
Genótipo , Cadeias HLA-DRB1/genética , Lúpus Eritematoso Sistêmico/etiologia , Troca Materno-Fetal/genética , Troca Materno-Fetal/imunologia , Adulto , Alelos , Autoanticorpos/sangue , Autoanticorpos/imunologia , Estudos de Casos e Controles , Criança , Feminino , Predisposição Genética para Doença , Humanos , Lúpus Eritematoso Sistêmico/epidemiologia , Pessoa de Meia-Idade , Razão de Chances , GravidezRESUMO
BACKGROUND: In chicken, loss of TALPID3 results in non-functional cilia and short-rib polydactyly syndrome. This phenotype is caused by a frameshift mutation in the chicken ortholog of the human KIAA0586 gene, which encodes a novel coiled-coil domain protein essential for primary ciliogenesis, suggesting that KIAA0586 can be associated with ciliopathy in human beings. METHODS: In our patients with ciliopathy (http://www.clinicaltrials.gov: NCT00068224), we have collected extensive clinical and neuroimaging data from affected individuals, and performed whole exome sequencing on DNA from affected individuals and their parents. We analysed gene expression on fibroblast cell line, and determined the effect of gene mutation on ciliogenesis in cells derived from patients. RESULTS: We identified biallelic mutations in the human TALPID3 ortholog, KIAA0586, in six children with findings of overlapping Jeune and Joubert syndromes. Fibroblasts cultured from one of the patients with Jeune-Joubert syndrome exhibited more severe cilia defects than fibroblasts from patients with only Joubert syndrome; this difference was reflected in KIAA0586 RNA expression levels. Rescue of the cilia defect with full-length wild type KIAA0586 indicated a causal link between cilia formation and KIAA0586 function. CONCLUSIONS: Our results show that biallelic deleterious mutations in KIAA0586 lead to Joubert syndrome with or without Jeune asphyxiating thoracic dystrophy. Furthermore, our results confirm that KIAA0586/TALPID3 is essential in cilia formation in human beings, expand the KIAA0586 phenotype to include features of Jeune syndrome and provide a pathogenetic connection between Joubert and Jeune syndromes, based on aberrant ciliogenesis.
Assuntos
Anormalidades Múltiplas/genética , Proteínas de Ciclo Celular/genética , Cerebelo/anormalidades , Síndrome de Ellis-Van Creveld/genética , Anormalidades do Olho/genética , Doenças Renais Císticas/genética , Retina/anormalidades , Animais , Sequência de Bases , Proteínas de Ciclo Celular/metabolismo , Células Cultivadas , Galinhas/genética , Criança , Pré-Escolar , Cílios/patologia , Análise Mutacional de DNA , Feminino , Fibroblastos/patologia , Mutação da Fase de Leitura , Expressão Gênica , Humanos , Masculino , Linhagem , Cultura Primária de CélulasRESUMO
Rubinstein-Taybi syndrome (RSTS) can be caused by heterozygous mutations or deletions involving CREBBP or, less commonly, EP300. To date, only 15 patients with EP300 mutations have been clinically described. Frequently reported manifestations in these patients include characteristic facial and limb features, varying degrees of neurocognitive dysfunction, and maternal preeclampsia. Other congenital anomalies are less frequently reported. We describe a child found to have a de novo EP300 mutation (c.4933C>T, predicted to result in p.Arg1645X) through research-based whole-genome sequencing of the family trio. The child's presentation involved dysmorphic features as well as unilateral renal agenesis, a myelomeningocele, and minor genitourinary anomalies. The involvement of congenital anomalies in all 16 clinically described patients with EP300 mutations (25% of which have been identified by "hypothesis free" methods, including microarray, exome, and whole-genome sequencing) is reviewed. In summary, genitourinary anomalies have been identified in 38%, cardiovascular anomalies in 25%, spinal/vertebral anomalies in 19%, other skeletal anomalies in 19%, brain anomalies in 13%, and renal anomalies in 6%. Our patient expands the phenotypic spectrum in EP300-related RSTS; this case demonstrates the evolving practice of clinical genomics related to increasing availability of genomic sequencing methods.
Assuntos
Proteína p300 Associada a E1A/genética , Mutação , Síndrome de Rubinstein-Taybi/genética , Anormalidades Urogenitais/genética , Sequência de Bases , Mapeamento Cromossômico , Exoma/genética , Feminino , Humanos , Lactente , Imageamento por Ressonância Magnética , Gravidez , Radiografia , Síndrome de Rubinstein-Taybi/diagnóstico por imagem , Síndrome de Rubinstein-Taybi/etiologia , Síndrome de Rubinstein-Taybi/fisiopatologia , Deleção de Sequência , Coluna Vertebral/diagnóstico por imagem , Coluna Vertebral/fisiopatologia , Anormalidades Urogenitais/fisiopatologiaRESUMO
There has been an increase in the prevalence of Clostridioides difficile (C. diff) causing significant economic impact on the health care system. Although toxigenic C. diff carriage is recognized in infancy, there is limited data regarding its longitudinal trends, associated epidemiolocal risk factors and intestinal microbiome characteristics. The objectives of our longitudinal cohort study were to investigate temporal changes in the prevalence of toxigenic C.diff colonization in children up to 2 years, associated epidemiological and intestinal microbiome characteristics. Pregnant mothers were enrolled prenatally, and serial stool samples were collected from their children for 2 years. 2608 serial stool samples were collected from 817 children. 411/817 (50%) were males, and 738/817 (90%) were born full term. Toxigenic C.diff was detected in 7/569 (1%) of meconium samples, 116/624 (19%) of 2 m (month), 221/606 (37%) of 6 m, 227/574 (40%) of 12 m and 18/235 (8%) of 24 m samples. Infants receiving any breast milk at 6 m were less likely to be carriers at 2 m, 6 m and 12 m than those not receiving it. (p = 0.002 at 2 m, p < 0.0001 at 6 m, p = 0.022 at 12 m). There were no robust differences in the underlying alpha or beta diversity between those with and without toxigenic C. diff carriage at any timepoint, although small differences in the relative abundance of certain taxa were found. In this largest longitudinal cohort study to date, a high prevalence of toxigenic C. diff carrier state was noted. Toxigenic C. diff carrier state in children is most likely a transient component of the dynamic infant microbiome.
Assuntos
Clostridioides difficile , Infecções por Clostridium , Microbioma Gastrointestinal , Masculino , Criança , Feminino , Humanos , Lactente , Pré-Escolar , Clostridioides , Estudos Longitudinais , Leite Humano , Fezes , Infecções por Clostridium/epidemiologiaRESUMO
Tumor stem cells or cancer initiating cells (CICs) are single tumor cells that can regenerate a tumor or a metastasis. The identification and isolation of CICs remain challenging, and a variety of putative CIC markers have been described. We hypothesized that cell lines of the NCI60 panel contain CICs and express putative CIC markers. We investigated expression of putative CIC surface markers (CD15, CD24, CD44, CD133, CD166, CD326, PgP) and the activity of aldehyde dehydrogenase in the NCI60 panel singly and in combination by six-color fluorescence-activated cell sorting analysis. All investigated markers were expressed in cell lines of the NCI60 panel. Expression levels of individual markers varied widely across the 60 cell lines, and neither single marker expression nor simple combinations nor co-expression patterns correlated with the colony-formation capacity of cell lines. Rather, marker expression patterns correlated with tumor types in multidimensional analysis. Whereas some expression patterns correlated with tumor entities such as basal breast cancer, other expression patterns occurred across different tumor types and largely related to expression of a more mesenchymal phenotype in individual breast, lung, renal, and melanoma cell lines. Our data for the first time demonstrate that tumor cell lines display CIC markers in a complex pattern that relates to the tumor type. The complexity and tumor type specificity of marker display creates challenges for the application of cell sorting and other approaches to isolation of putative tumor stem cell populations and suggests that therapeutic targeting strategies will need to take this into account.