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2.
Am J Hum Genet ; 106(6): 846-858, 2020 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-32470372

RESUMO

The burden of several common diseases including obesity, diabetes, hypertension, asthma, and depression is increasing in most world populations. However, the mechanisms underlying the numerous epidemiological and genetic correlations among these disorders remain largely unknown. We investigated whether common polymorphic inversions underlie the shared genetic influence of these disorders. We performed an inversion association analysis including 21 inversions and 25 obesity-related traits on a total of 408,898 Europeans and validated the results in 67,299 independent individuals. Seven inversions were associated with multiple diseases while inversions at 8p23.1, 16p11.2, and 11q13.2 were strongly associated with the co-occurrence of obesity with other common diseases. Transcriptome analysis across numerous tissues revealed strong candidate genes for obesity-related traits. Analyses in human pancreatic islets indicated the potential mechanism of inversions in the susceptibility of diabetes by disrupting the cis-regulatory effect of SNPs from their target genes. Our data underscore the role of inversions as major genetic contributors to the joint susceptibility to common complex diseases.


Assuntos
Inversão Cromossômica/genética , Diabetes Mellitus/genética , Predisposição Genética para Doença , Hipertensão/genética , Obesidade/complicações , Obesidade/genética , Polimorfismo Genético , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Cromossomos Humanos Par 16/genética , Cromossomos Humanos Par 8/genética , Conjuntos de Dados como Assunto/normas , Diabetes Mellitus/patologia , Europa (Continente)/etnologia , Feminino , Perfilação da Expressão Gênica , Haplótipos , Humanos , Hipertensão/complicações , Ilhotas Pancreáticas/metabolismo , Ilhotas Pancreáticas/patologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Reprodutibilidade dos Testes , Adulto Jovem
3.
Ann Hematol ; 99(3): 487-500, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32006151

RESUMO

Fusion partners of KMT2A affect disease phenotype and influence the current World Health Organization classification of hematologic neoplasms. The t(11;16)(q23;p13)/KMT2A-CREBBP is considered presumptive evidence of a myelodysplastic syndrome (MDS) and a MDS-related cytogenetic abnormality in the classification of acute myeloid leukemia (AML). Here, we report 18 cases of hematologic neoplasms with t(11;16). There were 8 males and 10 females with a median age of 51.9 years at time of detection of t(11;16). Of 17 patients with enough clinical information and pathological materials for review, 16 had a history of cytotoxic therapies for various malignancies including 12/15 patients who received topoisomerase II inhibitors, and 15 were classified as having therapy-related neoplasms. The median interval from the diagnosis of primary malignancy to the detection of t(11;16) was 23.2 months. Dysplasia, usually mild, was observed in 7/17 patients. Blasts demonstrated monocytic differentiation in 8/8 patients who developed AML at the time or following detection of t(11;16). t(11;16) was observed as the sole chromosomal abnormality in 10/18 patients. KMT2A rearrangement was confirmed in 11/11 patients. The median survival from the detection of t(11;16) was 15.4 months. In summary, t(11;16)(q23;p13) is rare and overwhelmingly associated with prior exposure of cytotoxic therapy. Instead of being considered presumptive evidence of myelodysplasia, we suggest that the detection of t(11;16) should automatically prompt a search for a history of malignancy and cytotoxic therapy so that proper risk stratification and clinical management are made accordingly. The dismal outcome of patients with t(11;16) is in keeping with that of therapy-related neoplasms.


Assuntos
Proteína de Ligação a CREB/genética , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 16/genética , Bases de Dados Factuais , Neoplasias Hematológicas , Histona-Lisina N-Metiltransferase/genética , Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Proteína de Leucina Linfoide-Mieloide/genética , Segunda Neoplasia Primária , Proteínas de Fusão Oncogênica/genética , Inibidores da Topoisomerase II/administração & dosagem , Translocação Genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/mortalidade , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/mortalidade , Segunda Neoplasia Primária/tratamento farmacológico , Segunda Neoplasia Primária/genética , Segunda Neoplasia Primária/mortalidade , Medição de Risco
4.
Genes (Basel) ; 10(12)2019 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-31817908

RESUMO

Non-syndromic cleft lip with or without cleft palate (nsCL/P) ranks among the most common human congenital malformations, and has a multifactorial background in which both exogenous and genetic risk factors act in concert. The present report describes a genome-wide association study (GWAS) involving a total of 285 nsCL/P patients and 1212 controls from the Netherlands and Belgium. Twenty of the 40 previously reported nsC/LP susceptibility loci were replicated, which underlined the validity of this sample. SNV-based analysis of the data identified an as yet unreported suggestive locus at chromosome 16p12.1 (p-value of the lead SNV: 4.17 × 10-7). This association was replicated in two of three patient/control replication series (Central European and Yemeni). Gene analysis of the GWAS data prioritized SH3PXD2A at chromosome 10q24.33 as a candidate gene for nsCL/P. To date, support for this gene as a cleft gene has been restricted to data from zebrafish and a knockout mouse model. The present GWAS was the first to implicate SH3PXD2A in non-syndromic cleft formation in humans. In summary, although performed in a relatively small sample, the present GWAS generated novel insights into nsCL/P etiology.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/genética , Cromossomos Humanos Par 16/genética , Fenda Labial/genética , Fissura Palatina/genética , Animais , Bélgica , Cromossomos Humanos Par 10/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Camundongos , Camundongos Knockout , Países Baixos , Fatores de Risco , Peixe-Zebra
6.
Am J Hum Genet ; 105(5): 947-958, 2019 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-31668704

RESUMO

Human-specific duplications at chromosome 16p11.2 mediate recurrent pathogenic 600 kbp BP4-BP5 copy-number variations, which are among the most common genetic causes of autism. These copy-number polymorphic duplications are under positive selection and include three to eight copies of BOLA2, a gene involved in the maturation of cytosolic iron-sulfur proteins. To investigate the potential advantage provided by the rapid expansion of BOLA2, we assessed hematological traits and anemia prevalence in 379,385 controls and individuals who have lost or gained copies of BOLA2: 89 chromosome 16p11.2 BP4-BP5 deletion carriers and 56 reciprocal duplication carriers in the UK Biobank. We found that the 16p11.2 deletion is associated with anemia (18/89 carriers, 20%, p = 4e-7, OR = 5), particularly iron-deficiency anemia. We observed similar enrichments in two clinical 16p11.2 deletion cohorts, which included 6/63 (10%) and 7/20 (35%) unrelated individuals with anemia, microcytosis, low serum iron, or low blood hemoglobin. Upon stratification by BOLA2 copy number, our data showed an association between low BOLA2 dosage and the above phenotypes (8/15 individuals with three copies, 53%, p = 1e-4). In parallel, we analyzed hematological traits in mice carrying the 16p11.2 orthologous deletion or duplication, as well as Bola2+/- and Bola2-/- animals. The Bola2-deficient mice and the mice carrying the deletion showed early evidence of iron deficiency, including a mild decrease in hemoglobin, lower plasma iron, microcytosis, and an increased red blood cell zinc-protoporphyrin-to-heme ratio. Our results indicate that BOLA2 participates in iron homeostasis in vivo, and its expansion has a potential adaptive role in protecting against iron deficiency.


Assuntos
Anemia/genética , Transtorno Autístico/genética , Duplicação Cromossômica/genética , Cromossomos Humanos Par 16/genética , Homeostase/genética , Proteínas/genética , Animais , Deleção Cromossômica , Transtornos Cromossômicos/genética , Variações do Número de Cópias de DNA/genética , Feminino , Genótipo , Heterozigoto , Humanos , Ferro , Masculino , Fenótipo
7.
Nat Commun ; 10(1): 4897, 2019 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-31653860

RESUMO

Rare genetic disorders (RGDs) often exhibit significant clinical variability among affected individuals, a disease characteristic termed variable expressivity. Recently, the aggregate effect of common variation, quantified as polygenic scores (PGSs), has emerged as an effective tool for predictions of disease risk and trait variation in the general population. Here, we measure the effect of PGSs on 11 RGDs including four sex-chromosome aneuploidies (47,XXX; 47,XXY; 47,XYY; 45,X) that affect height; two copy-number variant (CNV) disorders (16p11.2 deletions and duplications) and a Mendelian disease (melanocortin 4 receptor deficiency (MC4R)) that affect BMI; and two Mendelian diseases affecting cholesterol: familial hypercholesterolemia (FH; LDLR and APOB) and familial hypobetalipoproteinemia (FHBL; PCSK9 and APOB). Our results demonstrate that common, polygenic factors of relevant complex traits frequently contribute to variable expressivity of RGDs and that PGSs may be a useful metric for predicting clinical severity in affected individuals and for risk stratification.


Assuntos
Estatura/genética , Índice de Massa Corporal , LDL-Colesterol/sangue , Herança Multifatorial , Obesidade/genética , Doenças Raras/genética , Apolipoproteínas B/genética , Transtorno Autístico/genética , LDL-Colesterol/genética , Deleção Cromossômica , Transtornos Cromossômicos/genética , Duplicação Cromossômica/genética , Cromossomos Humanos Par 16/genética , Cromossomos Humanos X/genética , Feminino , Humanos , Hiperlipoproteinemia Tipo II/genética , Hipobetalipoproteinemias/genética , Deficiência Intelectual/genética , Síndrome de Klinefelter/genética , Masculino , Pessoa de Meia-Idade , Pró-Proteína Convertase 9/genética , Receptor Tipo 4 de Melanocortina/deficiência , Receptor Tipo 4 de Melanocortina/genética , Receptores de LDL/genética , Aberrações dos Cromossomos Sexuais , Transtornos do Cromossomo Sexual no Desenvolvimento Sexual/genética , Trissomia/genética , Síndrome de Turner/genética , Cariótipo XYY/genética
8.
Science ; 366(6463)2019 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-31624180

RESUMO

Copy number variants (CNVs) are subject to stronger selective pressure than single-nucleotide variants, but their roles in archaic introgression and adaptation have not been systematically investigated. We show that stratified CNVs are significantly associated with signatures of positive selection in Melanesians and provide evidence for adaptive introgression of large CNVs at chromosomes 16p11.2 and 8p21.3 from Denisovans and Neanderthals, respectively. Using long-read sequence data, we reconstruct the structure and complex evolutionary history of these polymorphisms and show that both encode positively selected genes absent from most human populations. Our results collectively suggest that large CNVs originating in archaic hominins and introgressed into modern humans have played an important role in local population adaptation and represent an insufficiently studied source of large-scale genetic variation.


Assuntos
Introgressão Genética , Animais , Duplicação Cromossômica , Cromossomos Humanos Par 16/genética , Cromossomos Humanos Par 8/genética , Variações do Número de Cópias de DNA , Evolução Molecular , Genoma Humano , Haplótipos , Hominidae/genética , Humanos , Melanesia , Modelos Genéticos , Homem de Neandertal/genética , Polimorfismo Genético , Seleção Genética , Sequenciamento Completo do Genoma
9.
Arch Dermatol Res ; 311(10): 735-740, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31435740

RESUMO

Primary hyperhidrosis is a condition characterized by excessive sweating. The estimated prevalence is between 0.6 and 4.4%, and it can have economic, psychological, and social consequences for affected individuals. Family and genetic studies have suggested a genetic component in the inheritance of the disease. In this review, we summarize the current literature on genetic disposition to primary hyperhidrosis. We Identified 20 studies on Pubmed and Embase in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Probands reported a positive family history in 5.7-65% of cases, and the inheritance appeared to be either autosomal dominant or recessive. Individuals with palmoplantar phenotypes and a positive family history had a younger age of onset. Genetic linkage and genome-wide association studies have identified loci on chromosome 2, 14, and 16. However, the evidence is heterogeneous and limited. It seems that primary hyperhidrosis is polygenically inherited, and considering the impairment, further data to understand the genetic etiology of the disease are needed.


Assuntos
Loci Gênicos/genética , Predisposição Genética para Doença , Hiperidrose/genética , Idade de Início , Cromossomos Humanos Par 14/genética , Cromossomos Humanos Par 16/genética , Cromossomos Humanos Par 2/genética , Estudo de Associação Genômica Ampla , Humanos , Hiperidrose/epidemiologia , Anamnese , Prevalência
10.
Am J Hum Genet ; 105(2): 373-383, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31353025

RESUMO

Copy-number variations (CNVs) represent a significant proportion of the genetic differences between individuals and many CNVs associate causally with syndromic disease and clinical outcomes. Here, we characterize the landscape of copy-number variation and their phenome-wide effects in a sample of 472,228 array-genotyped individuals from the UK Biobank. In addition to population-level selection effects against genic loci conferring high mortality, we describe genetic burden from potentially pathogenic and previously uncharacterized CNV loci across more than 3,000 quantitative and dichotomous traits, with separate analyses for common and rare classes of variation. Specifically, we highlight the effects of CNVs at two well-known syndromic loci 16p11.2 and 22q11.2, previously uncharacterized variation at 9p23, and several genic associations in the context of acute coronary artery disease and high body mass index. Our data constitute a deeply contextualized portrait of population-wide burden of copy-number variation, as well as a series of dosage-mediated genic associations across the medical phenome.


Assuntos
Transtorno Autístico/genética , Transtornos Cromossômicos/genética , Cromossomos Humanos Par 9/genética , Doença da Artéria Coronariana/genética , Variações do Número de Cópias de DNA , Síndrome de DiGeorge/genética , Deficiência Intelectual/genética , Fenômica , Polimorfismo de Nucleotídeo Único , Bancos de Espécimes Biológicos , Estudos de Casos e Controles , Deleção Cromossômica , Cromossomos Humanos Par 16/genética , Feminino , Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Fenótipo , Reino Unido
11.
Brain Dev ; 41(10): 888-893, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31353122

RESUMO

In partial monosomy of the distal part of chromosome 16q, abnormal facial features, intellectual disability (ID), and feeding dysfunction are often reported. However, seizures are not typical and the majority of them were seizure-free. Here we present the case of a 16q22.2-q23.1 interstitial deletion identified in a male patient with severe ID, facial anomalies including forehead protrusions and flat nose bridge, patent ductus arteriosus, bilateral vocal cord atresia treated by tracheotomy, and West syndrome, which were developed 10 months after birth. Although phenobarbital, sodium valproate (VPA), and zonisamide were not effective as monotherapies or combination therapies, the patient's epileptic seizures and electroencephalogram anomalies disappeared following combined therapy with lamotrigine and VPA. Although WW Domain Containing Oxidoreductase (WWOX), which is known as a cause of autosomal recessive epileptic encephalopathy, was included within the 6.8-Mb deleted region which identified by targeted panel sequencing and validated by chromosomal microarray analysis, no pathogenic variants were detected in the other allele of WWOX. Therefore, it is possible that other genes within or outside of the long deleted region or their interactions may cause West syndrome in this patient.


Assuntos
Cromossomos Humanos Par 16/genética , Espasmos Infantis/genética , Anticonvulsivantes/uso terapêutico , Epilepsia/genética , Humanos , Lactente , Deficiência Intelectual/genética , Lamotrigina/uso terapêutico , Masculino , Fenobarbital/uso terapêutico , Convulsões/tratamento farmacológico , Deleção de Sequência/genética , Ácido Valproico/uso terapêutico
12.
Nature ; 571(7763): 107-111, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31217582

RESUMO

Large-scale genome sequencing is poised to provide a substantial increase in the rate of discovery of disease-associated mutations, but the functional interpretation of such mutations remains challenging. Here we show that deletions of a sequence on human chromosome 16 that we term the intestine-critical region (ICR) cause intractable congenital diarrhoea in infants1,2. Reporter assays in transgenic mice show that the ICR contains a regulatory sequence that activates transcription during the development of the gastrointestinal system. Targeted deletion of the ICR in mice caused symptoms that recapitulated the human condition. Transcriptome analysis revealed that an unannotated open reading frame (Percc1) flanks the regulatory sequence, and the expression of this gene was lost in the developing gut of mice that lacked the ICR. Percc1-knockout mice displayed phenotypes similar to those observed upon ICR deletion in mice and patients, whereas an ICR-driven Percc1 transgene was sufficient to rescue the phenotypes found in mice that lacked the ICR. Together, our results identify a gene that is critical for intestinal function and underscore the need for targeted in vivo studies to interpret the growing number of clinical genetic findings that do not affect known protein-coding genes.


Assuntos
Diarreia/congênito , Diarreia/genética , Elementos Facilitadores Genéticos/genética , Regulação da Expressão Gênica no Desenvolvimento , Genes , Intestinos/fisiologia , Deleção de Sequência/genética , Animais , Cromossomos Humanos Par 16/genética , Modelos Animais de Doenças , Feminino , Genes Reporter , Loci Gênicos/genética , Humanos , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Linhagem , Fenótipo , Ativação Transcricional , Transcriptoma/genética , Transgenes/genética
13.
Ned Tijdschr Geneeskd ; 1632019 03 21.
Artigo em Holandês | MEDLINE | ID: mdl-30945833

RESUMO

16p11.2 deletion syndrome is one of the most prevalent microdeletion syndromes in the world. Nevertheless, many doctors are not (yet) familiar with this syndrome. Prevalence has been estimated at approximately 3 in 10,000. The deletion can be identified in around 1 out of 100 people with autism. The syndrome is characterized by a wide range of phenotypic features including developmental delay, autism, obesity, increased head circumference, and epilepsy. Here we describe an 8-year-old female patient with developmental delay, autistic features and hyperphagia. After diagnosis of 16p11.2 deletion syndrome, her parents struggled due to limited information and support provision by healthcare staff. Since then, multidisciplinary healthcare has been introduced for this condition. In parallel, the patient's parents started an online support group for Dutch patients and parents. Given the diverse phenotype of 16p11.2 deletion syndrome, multidisciplinary collaboration is important. Establishing the diagnosis contributes to better treatment and understanding for parents and healthcare providers.


Assuntos
Transtorno Autístico/genética , Transtornos Cromossômicos/genética , Testes Genéticos/métodos , Deficiência Intelectual/genética , Transtorno Autístico/diagnóstico , Criança , Deleção Cromossômica , Transtornos Cromossômicos/diagnóstico , Cromossomos Humanos Par 16/genética , Feminino , Humanos , Deficiência Intelectual/diagnóstico , Pais , Fenótipo
14.
Clin Epigenetics ; 11(1): 60, 2019 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-30961659

RESUMO

BACKGROUND: Congenital malformations associated with maternal uniparental disomy of chromosome 16, upd(16)mat, resemble those observed in newborns with the lethal developmental lung disease, alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV). Interestingly, ACDMPV-causative deletions, involving FOXF1 or its lung-specific upstream enhancer at 16q24.1, arise almost exclusively on the maternally inherited chromosome 16. Given the phenotypic similarities between upd(16)mat and ACDMPV, together with parental allelic bias in ACDMPV, we hypothesized that there may be unknown imprinted loci mapping to chromosome 16 that become functionally unmasked by chromosomal structural variants. RESULTS: To identify parent-of-origin biased DNA methylation, we performed high-resolution bisulfite sequencing of chromosome 16 on peripheral blood and cultured skin fibroblasts from individuals with maternal or paternal upd(16) as well as lung tissue from patients with ACDMPV-causative 16q24.1 deletions and a normal control. We identified 22 differentially methylated regions (DMRs) with ≥ 5 consecutive CpG methylation sites and varying tissue-specificity, including the known DMRs associated with the established imprinted gene ZNF597 and DMRs supporting maternal methylation of PRR25, thought to be paternally expressed in lymphoblastoid cells. Lastly, we found evidence of paternal methylation on 16q24.1 near LINC01082 mapping to the FOXF1 enhancer. CONCLUSIONS: Using high-resolution bisulfite sequencing to evaluate DNA methylation across chromosome 16, we found evidence for novel candidate imprinted loci on chromosome 16 that would not be evident in array-based assays and could contribute to the birth defects observed in patients with upd(16)mat or in ACDMPV.


Assuntos
Metilação de DNA , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA/métodos , Dissomia Uniparental/genética , Células Cultivadas , Cromossomos Humanos Par 16/genética , Feminino , Fibroblastos/química , Fibroblastos/citologia , Impressão Genômica , Humanos , Masculino , Pele/química , Pele/citologia
15.
Cytogenet Genome Res ; 157(4): 213-219, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30974445

RESUMO

Patients with childhood acute myeloid leukemia (AML) with complex karyotypes (CKs) have a dismal outcome. However, for patients with a KMT2A rearrangement (KMT2A-r), the prognosis appears to depend on the fusion partner gene rather than the karyotype structure. Thus, a precise characterization of KMT2A-r and the fusion partner genes, especially in CKs, is of interest for managing AML. We describe the clinical and molecular features of a child who presented with a large abdominal mass, AML, and a new CK, involving chromosomes 11, 16, and 19 leading to a KMT2A-MLLT1 fusion and 2 extra copies of the ELL gene, thus resulting in the concurrent overexpression of MLLT1 and ELL. Molecular cytogenetic studies defined the karyotype as 47,XY,der(11)t(11;16)(q23.3;p11.2),der(16)t(16;19)(p11.2;p13.3),der(19)t(11;19)(q23.3;p13.3),+der(19)t(16;19)(16pter→p11.2::19p13.3→19q11::19p11→19p13.3::16p11.2→16pter). Array CGH revealed a gain of 30.5 Mb in the 16p13.3p11.2 region and a gain of 18.1 Mb in the 19p13.3p12 region. LDI-PCR demonstrated the KMT2A-MLLT1 fusion. Reverse sequence analysis showed that the MLLT1 gene was fused to the 16p11.2 region. RT-qPCR quantification revealed that ELL and MLLT1 were overexpressed (4- and 10-fold, respectively). In summary, this is a pediatric case of AML presenting a novel complex t(11;16;19) variant with overexpression of ELL and MLLT1.


Assuntos
Histona-Lisina N-Metiltransferase/genética , Leucemia Mieloide Aguda/genética , Proteína de Leucina Linfoide-Mieloide/genética , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Fatores de Transcrição/genética , Fatores de Elongação da Transcrição/genética , Translocação Genética , Criança , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 16/genética , Cromossomos Humanos Par 19/genética , Humanos , Cariótipo , Masculino , Proteínas de Fusão Oncogênica/genética , Regulação para Cima
16.
Int J Mol Sci ; 20(5)2019 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-30836598

RESUMO

Chromosome 16 is one of the most gene-rich chromosomes of our genome, and 10% of its sequence consists of segmental duplications, which give instability and predisposition to rearrangement by the recurrent mechanism of non-allelic homologous recombination. Microarray technologies have allowed for the analysis of copy number variations (CNVs) that can contribute to the risk of developing complex diseases. By array comparative genomic hybridization (CGH) screening of 1476 patients, we detected 27 cases with CNVs on chromosome 16. We identified four smallest regions of overlapping (SROs): one at 16p13.11 was found in seven patients; one at 16p12.2 was found in four patients; two close SROs at 16p11.2 were found in twelve patients; finally, six patients were found with atypical rearrangements. Although phenotypic variability was observed, we identified a male bias for Childhood Apraxia of Speech associated to 16p11.2 microdeletions. We also reported an elevated frequency of second-site genomic alterations, supporting the model of the second hit to explain the clinical variability associated with CNV syndromes. Our goal was to contribute to the building of a chromosome 16 disease-map based on disease susceptibility regions. The role of the CNVs of chromosome 16 was increasingly made clear in the determination of developmental delay. We also found that in some cases a second-site CNV could explain the phenotypic heterogeneity by a simple additive effect or a pejorative synergistic effect.


Assuntos
Anormalidades Múltiplas/genética , Cromossomos Humanos Par 16/genética , Hibridização Genômica Comparativa , Deficiências do Desenvolvimento/genética , Anormalidades Múltiplas/classificação , Anormalidades Múltiplas/fisiopatologia , Adolescente , Adulto , Criança , Pré-Escolar , Aberrações Cromossômicas , Deleção Cromossômica , Variações do Número de Cópias de DNA/genética , Deficiências do Desenvolvimento/classificação , Deficiências do Desenvolvimento/fisiopatologia , Feminino , Recombinação Homóloga/genética , Humanos , Lactente , Recém-Nascido , Cariótipo , Masculino , Fenótipo , Duplicações Segmentares Genômicas/genética , Adulto Jovem
17.
Ann Hematol ; 98(5): 1149-1157, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30759270

RESUMO

t(8;16)(p11.2;p13.3)/KAT6A-CREBBP is a rare recurrent cytogenetic abnormality associated with acute myeloid leukemia (AML). We report 15 cases with t(8;16)(p11.2;p13.3). All patients were adult and had AML: 13 women and 2 men, with a median age of 50 years. Ten patients had a history of malignancy and received cytotoxic therapies before therapy-related AML (t-AML), and five patients had de novo AML. All cases of AML showed monoblastic (n = 12) or myelomonocytic (n = 3) differentiation. Hemophagocytosis was observed in seven patients. All patients had t(8;16) in the stemline: seven had t(8;16) as the sole abnormality, two had one additional abnormality, and six had a complex karyotype. KAT6A/CREBBP rearrangement was confirmed by fluorescence in situ hybridization in 13 patients who had material available for analysis. All patients received induction chemotherapy, and 11 achieved complete remission after first induction. At the time of last follow-up, nine patients (eight t-AML and one de novo AML) died and six were alive, with a median overall survival of 18.2 months. The patients with de novo AML and/or patients with non-complex karyotype showed an "undefined" overall survival. We conclude that t(8;16)(p11.2;p13.3) commonly exhibits monoblastic or myelomonocytic differentiation and commonly arises in patients with a history of cancer treated with cytotoxic therapies. Patients with de novo AML with t(8;16) or t-AML with t(8;16) without adverse prognostic factors (e.g., complex karyotype) have a good outcome.


Assuntos
Proteína de Ligação a CREB , Cromossomos Humanos Par 16 , Cromossomos Humanos Par 8 , Histona Acetiltransferases , Leucemia Mieloide Aguda , Proteínas de Fusão Oncogênica , Translocação Genética , Adulto , Proteína de Ligação a CREB/genética , Proteína de Ligação a CREB/metabolismo , Cromossomos Humanos Par 16/genética , Cromossomos Humanos Par 16/metabolismo , Cromossomos Humanos Par 8/genética , Cromossomos Humanos Par 8/metabolismo , Feminino , Histona Acetiltransferases/genética , Histona Acetiltransferases/metabolismo , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Estudos Retrospectivos
18.
Br J Haematol ; 185(3): 450-467, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30729512

RESUMO

The Myeloma X trial (ISCRTN60123120) registered patients with relapsed multiple myeloma. Participants were randomised between salvage autologous stem cell transplantation (ASCT) or weekly cyclophosphamide following re-induction therapy. Cytogenetic analysis performed at trial registration defined t(4;14), t(14;16) and del(17p) as high-risk. The effect of cytogenetics on time to progression (TTP) and overall survival was investigated. At 76 months median follow-up, ASCT improved TTP compared to cyclophosphamide (19 months (95% confidence interval [95% CI] 16-26) vs. 11 months (9-12), hazard ratio [HR]: 0·40, 95% CI: 0·29-0·56, P < 0·001), on which the presence of any single high-risk lesion had a detrimental impact [likelihood ratio test (LRT): P = 0·011]. ASCT also improved OS [67 months (95% CI 59-not reached) vs. 55 months (44-67), HR: 0·64, 95% CI: 0·42-0·99, P = 0·0435], with evidence of a detrimental impact with MYC rearrangement (LRT: P = 0·021). Twenty-one (24·7%) cyclophosphamide patients received an ASCT post-trial, median OS was not reached (95% CI: 39-not reached) for these participants compared to 31 months (22-39), in those who did not receive a post-trial ASCT. The analysis further supports the benefit of salvage ASCT, which may still be beneficial after second relapse in surviving patients. There is evidence that this benefit reduces in cytogenetic high-risk patients, highlighting the need for targeted study in this patient group.


Assuntos
Mieloma Múltiplo/genética , Idoso , Antineoplásicos Alquilantes/uso terapêutico , Cromossomos Humanos Par 14/genética , Cromossomos Humanos Par 14/ultraestrutura , Cromossomos Humanos Par 16/genética , Cromossomos Humanos Par 16/ultraestrutura , Cromossomos Humanos Par 17/genética , Cromossomos Humanos Par 17/ultraestrutura , Cromossomos Humanos Par 4/genética , Cromossomos Humanos Par 4/ultraestrutura , Ensaios Clínicos Fase III como Assunto/estatística & dados numéricos , Terapia Combinada , Ciclofosfamida/uso terapêutico , Intervalo Livre de Doença , Feminino , Seguimentos , Transplante de Células-Tronco Hematopoéticas , Humanos , Hibridização in Situ Fluorescente , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto/estatística & dados numéricos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/terapia , Modelos de Riscos Proporcionais , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Terapia de Salvação , Deleção de Sequência , Translocação Genética , Transplante Autólogo
19.
Clin Pharmacol Ther ; 106(1): 219-227, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30648747

RESUMO

Anastrozole is a widely prescribed aromatase inhibitor for the therapy of estrogen receptor positive (ER+) breast cancer. We performed a genome-wide association study (GWAS) for plasma anastrozole concentrations in 687 postmenopausal women with ER+ breast cancer. The top single-nucleotide polymorphism (SNP) signal mapped across SLC38A7 (rs11648166, P = 2.3E-08), which we showed to encode an anastrozole influx transporter. The second most significant signal (rs28845026, P = 5.4E-08) mapped near ALPPL2 and displayed epistasis with the SLC38A7 signal. Both of these SNPs were cis expression quantitative trait loci (eQTL)s for these genes, and patients homozygous for variant genotypes for both SNPs had the highest drug concentrations, the highest SLC38A7 expression, and the lowest ALPPL2 expression. In summary, our GWAS identified a novel gene encoding an anastrozole transporter, SLC38A7, as well as epistatic interaction between SNPs in that gene and SNPs near ALPPL2 that influenced both the expression of the transporter and anastrozole plasma concentrations.


Assuntos
Fosfatase Alcalina/genética , Anastrozol/farmacocinética , Inibidores da Aromatase/farmacocinética , Epistasia Genética/genética , Anastrozol/sangue , Anastrozol/uso terapêutico , Inibidores da Aromatase/sangue , Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Cromossomos Humanos Par 16/genética , Cromossomos Humanos Par 2/genética , Feminino , Proteínas Ligadas por GPI/genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único , Pós-Menopausa , Receptores Estrogênicos/biossíntese
20.
Transl Psychiatry ; 9(1): 8, 2019 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-30664628

RESUMO

Deletion and duplication of 16p11.2 (BP4-BP5) have been associated with an increased risk of intellectual disability and psychiatric disorder. This is the first study to compare the frequency of a broad spectrum of psychiatric disorders in children with 16p11.2 deletion and duplication. We aimed to evaluate (1) the nature and prevalence of psychopathology associated with copy number variation (CNV) in children with 16p11.2 by comparing deletion and duplication carriers with family controls; (2) whether deletion and duplication carriers differ in frequency of psychopathology. 217 deletion carriers, 77 deletion family controls, 114 duplication carriers, and 32 duplication family controls participated in the study. Measures included standardized research diagnostic instruments. Deletion carriers had a higher frequency of any psychiatric disorder (OR = 8.9, p < 0.001), attention deficit hyperactivity disorder (ADHD) (OR = 4.0, p = 0.01), and autism spectrum disorder (ASD) (OR = 39.9, p = 0.01) than controls. Duplication carriers had a higher frequency of any psychiatric diagnosis (OR = 5.3, p = 0.01) and ADHD (OR = 7.0, p = 0.02) than controls. The prevalence of ASD in child carriers of deletions and duplications was similar (22% versus 26%). Comparison of the two CNV groups indicated a higher frequency of ADHD in children with the duplication than deletion (OR = 2.7, p = 0.04) as well as a higher frequency of overall psychiatric disorders (OR = 2.8, p = 0.02) and psychotic symptoms (OR = 4.7, p = 0.02). However, no differences between deletion and duplications carriers in the prevalence of ASD were found. Both deletion and duplication are associated with an increased risk of psychiatric disorder, supporting the importance of early recognition, diagnosis, and intervention in these groups.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Espectro Autista/genética , Duplicação Cromossômica , Cromossomos Humanos Par 16/genética , Deleção de Sequência , Adolescente , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Transtorno do Espectro Autista/diagnóstico , Estudos de Casos e Controles , Criança , Pré-Escolar , Variações do Número de Cópias de DNA , Feminino , Heterozigoto , Humanos , Masculino
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