3329 results for "*geneti*"

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• NHLBI GO-ESP Family Studies: Idiopathic Bronchiectasis of unknown etiology that is not related to cystic fibrosis or classic primary ciliary dyskinesia or immune deficiency or any other known causes

  The NHLBI "Grand Opportunity" Exome Sequencing Project (GO-ESP), a signature project of the NHLBI Recovery Act investment, was designed to identify genetic variants in coding regions (exons) of the human genome (the "exome") that are associated with heart, lung and blood diseases. These and related diseases that are of high impact to public health and individuals from diverse racial and ethnic groups will be studied. These data may help researchers understand the causes of disease, contributing to better ways to prevent, diagnose, and treat diseases, as well as determine whether to tailor prevention and treatments to specific populations. This could lead to more effective treatments and reduce the likelihood of side effects. GO-ESP is comprised of five collaborative components: 3 cohort consortia - HeartGO, LungGO, and WHISP - and 2 sequencing centers - BroadGO and SeattleGO. The major goal of this project is to apply next generation resequencing technology to identify disease-causing variants that cause bronchiectasis of unknown etiology (e.g. non cystic fibrosis (CF), classic primary ciliary dyskinesia (PCD), immune deficiency, or any other known cause of bronchiectasis), i.e., "idiopathic bronchiectasis." As part of our ongoing efforts to define the genetic cause of rare lung diseases, we have also studied families in whom diagnosis of PCD or other known etiologies could not be confirmed. We have systematically collected and stored the DNA and phenotypic data on each of the families in our cohort. The phenotypic data includes age, gender, ethnicity information, clinical data pertaining to the airways disease, including neonatal respiratory distress, otitis media, sinusitis and bronchiectasis, ciliary ultrastructure analysis, and microbial colonization (status of nontuberculosis mycobacterium). During the course of our study, we have acquired 98 unrelated patients in whom bronchiectasis seemed to be of unknown causes. We will be using 11 unrelated patients, 5 unrelated affected sib-pairs, and 3 affected sibs from a family from this cohort, based on 1) development of bronchiectasis in the absence of smoking, 2) a good family pedigree with available DNA, and 3) a family history of bronchiectasis and/or occurrence of airways disease in a sibling. Classic CF, PCD and immune deficiency were ruled out, based on the tests described above. Alpha-1 antiprotease deficiency work up was negative and none of the patients were tobacco users or smokers.

  Study phs000518

• Study of Melanoma Risk in Australia and the United Kingdom

  The results from a small number of melanoma GWAS have been published. Initial studies identified several pigmentation- and nevus-associated loci that mediate an effect on melanoma risk, however, these studies were somewhat limited in that sample number (hence power) was low, they used first-generation low density SNP arrays, or used pools of DNA samples. Subsequently, additional melanoma GWAS have been completed, including a "Phase 2" study by the International Melanoma Genetics Consortium (GenoMEL), a full GWAS of the Australian sample resource previously used in a pooled-DNA GWAS, and study conducted through the MD Anderson Cancer Center and the Brigham and Women's Hospital. The groups who performed these studies have recently shared data and replicated a number of new melanoma susceptibility loci. Aside from the identification of novel loci, there are two additional notable outcomes of these studies. Firstly, an examination of the observed versus expected test statistics (Q-Q plot) from the Australian study, even after removing data from SNPs within known replicated susceptibility loci, reveals that there remains an excess of positive results. Similarly, the latest GenoMEL study finds almost three times as many SNPs reaching p-values between 10-4 and 10-5 as would be expected by chance. In the light of other studies of complex traits [1], these data suggest that studies based on additional melanoma samples from the same population are likely to identify an even larger "polygenic tail" and should prove invaluable in identifying and characterizing the underlying loci. A second observation, is that the effect size for replicated associations differs very little between GWAS. Given the strong effect of ultraviolet radiation (UVR) on risk of melanoma this might be expected to affect penetrance, particularly in the Australian and English samples, which are ethnically similar, but have very different sun exposures. We hypothesize that those SNPs whose effects are strongly mediated by UVR exposure may have smaller marginal effects on risk and are therefore harder to detect initially, suggesting a whole category of genetic effects that are unexplored.Indeed, most melanoma GWAS performed to date used samples from both European and Australian populations in discovery and or replication, and thus, existing studies have been poorly powered to detect associations with a wide difference in effect between these low- and high-UVR populations. Here, we wish to pursue this hypothesis further and plan to genotype additional cases drawn from the English and Australian populations. This will serve two complementary objectives: firstly, it will greatly increase our collective power to detect additional new melanoma risk alleles; secondly, it will highlight associations that are stronger specifically within the context of either low-UVR or high-UVR exposure environments. We posit that these data will be invaluable, not just for identifying novel melanoma-associated loci, but also for addressing gene-environment interactions. We have available a collection of valuable resources to help fulfill our aims. These include a considerable number of well-characterized and ungenotyped Australian and UK melanoma cases, as well as existing genotype data from sets of Australian and UK cases and population-based controls. We propose the following Specific Aims: To extend our current collective melanoma GWAS by genotyping a large number of additional UK and Australian cases. To jointly analyze these data and identify new melanoma risk loci. To determine whether pre-existing and new melanoma risk alleles show different degrees of association between the English and Australian populations, and assess whether these differences might be due to differences in sunlight exposure.

  Study phs000519

• Episodic Ataxia Syndrome: Longitudinal Study

  Individuals with episodic ataxia experience recurrent attacks of dizziness and incoordination; between attacks patients are typically normal. The majority of cases are likely caused by an inherited genetic mutation. However, in some patients we are unable to identify the mutation. So far, 2 genes have been identified which cause different types of episodic ataxia. Ultimately, when the actual mutation is identified the protein product of the gene can be studied and specific medications can be designed. During this study, we will clinically evaluate patients with EA and follow them over time to help us better characterize the disease. We will also obtain blood samples to test for the known genetic mutations. In the future, we plan to coordinate trials of medications for the treatment of these disorders.

  Study phs000521

• Hyperdiploid Acute Lymphoblastic Leukemia RNA-Seq

  Few genetic drivers of children with hyperdiploid precursor B-cell acute lymphoblastic leukemia (ALL) have been identified to date. In an effort to detect novel genomic rearrangements that could be promoting leukemogenesis in this subset of patients, we sequenced ribosomal RNA-depleted transcriptomes isolated from 5 hyperdiploid acute lymphoblastic leukemia samples. In addition to looking for novel genomic rearrangements, we also sought to identify transcripts that could be created as a result of a novel posttranscriptional process. Surprisingly, we identified transcripts created as the result of exon circularization. The results of our studies are present in the paper "Circular RNAs Are the Predominant Transcript Isoform from Hundreds of Human Genes in Diverse Cell Types" published in PLoS ONE (PMID: 22319583).

  Study phs000522

• Whole Genome and Exon Capture Sequencing of Bladder Cancers

  One primary bladder cancer and paired peripheral blood sample were subjected to whole genome sequencing on an Illumina HiSeq 2000 platform. This technology was utilized to investigate the genetic basis of a durable remission of metastatic bladder cancer in a patient treated with everolimus, a drug that inhibits the mTOR (mammalian target of rapamycin) signaling pathway. Among the somatic mutations found was a loss-of-function mutation in TSC1 (Tuberous Sclerosis Complex 1), a regulator of mTOR pathway activation. Targeted sequencing using an exon capture and sequencing assay was performed on 13 tumors derived from patients on the same everolimus trial as the index patient and the sequencing data from these tumors is included. TSC1 mutation status was correlated with response to everolimus. The index patient responder tumor and peripheral blood DNA were also subjected to exon capture and sequencing.

  Study phs000535

• Next Generation Mendelian Genetics: Familial Hemophagocytic Lymphohistiocytosis

  The NHGRI Next Generation Mendelian Genetics project uses exome resequencing to identify variants in unsolved Mendelian diseases. Familial hemophagocytic lymphohistiocytosis (fHLH) is a serious immune disorder that results from defective cytotoxic lymphocyte function. Autosomal recessive mutations in PFP1, UNC13D, STX11, STBP2, or RAB27, and hemizygous mutations in SH2D1A or BIRC4, account for known causes of the disease, but 30-70% of patients in North America lack a known genetic etiology. This project was designed to identify additional genetic abnormalities from HLH patients. The exome sequences of four unrelated individuals with a diagnosis of HLH, but without mutations in genes known to cause disease, were obtained by massively parallel DNA sequencing.

  Study phs000537

• Next Generation Mendelian Genetics: Familial Combined Hyperlipidemia

  The NHGRI Next Generation Mendelian Genetics project uses exome resequencing to identify variants in unsolved Mendelian diseases. The research study procedures included the collection of a fasting blood sample, 2 medical history/life style questionnaires and a measurement of subjects' waist circumference that were completed many years ago. Blood samples were analyzed for metabolic markers including cholesterol, HDL, triglycerides and APOE. Genetic tests targeted known and novel genes and polymorphisms associated with carotid artery disease.

  Study phs000538

• Next Generation Mendelian Genetics: Congenital Hyperinsulinism

  The NHGRI Next Generation Mendelian Genetics project uses exome resequencing to identify variants in unsolved Mendelian diseases. Congenital Hyperinsulinism (CHI) is the most common cause of hypoglycemia in the newborn and it is due to mutations in 8 different genes (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, HNF4A and UCP2). It is a heterogeneous disease with variable onset (birth to adulthood) and a persistent, intermittent, or transient course with possible later conversion to non-autoimmune diabetes. Although mutations in the two subunits of the KATP channel (ABCC8 and KCNJ11) account for 50% of the cases, the other half is still genetically unexplained. CHI can be inherited in a dominant or recessive and can also present as a 'de novo' mutation. We became part of this study when we submitted 8 DNA samples for exome sequencing, from patients with CHI of Caucasian ancestry, which had no mutations identified in ABCC8 or KCNJ1, with the goal to identify new mutations in known genes or new mutations in new genes or genetic variants.

  Study phs000539

• Next Generation Mendelian Genetics: Ehlers-Danlos Syndrome Type VIII

  The NHGRI Next Generation Mendelian Genetics project uses exome resequencing to identify variants in unsolved Mendelian diseases. Ehlers-Danlos syndrome Type VIII is a dominantly inherited connective tissue disorder that is distinguished from other forms of EDS by significant early-onset periodontal disease. Although the clinical phenotype is well delineated, the underlying molecular basis remains unknown. By studying a large family of affected and unaffected individuals with the EDS VIII by exome sequencing, we hope to identify unique regions of homology to assist in identifying the causative gene.

  Study phs000540

• Next Generation Mendelian Genetics: Muscle Hypertrophy

  The NHGRI Next Generation Mendelian Genetics project uses exome resequencing to identify variants in unsolved Mendelian diseases. Samples were collected from a single, multi-generational family with the same phenotype of exaggerated muscular development (muscular hypertrophy) and strength characterized by reduced fat pad thickness under the skin. All family members deny "body building" activities, and are so far negative for known gene mutation that have been identified as associated with excessive muscle development. All family members have examples of demonstrating extraordinary strength occurring both in childhood and old age. No negative associated phenotype traits with the muscle hypertrophy phenotype have been identified.

  Study phs000541