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• NHLBI GO-ESP: Family Studies (Mendelian Lipid Disorders)

  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. In this study, we seek to identify the genetic cause of two monogenic lipid disorders-severe hypercholesterolemia and familial hypoalphalipoproteinemia. Monogenic severe hypercholesterolemia is clinically characterized by elevated total and low-density lipoprotein (LDL) cholesterol levels in plasma. Elevated LDL-cholesterol levels lead to excessive deposition of cholesterol in arterial walls, which eventually results in accelerated atherosclerosis and premature cardiovascular disease (CVD). Monogenic hypercholesterolemia has a prevalence of approximately one in 500 individuals, making it one of the most common inherited disorders. To date, mutations in the LDL receptor (LDLR) ligand-binding domains of APOB and PCSK9 have been shown to cause hypercholesterolemia. While mutations in these genes can explain a large percentage of clinically diagnosed patients, the underlying molecular determinant in a substantial fraction of patients remains unknown. Familial hypoalphalipoproteinemia (low HDL-C) is defined by an HDL-C below the age- and sex- specific 10th percentile. ABCA1, LCAT, and APOA1 are known to cause familial hypoalphalipoproteinemia. We hypothesize that: (1) additional novel genes responsible for Mendelian forms of low HDL-C exist; and (2) the causal gene and mutation(s) in each family may be discovered with exome analysis of just a few affected individuals in each pedigree.

  Study phs000587

• Longitudinal Studies of Patients with Familial Platelet Disorder with Associated Myeloid Malignancy (FPDMM)

  FPDMM (OMIM #601399) is a rare autosomal dominant disease characterized by defective megakaryocytic development, thrombocytopenia, platelet functional defects, and a life-long risk of developing hematological malignancies. FPDMM is caused by germline mutations in the RUNX1 gene, which encodes a master regulator of hematopoiesis. The overall lifetime risk of hematological malignancies in FPDMM patients is 35 - 45%. It is hypothesized that mutations in other genes cooperate with the germline RUNX1 mutations for leukemia development. However, it is not clear which genes need to be mutated for leukemia to develop and which biomarkers or clinical tests can be used to predict which patients will progress to leukemia. Likewise, there are no treatments and/or preventative measures that can reduce or stop disease progression except for stem cell transplantation, which is not available for all patients and may be associated with significant complications. To address these questions, we launched a longitudinal natural history study of patients associated with RUNX1 germline mutations at the NIH Clinical Center in early 2019 (Trial Registration ID: NCT03854318). The goals of this study are to: (1) perform comprehensive longitudinal phenotyping of FPDMM patients to document the full spectrum of both hematopoietic and non-hematopoietic manifestations of the disease; and (2) perform extensive genomic analyses of FPDMM patient samples to identify cooperating genomic variants, which may confer growth advantage that leads to clonal expansion of affected hematopoietic cells that may serve as the precursor to malignancies. The data available through dbGaP include exome sequencing and RNA-seq data from these patients. Diverse germline mutation types were identified in the RUNX1 gene, including splice site mutations and large deletions, in addition to nucleotide substitutions and small indels. Somatic mutations, especially in genes associated with clonal hematopoiesis of indeterminate potential (CHIP), were found in a substantial proportion of FPDMM patients who were leukemia-free. The findings suggest that the genomes in these patients are prone to somatic mutations and monitoring the dynamic changes of these somatic mutations prospectively may provide a way to predict progression to malignancies.

  Study phs003075

• Center Common Disease Genomics [CCDG] - CVD - TAICHI

  The TaiChi consortium consists of 6 studies that collaborated initially in a large scale metabochip study, and became an ongoing consortium for studies of cardiometabolic disease in the Chinese population in Taiwan. The six studies included the following: 1) SAPPHIRe (Stanford-Asian Pacific Program in Hypertension and Insulin Resistance), a family based study established in 1995 with an initial goal of identifying major genetic loci underlying hypertension and insulin resistance in East Asian populations, with Taiwan subjects participating in the TaiChi consortium; 2) TCAGEN (Taiwan Coronary Artery Disease GENetic), a cohort study that the enrolled patients undergoing coronary angiography or percutaneous intervention at the National Taiwan University Hospital (NTUH) in the setting of either stable angina pectoris or prior myocardial infarction; 3) TACT (TAiwan Coronary and Transcatheter intervention), a cohort study enrolled patients with angina pectoris and objective documentation of myocardial ischemia who underwent diagnostic coronary angiography and/or revascularization any time after October 2000 at the National Taiwan University Hospital (NTUH) (similar to TCAGEN but recruitment was independent of TCAGEN); 4) Taiwan DRAGON (Taiwan Diabetes and RelAted Genetic COmplicatioN), a cohort study of Type 2 diabetes at Taichung Veterans General Hospital (Taichung VGH) in Taiwan, with participants including individuals with either newly diagnosed or established diabetes (subjects with hyperglycemia who did not meet diagnostic criteria for Type 2 DM were not included); 5) TCAD (Taichung CAD study), includes patients with a variety of cardiovascular diseases who received care at the Taichung Veterans General Hospital (Taichung VGH), i.e. specifically individuals who were hospitalized for diagnostic and interventional coronary angiography examinations and treatment; 6) TUDR (Taiwan US Diabetic Retinopathy) enrolled subjects with Type 2 diabetes who received care at Taichung Veteran General Hospital (Taichung VGH), and a small number of subjects from Taipei Tri-Service General Hospital (TSGH); TUDR subjects underwent a complete ophthalmic and fundus examination to carefully document the presence and extent of retinopathy. From these 6 studies, subjects were selected based on completeness of standard metabolic phenotyping and knowledge of cardiac disease status (early onset coronary disease), to undergo whole genome sequencing at the Broad.

  Study phs001487

• Temporal Lobe Epilepsy and Retrotransposons

  Idiopathic (cryptogenic) epilepsy is a common, chronic group of brain disorders, affecting 1-2% of the US population, creating a significant public health problem because of the associated morbidity and mortality. One subtype of this complex group of brain disorders, temporal lobe epilepsy (TLE), is particularly burdensome, because a substantial fraction of patients do not respond to anticonvulsant medications. If the seizure focus can be localized by imaging and/or EEG, the TLE patient often elects to have a partial resection of the affected temporal lobe, because they have daily seizures, despite multiple pharmacotherapy regimens. Although genetic risk is thought to play a role in TLE, identification of common risk alleles has had limited success. In the past 5 years, data have accumulated to prove that neuronal embryogenesis is accompanied by activation of LINE1 (L1) retrotransposons (RTPs) to an unexpected degree, such that developing neurons may accumulate de novo L1 insertions. This results in a substantial mosaicism within populations of CNS neurons. While most of these somatic de novo L1s will have little effect on neuronal function (perhaps because they occur in gene deserts or in large introns or in genes not required for that cell's function), some may interfere with normal neuronal activity because they have inserted into a gene needed by that particular neuron for normal function. If one or more functional de novo L1s occur early in CNS development, all the daughter neurons that derive from that neuronal precursor will also carry the L1 insertion, perhaps leading to a dysfunctional population of neurons destined to become an epileptic focus. This study leveraged CNS tissue (obtained at craniotomy) from patients with intractable TLE, who have undergone a therapeutic partial resection of one temporal lobe. Using fluorescence-assisted cell sorting of temporal lobe neuronal nuclei, followed by high-throughput sequencing and alignment to the reference genome, detection of de novo L1s will be done. In this manner, it is expected that de-novo intragenic L1s, contributing to idiopathic TLE, will be discovered.

  Study phs002067

• NHLBI GO-ESP: Early-Onset Myocardial Infarction (Broad EOMI)

  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. In the Grand Opportunities Exome Sequencing Program Early MI Project (GO ESP - EOMI), we are sequencing cases with extremely early-onset MI drawn from 8 cohorts. These cohorts include five hospital or community-based studies that ascertained individuals based on MI status. These include PennCATH, Cleveland Clinic Genebank, Massachusetts General Hospital Premature Coronary Artery Disease Study (MGH-PCAD), Heart Attack Risk in Puget Sound (HARPS), and Translational Research Investigating Underlying Disparities in Myocardial Infarction Patients' Health Status (TRIUMPH). Cases were selected based on MI occurring in men aged ≤50 years and women aged ≤60 years. In addition, early-MI cases are being drawn from three population-cohort studies including the Framingham Heart Study, the Women's Health Initiative, and the Atherosclerosis Risk in Communities Study. MI-free controls are being drawn from five population-based cohort studies including the Framingham Heart Study, the Women's Health Initiative, Atherosclerosis Risk in Communities Study, Cardiovascular Health Study, and the Jackson Heart Study. Controls were selected based on two factors: (1) highest predicted risk for MI based on Framingham risk score; and (2) absence of prevalent or incident MI despite a high predicted risk.

  Study phs000279

• NIDDK IBD Genetics Consortium Crohn's Disease Genome-Wide Association Study

  This dataset contains data from a genome-wide association study performed with 968 Inflammatory Bowel Disease (IBD) affected cases and 995 unrelated controls using the Illumina HumanHap300 Genotyping BeadChip. Cases were selected to have Crohn's disease with ileal involvement, and controls were matched to cases based on sex and year of birth. Subjects were drawn from two cohorts: (1) persons with non-Jewish, European ancestry (561 cases and 563 controls), and (2) persons with Jewish ancestry (407 cases and 432 controls). Genotyping was performed at the Feinstein Institute for Medical Research. Seven-hundred fifty-four of the samples (468 cases and 286 controls) were taken from the NIDDK IBD Genetics Consortium cell line repository. These samples are identified in the IBD_Sample file. The subject IDs for these individuals may be used to request corresponding samples for follow-up research through the repository. In addition, complete phenotype data for these individuals are available, together with the Consortium's phenotyping manual and the forms used to collect the data. The remaining 1,209 samples were obtained from pre-existing collections ascertained through Cedars-Sinai Medical Center, Johns Hopkins University, University of Chicago, University of Montreal, University of Pittsburgh, University of Toronto, and the New York Health project (controls only). For these samples, only sex, cohort (Jewish vs. non-Jewish), and age at diagnosis (cases only) are available. Two-hundred three individuals from among the pre-existing samples did not provide consent to release their genotype data (designated as consent group 2 in the file IBD_Subject). Thus, individual genotype data are only provided for 1,760 samples. To compensate for this, we have provided summary results for each SNP. These are based on a stratified analysis testing case/control association. Fifty-one samples had a call rate less than 93% and were therefore excluded from this analysis, leaving an overall sample size of 1,963 - 51 = 1,912. X Chromosome Heterozygosity Nine samples have X chromosome heterozygosity that is neither consistent nor inconsistent with their phenotypic sex. One of these samples was found to have Turner Syndrome. The remaining 8 samples have heterozygosity ranging from 35-76%.

  Study phs000130

• CTN - 0051: Extended-Release Naltrexone vs. Buprenorphine for Opioid Treatment (X:BOT)

  The overarching goal of CTN-0051 is to foster adoption of new relapse-prevention pharmacotherapies in community-based treatment programs (CTPs) where these could have a substantial public health impact. To this end CTN-0051 will assess the comparative effectiveness of extended-release injectable naltrexone (XR-NTX, Vivitrol®), an opioid antagonist recently approved and indicated for the prevention of relapse to opioid dependence, versus buprenorphine-naloxone (BUP-NX, Suboxone®), a high affinity partial agonist indicated for maintenance treatment of opioid dependence, as pharmacotherapeutic aids to recovery. The study is conducted in 8 CTN-affiliated CTPs that provide or partner with detoxification services (inpatient/residential) which have the capacity to maintain participants opioid-free for approximately 3-7 days, have the capacity to provide medication-assisted therapy, and can provide a minimum of one group or individual counseling session per week during the 24-week treatment period. Up to 600 eligible participants will be randomized to treatment with XR-NTX or BUP-NX for 24 weeks (sufficient to include 350 participants who are randomized more than 72 hours after their last opioid). To maximize generalizability, the point of randomization is flexible, from shortly after program admission until just prior to program discharge. The primary goal of the study is to estimate the difference, if one exists, between XR-NTX and BUP-NX in the distribution of the time to relapse (i.e., loss of persistent abstinence) during the 6-month trial. The primary outcome measure is the time to the event, with the event called relapse. Secondary objectives are to: (1) compare outcome on XR-NTX versus BUP-NX across a range of clinical safety and secondary efficacy domains, (2) explore demographic, clinical, and genetic predictors of successful treatment and moderators of differential effectiveness (i.e., what variables may help clinicians choose which of these treatments is best for a given patient), and (3) collect a limited dataset to permit analyses of economic costs and benefits of the two treatments.

  Study phs002876

• NHLBI GO-ESP: Lung Cohorts Exome Sequencing Project (Pulmonary Arterial Hypertension)

  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 syndrome of pulmonary hypertension (PH) is a pulmonary disease that carries very high morbidity and mortality. Pulmonary arterial hypertension (PAH) is a category of PH (WHO Group 1) that includes several entities (idiopathic or heritable PAH, and PAH associated with other diseases such as connective tissue diseases including scleroderma-associated PAH) and carries a dismal prognosis, in particular when it relates to scleroderma-associated PAH (median survival of about 4 years). It is believed that the severity of structural changes involving the pulmonary vasculature and right ventricular failure are genetically determined. The 'Genomics and Genetics of Pulmonary Arterial Hypertension' study at Johns Hopkins University aims to identify genetic determinants associated with risk of PAH in a cohort of European American and African American participants with and without PAH. The study also focuses on patients with scleroderma, who are further stratified according to those who have or do not have PAH. The broad goals of the Lung GO/ESP-GO falls into two general categories: (i) discovery of all variants (i.e., common and rare) in all protein-coding regions of the human genome (i.e., the exome) conferring risk to complex pulmonary diseases including PAH. The Johns Hopkins University PAH cohort offers a unique opportunity to elucidate genetic variants that cause PAH.

  Study phs000290

• A Phase I/II Trial of Sirolimus (Rapamune®) and Cyclosporine in Patients with Refractory Aplastic Anemia

  The most successful treatment for aplastic anemia is bone marrow transplantation. However, few patients are eligible for this procedure. For others, treatment usually consists of immunosuppressive agents, such as antithymocyte globulin (ATG) and cyclosporine. Unfortunately, even with immunosuppressive therapy, relapse is common. New combinations of medications may offer alternative and more effective treatment options. Sirolimus and cyclosporine are two drugs routinely used to suppress the immune system and prevent rejection in patients who have received organ transplants. While cyclosporine has been proven effective for treating aplastic anemia, sirolimus has not been tested for this disease. This study will evaluate the safety and efficacy of sirolimus in combination with cyclosporine for treating individuals with aplastic anemia that have not responded to other treatments. This study will last at least 6 months. Participants will first be screened to verify diagnosis of aplastic anemia. The screening will include a physical examination, blood test, bone marrow biopsy from the pelvic bone, and review of medications and medical history. Individuals who are eligible will then start the first treatment period. Participants will receive two medications: cyclosporine will be taken twice a day and sirolimus will be taken once a day. Depending on side effects, the dose of either drug may be temporarily stopped or lowered. On Day 1, blood will be drawn and females will undergo a pregnancy test. Subsequent study visits will occur weekly for the first month, every 2 weeks for 2 months, and then once a month for the remainder of the study. Each visit will include a physical examination, vital sign assessment, and review of side effects and medications. Blood tests will be performed weekly for the first 3 weeks, and then every 2 weeks. After 6 months of treatment, if a participant has shown improvements in disease status without major side effects, the treatment will continue. Over time the doses may be lowered. If a participant has not improved while on the study medication, treatment will stop at 6 months. Whenever treatment is discontinued, the participant will again undergo a physical examination, blood tests, and bone marrow biopsy.

  Study phs000695

• NSIGHT North Carolina Newborn Exome Sequencing for Universal Screening (NC NEXUS)

  Since newborn screening (NBS) began in the 1960s, technological advances have resulted in its use in an increasing number of disorders. Recent developments in whole-genome sequencing and its simpler corollary, whole-exome sequencing (WES), now afford the opportunity to comprehensively define the variation within an individual's genome in a rapid and affordable manner. Many challenges arise with the clinical application of genome-scale sequencing and in deriving practical benefits to infants and children. Its utility in NBS has yet to be demonstrated and its application in the pediatric population requires special examination, not only for potential clinical benefits but also for the unique ethical challenges it presents. In this proposal, we outline a highly interdisciplinary approach to identify, confront, and overcome the major challenges that must be met in order to implement deep sequencing technology to enhance current newborn screening in a diverse pediatric population. Overarching Aim 1 will evaluate the utility of WES as a diagnostic tool to extend the utility of current NBS. Using diverse cohorts of infants and young children with known conditions identified through NBS, we will examine the sensitivity and specificity of WES. We will also utilize WES in cohorts of children with known conditions not currently screened as potential candidates for NBS in the future. Overarching Aim 2 will develop and assess a framework for analyzing WES in a clinically oriented framework based on principles of ethics and evidence-based medicine. We will develop strategies to guide clinicians, clinical laboratories, and patients/families in their decisions regarding the inevitable incidental findings that will be detected, in ways that respect the child and protect his/her future autonomy, while also respecting parental interests and rights. Overarching Aim 3 will explore ethical, legal, and social issues (ELSI) involved in informed decision making and develop best practices regarding the return of results after testing. We will develop novel decision support tools and evaluate their usefulness in parental decision making, and examine the burdens placed on clinicians as this new technology is deployed in the vulnerable and special population that are newborns and their families.

  Study phs002095