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• HudsonAlpha Institute for Biotechnology Clinical Sequencing Exploratory Research (CSER): Genomic Diagnosis in Children with Developmental Delay

  The overarching goal of this project is to explore the ability for whole exome and genome sequencing technologies to identify the genetic causes of unexplained developmental delay, intellectual disability (DD/ID), and related congenital anomalies in children. Such information may be useful as an endpoint to the otherwise fruitless "diagnostic odyssey" that many DD/ID affected families undergo and in some cases, identification of these genetic variants may point to better therapeutic or educational options by precisely defining the root cause(s) of the child's condition. We seek to identify causal, diagnostically relevant, genetic variants in children with developmental delay and/or intellectual disability (DD/ID). In addition, because our analytical approach includes sequencing probands and their parents (parent-offspring trios and duos; parents are sequenced when available), secondary findings will be returned to adults (parents) at their request. The aims of this research project include: 1) Use exome and whole genome sequencing to identify genetic variation that results in DD/ID. 2) Return primary genetic results (DD/ID causative) as well as secondary findings to probands and their parents, respectively. 3) Understand how the return of genomic test results affects the health and well-being of study participants. The children participating in this study are patients at, or referrals to, North Alabama Children's Specialist (NACS) in Huntsville, Alabama. All blood samples from probands and their parents will be collected at NACS (project 1). Sequencing will be completed at the HudsonAlpha Institute for Biotechnology, with validation (via Sanger sequencing) conducted at Emory University for all returned variants (project 2). The University of Louisville will oversee questionnaires, surveys and interviews aimed at understanding study participants' perception of, and response to, genetic test results, in addition to assessment of secondary findings preferences (project 3).A subset of variants, largely those determined to be diagnostic or variants of uncertain significance for study participants at the time of disclosure, have been submitted to ClinVar. These variants are listed as part of the "CSER-HudsonAlpha" study within the database.

  Study phs001089

• RNA-Seq of Whole Blood from Patients with Intracranial Aneurysms

  Rupture of intracranial aneurysms (IAs) causes intracranial hemorrhaging that leads to high rates of neurological deficits and death. Although rupture rates are low, clinicians must decide whether to treat or monitor these potentially dangerous lesions. In the current clinical practice, the most common metric to measure risk of rupture is aneurysm size. However, clinical data show that small aneurysms can also rupture. As a result, alternative clinical stratification scores have been proposed, including the PHASES (Population, Hypertension, Age, Size, Earlier subarachnoid hemorrhage, and Site) score based on patient demographics and IA characteristics to stratify ruptured and unruptured IAs, and the Rupture Resemblance Score (RRS) that stratifies ruptured and unruptured IAs based on hemodynamic and morphological properties. However, all metrics require imaging on digital subtraction angiography (DSA), which is invasive, expensive, requires the use of X-rays, and is associated with transient or permanent neurological and non-neurological complications. We hypothesize that individuals with dangerous IAs have detectable gene expression differences in their blood that could be used as biomarkers to determine rupture risk. We propose to use whole blood transcriptomes to develop a "one-stop" diagnostic test that can detect the presence of IAs and determine the risk of rupture based on circulating RNA expression biomarkers using our prototype AneuScreenTM platform. We aim to develop and validate biomarkers to predict risk, as calculated by the currently-used metric of aneurysm size, the clinical PHASES score, and the RRS. Here, we collected blood samples from consented individuals who were receiving cerebral imaging at the Gates Vascular Institute (Buffalo, NY) for intracranial aneurysm. RNA extracted from blood samples (n=43) was subjected to RNA-sequencing and added to our existing database (n=44). When combined with our previous data, we had transcriptome data from 68 aneurysms (after additional sample filtering). This dataset was stratified into low- and high-risk according to IA size, PHASES score, and RRS score. Differentially expressed genes were identified and used to construct predictive models. Fastq files and basic demographic information for the 43 newly-sequenced intracranial aneurysm samples on this project will be available through dbGaP.

  Study phs003072

• Longitudinal Studies of Brain Structure and Function in MPS Disorders

  Mucopolysaccharidosis (MPS) types I, II, IV, VI and VII, are inherited diseases that result from the bodies inability to break down large sugar molecules that are by-products of metabolism. MPS affects most organs of the body and causes abnormalities in the liver, spleen, bones, and brain. We are studying the central nervous system (primarily the brain) so we can better understand the nature of the problems individuals with MPS I, II, IV, VI and VII have so we can find ways of better treating these problems. We would like to find out about the changes in the brain of individuals with MPS I, II, IV, VI and VII using data from MRI and neuropsychological tests. This is a longitudinal study so patients who enroll will need to be seen 3 times over 5 years. The longitudinal nature of the study allows us to make conclusions about how changes in some structures of the brain and changes in cognitive ability are related. The research objectives are: To identify abnormalities of brain (and central nervous system) structure and function in patients with MPS I, II, IV, VI and VII, regardless of how they are being treated or have been treated in the past; and to track disease progression over time. To examine the degree to which independent variables (e.g., age at first treatment, severity of disease, types of medical abnormalities, mutation, medical events, and sensory abnormalities) have an impact on both functional and structural outcomes as well as on quality-of-life. To identify, through longitudinal study, those measures that most accurately reflect the current disease state. This is a longitudinal study of 75-100 individuals with either MPS I, II, IV, VI and VII. Those participating in the study will be evaluated 3 times over 5 years. The primary site for this study is the University of Minnesota but there are an additional 6 centers in the United States and Canada that are also participating and will provide data for analysis. You will need to be able to travel to Minnesota or one of the participating centers in order to be a part of this study.

  Study phs001328

• Genome-Wide Association Study of Patients with Coccidioidomycosis

  BackgroundValley Fever is typically an infection of the lungs caused by the fungi Coccidioides immitis and Coccidioides posadasii. The incidence of Coccidioidomycosis (CM), or infection with Coccidioides, has dramatically increased over the last 20 years. This is particularly true in the Southwest of the United States, where people often breathe fungal spores that arise from the soil. Reasons for increased infection rates are thought to include population growth and construction in these endemic regions, an increase in the number of people whose immune systems are compromised due to infection or treatment with drugs required for organ transplants, climate change, as well as improved testing practices and greater physician awareness. Mild CM most commonly presents itself with flu-like symptoms and rashes, which can last weeks to months. Individuals with compromised immune systems, specifically-- substantial suppression of the immune cells known as T cells, can develop severe pulmonary and disseminated disease. Infection that remains localized to the lungs is referred to as pulmonary disease, but when the infection spreads out of the lungs into other parts of the body it represents a more serious condition referred to as a disseminated disease, or disseminated CM. In nature, Coccidioides spp. exists as mold and lives in dust and soil. When the contaminated soil or dust is disturbed by human activity, animals, or weather, the Coccidiodies spores are released into the air. Airborne spores are taken up by breathing and settle in the lungs. Once in the moist and warm environment of the lung, spores transform into spherules, which divide and become filled with smaller spores, called endospores. When the spherules get large enough, they rupture and release these endospores, which can spread and disseminate to surrounding tissue. The cycle then repeats itself as these endospores develop into new spherules3. Different ethnic groups have been described to vary in their susceptibility to developing disseminated CM after initial infection with Coccidioides. For example, evidence suggests that African-American and Filipino patients suffer the disseminated disease at a greater rate than other ethnicities. The suggestion that race plays a role in the clinical expression of the disease is still a source of debate amongst the scientific community and any genetic mechanisms responsible for these differences have yet to be fully elucidated. If our genetic makeup influences our ability to limit the spread of infection, finding which DNA differences cause these variances could provide clues to how the body successfully fights infection, and provide opportunities to boost the body’s ability to do this. Further, if we are able to identify the specific genetic risk factors that correlate with the development of disseminated infection, physicians could perform genetic screenings to identify high-risk patients and provide them with preemptive antifungal therapy prior to developing disseminated disease.The genome, made up of DNA, contains all of the information needed for humans to develop and grow. Genome-wide association studies (GWAS) allow us to look for inherited differences that are more common between people who share a particular trait, for example, height or susceptibility to certain diseases, compared to those who do not share the trait. Although some traits and diseases are controlled by a single gene, the majority are influenced by contribution from several, or even many, different genes. To find evidence of genes that contribute to specific traits, GWAS typically compares genome information from large numbers of people who have a particular disease (referred to as “cases”) looking for DNA sequences that are common among these samples, and are different from DNA sequences seen in large numbers of people who lack the trait, but are as much like the cases as possible (referred to as “controls”). The DNA sequence data from each group, cases versus controls, are analyzed to see if there are specific genomic differences that tend to be associated with the disease. MethodsTwo separate GWAS approaches were taken to look for genetic differences that could be responsible for the observed differences between the different patient populations we are studying. The first method, known as genotyping, scans for differences at a set of positions across the genome, which includes both the genes that encode our proteins and the larger amount of DNA that does not. The second method, known as exome sequencing, allows us to compare the entire sequence of the portion of the genome that codes for proteins.  For this study, DNA from patients with either pulmonary or disseminated CM were genotyped and exome sequenced to look for DNA differences that are associated with one condition or the other. All patients were at least 18 years old, had no evidence of immunosuppression, and had proven or probable pulmonary coccidioidomycosis according to established diagnostic criteria. Of these patients, a subset demonstrated disseminated disease, i.e., they showed evidence of coccidioidal infection outside of the thorax by biopsy/aspiration, had radiographic imaging, and show positive coccidioidal serology. Our criteria for including patients with the pulmonary disease were that they must not require ongoing antifungal treatment or show evidence of active CM (in skin test positive patients), show no evidence of extrapulmonary dissemination, and have no evidence of ongoing pulmonary infection (pulmonary nodules are accepted) beyond six months from diagnosis.Patient DNA was purified from blood or from sputum samples by the labs of our collaborators, Drs. George Thompson (UC Davis School of Medicine) and John Galgiani (University of Arizona Health Sciences). Genome-wide association (GWAS) analysis was carried out to look for candidate loci associated with pulmonary versus disseminated disease, taking into account the population structure of the samples. Single nucleotide or insertion/deletion variants were identified from whole-exome sequences (WES) using the Picard/BWA/GATK pipeline. ResultsTable 1. Pulmonary versus Disseminated Cases of Coccidiomycosis for GWAS, Sorted by EthnicityEthnicityPulmonary CasesDisseminated CasesAsian85Black/African American1664Caucasian/White4015Filipino03Hispanic/Latino3414Indian21Mexican American1039Pacific Islander01Samoan03Vietnamese10Unknown16917More than one race02Total373134Table 1 shows the number of samples analyzed from patients with pulmonary versus disseminated disease, and patient ethnicity, where known. In all, we worked with 507 samples, including 134 samples from patients with disseminated disease and 373 samples from patients with pulmonary disease. Of these, 505 samples were genotyped using the Multi-Ethnic Global Array from Illumina Inc. In addition, we were able to generate whole-exome sequence from 498 patient samples. No significant associations were detected that differed between samples from patients with pulmonary versus disseminated disease; that is, no particular DNA sequences were found to be significantly enriched in patients with disseminated disease compared to patients with pulmonary disease. The ability to detect genetic association between specific sequences and genetically determined traits is influenced by several factors, including how many patient samples are available to compare, how many different genes contribute to the trait and how strong their contributions are. When the number of genes is small and the contribution of each gene is great, smaller numbers of patient samples are needed to detect an association. When more genes are involved, or the contribution from each gene is more modest, larger numbers of patient samples must be examined. While we were not able to detect any associated within this study, it does not mean that subsequent studies would not find this connection. Our study suggests significantly more samples should be analyzed in further studies.Whole-exome sequences were generated from 498 samples and were aligned to reference sequences to identify positions where the sequences differed from the reference. These data are being analyzed to determine if any variants are associated with pulmonary, versus disseminated, disease. 

  Study phs002170

• Deletion of FUNDC2 and CMC4 on chromosome Xq28 is sufficient to cause hypergonadotropic hypogonadism in men

  Hypergonadotropic hypogonadism (HH) is characterized by low sex steroid levels and secondarily elevated gonadotropin levels with either congenital or acquired etiology. Genetic factors leading to HH have yet to be fully elucidated. We submit genome and transcriptome data analyses from a male patient with HH and history of growth delay who has an inherited deletion of chromosome Xq28. Expression analyses were done for this patient and his unaffected family members, and compared to normal controls to identify dysregulated genes due to this deletion. Our patient's Xq28 deletion is 44,806 bp and contains only two genes, FUNDC2 and CMC4. Expressions of both FUNDC2 and CMC4 are completely abolished in the patient. Gene ontology analyses of differentially expressed genes in the patient in comparison to controls show that significantly up-regulated genes in the patient are enriched in Sertoli cell barrier regulation, apoptosis, inflammatory response and gonadotropin-releasing regulation. Indeed, our patient has an elevated FSH level, which regulates Sertoli cell proliferation and spermatogenesis. In his mother and sister, who are heterozygous for this deletion, X-chromosome inactivation is skewed towards the deleted X, suggesting a mechanism to avoid FSH dysregulation. Compared to the previously reported men with variable sized Xq28 deletions, our study suggests that the loss of function of FUNDC2 and/or CMC4 results in dysregulation of apoptosis, inflammation and FSH, and is sufficient to cause Xq28-associated HH.

  Study phs002234

• Initial whole genome sequencing of plasma cell neoplasms in First Responders exposed to the World Trade Center attack of September 11, 2001

  The World Trade Center (WTC) attack of September 11, 2001 created an unprecedented environmental exposure to known and suspected carcinogens. High incidence of multiple myeloma (MM) and precursor conditions has been reported among first responders to the WTC disaster. To expand on our prior screening studies, and to characterize the genomic impact of the exposure to known and potential carcinogens in the WTC debris, we were motivated to perform whole genome sequencing (WGS) of WTC first responders and recovery workers who developed a plasma cell disorder after the attack. PATIENTS AND METHODS: We performed WGS of 9 CD138-positive bone marrow mononuclear samples from patients who were diagnosed with plasma cell disorders after the WTC disaster. RESULTS: No significant differences were observed in comparing the post-WTC driver and mutational signatures landscape with 110 previously published WGS from 56 patients with MM and the CoMMpass WGS cohort (n=752). Leveraging constant activity of the single base substitution mutational signatures 1 and 5 over time, we estimated that tumor-initiating chromosomal gains were windowed to both pre- and post-WTC exposure. CONCLUSIONS: Although limitations in sample size preclude any definitive conclusions, our findings suggest that the observed increased incidence of plasma cell neoplasms in this population is due to complex and heterogeneous effects of the WTC exposure that may have initiated or contributed to progression of malignancy.

  Study EGAS00001004467

• Genomic Characterization of Metastatic Castration Resistant Prostate Cancer

  Biopsies of castration resistant prostate cancer metastases were subjected to whole genome sequencing (WGS), along with RNA-sequencing (RNA-Seq). The overarching goal of the study is to illuminate molecular mechanisms of acquired resistance to therapeutic agents, and particularly androgen signaling inhibitors, in the treatment of metastatic castration resistant prostate cancer (mCRPC).

  Study phs001648

• Whole genome sequence: cardiomyopathy, 1 HCM patient

  In this study, we analyzed the genomic information by whole genome sequencing using peripheral blood samples from patients with various cardiovascular diseases including severe heart failure to identify genetic variants related to the pathology of cardiovascular diseases. The purpose is to elucidate the underlying mechanism and develop new therapeutic interventions for cardiovascular disease.

  Study JGAS000704

• Whole genome sequence: cardiomyopathy, 1 ARVC patient

  In this study, we analyzed the genomic information by whole genome sequencing using peripheral blood samples from patients with various cardiovascular diseases including severe heart failure to identify genetic variants related to the pathology of cardiovascular diseases. The purpose is to elucidate the underlying mechanism and develop new therapeutic interventions for cardiovascular disease.

  Study JGAS000705

• RNA-seq analysis of BMP-stimulated glioma initiating cells

  Bone morphogenetic protein (BMP) signaling has been shown to suppress progression of glioblastoma by promoting astrocytic differentiation; however, roles of BMP signaling in cell proliferation and apoptosis of glioblastoma cells remains to be elucidated. We here performed RNA-seq analysis of glioma initiating cells to identify transcriptional target(s) of BMP.

  Study JGAS000077