Clinical Research Directory

Familial Mediterranean Fever and Related Disorders: Genetics and Disease Characteristics

This study is designed to explore the genetics and pathophysiology of diseases presenting with intermittent fever, including familial Mediterranean fever, TRAPS, hyper-IgD syndrome, and related diseases. The following individuals may be eligible for this natural history study: 1) patients with known or suspected familial Mediterranean fever, TRAPS, hyper-IgD syndrome or related disorders; 2) relatives of these patients; 3) healthy, normal volunteers 7 years of age or older. Patients will undergo a medical and family history, physical examination, blood and urine tests. Additional tests and procedures may include the following: 1. X-rays 2. Consultations with specialists 3. DNA sample collection (blood or saliva sample) for genetic studies. These might include studies of specific genes, or more complete sequencing of the genome. 4. Additional blood samples a maximum of 1 pint (450 ml) during a 6-week period for studies of white cell adhesion (stickiness) 5. Leukapheresis for collecting larger amounts of white cells for study. For this procedure, whole blood is collected through a needle in an arm vein. The blood flows through a machine that separates it into its components. The white cells are removed and the rest of the blood is returned to the body through another needle in the other arm. Patients may be followed approximately every 6 months to monitor symptoms, adjust medicine dosages, and undergo routine blood and urine tests. They will receive genetic counseling by the study team on the risk of having affected children and be advised of treatment options. Participating relatives will undergo a medical and family history, possibly with a review of medical records, physical examination, blood and urine tests. Additional procedures may include a 24-hour urine collection, X-rays, and consultations with medical specialists. A DNA sample (blood or saliva) will also be collected for genetic studies. Additional blood samples of no more than 550 mL during an 8-week period may be requested for studies of white cell adhesion (stickiness). Relatives who have familial Mediterranean fever, TRAPS, or hyper-IgD syndrome will receive the same follow-up and counseling as described for patients above. Normal volunteers and patients with gout will have a brief health interview and check of vital signs (blood pressure and pulse) and will provide a blood sample (up to 90 ml, or 6 tablespoons). Additional blood samples of no more than 1 pint over a 6-week period may be requested in the future....

BAG3-DCM Natural History Study

The goal of this international observational study is to learn about the natural history of Dilated Cardiomyopathy (DCM) arising from pathogenic BAG3 variants in adult patients ≥18 years of age.

PKP2-ACM Natural History Study

The goal of this study is to describe the natural history and clinical events for patients who have Arrhythmogenic Cardiomyopathy with Pathogenic Plakophilin-2 Variants (PKP2-ACM) managed with standard of care.

Genotype-phenotype Characterization Study on Genetic Diseases With Immune and Neurological Dysfunctions

Over the past twenty years, Prof. Yanick Crow and his team have developed internationally recognized expertise in genetic pathologies affecting the immune and neurological systems. The pathologies studied have a particularly severe impact on patients' quality of life, with a high mortality rate and a significant risk of occurrence in affected families. These pathologies are rare, and very often under-diagnosed. To date, there is virtually no effective curative treatment. Prof. Crow's team operates at the frontier between clinical and research work, and from experience, the team knows that patients and families affected by these serious pathologies are often highly motivated to help research into the pathology that affects them. Initially, Prof. Crow's research focused primarily on the study of the genetic disease Aicardi-Goutières Syndrome (AGS). However, there is an undeniable clinical and pathological overlap between AGS and other forms of disease such as autoimmune systemic lupus erythematosus and many other genetic pathologies - e.g. familial lupus engelure, spondyloenchondromatosis and COPA syndrome. This is why research is being extended to all genetic diseases with immune and neurological dysfunctions.

Impaired Type I IFN Immunity Due to Autoantibodies or a Genetic Defect: a Prospective National Cohort

The major role of human genetic factors in the immune response to infections is now well established, particularly for viral infections. In the context of the COVID-19 pandemic, the following results have identified 1) several inborn errors of immunity (IEI) affecting the response or production of type I interferons (type I IFNs) in around 4% of adult patients with severe clinical disease, and 2) the presence of type I IFN-neutralizing autoantibodies (auto-Abs) in around 15% of severe cases, and 20% of deaths. The investigators would like to carry out a longitudinal immunological and clinical follow-up study on a prospective cohort of patients with either a genetic defect affecting the type I IFN-dependent immune response, or anti-IFN-I auto-Abs, to monitor the incidence of infectious and/or autoimmune events in these individuals, the evolution of neutralizing power, and the kinetics of auto-Abs. This should lead to a better understanding of the prevention and management of these patients. The research design is a national multicenter prospective cohort of adults with 1) anti-IFN-I auto-Abs or 2) IEI- IFN-I, with follow-up from 1 to 4 years. These individuals may be: 1) patients who have or have had clinical disease (related to COVID-19, other viral infections, autoimmune disorders); or 2) "healthy" participants (e.g. blood donors, relatives of an IEI patient). Follow-up will include: * yearly visits to the Clinical Investigation Center (CIC) or a clinical department with blood sampling; * specific visit in case of hospitalization for infectious events or adverse effects of vaccination, exacerbation or new diagnosis of auto-immune disease, new diagnosis of cancer, or SARS-CoV-2 infection whether or not patients are admitted to hospital, with blood sampling. In addition, a retrospective "passive" follow-up will be implemented through matching with the data from the SNDS (National Health Data System), in order to collect clinical events of and healthcare resource consumption. Moreover, matching with controls adults from the national CONSTANCES cohort, not carrying auto-Abs against type I IFNs nor IEI-IFN-I, will be performed. (ratio 3:1; matching on age (+/- 5 years), gender and geographic region of recruitment). Individuals under long-lasting immunosuppressive or immunomodulatory drugs will not be eligible. Follow-up of controls, which will be carried out as part of the CONSTANCES cohort, will include web-based questionnaires, every 12 months, in addition to linking with SNDS data as already done in this cohort. Inclusion visit: After signing the consent form, the following tests will be performed: * Demographic characteristics (sex, age, country of birth) * Medical history from participant and family member(s) including infectious and auto-immune diseases, cancers and vaccination status and side effects * Blood samples for: * full blood cell count; * classical autoimmune investigations (anti-nuclear, anti-ENA, native anti-DNA, anti- thyroid antibodies, rheumatoid factor); * immunophenotyping\*; * auto-Abs against type I IFNs, other cytokines\*, or other target proteins\* (dosage and neutralization activity); * Genetic explorations by whole-exome or whole-genome sequencing\*; * Biobanking (DNA, plasma/sera; cryopreserved peripheral blood mononuclear cells (PBMCs). * these biological analyses will be carried out as part of dedicated COVIFERON RHU5 workpackages. In addition, vaccination against SARS-CoV-2 and influenza will be offered to these subjects as a priority, as part of their usual care. Follow-up visits : Annual visits to the CIC : * Medical history since last visit, including infectious, auto-immune and oncologic events, vaccination status and side effects * Blood samples for: * full blood cell count; * classical autoimmune investigation (anti-nuclear, anti-ENA, native anti- DNA, anti-thyroid antibodies, rheumatoid factor); * immunophenotyping; * Auto-Abs against type I IFNs, other cytokines, or other target proteins (dosage and neutralization) * Biobanking (DNA, plasma, cryopreserved peripheral blood mononuclear cells (PBMCs)) Additional specific visit in the event of a clinical event of interest, at any time during follow-up: * In case of SARS-CoV-2 infection, whatever the severity of the disease: blood sampling for determination and neutralization of type I anti-IFN autoAbs, CBC, and biobanking (plasma and PBMC) and teleconsultation with the CIC in charge of patients, as soon as possible. * In the event of hospitalization for infectious events or exacerbation or new diagnosis of an auto-immune disease: blood sampling for determination and neutralization of anti-IFN-I autoAbs, CBC, and biobanking (plasma and PBMCs) and collection of the hospitalization report in the case report form on a dedicated page.

Genetic and Metabolic Disease in Children

This is a prospective, non-randomized, non-blinded observational study. The overarching goal is to discover new disease-associated genes in children, while establishing a specific focus on disorders where molecular characterization is most likely to lead to novel therapies. This study will merge detailed phenotypic characterization of patients presenting to the Pediatric Genetics and Metabolism Division in the Department of Pediatrics/Children's Medical Center at Dallas and collaborating clinics with Next-Generation sequencing techniques to identify disease-producing mutations. The primary objective of the study is to identify novel pathogenic mutations in children with rare Mendelian disorders. A secondary objective of the study is to establish normative ranges of a large number of metabolites from healthy newborns and older children.

Rady Children's Institute Genomic Biorepository

Rady Children's Institute for Genomic Medicine (RCI) will collect biological samples (such as blood), derived genomic sequences (from DNA and RNA), and clinical features in a Biorepository as a standardized resource for future research studies. The purpose of the Genomic Institute Biorepository is to provide consented samples and data for basic and clinical research related to the genomic cause and treatment of childhood disease, and, in the future, as reference (Quality Control) data to improve the ability to make clinical diagnoses or clinical decisions. In addition, the Biorepository will provide a mechanism for making a diagnosis of a genetic disease. That is, once genomic sequences have been derived from biological samples, they will be immediately analyzed. If a genetic disease is identified that appears to explain an affected child's clinical features, then those results will be confirmed by the medically accepted standard, and placed in the electronic health record.

Rapid Whole Genome Sequencing Study

Rapid Whole Genome Sequencing (rWGS) has proven to provide much faster diagnoses than traditional clinical testing, including clinical Whole Exome Sequencing (WES) and standard Whole Genome Sequencing (WGS). This collaborative study seeks to provide rWGS as a research test to additional pediatric hospitals nationwide to assist in the rapid diagnosis of acutely ill children suspected of a genetic condition. The study will examine diagnosis rates, changes in clinical care as a result of a genetic diagnosis, and health economics including potential cost-effectiveness of rWGS. This study will also serve as a biorepository for future research on samples and data generated from genomic sequencing.