Genetic Disease

The Rett Syndrome Registry is a longitudinal observational study of individuals with MECP2 mutations and a diagnosis of Rett syndrome. Designed together with the IRSF Rett Syndrome Center of Excellence Network medical directors, this study collects data on the signs and symptoms of Rett syndrome as reported by the Rett syndrome experts and by the caregivers of individuals with Rett syndrome. This study will be used to develop consensus based guidelines for the care of your loved ones with Rett syndrome and to facilitate the development of better clinical trials and other aspects of the drug development path for Rett syndrome.

Next generation sequencing (NGS) allows some better diagnostic results, particularly, in the rare diseases field. At a twenty five percent rate, those exams highlight some variants which are not yet described in human pathology. The relationship between a variant found inside a candidate gene and a pathology, is able to be confirmed by functional studies at a protein level. This study aims to build a biological collection to feed further functional studies to confirm the relationship between NGS identified variants, and the clinical signs and symptoms.

This study evaluates the efficacy of rifampin in the treatment of hypercalcemia and/or hypercalciuria in participants with at least one inactivating mutation of the CYP24A1 gene. Eligible subjects will receive rifampin for a total of 16 weeks during this study.

Without an explanation for severe and sometimes life-threatening symptoms, patients and their families are left in a state of unknown. Many individuals find themselves being passed from physician to physician, undergoing countless and often repetitive tests in the hopes of finding answers and insight about what the future may hold. This long and arduous journey to find a diagnosis does not end for many patients- the Office of Rare Diseases Research (ORDR) notes that 6% of individuals seeking their assistance have an undiagnosed disorder. In 2008, the National Institutes of Health (NIH) Undiagnosed Diseases Program (UDP) was established with the goal of providing care and answers for these individuals with mysterious conditions who have long eluded diagnosis. The NIH UDP is a joint venture of the NIH ORDR, the National Human Genome Research Institute Intramural Research Program (NHGRI-IRP), and the NIH Clinical Research Center (CRC) (1-3). The goals of the NIH UDP are to: (1) provide answers for patients with undiagnosed diseases; (2) generate new knowledge about disease mechanisms; (3) assess the application of new approaches to phenotyping and the use of genomic technologies; and (4) identify potential therapeutic targets, if possible. To date, the UDP has evaluated 3300 medical records and admitted 750 individuals with rare and undiagnosed conditions to the NIH Clinical Center. The NIH UDP has identified more than 70 rare disease diagnoses and several new conditions. The success of the NIH UDP prompted the NIH Common Fund to support the establishment of a network of medical research centers, the Undiagnosed Diseases Network (UDN), for fiscal years 2013-2020. The clinical sites will perform extensive phenotyping, genetic analyses, and functional studies of potential disease-causing variants. The testing performed on patients involves medically indicated studies intended to help reach a diagnosis, as well as research investigations that include a skin biopsy, blood draws, and DNA analysis. In addition, the UDN will further the goals of the UDP by permitting the sharing of personally identifiable phenotypic and genotypic information within the network. By sharing participant information and encouraging collaboration, the UDN hopes to improve the understanding of rare conditions and advance the diagnostic process and care for individuals with undiagnosed diseases.

The primary purpose of this study is to discover new disease genes for rare Mendelian disorders and its secondary purpose include diagnosing people with rare genetic disorders that have not been previously diagnosed through conventional clinical means, learning more about the pathobiology of genetic disorders, and developing novel diagnostic technologies and analytics. 500 participants with undiagnosed and suspected genetic disorders will be recruited.

Individuals with rare genetic conditions may experience a delay or loss of developmental skills. Many have limited verbal speech. The aim of this clinical trial is to examine how well a speech-generating device supports the communication skills of participants with a rare genetic condition. The speech-generating device is a communication program loaded onto an iPad. This is a crossover trial, meaning that each participant will receive both the treatment (device) and a control (usual care; no device) phase. The order in which each participant receives the device versus the usual care (no device) will depend on which group the participant is assigned to. The changes in communication in each phase will then be compared. During the trial, participants can expect to complete a series of assessments and attend a total of 2 x 1-hour therapy session per week for 6 weeks.

Type I interferonopathies are rare autoinflammatory disorders caused by genetic defects and associated with significant morbidity and mortality. These diseases are refractory to conventional immunosuppressive therapies. They typically occur in childhood, although disease onset in adulthood has been observed. The clinical spectrum is wide and mainly involves the central nervous system. Joint involvement is also common, and more rarely, haematological features such as cytopenias or immunodeficiency may be observed. Nearly all patients show consistent over-activation of the type I IFN pathway, as evidenced, the expression of IFN-stimulated genes, the so-called 'interferon signature'. To date, the natural history of interferonopathies remains unclear. In this context, the establishment of a natural history of type I interferonopathy in patients is proposed to elucidate the pathophysiological mechanisms and identify biomarkers for diagnosis, prognosis, and disease activity, with the aim of better characterising the diversity of interferonopathies. The main objective is to characterise the evolution of the pathology in paediatric and adult patients with type I interferonopathies. The overall aim of this research is to propose therapeutic options tailored to patient phenotypes and to better define patient sub-groups in order to optimise the preparation of future clinical trials.

Recent advances have shown that cells from human blood, skin and urine samples can be reprogrammed to become stem cells. These are called induced Pluripotent Stem Cells (iPSCs) and share many characteristics with embryonic stem cells, including an unlimited capacity for proliferation and the potential to become any cell in the body. Beneficially, the use of iPSCs avoids the ethical difficulties which surround embryonic stem cells and allows generation of iPSC lines which are disease representative. For example, we could take skin samples from an individual diagnosed with Huntington's disease and their unaffected sibling and using this technology, generate iPSC lines from both individuals. Using these iPSCs, we could produce disease affected cell populations from the affected and unaffected individuals, use these cells to research why specific cell populations are affected by disease and test new treatments to combat disease progression, essentially producing a 'disease in a dish'. This is just one example of many for which this technology could be applied. We can also utilise gene-editing techniques to generate isogenic controls or insert disease related mutations to assess disease phenotype. Although generation of iPSC lines has been robustly proven across multiple disease backgrounds, many aspects of their downstream use still remain to be determined. Particularly, robust protocols for directing iPSCs towards cell fates such as neurons or blood cells must be developed to fully realise application of iPSCs in disease modelling and drug screening. This study involves the collection of human blood, skin or urine samples from subjects bearing a range of genetic diseases alongside those from individuals who have not been diagnosed with a disease, as controls. These samples will be used to generate iPSC lines for development of differentiation and disease phenotyping protocols.

This study collects data on children with severe, early-onset obesity.

This is a Prospective Observational study. The aim of the study is to understand the underlying photoreceptor, retinal pigment epithelium or retinal vascular aberrations in inherited and acquired retinal disorders. The study would use adaptive optics (AO) technology to assist in-vivo visualization of these retinal structures and ascertain changes from normal. Further, by using the AO imaging in patients before and after treatments, this study aims to better understand the effect of various interventions and develop AO as an outcome measure in various retinal disorders.

The Natural History of Mitochondrial (MITO) Diseases (a longitudinal study observing the natural history of mitochondrial diseases) The goal of this observational study (non-randomised retrospective and prospective) is to fully characterise primary MITO disease; that includes both sexes/genders, over 18 years of age and healthy volunteers\]. The main question\[s\] it aims to answer is to: • better characterise MITO phenotypes (organ involvement, severity, progression) and collect biospecimens to create a biobank that can be used for future biomarker discovery to improve early diagnosis, prognostication and management of mitochondrial disease. The study will be a longitudinal, retrospective, prospective, observational study of participants (400) with confirmed MITO and relevant controls followed for up to 10 years. Data will be collected at regularly scheduled standard-of-care (SOC), 6 to 12 monthly appointments. The 100 control participants will therefore be comprised of (i) unaffected asymptomatic family members of MITO participants with no genetic risk; (ii) participants with non-MITO movement disorders that are not classified as MITO by their clinical presentation and genetic tests (for example Parkinson's disease) and/or (iii) age-matched healthy controls recruited from the NeuRA database of volunteers. Demographic data, medical history, biochemical, histological, genetic, social and other clinical SOC data will be collected. Additionally, seizure and migraine frequency in participants who experience these, will be collected and a quality-of-life questionnaire (SF-12v2), as part of the validated neurological assessment using the Newcastle Mitochondrial Disease Adult Scale (NMDAS).

Systemic autoinflammatory diseases (SAIDs) are a set of rare clinically and genetically heterogeneous conditions. The project proposes to identify novel genes and specific signatures in subgroups of patients with SAIDs.

The purpose of the study are: 1. To make quality, characterized samples and related data available for future studies, including Genome Wide Association Studies (GWAS), genomics, and biomarker research; 2. To use these samples and related medical information to answer research questions aimed at understanding the genetics and underlying biology of acquired disease and injury to the brain, heart and blood vessels with the express purpose of advancing the search for effective modalities for prevention, treatment, and recovery; 3. To develop additional operational infrastructure to support this project across the Prince of Wales Hospital and divisions, including (1) tracking of patient consent, (2) management of collection and sample processing processes, (3) sample inventory and QC/QA processes, and (4) release of materials to investigators for further research.

The purpose of this study is to establish the longitudinal natural history of individuals with confirmed or suspected Chopra-Amiel-Gordon Syndrome (CAGS) to learn more about the range of symptoms, changes in the structure of the brain seen on imaging, and learning difficulties that individuals with this disorder may experience. The investigators will obtain medical history, family history, MRI records, patient photographs, genetic test results, neurobehavioral and quality of life questionnaires from individuals with confirmed or suspected CAGS at annual research visits. Participants may also complete standardized research neurobehavioral assessments, research EEGs, and sample collections at each visit. This data will be maintained on a secure research database. Samples collected will be used for functional testing and the generation of iPSC cell lines, for neuronal reprogramming and phenotyping.

Maternal and infant health is the foundation of public health, and its status directly reflects the overall health level of the population. With rapid socioeconomic development and increasingly severe environmental issues, health problems among women and children have become more widespread and diverse. In the new era, maternal and child health faces new challenges, with higher demands in areas such as reproductive health promotion, birth defect prevention, maternal and infant safety, and childhood disease prevention. Cohort studies, as an epidemiological research method for exploring disease etiology, involve recruiting participants before or during pregnancy and conducting follow-ups on pregnancy, childbirth, and maternal and child health outcomes after birth to identify various factors influencing diseases and health. Focusing on the early stages of life, this approach is an effective method for studying the associations between environmental, genetic, and behavioral risk factors during early life and embryonic development, fetal health, and infant health. This project plans to conduct long-term follow-ups on couples and their offspring on a family basis, while collecting biological samples at multiple time points. A systematic multi-dimensional assessment, based on clinical information and multi-omics data from the enrolled population, will be used to infer the causes of reproductive and pregnancy-related diseases and developmental abnormalities, identify new biomarkers for pregnancy-related diseases, establish predictive models, and recognize risk factors in the early life of offspring, thereby providing guidance for the prevention and control of reproductive and developmental diseases.

Rare diseases are defined as those that affect one person in 2,000, or around three million people in France. The majority of rare diseases are caused by genetics and tend to be severe when they begin in childhood. Autoimmune and autoinflammatory diseases, such as systemic lupus, juvenile dermatomyositis, and juvenile idiopathic arthritis, are examples of rare pediatric diseases. While autoimmune diseases are characterized by an inappropriate adaptive immune response, autoinflammatory diseases involve an excess of the innate immune response. The precise mechanisms of these diseases are not yet fully understood, but recent research has led to advances in their diagnosis and identification, particularly in early onset and familial forms. However, the rarity of these diseases and limited availability of biological samples pose significant challenges. This study aims to create a biological collection, which includes primary cells (PBMC), DNA, RNA, lymphoblastic lines, and serum, that will help identify genetic and immunological abnormalities in rare autoimmune and autoinflammatory diseases through various research projects.

The purpose of this study is to find out more about STXBP1 and SYNGAP1 related disorders. The information gathered by this study will be used to prepare for clinical treatment trials. The primary objective of the study is to better define and outline the clinical spectrum of STXBP1 and SYNGAP1 through detailed developmental, seizure, and quality of life assessments as an extension of routine clinical care.

Collection of coded biomaterial and clinical data with patients consent for future research.

The purpose of study is to evaluate the benefits of using the Next Generation Sequencing Technology to diagnose birth defects and genetic diseases. The results from genomic sequencing can also significantly shorten the time of examination, improve the diagnosis rate, guide the clinical treatments. So the ultimate goal is individualized or personalized therapy and promote prognosis.

This cohort study aims to explore the trends and differences in multidimensional perceptual levels of patients after cochlear implants or gene therapy, as well as to comprehensively assess the efficacy of gene therapy for congenital deafness, thus providing a reference for making a well-rounded postoperative rehabilitation protocol for gene therapy patients.

The main purpose of this study is to perform longitudinal evaluations of clinical outcomes and personal perspectives following utilization of preimplantation genetic testing (PGT). Patients indicating willingness to participate in research during informed consent to perform PGT will be eligible for inclusion. A licensed genetic counselor will conduct a recorded interview.

Phelan-McDermid syndrome (PMS) is a neurodevelopmental disorder with extensive clinical and genetic heterogeneity that is still poorly understood. The phenotype includes hypotonia, delayed psychomotor development, intellectual disability of varying severity, and consistent language impairment ranging from delayed to absent speech. Autism spectrum disorders are present in 60-80% of patients, and other comorbidities may be present. The major candidate gene for PMS is SHANK3, which encodes a scaffolding protein in the dense postsynaptic region of glutamatergic synapses. Its loss of function is caused by deletions in the distal region of chromosome 22, 22q13.3, or by intragenic genomic variants. Several studies, including the one conducted by our team, have shown that part of the variability in the phenotype is related to the size of the 22q13.3 deletion. However, two patients with a deletion of similar size or an identical point variation in SHANK3 can have phenotypes of very variable severity. The existence of additional genomic variants not identified by standard diagnostic techniques, particularly DNA chip chromosomal analysis (ACPA), which may act as modulating elements of the phenotype, has been suggested. The limitations of the proposed studies are the highly heterogeneous genomic tools used (variable DNA chip design in terms of probe distribution and resolution) and the often imprecise phenotypes. Our study will bring together a large number of SPM patients (related to a 22q13.3 deletion or a variation of the SHANK3 gene) as well as their parents and possible relatives (first or second degree of the patient), very well phenotyped and explored by complete genome sequencing on the same sequencing platform.

This multicenter study aims to recruit a minimum of 1,600 pregnant women, encompassing individuals with varying levels of genetic risk. The study particularly focuses on cases with increased fetal nuchal translucency (NT ≥3.5 mm), additional ultrasound markers, and/or fetal structural anomalies. Peripheral blood samples of eligible participants will be collected for two state-of-the-art cfDNA tests based on coordinative allele-aware target enrichment sequencing (COATE-seq): (1) a targeted panel to screen for frequent chromosomal aneuploidies, microdeletions/duplications, and dominant single-gene conditions, and (2) comprehensive whole-exome cfDNA sequencing for aneuploidies, microdeletions/duplications, monogenic variants (both dominant and recessive variants), uniparental disomy, and hydatidiform moles. The results of both cfDNA tests will be compared with those from invasive or postnatal diagnostic testing. Pregnancy outcome will be followed up to six weeks postpartum. The primary goal is to determine the clinical validity of targeted and whole exome cfDNA analyses, assessed through sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) relative to diagnostic standards. Secondary goal is to assess efficacy across diverse genetic risk populations by analyzing detection rates of pathogenic variants associated with fetal indications. The clinical utility of cfDNA screening will also be evaluated by its impact on clinical management decisions, including follow-up diagnostic procedures or prenatal/perinatal interventions.

The purpose of this research study is to learn more about the inherited risk for developing lung cancer.

The project "Unraveling the Impact of Thalidomide at Diverse Doses in Transfusion Dependent Beta Thalassemia" investigates the safety and efficacy of low-dose thalidomide in managing beta thalassemia, a genetic disorder causing anemia. Conducted over two years at NIBD hospital, the study involves 54 transfusion-dependent patients aged 8-35. The primary objective is to correlate thalidomide doses with disease severity, adverse effects, and treatment response, aiming to optimize treatment strategies and reduce side effects. Data will be collected through clinical interviews and medical record reviews and analyzed using SPSS. Key variables include hemoglobin levels, leukocyte and reticulocyte counts, platelets, liver and spleen size, genetic modifiers, and transfusion frequency. Inclusion criteria are specific to beta thalassemia patients, while exclusion criteria rule out those with liver dysfunction, married patients, lactating mothers, and those with a history of thrombosis or fits.