NCT02650622 - Genetic and Metabolic Disease in Children

Discovery of genetic basis of impaired metabolism has greatly advanced treatment of patients with known metabolic diseases. However, many more genetic and metabolic disorders and their molecular causes remain to be discovered. The overall goal of this study is to discover new disease-associated genes in children, while establishing a specific focus on metabolic disorders where molecular characterization is most likely to lead to novel therapies. The primary objective is to identify novel pathogenic mutations in children with rare Mendelian disorders. The secondary objectives are: 1) Optimize methodology for metabolomic sample collection, processing and analysis; and 2) Establish normative ranges for a large number (potentially up to 1000) of metabolites in healthy newborns and older children. Approximately one in three admissions to tertiary care pediatric hospitals results from conditions with a genetic basis. Although the majority of these conditions are rare, they collectively account for a disproportionate amount of illness and death in children. Discovery of the genetic basis of rare conditions often uncovers the pathophysiological basis of common diseases. This is particularly true for genetic diseases of impaired metabolism (inborn errors of metabolism, IEMs). There are many more genetic and metabolic disorders yet to be discovered. Of approximately 20,000 known human genes, less than one-fifth are currently associated with a disease phenotype. IEMs are a particular area of focus for us for two major reasons. First, of the several hundred known IEMs, many are already effectively treated with dietary modifications and/or medical therapy. This indicates to us that discovery of new IEM genes has great potential to produce clinically actionable insights into pathophysiology and therapeutic opportunities, ultimately leading to treatment of children that would otherwise be impossible to treat. Second, the PI of this study, Dr. Ralph DeBerardinis, is an expert in metabolomics, the practice of identifying and quantifying metabolites from biological systems. We will therefore implement research-based metabolomic profiling to the evaluation of patients with suspected IEMs or other genetic diseases. This detailed analysis will substantially increase the likelihood of identifying clinically relevant metabolic perturbations in children with growth failure, acidosis, hypoglycemia, hyperammonemia, and other abnormalities of putative genetic origin. It would also enable us to interpret mutations uncovered by clinical or research-based genomic sequencing. We believe that establishing a systematic procedure to evaluate both the metabolome and the genome in sick children will produce new insights into the genetic basis of pediatric disease, and ultimately new ways to treat these conditions. In this study, subjects will be recruited as two populations: control and diseased. In the control population, plasma samples of healthy newborns will be acquired at the time of blood collection for state-mandated newborn screening from Parkland. We will also collect blood from healthy children from the clinics at Children's Medical Center (CMC), again piggybacking this research sample with venipuncture for clinically indicated blood collection. All plasma samples will be subjected to metabolomics to determine the healthy ranges for a large number of metabolites. This comprehensive profile of metabolites in children will be used as normative ranges to identify outlying metabolites in diseased subjects. Additionally, if suspected metabolic outliers are detected from this normal population, DNA samples extracted from the leftover packed cells or blood samples will be subjected to genomic sequencing to profile the associated gene mutations. The diseased population will be recruited from the clinics of the Pediatric Genetics and Metabolism Division in the Department of Pediatrics/CMC. Blood and DNA samples will be collected from patients for metabolomic analysis and next-generation sequencing respectively to define the metabolic abnormalities and associated gene mutations. Skin fibroblasts from patients will also be collected and used for biological validation of the metabolic effects of novel mutations, in particular by complementing diseased fibroblasts with wild-type alleles of genes mutated in the patient. If any rare Mendelian disorder is considered in a subject, blood from his/her family members will be acquired and subjected to metabolomic and genomic analyses to facilitate identification of the diseased-associated genes.