Solving the Unsolved. Integrating Omic Approaches to Enable Genomic Diagnosis of Virtually All Patients with Mitochondrial Disease
Abstract
Our project addresses the Fiscal Year 2017 Peer Reviewed Medical Research Program Priority Research Topic Area of Mitochondrial Disease. The relevant Areas of Encouragement are: (1) identification and testing of non-invasive techniques and biomarkers; (2) development of improved tools and animal models; and (3) research on the basic biology and physiology. Background: Food is converted to energy by power plants in our cells called mitochondria. Inherited disorders of mitochondrial energy generation comprise more than 280 different genetic disorders that cause impaired physical or cognitive development, neurodegenerative disease, and other disabilities, as well as early death in infants, children, and adults. They are the most common group of inherited metabolic diseases, affecting at least 800 people born in the USA each year. Hundreds of serving members of the military, Veterans, and their family members will develop a severe mitochondrial disease. Milder mitochondrial disease can also impact on common diseases such as metabolic syndrome, diabetes, neurodegeneration, inflammation, cancer, critical care medicine, and toxicology. Mitochondria are unique in containing their own small genome, the mitochondrial DNA, inherited only from the mother, so some mitochondrial diseases are inherited maternally. However, any form of inheritance can cause mitochondrial disease. Mitochondrial disorders can affect any or all organ systems, have onset at any age, and have no treatments that are proven to be effective. Rationale: New genomic technologies are transforming diagnosis of inherited disease but perhaps half of all children with mitochondrial diseases or other inherited disorders are not currently being diagnosed. This is partly because genomics has focused on DNA encoding the genes, rather than the molecules encoded by DNA, namely RNA and proteins. Proteins are the molecules responsible for cellular structure and for nearly all the reactions and processes our cells and organs rely on to survive. Our research strategy stems from being one of few skilled international centers that have been referred virtually all children suspected of mitochondrial disease in a large region for a long period of time, now more than 25 years. We have reported some of the largest well-characterized representative groups of patients internationally and discovered more than 20 novel disease genes. The major focus of this grant is a cohort of 250 children comprising the most common clinical diagnosis (Leigh disease), the most common biochemical diagnosis (Complex I deficiency) and the largest population-based cohort with mitochondrial disease. For each group, we have published some of the largest and most cited publications internationally, and we already have one of the highest rates of molecular diagnosis in over 70% of each group. Our team of investigators and collaborators have also been among the first to develop and describe “wet lab” and computational approaches to diagnosis at the DNA, RNA, and most recently the protein level. We have already sequenced the entire coding region of nuclear and mitochondrial genes in our patient group. We will now apply state-of-the-art approaches to sequencing the entire genome (all the DNA), the transcriptome (RNA) and the proteome (proteins) in the remaining patients lacking a molecular diagnosis. We anticipate this will solve up to 90% of these tightly defined patient cohorts. We have developed a statistical framework that implies some unsolved patients will have complex genetic inheritance, that is to say their disease is caused by mutations in multiple genes rather than a single gene. Many of these patients do not show a biochemical abnormality in cultured skin cells, so we propose a strategy to investigate correcting one or more genes in patient stem cells converted into cells resembling heart or brain cells, which are the major cell types affected by mitochondrial disease. We antic
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810215
Entities
People
- David Thorburn
Organizations
- United States Army