GENOMIT - Global registry, genomics, toward clinical trials

Mitochondrial disorders are a genetically diverse group of individually rare, but severe human diseases for which causal treatments are widely missing, so far. The GENOMIT consortium assembles the national networks from Germany, Italy, UK and Japan and the main centres for mitochondrial diseases in Austria and France, collectively following more than 6,000 patients. GENOMIT acts in close collaboration wi th the national patient organizations to improve diagnosis and care of mitochondrial disease patients. GENOMIT will i) further develop its global mitochondrial patient registry and establish disease-specific outcome measures and natural history data to prepare for clinical trials, ii) boost genome-wide diagnostics and optimize interpretation of genomic data by aggregating >3,000 exome and RNA sequencing and proteomics datasets, iii) extend functional studies on novel variants, genes and pathways involved in the pathophysiology of mitochondrial diseases. GENOMIT partners are established national hubs for molecular diagnosis and state-of- the-art care for patients with mitochondrial disease. They leverage on national networks collaborating on a global registry and the largest collection of genomic data pertaining to mitochondrial disease world-wide. Each partner has also developed unique expertise that will be shared synergistically within the network. GENOMIT will thus create the critical mass to expand knowledge on the natural history, to identify novel mitochondrial disease genes, to gain insight into disease mechanisms and will be an invaluable resource for clinical trials.

Mitochondria are a central organelle in the cell's energy supply. To date, defects have been found in more than 370 genes that lead to diseases. The clinical picture is very heterogeneous. In the multicenter European Joint Programme on Rare Diseases project GENOMIT, we were able to (1) discover nine new genes that cause diseases in humans, (2) describe the course of disease in patient cohorts with individual genetic defects, (3) determine the pathomechanism of various genetic defects and (4) investigate therapy options based on this. A total of 27 scientific publications were published in peer-reviewed journals, new scientific collaborations were started and laboratory methods were developed. Four students were able to complete their academic training. The newly discovered genetic defects include ATP5MC3 and ATP5PO, both of which lead to a reduction in ATP synthase, the central enzyme for ATP formation in mitochondria. While variants in ATP5MC3 are already disease-relevant in monoallelic, heterozygous form, biallelic variants in ATP5O are inherited in an autosomal recessive manner. Defects in PPA1, the pyrophosphatase outside the mitochondria, result in impaired metabolization of galactose, which can already be seen in newborn screening. The clinical picture of those affected was mild despite a significant loss of function. This was surprising, as the function of PPA1 had been shown to be essential for life in animal models. The treatment of genetic defects and, in particular, mitochondrial disorders is often very limited and often restricted to alleviating symptoms. Nevertheless, there are also examples of very simple and inexpensive treatment options, such as the PPA2 defect, which affects mitochondrial pyrophosphatase. This disease was first described by our group in an earlier project and in an international review we were able to further specify the clinical phenotype in 34 affected individuals from 20 families. One group of affected children fell ill in infancy or early childhood as a result of febrile infections, and many of these children died with cardiac involvement. The other group reached adolescence, with 4 of them dying of sudden cardiac death after consuming small amounts of alcohol. PPA2 is required for the metabolization of alcohol and avoiding alcohol is a simple and effective therapeutic measure. Screening for a genetic defect in PPA2 would therefore be very reasonable and therapy would even be free of charge.