New gene for inborn error of metabolism discovered


Under the direction of Prof. Dr. med. Ingo Kurth and Dr. rer. nat. Florian Kraft as well as other participants from the Institute of Human Genetics at the University Hospital RWTH Aachen, the genetic cause of a previously undescribed inborn metabolic disease has been successfully identified.

The University Hospital's Department of Paediatrics and Adolescent Medicine, the Institute of Pathology and the Institute of Neuropathology as well as other national and international cooperation partners are also involved in the research success.

In the affected children, disease-causing variants in the C2orf69 gene, whose function was previously completely unknown, could be detected using high-throughput sequencing (NGS). Using functional analyses, the first author of the study, Eva Lausberg, showed that the genetic changes affect, among other things, the metabolism of the mitochondria, the so-called "power plants of the cell". Quality 07 05/2021 Although the human genome has now been decoded since 2003, there are still many genes whose tasks are completely unknown.

One way of demonstrating the importance of these genes is to study families with rare hereditary diseases, as the study "A human multisystem disorder with autoinfl ammation, leukoencephalopathy and hepatopathy is caused by mutations in C2orf69" shows. Within the framework of so-called trio exome sequencing, in which the DNA sequence of all 23,000 genes of a patient is compared with the parental samples, the working group was able to determine causal genetic changes in the previously uncharacterised gene C2orf69.

Through scientific cooperation, it was possible to identify a further seven patients with the same or similar changes in this gene and thus to clarify the cause of the complex multisystem disease present in all eight children. In addition to a general developmental disorder, the affected children often show severe brain malformations, epilepsies, functional disorders of the liver and an immunological disorder that leads to recurrent infections, especially in the joints and internal organs. Overall, the courses of the disease are severe and associated with a high lethality. The affected gene product can be found in the mitochondria, where it is responsible for the function of the respiratory chain. Thus, a reduced activity of various mitochondrial respiratory chain complexes could be shown both in cells of the affected children and in a knockout cell model. In addition, glycogen metabolism is also impaired in the clinical picture. The changes in the energy metabolism and a dysregulation of the immune system could also be detected at the gene regulatory level in the patients' blood cells with the help of RNA sequencing.

The results of the study were published in the renowned Journal of Clinical Investigation (JCI) at the beginning of May 2021.