Bavarian Genomes: 1000 Clinical Genomes for Rare Diseases
The Project „1000 Clinical Genomes“ is based on a networking of the centers for rare diseases in Bavaria and aims to identify causative sequence variants in the genome of at least 1,000 patients with a rare disease but genetically unclear diagnosis. The determination of DNA and RNA sequences is performed in a central laboratory using state-of-the-art genome sequencing technology. Calculation and storage of the data is also performed centrally at the Leibniz Computing Center. Physicians and patients at the centers will have network-based, controlled access for decentralized evaluation and interpretation. The project improves the care of patients with rare diseases and creates focal points for research into new treatment strategies.
The selection of 1,000 undiagnosed patients with rare diseases will take place at the centers for rare diseases in München, Regensburg, Erlangen and Würzburg over a period of 3 years (2018-2021). The procedure for sending samples and returning the collected data will be discussed and agreed upon by all participating centers. All four sites already have experience with exome analyses that examine only coding portions of the genome. The analysis of the data in the „1000 Clinical Genomes“ project will now be extended to the study of complete sequences, both coding and non-coding portions of the genome. Quantitatively, this represents an increase in sequencing effort of more than an order of magnitude. Genome data and a selection of phenotype data are stored on a central database at the LRZ in Garching and made available to the five participating centers in a controlled manner.
Genomic analysis is performed in four steps. First, a clinical team creates a synopsis of a patient's disease course to date. After preservation of the biospecimens, sequencing of the patient's entire genome and transcriptome DNA and RNA is performed on the central sequencing platform in Munich. This was created in 2016 jointly by the Munich universities LMU and TU as well as Max Planck Institute of Psychiatry and Helmholtz Zentrum. On it, genotype (DNA sequence variance) and phenotype (clinical signs and symptoms) mapping is performed at the individual centers by the local analysis teams with online access to the central database for genotypes and phenotypes. An analysis pipeline with access to a central exome database is already established and will be used for the project and available to all ZSEs. The central database will allow both joint analyses based on all recorded datasets and decentralized analyses of the respective genome and transcript sequences of a site. In a final step, a genome finding and a diagnosis or therapy recommendation will be generated.
