Abstract
Solve-RD is a Horizon2020 supported EU flagship project aiming to solve rare diseases for which a molecular cause is not yet established. European Reference Network (ERN) Intellectual disability, TeleHealth And Congenital Anomalies (ERN-ITHACA) is one of four core ERNs contributing to this project. Here we describe our achievements so far.
(i) Unsolved exome negative patients
Over 5,200 data sets consisting of phenotypic and genomic information have been internationally shared in the Genome-Phenome Analysis Platform for systematic re-analysis. This has resulted in ~6-8% of novel diagnoses. Additionally, for 9 candidate disease genes, Solve-RD researchers have been matched with functional scientists via 'Rare Diseases: Models and Mechanisms (RDMM)'-Europe to study the molecular mechanism of disease.
(ii) ITHACA-specific cohorts
We are collecting genetically unsolved patients for the following syndromes: Moebius/Poland, Goldenhar, Wildervanck, Baraitser-Winter, primary microcephalic dwarfism, MURCS, RAS-opathies and 'Rett-like'-phenotypes. For these cohorts, the first short-read genomes are being performed.
(iii) Ultra-rare patients
All ~80 Health Care Providers in ITHACA are collecting (ultra-)rare unsolved patients. Though phenotypic jamborees, 100 families are selected for WGS.
(iv) Unsolvable syndromes
We aim to unravel the genetic etiology of Aicardi, Gomez-Lopez-Hernandez, Pai, OAFNS and Hallermann-Streiff syndrome. Hereto, a multi-omics approach is planned for, including long-read genomes, transcriptomics, epigenomics, deep-WES and metabolomics on multiple tissues per patient-parent trio. First analyses are ongoing.
The Solve-RD project has enabled ITHACA data sharing and clinical patient selection at a pan-European level. We expect to facilitate diagnoses for unsolved patients, and to elucidate the molecular underpinning of ITHACA-related unexplained syndromes.