Utveckling av sekvensbaserade strategier för genetisk diagnostik för att identifiera gener som orsakar utvecklingsstörning

Tidsperiod: 2013-01-01 till 2016-12-31

Projektledare: Lars Feuk

Medarbetare: Patrik Georgii-Hemming, Ann-Charlotte Thuresson

Finansiär: Vetenskapsrådet

Bidragstyp: Projektbidrag

Budget: 6 000 000 SEK

The advent of massively parallel sequencing (MPS) has brought about significant changes genomics research. However, for use of MPS in genetic diagnostics, there are still many unsolved issues including study design, accuracy, analysis and data interpretation. One group of patients referred for genetic screening today are children with intellectual disability. With current array screening, causative aberrations are identified in 15-20% of samples. The goal of this proposal is to increase the diagnostic yield for this group of patients by use of MPS strategies, and to identify new causative genes that will provide novel insight into pathways central to brain development. Two experimental strategies will be tested: low coverage sequencing and trios sequencing. Low coverage sequencing will be evaluated for its potential to replace arrays, with increased accuracy and lower cost. Trio (parents and offspring) based exome sequencing for de novo mutations will be implemented to increase the diagnostic yield, as many patients are expected to carry point mutations not detectable by arrays. Identification of new causative genes will be followed up by mutation screening in additional samples and by functional studies. We will also develop the necessary bioinformatics infrastructure, including a database for variants identified by MPS. Finally, we aim to facilitate improvement in clinical phenotype descriptions by development and implementation of a Swedish phenotype ontology.