Genetic diagnosis of Mendelian disorders via RNA sequencing

Across a variety of Mendelian disorders, ∼50-75% of patients do not receive a genetic diagnosis by exome sequencing indicating disease-causing variants in non-coding regions. Although genome sequencing in principle reveals all genetic variants, their sizeable number and poorer annotation make prioritization challenging. Here, we demonstrate the power of transcriptome sequencing to molecularly diagnose 10% (5 of 48) of mitochondriopathy patients and identify candidate genes for the remainder. We find a median of one aberrantly expressed gene, five aberrant splicing events and six mono-allelically expressed rare variants in patient-derived fibroblasts and establish disease-causing roles for each kind. Private…

• DZ
  Deutsches Zentrum für Herz-Kreislaufforschung
• E
  E-Rare
• DF
  Deutsche Forschungsgemeinschaft

  Award: EXC 1010
• BF
  Bundesministerium für Bildung und Forschung

  Awards: 01GM1207, 01ZX1405C, 01GM1603, FKZ 01ZX1405A, FKZ 01ZX1405C
• AS
  Austrian Science Fund
• FP
  Fondazione Pierfranco e Luisa Mariani
• MR
  Medical Research Council

  Awards: G0601943, EU FP7