Details

Autor(en) / Beteiligte

• Cummings, Beryl B
• Marshall, Jamie L
• Tukiainen, Taru
• Lek, Monkol
• Donkervoort, Sandra
• Foley, A Reghan
• Bolduc, Veronique
• Waddell, Leigh B
• Sandaradura, Sarah A
• O'Grady, Gina L
• Estrella, Elicia
• Reddy, Hemakumar M
• Zhao, Fengmei
• Weisburd, Ben
• Karczewski, Konrad J
• O'Donnell-Luria, Anne H
• Birnbaum, Daniel
• Sarkozy, Anna
• Hu, Ying
• Gonorazky, Hernan
• Claeys, Kristl
• Joshi, Himanshu
• Bournazos, Adam
• Oates, Emily C
• Ghaoui, Roula
• Davis, Mark R
• Laing, Nigel G
• Topf, Ana
• Kang, Peter B
• Beggs, Alan H
• North, Kathryn N
• Straub, Volker
• Dowling, James J
• Muntoni, Francesco
• Clarke, Nigel F
• Cooper, Sandra T
• Bönnemann, Carsten G
• MacArthur, Daniel G

Titel

Improving genetic diagnosis in Mendelian disease with transcriptome sequencing

Ist Teil von

• Science translational medicine, 2017-04, Vol.9 (386)

Ort / Verlag

United States

Erscheinungsjahr

2017

Quelle

MEDLINE

Beschreibungen/Notizen

• Exome and whole-genome sequencing are becoming increasingly routine approaches in Mendelian disease diagnosis. Despite their success, the current diagnostic rate for genomic analyses across a variety of rare diseases is approximately 25 to 50%. We explore the utility of transcriptome sequencing [RNA sequencing (RNA-seq)] as a complementary diagnostic tool in a cohort of 50 patients with genetically undiagnosed rare muscle disorders. We describe an integrated approach to analyze patient muscle RNA-seq, leveraging an analysis framework focused on the detection of transcript-level changes that are unique to the patient compared to more than 180 control skeletal muscle samples. We demonstrate the power of RNA-seq to validate candidate splice-disrupting mutations and to identify splice-altering variants in both exonic and deep intronic regions, yielding an overall diagnosis rate of 35%. We also report the discovery of a highly recurrent de novo intronic mutation in that results in a dominantly acting splice-gain event, disrupting the critical glycine repeat motif of the triple helical domain. We identify this pathogenic variant in a total of 27 genetically unsolved patients in an external collagen VI-like dystrophy cohort, thus explaining approximately 25% of patients clinically suggestive of having collagen VI dystrophy in whom prior genetic analysis is negative. Overall, this study represents a large systematic application of transcriptome sequencing to rare disease diagnosis and highlights its utility for the detection and interpretation of variants missed by current standard diagnostic approaches.