Targeted long-read sequencing enables comprehensive analysis of the genetic and epigenetic landscape of inherited myopathies
Abstract
Abstract The genetic variants that cause inherited myopathies vary widely in type, size and sequence context, encompassing small sequence variants, large structural variants, repeat expansions, and more complex events, such as the D4Z4 macrosatellite contraction and hypomethylation that causes facioscapulohumeral muscular dystrophy. Many of these are challenging to characterise using next-generation sequencing and other older molecular technologies. To address this, we developed a targeted long-read sequencing assay and bioinformatics analysis framework that captures the full suite of genes, variants and epigenetic signatures currently implicated in inherited myopathies. Applying this to a cohort of myopathy patients, we demonstrate the analytical validity of our approach and its improved accuracy and resolution compared to existing methods. Our assay led to new genetic diagnoses in 35.5% (11/31) of patients who remained undiagnosed after standard clinical genetic testing. This methodology constitutes a single streamlined assay for comprehensive genetic and epigenetic characterisation of inherited myopathies.
Article Details
Authors (40)
Dennis Yeow
Andre L. M. Reis
Igor Stevanovski
Neysa Njo
Laura I. Rudaks
Bianca R. Grosz
Joanne S. Sy
Leah Kemp
Sanjog R. Chintalaphani
Michael Chin
Marion Stoll
Danqing Zhu
Christina Liang
Katrina A. Morris
Andrew Hannaford
Ehsan Shandiz
Kate E. Ahmad
Shadi El-Wahsh
Stephen W. Reddel
Robert Boland-Freitas
Roula Ghaoui
Stephanie Barnes
Jonathan Sturm
Anna Willard
Mahi Jasinarachchi
Simon Hawke
Neil G. Simon
Lisa Worgan
David Manser
Michel Tchan
Neil C. Griffith
Ryan L. Davis
Michael C. Fahey
Carolyn M. Sue
Pamela A. McCombe
Karl Ng
Marina L. Kennerson
Pak Leng Cheong
Kishore R. Kumar
Ira W. Deveson