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WGS and RNA Studies Diagnose Noncoding DMD Variants in Males With High Creatine Kinase.

Leigh B WaddellSamantha J BryenBeryl B CummingsAdam M BournazosFrances J EvessonHimanshu JoshiJamie L MarshallTaru TukiainenElise ValkanasBen WeisburdSimon SadedinMark R DavisFathimath FaizRebecca GoodingSarah A SandaraduraGina L O'GradyMichel C TchanDavid R MowatEmily C OatesMichelle A FarrarHugo SampaioAlan Sl MaKatherine NeasMin-Xia WangAmanda CharltonCharles ChanDiane N KenwrightNicole GrafSusan ArbuckleNigel F ClarkeDaniel G MacArthurKristi J JonesMonkol LekSandra T Cooper
Published in: Neurology. Genetics (2021)
Whole-genome sequencing relied heavily on RNA studies to identify DMD splice-altering variants. Short-read RNA sequencing was regularly confounded by the effectiveness of nonsense-mediated mRNA decay and low read depth of the giant DMD mRNA. PCR of muscle cDNA provided a simple, yet informative approach. Highly relevant to genetic therapies for dystrophinopathies, our data align strongly with previous studies of mutant dystrophin in Becker muscular dystrophy, with the collective conclusion that a fractional increase in levels of normal dystrophin between 5% and 20% is clinically significant.
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