A multistage sequencing strategy pinpoints many novel and candidate disease alleles for orphan Disease Emery-Dreifuss Muscular Dystrophy and Supports Gene Misregulation as its Pathomechanism

Peter Meinke, Alastair Kerr, Rafal Czapiewski, Jose de las Heras, Manfred Wehnert, Eric Schirmer, Elizabeth Harris, Heike Kölbel, Francesco Muntoni

Research output: Contribution to journalArticlepeer-review

Abstract

Limitations of genome-wide approaches for genetically-heterogenous orphan diseases led us to develop a new approach to identify novel Emery-Dreifuss muscular dystrophy (EDMD) candidate genes. We generated a primer library to genes: (I) linked to EDMD, (II) mutated in related muscular dystrophies, (III) highlighted from limited exome sequencing, (IV) encoding muscle-specific nuclear membrane proteins. Sequencing 56 unlinked EDMD patients yielded confirmed or strong candidate alleles from all categories, accounting for most remaining unlinked patients. Known functions of newly-linked genes argue the EDMD pathomechanism is from altered gene regulation and mechanotransduction through connectivity of candidates from the nuclear envelope to the plasma membrane.
Original languageEnglish
Article number102587
JournalEBioMedicine
Volume51
Early online date17 Dec 2019
DOIs
Publication statusPublished - 1 Jan 2020

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