RT Journal Article
SR Electronic
T1 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
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 705780
DO 10.1101/705780
A1 Peter Meinke
A1 Alastair R. W. Kerr
A1 Rafal Czapiewski
A1 Jose I. de las Heras
A1 Elizabeth Harris
A1 Heike Kölbel
A1 Francesco Muntoni
A1 Ulrike Schara
A1 Volker Straub
A1 Benedikt Schoser
A1 Manfred Wehnert
A1 Eric C. Schirmer
YR 2019
UL http://biorxiv.org/content/early/2019/07/17/705780.abstract
AB 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.