From shadows to clarity: A new paradigm for comprehensive variant detection in undiagnosed dystrophinopathy using combined long-read and RNA sequencing.

ABSTRACT: Approximately 2-5 % of dystrophinopathy cases remain undiagnosed at the molecular level following standard multiplex ligation-dependent probe amplification (MLPA) and exome sequencing (ES), precluding these patients from variant-specific genetic counseling and therapy eligibility assessment. We developed an integrated diagnostic pipeline combining targeted long-read sequencing (LRS) with muscle RNA-seq and applied it to 50 Chinese patients (46 males, 4 females) with biopsy-confirmed dystrophinopathy in whom MLPA and ES had yielded negative results. A molecular diagnosis was achieved for all 50 probands: 30 (60 %) harbored intronic single nucleotide variants (SNVs) leading to pseudoexon inclusion or exon skipping, while the remaining 20 (40 %) carried complex structural variants (SVs), incl

SUBMITTER: Zhao L 

PROVIDER: S-EPMC12663668 | biostudies-literature | 2025

REPOSITORIES: biostudies-literature