High-resolution mapping of DMD duplications using long-read sequencing enables precise carrier screening for Duchenne muscular dystrophy
Yang, J.; Dong, Y.; Wang, Z.; Sun, X.; Song, N.; Gu, S.; Zhang, X.; Guo, Y.; Sun, X.; Chen, S.; Wang, J.; Xiang, J.
Show abstract
PurposeExon-level duplications in the DMD gene present interpretive challenges due to limitations in resolving their genomic context. We aimed to assess the utility of long-read genome sequencing (lrGS) in characterizing DMD duplications and guiding clinical interpretation. MethodsWe applied low coverage lrGS (3-10x depth; [~]8.2 kb mean read length) to 18 individuals with DMD duplications identified via short-read sequencing. Structural variant calling and breakpoint localization were validated by Sanger sequencing. In addition, the genomic characteristics of the duplication breakpoints were systematically analyzed. ResultslrGS resolved duplication architecture in all cases. Two duplications (11%, 2/18) were extragenic and reclassified as benign; 16 (89%, 16/18) were tandem events within DMD. Among tandem duplications, 50% (8/16) were classified as pathogenic/likely pathogenic and 50% (8/16) as variants of uncertain significance. Breakpoints were consistently located in intronic regions, often flanked by repetitive elements. ConclusionLow-coverage lrGS enables high-resolution mapping of DMD duplications and improves variant classification. This approach addresses a key gap in carrier screening and molecular diagnosis of dystrophinopathies, and provides lrGS as a prototype for decoding duplication architecture of monogenic disorders, which is a critical advance in genetic diagnosis.
Matching journals
The top 8 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Genetic Diagnosis of Facioscapulohumeral Muscular Dystrophy Type 1 Using Rare Variant Linkage Analysis and Long Read Genome Sequencing 94%
- Combined Bioinformatic and Splicing Analysis of Likely Benign Intronic and Synonymous Variants Reveals Evidence for Pathogenicity 90%
- 3-hour genome sequencing and targeted analysis to rapidly assess genetic risk 90%
Similar papers in this journal
- Using single molecule Molecular Inversion Probes as a cost-effective, high-throughput sequencing approach to target all genes and loci associated with macular diseases 93%
- AutoPVS1: An automatic classification tool for PVS1 interpretation of null variants 93%
- Whole genome sequencing of ‘mutation-negative’ individuals with Cornelia de Lange Syndrome 90%
Similar papers in this journal
- Identification of gene fusions associated with amyotrophic lateral sclerosis 90%
- Development of a major histocompatibility complex class II conditional knockout mouse to study cell-specific and time-dependent adaptive immune responses in peripheral nerves. 89%
- Mitochondrial genome variants associated with Amyotrophic Lateral Sclerosis and their haplogroup distribution 88%
Similar papers in this journal
- Identification of a CCG-enriched expanded allele in DM1 patients using Amplification-free long-read sequencing 94%
- Concordance of whole-genome long-read sequencing with standard clinical testing for Prader-Willi and Angelman syndromes 92%
- Overcoming the pitfalls of NGS-based molecular diagnosis of Shwachman-Diamond syndrome 92%
Similar papers in this journal
- Comprehensive reanalysis for CNVs in ES data from unsolved rare disease cases results in new diagnoses 91%
- Biallelic truncation variants in ATP9A are associated with a novel autosomal recessive neurodevelopmental disorder 90%
- Discordance between a deep learning model and clinical-grade variant pathogenicity classification in a rare disease cohort 90%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.