Rethinking the pathogenicity of intragenic DMD duplications detected by carrier screening: high prevalence of non-tandem duplications revealed by long-read sequencing

致病性 遗传学 生物 串联 节段重复 计算生物学 进化生物学 基因组 基因 微生物学 基因家族 复合材料 材料科学
作者
Qiliang Ding,Jagadheshwar Balan,Noemi Vidal‐Folch,Angela M. Pickart,Guangchao Sun,Jesse R. Walsh,Ramanath Majumdar,Eric W. Klee,Stephen J. Murphy,Devin Oglesbee,Ross Rowsey,Linda Hasadsri
出处
期刊:medRxiv
标识
DOI:10.1101/2025.04.10.25325596
摘要

Abstract Purpose The pathogenicity of intragenic duplications depends on their structural configuration. Tandem duplications often disrupt reading frames and cause gene loss-of-function, whereas interspersed (non-tandem) duplications are largely benign. When the configuration cannot be determined, current guidelines presume a tandem structure, leading to some laboratories automatically classifying such variants as likely pathogenic or pathogenic. This study evaluates the validity of this presumption for DMD , in patients with and without clinical indications of dystrophinopathy. Methods We performed high-coverage whole-genome long-read sequencing on 15 patients with intragenic DMD duplications. Four patients had clinically indicated dystrophinopathy testing, while in the remaining 11 patients, the duplications were detected without clear indications of dystrophinopathy (e.g., “incidentally detected” through carrier screening). Results All four patients with clinical indications had tandem duplications. In contrast, 64% (7/11) of the incidentally detected cases had interspersed duplications, with four subsequently re-classified as likely benign, two likely pathogenic, and one uncertain. These duplications were often complex, involving co-duplications or co-deletions with other regions. Conclusion Our findings challenge the presumption that intragenic DMD duplications are predominantly tandem. This highlights the need for a cautious variant interpretation approach, particularly in carrier screening and other settings where variants are identified without indications of dystrophinopathy.
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