Spectrum and carrier frequency of DMD in Yueyang, China: a population-based analysis using NGS and MLPA.

Background: Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder caused by mutations in the Methods: A total of 25,611 women of childbearing age or early pregnancy from Yueyang City were enrolled. Combined next-generation sequencing and multiplex ligation-dependent probe amplification were used to detect pathogenic/likely pathogenic (P/LP) variants, copy number variants (CNVs), and small indels. Variants were classified per established guidelines. Carrier rates and geographical distribution were analyzed. Prenatal diagnosis was offered to identified carriers with follow-up to assess outcomes. Results: Twenty-eight women were identified as P/LP carriers (0.11%), representing 25 distinct variants. CNVs constituted the majority (71.43%), with exon 45-55 deletions (64.29%) predominating over duplications (7.14%); notably, 13/18 CNVs clustered in this hotspot. SNVs and small indels accounted for the remaining 28.57%. Intra-regional variation was marked, with the highest rate in Yunxi District (0.74%). Additionally, 81 VUSs (51 distinct types) were detected, 66.67% being missense. One male fetus inheriting a maternal VUS developed DMD-like features postpartum. Overall, 12 variants (1 LP, 11 VUSs) were previously unreported, including a nonsense variant c.3502G>T (p.E1168*) classified as LP. Conclusion: This first population-based study in Yueyang City, China, characterized the DMD carrier frequency (0.11%) and mutation spectrum among women of childbearing age or in early pregnancy. It revealed geographical heterogeneity and a high prevalence of CNVs, especially exon 45-55 deletions. Crucially, it highlights the underappreciated screening value of VUS. We recommend focused attention on VUS, particularly those with Bayesian scores ≥3, in genetic counseling and prenatal diagnosis to improve preventive strategies and reduce DMD incidence.