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<p>Spinal muscular atrophy (SMA) is a severe neuromuscular disorder caused by biallelic disruption of the Survival Motor Neuron 1 (<i>SMN1</i>) gene. Accurate quantification of Survival Motor Neuron 2 (<i>SMN2</i>) copy number is essential for patient stratification, prognosis, and treatment decisions, yet remains challenging at high copy numbers and does not fully explain phenotypic variability. We compared complementary molecular approaches in 78 Spanish patients with genetically confirmed SMA. Multiplex ligation-dependent probe amplification (MLPA) and digital PCR (dPCR) showed complete concordance, supporting their reliability for <i>SMN2</i> quantification. In contrast, the AmplideX PCR/CE <i>SMN1/2</i> Plus Kit showed discrepancies in seven patients, mainly at clinically relevant thresholds (three <i>vs</i>. four <i>SMN2</i> copies), indicating higher sensitivity to technical variability. Notably, dPCR resolved a case with &gt;5 <i>SMN2</i> copies, demonstrating superior resolution. Long-read sequencing (LRS) in ten patients with MLPA-detected rearrangements enabled high-resolution reconstruction of the <i>SMN</i> locus and revealed six previously undescribed <i>SMN</i> hybrid structures. Structural haplotype architecture, rather than copy number alone, may further determine <i>SMN</i> variability and contribute to phenotype heterogeneity. Overall, our findings support an integrated diagnostic strategy in which copy-number quantification is complemented by structural characterisation in complex cases, improving molecular resolution of the <i>SMN</i> locus.</p><p></p>

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Multimodal characterisation of the SMN locus in SMA: copy number quantification and hybrid gene identification

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月20日

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  • Alba Berzal-Serrano,
  • Sonia González-Alvaredo,
  • Iván Lesende,
  • Lidón Carretero-Vilarroig,
  • Teresa Jaijo,
  • Ignacio Onsurbe,
  • Karolina Aragon-Gawinska,
  • Nancy Carolina Ñungo-Garzón,
  • Inmaculada Pitarch-Castellano,
  • Juan Francisco Vázquez-Costa,
  • Elena Aller,
  • José María Millán,
  • Gema García-García

摘要

Spinal muscular atrophy (SMA) is a severe neuromuscular disorder caused by biallelic disruption of the Survival Motor Neuron 1 (SMN1) gene. Accurate quantification of Survival Motor Neuron 2 (SMN2) copy number is essential for patient stratification, prognosis, and treatment decisions, yet remains challenging at high copy numbers and does not fully explain phenotypic variability. We compared complementary molecular approaches in 78 Spanish patients with genetically confirmed SMA. Multiplex ligation-dependent probe amplification (MLPA) and digital PCR (dPCR) showed complete concordance, supporting their reliability for SMN2 quantification. In contrast, the AmplideX PCR/CE SMN1/2 Plus Kit showed discrepancies in seven patients, mainly at clinically relevant thresholds (three vs. four SMN2 copies), indicating higher sensitivity to technical variability. Notably, dPCR resolved a case with >5 SMN2 copies, demonstrating superior resolution. Long-read sequencing (LRS) in ten patients with MLPA-detected rearrangements enabled high-resolution reconstruction of the SMN locus and revealed six previously undescribed SMN hybrid structures. Structural haplotype architecture, rather than copy number alone, may further determine SMN variability and contribute to phenotype heterogeneity. Overall, our findings support an integrated diagnostic strategy in which copy-number quantification is complemented by structural characterisation in complex cases, improving molecular resolution of the SMN locus.