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    Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder primarily caused by the deletion or mutation of the survival motor neuron 1 (SMN1) gene. This study assesses the diagnostic potential of long-read sequencing (LRS) in three patients with SMA. For Patient 1, who has a heterozygous SMN1 deletion, LRS unveiled a missense mutation in SMN1 exon 5. In Patient 2, an Alu/Alu-mediated rearrangement covering the SMN1 promoter and exon 1 was identified through a blend of multiplex ligation-dependent probe amplification, LRS, and PCR across the breakpoint. The third patient, born to a consanguineous family, bore four copies of hybrid SMN genes. LRS determined the genomic structures, indicating two distinct hybrids of SMN2 exon 7 and SMN1 exon 8. However, a discrepancy was found between the SMN1/SMN2 ratio interpretations by LRS (0:2) and multiplex ligation-dependent probe amplification (0:4), which suggested a limitation of LRS in SMA diagnosis. In conclusion, this newly adapted long PCR-based third-generation sequencing introduces an additional avenue for SMA diagnosis. Copyright © 2024 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

    Citation

    Ningning Wang, Kexin Jiao, Jin He, Bochen Zhu, Nachuan Cheng, Jian Sun, Lan Chen, Wanjin Chen, Lingyun Gong, Kai Qiao, Jianying Xi, Qihan Wu, Chongbo Zhao, Wenhua Zhu. Diagnosis of Challenging Spinal Muscular Atrophy Cases with Long-Read Sequencing. The Journal of molecular diagnostics : JMD. 2024 May;26(5):364-373

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    PMID: 38490302

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