Biallelic pathogenic variants in the gene encoding nebulin (NEB) are a known cause of congenital myopathy. We present two brothers with congenital myopathy and compound heterozygous variants (NM_001271208.2: c.2079C>A; p.(Cys693Ter) and c.21522+3A>G ) in NEB. Transcriptomic sequencing on patient muscle revealed that the extended splice variant c.21522+3A>G causes exon 144 skipping. Nebulin isoforms containing exon 144 are known to be mutually exclusive with isoforms containing exon 143, and these isoforms are differentially expressed during development and in adult skeletal muscles. Patients MRIs were compared to the known pattern of relative abundance of these two isoforms in muscle. We propose that the pattern of muscle involvement in these patients better fits the distribution of exon 144-containing isoforms in muscle than with previously published MRI findings in NEB-related disease due to other variants. To our knowledge this is the first report hypothesizing disease pathogenesis through the alteration of isoform distributions in muscle.

中文翻译：

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NEB 外显子 143 和 144 的差异包含可深入了解 NEB 相关肌病变异解释和疾病表现

编码星云蛋白 (NEB) 的基因中的双等位基因致病性变异是先天性肌病的已知原因。我们在 NEB 中介绍了患有先天性肌病和复合杂合变异 (NM_001271208.2: c.2079C>A; p.(Cys693Ter) 和 c.21522+3A>G ) 的两兄弟。对患者肌肉的转录组测序表明，延伸剪接变体 c.21522+3A>G 导致外显子 144 跳跃。已知含有外显子 144 的星云蛋白同种型与含有外显子 143 的同种型是相互排斥的，并且这些同种型在发育过程中和成年骨骼肌中存在差异表达。将患者的 MRI 与肌肉中这两种异构体的相对丰度的已知模式进行比较。我们认为，这些患者的肌肉受累模式比之前发表的由于其他变异导致的 NEB 相关疾病的 MRI 结果更适合肌肉中含有外显子 144 的亚型分布。据我们所知，这是第一份通过肌肉中异构体分布的改变来假设疾病发病机制的报告。