Mutations in the skeletal muscle ryanodine receptor (RYR1) gene have been linked to malignant hyperthermia susceptibility, central core disease, and minicore myopathy with external ophthalmoplegia. RYR1 is an intracellular calcium release channel and plays a crucial role in the sarcoplasmic reticulum and transverse tubule connection. Here, we report 2 fetuses from the same parents with compound heterozygous mutations in the RYR1 gene (c.10347+1G>A and c.10456-2#x0391;>G) who presented with fetal akinesia and polyhydramnios at 27 and 19 weeks of gestation with intrauterine growth restriction in the third pregnancy. The prospective parents of the fetuses were heterozygous carriers for c.10456-2#x0391;>G (mother) and c.10347+1G>A (father). Both mutations affect splice sites resulting in dysfunctional protein forms probably missing crucial domains of the C-terminus. Our findings reveal a new RYR1 splice site mutation (c.10456-2#x0391;>G) that may be associated with the clinical features of myopathies, expanding the RYR1 spectrum related to these pathologies.
Mol Syndromol 2020;11:104-109

中文翻译：

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骨骼肌Ryanodine受体（RYR1）基因的新化合物杂合剪接位点突变证明胎儿运动障碍：与先天性肌病的联系。

骨骼肌ryanodine受体（RYR1）基因的突变与恶性高热敏感性，中枢核心疾病和伴有外部眼肌麻痹的小核心肌病有关。RYR1是细胞内钙释放通道，在肌浆网和横管连接中起关键作用。在这里，我们报告了RYR1中具有复合杂合突变的同一父母的2胎该基因（c.10347 + 1G> A和c.10456-2＃x0391;> G）在第三次妊娠的妊娠27和19周出现宫缩受限，出现胎儿运动障碍和羊水过少。胎儿的预期父母是c.10456-2＃x0391;> G（母亲）和c.10347 + 1G> A（父亲）的杂合子携带者。两种突变都影响剪接位点，导致功能失调的蛋白质形式可能缺少C端的关键域。我们的发现揭示了新的RYR1剪接位点突变（c.10456-2＃x0391;> G），可能与肌病的临床特征有关，从而扩大了与这些病理相关的RYR1谱。
Mol Syndromol 2020； 11：104-109