The majority of patients with spinal muscular atrophy (SMA) identified to date harbor a biallelic exonic deletion of SMN1. However, there have been reports of SMA-like disorders that are independent of SMN1, including those due to pathogenic variants in the glycyl-tRNA synthetase gene (GARS1). We report three unrelated patients with de novo variants in GARS1 that are associated with infantile-onset SMA (iSMA). Patients were ascertained during inpatient hospital evaluations for complications of neuropathy. Evaluations were completed as indicated for clinical care and management and informed consent for publication was obtained. One newly identified, disease-associated GARS1 variant, identified in two out of three patients, was analyzed by functional studies in yeast complementation assays. Genomic analyses by exome and/or gene panel and SMN1 copy number analysis of three patients identified two previously undescribed de novo missense variants in GARS1 and excluded SMN1 as the causative gene. Functional studies in yeast revealed that one of the de novo GARS1 variants results in a loss-of-function effect, consistent with other pathogenic GARS1 alleles. In sum, the patients' clinical presentation, assessments of previously identified GARS1 variants and functional assays in yeast suggest that the GARS1 variants described here cause iSMA. GARS1 variants have been previously associated with Charcot-Marie-Tooth disease (CMT2D) and distal SMA type V (dSMAV). Our findings expand the allelic heterogeneity of GARS-associated disease and support that severe early-onset SMA can be caused by variants in this gene. Distinguishing the SMA phenotype caused by SMN1 variants from that due to pathogenic variants in other genes such as GARS1 significantly alters approaches to treatment.

中文翻译：

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婴儿脊髓性肌萎缩症中的 GARS 相关疾病：对诊断和治疗的意义。

迄今为止，大多数脊髓性肌萎缩症 (SMA) 患者都存在 SMN1 的双等位基因外显子缺失。然而，有报道称不依赖于 SMN1 的 SMA 样疾病，包括由甘氨酰-tRNA 合成酶基因 (GARS1) 的致病变异引起的疾病。我们报告了三名不相关的患者，这些患者在 GARS1 中具有与婴儿发病 SMA (iSMA) 相关的从头变异。在住院医院评估神经病变并发症期间确定患者。根据临床护理和管理的指示完成了评估，并获得了发表的知情同意书。通过酵母互补测定中的功能研究分析了一种新发现的与疾病相关的 GARS1 变体，在三分之二的患者中发现。通过外显子组和/或基因组的基因组分析和对三名患者的 SMN1 拷贝数分析确定了 GARS1 中两个先前未描述的从头错义变体，并将 SMN1 作为致病基因排除在外。酵母的功能研究表明，其中一种从头 GARS1 变体导致功能丧失效应，这与其他致病性 GARS1 等位基因一致。总之，患者的临床表现、对先前鉴定的 GARS1 变体的评估和酵母中的功能测定表明，此处描述的 GARS1 变体导致 iSMA。GARS1 变体以前与 Charcot-Marie-Tooth 病 (CMT2D) 和远端 SMA V 型 (dSMAV) 相关。我们的研究结果扩展了 GARS 相关疾病的等位基因异质性，并支持严重的早发性 SMA 可能由该基因的变异引起。