Purpose

Several hundred genetic muscle diseases have been described, all of which are rare. Their clinical and genetic heterogeneity means that a genetic diagnosis is challenging. We established an international consortium, MYO-SEQ, to aid the work-ups of muscle disease patients and to better understand disease etiology.

Methods

Exome sequencing was applied to 1001 undiagnosed patients recruited from more than 40 neuromuscular disease referral centers; standardized phenotypic information was collected for each patient. Exomes were examined for variants in 429 genes associated with muscle conditions.

Results

We identified suspected pathogenic variants in 52% of patients across 87 genes. We detected 401 novel variants, 116 of which were recurrent. Variants in CAPN3, DYSF, ANO5, DMD, RYR1, TTN, COL6A2, and SGCA collectively accounted for over half of the solved cases; while variants in newer disease genes, such as BVES and POGLUT1, were also found. The remaining well-characterized unsolved patients (48%) need further investigation.

Conclusion

Using our unique infrastructure, we developed a pathway to expedite muscle disease diagnoses. Our data suggest that exome sequencing should be used for pathogenic variant detection in patients with suspected genetic muscle diseases, focusing first on the most common disease genes described here, and subsequently in rarer and newly characterized disease genes.

中文翻译：

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对 1001 名受不明原因肢带无力影响的患者进行连续靶向外显子组测序。

目的

已经描述了数百种遗传性肌肉疾病，所有这些疾病都很罕见。它们的临床和遗传异质性意味着遗传诊断具有挑战性。我们建立了一个国际联盟 MYO-SEQ，以帮助肌肉疾病患者的检查并更好地了解疾病病因。

方法

外显子组测序应用于从 40 多个神经肌肉疾病转诊中心招募的 1001 名未确诊患者；为每位患者收集标准化的表型信息。检查了外显子组中与肌肉状况相关的 429 个基因的变异。

结果

我们在 52% 的患者中发现了 87 个基因的可疑致病变异。我们检测到 401 个新变体，其中 116 个是复发性变体。CAPN3、DYSF、ANO5、DMD、RYR1、TTN、COL6A2和SGCA中的变体合计占解决案例的一半以上；同时也发现了新疾病基因的变异，例如BVES和POGLUT1 。其余特征明确的未解决患者（48%）需要进一步调查。

结论

利用我们独特的基础设施，我们开发了一种加快肌肉疾病诊断的途径。我们的数据表明，外显子组测序应该用于疑似遗传性肌肉疾病患者的致病性变异检测，首先关注此处描述的最常见疾病基因，然后关注罕见和新发现的疾病基因。