Mitochondrial diseases (MDs) are the commonest group of heritable metabolic disorders. Phenotypic diversity can make molecular diagnosis challenging, and causative genetic variants may reside in either mitochondrial or nuclear DNA. A single comprehensive genetic diagnostic test would be highly useful and transform the field. We applied whole-genome sequencing (WGS) to evaluate the variant detection rate and diagnostic capacity of this technology with a view to simplifying and improving the MD diagnostic pathway.

Adult patients presenting to a specialist MD clinic in Sydney, Australia, were recruited to the study if they satisfied clinical MD (Nijmegen) criteria. WGS was performed on blood DNA, followed by clinical genetic analysis for known pathogenic MD-associated variants and MD mimics.

Of the 242 consecutive patients recruited, 62 participants had "definite," 108 had "probable," and 72 had "possible" MD classification by the Nijmegen criteria. Disease-causing variants were identified for 130 participants, regardless of the location of the causative genetic variants, giving an overall diagnostic rate of 53.7% (130 of 242). Identification of causative genetic variants informed precise treatment, restored reproductive confidence, and optimized clinical management of MD.

Comprehensive bigenomic sequencing accurately detects causative genetic variants in affected MD patients, simplifying diagnosis, enabling early treatment, and informing the risk of genetic transmission.

线粒体疾病 (MDs) 是最常见的一组遗传性代谢紊乱。表型多样性会使分子诊断具有挑战性，致病基因变异可能存在于线粒体或核 DNA 中。单一的综合基因诊断测试将非常有用并改变该领域。我们应用全基因组测序 (WGS) 来评估该技术的变异检出率和诊断能力，以期简化和改进 MD 诊断途径。

如果成人患者满足临床 MD (Nijmegen) 标准，他们将被招募到澳大利亚悉尼一家 MD 专科诊所就诊的成年患者。对血液 DNA 进行全基因组测序，然后对已知致病性 MD 相关变异和 MD 模拟物进行临床遗传分析。

在连续招募的 242 名患者中，根据 Nijmegen 标准，62 名参与者“确定”，108 名“可能”，72 名“可能”MD 分类。为 130 名参与者确定了致病变异，无论致病基因变异的位置如何，总体诊断率为 53.7%（242 人中的 130 人）。致病基因变异的鉴定为精确治疗、恢复生育信心和优化 MD 临床管理提供了信息。

全面的双基因组测序可准确检测受影响的 MD 患者的致病基因变异，简化诊断，实现早期治疗，并告知遗传传播的风险。