We hypothesized that novel investigative pathways are needed to decrease diagnostic odysseys in pediatric mitochondrial disease and sought to determine the utility of clinical exome sequencing in a large cohort with suspected mitochondrial disease and to explore whether any of the traditional indicators of mitochondrial disease predict a confirmed genetic diagnosis.

We investigated a cohort of 85 pediatric patients using clinical exome sequencing and compared the results with the outcome of traditional diagnostic tests, including biochemical testing of routine parameters (lactate, alanine, and proline), neuroimaging, and muscle biopsy with histology and respiratory chain enzyme activity studies.

We established a genetic diagnosis in 36.5% of the cohort and report 20 novel disease-causing variants (1 mitochondrial DNA). Counterintuitively, routine biochemical markers were more predictive of mitochondrial disease than more invasive and elaborate muscle studies.

We propose using biochemical markers to support the clinical suspicion of mitochondrial disease and then apply first-line clinical exome sequencing to identify a definite diagnosis. Muscle biopsy studies should only be used in clinically urgent situations or to confirm an inconclusive genetic result.

This is a Class II diagnostic accuracy study showing that the combination of CSF and plasma biochemical tests plus neuroimaging could predict the presence or absence of exome sequencing confirmed mitochondrial disorders.

我们假设需要新的研究途径来减少小儿线粒体疾病的诊断困难，并试图确定临床外显子组测序在疑似线粒体疾病的大型队列中的效用，并探索线粒体疾病的任何传统指标是否可以预测确诊的遗传诊断。

我们使用临床外显子组测序调查了一组 85 名儿科患者，并将结果与​​传统诊断测试的结果进行了比较，包括常规参数（乳酸、丙氨酸和脯氨酸）的生化测试、神经影像学以及组织学和呼吸链酶的肌肉活检活动研究。

我们在 36.5% 的队列中建立了基因诊断，并报告了 20 种新的致病变异（1 种线粒体 DNA）。与直觉相反，常规生化标志物比更具侵入性和精细的肌肉研究更能预测线粒体疾病。

我们建议使用生化标志物来支持线粒体疾病的临床怀疑，然后应用一线临床外显子组测序来确定明确的诊断。肌肉活检研究应仅用于临床紧急情况或确认不确定的遗传结果。

这是一项 II 类诊断准确性研究，表明 CSF 和血浆生化测试与神经影像学相结合可以预测是否存在外显子组测序证实的线粒体疾病。