Ferrodoxin reductase (FDXR) deficiency is a mitochondrial disease described in recent years primarily in association with optic atrophy, acoustic neuropathy, and developmental delays. Here, we identified seven unpublished patients with FDXR deficiency belonging to six independent families. These patients show a broad clinical spectrum ranging from Leigh syndrome with early demise and severe infantile‐onset encephalopathy, to milder movement disorders. In total nine individual pathogenic variants, of which seven were novel, were identified in FDXR using whole exome sequencing in suspected mitochondrial disease patients. Over 80% of these variants are missense, a challenging variant class in which to determine pathogenic consequence, especially in the setting of nonspecific phenotypes and in the absence of a reliable biomarker, necessitating functional validation. Here we implement an Arh1‐null yeast model to confirm the pathogenicity of variants of uncertain significance in FDXR, bypassing the requirement for patient‐derived material.

中文翻译：

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通过对意义不确定的变异进行功能验证，扩大 FDXR 缺乏症的临床和遗传谱

铁氧还蛋白还原酶 (FDXR) 缺乏症是近年来描述的一种线粒体疾病，主要与视神经萎缩、听神经病变和发育迟缓有关。在这里，我们确定了属于 6 个独立家庭的 7 名未发表的 FDXR 缺陷患者。这些患者表现出广泛的临床范围，从早期死亡和严重婴儿期脑病的 Leigh 综合征到轻度运动障碍。在FDXR中总共发现了 9 个单独的致病变异，其中 7 个是新的在疑似线粒体疾病患者中使用全外显子组测序。超过 80% 的这些变异是错义的，这是一个具有挑战性的变异类别，以确定致病后果，特别是在非特异性表型的设置和缺乏可靠的生物标志物的情况下，需要进行功能验证。在这里，我们实施了一个Arh1- null 酵母模型来确认FDXR中不确定性变异的致病性，绕过了对患者来源材料的要求。