Iron‑sulfur clusters (FeSCs) are vital components of a variety of essential proteins, most prominently within mitochondrial respiratory chain complexes I-III; FeS assembly and distribution is performed via multi-step pathways. Variants affecting several proteins in these pathways have been described in genetic disorders, including severe mitochondrial disease. Here we describe a Christian Arab kindred with two infants that died due to mitochondrial disorder involving FeS containing respiratory chain complexes and a third sibling who survived the initial crisis. A homozygous missense variant in NFS1: c.215G>A; p.Arg72Gln was detected by whole exome sequencing. The NFS1 gene encodes a cysteine desulfurase, which, in complex with ISD11 and ACP, initiates the first step of FeS formation. Arginine at position 72 plays a role in NFS1-ISD11 complex formation; therefore, its substitution with glutamine is expected to affect complex stability and function. Interestingly, this is the only pathogenic variant ever reported in the NFS1 gene, previously described once in an Old Order Mennonite family presenting a similar phenotype with intra-familial variability in patient outcomes. Analysis of datasets from both populations did not show a common haplotype, suggesting this variant is a recurrent de novo variant.

Our report of the second case of NFS1-related mitochondrial disease corroborates the pathogenicity of this recurring variant and implicates it as a hot-spot variant. While the genetic resolution allows for prenatal diagnosis for the family, it also raises critical clinical questions regarding follow-up and possible treatment options of severely affected and healthy homozygous individuals with mitochondrial co-factor therapy or cysteine supplementation.

铁硫簇（FeSC）是多种必需蛋白质的重要​​组成部分，最主要的是线粒体呼吸链复合体I-III。Fe S的组装和分配是通过多步路径进行的。已经在遗传疾病（包括严重的线粒体疾病）中描述了在这些途径中影响几种蛋白质的变异体。在这里，我们描述了一个阿拉伯基督教家庭，其中有两名婴儿死于线粒体疾病，死亡的原因是线粒体疾病涉及含呼吸链复合物的Fe S，第三名兄弟姐妹在最初的危机中幸存下来。NFS1中的纯合错义变体：c.215G> A；通过全外显子组测序检测到p.Arg72Gln。该NFS1该基因编码一个半胱氨酸脱硫酶，与ISD11和ACP结合，启动了Fe S形成的第一步。72位的精氨酸在NFS1-ISD11复合物的形成中起作用；因此，它被谷氨酰胺取代有望影响复杂的稳定性和功能。有趣的是，这是有史以来唯一在NFS1基因中报道的致病变体，以前曾在Old Order Mennonite家族中进行过描述，在患者结局中表现出相似的表型和家族内差异。来自两个种群的数据集的分析未显示出常见的单倍型，这表明该变异是复发的从头变异。

我们关于NFS1相关线粒体疾病的第二例报告证实了该复发变异的致病性，并暗示其为热点变异。尽管遗传分辨率可以为该家庭进行产前诊断，但它也提出了关于线粒体辅助因子治疗或补充半胱氨酸的严重影响和健康纯合个体的随访和可能的治疗选择的关键临床问题。