The mitochondrial aconitase gene (ACO2 ) encodes an enzyme that catalyzes the conversion of citrate to isocitrate in the tricarboxylic acid cycle. Biallelic variants in ACO2 are purported to cause two distinct disorders: infantile cerebellar‐retinal degeneration (ICRD) which is characterized by CNS abnormalities, neurodevelopmental phenotypes, optic atrophy and retinal degeneration; and optic atrophy 9 (OPA9), characterized by isolated ophthalmologic phenotypes including optic atrophy and low vision. However, some doubt remains as to whether biallelic ACO2 variants can cause isolated ophthalmologic phenotypes. A review of the literature revealed five individuals from three families who carry biallelic ACO2 variants whose phenotypes are consistent with OPA9. Here, we describe a brother and sister with OPA9 who are compound heterozygous for novel missense variants in ACO2 ; c.[487G>T];[1894G>A], p.[(Val163Leu)];[(Val632Met)]. A review of pathogenic ACO2 variants revealed that those associated with OPA9 are distinct from those associated with ICRD. Missense variants associated with either OPA9 or ICRD do not cluster in distinct ACO2 domains, making it difficult to predict the severity of a variant based on position alone. We conclude that biallelic variants in ACO2 can cause the milder OPA9 phenotype, and that the OPA9‐related ACO2 variants identified to date are distinct from those that cause ICRD.

中文翻译：

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隐性ACO2变异是孤立的眼科表型的原因。

线粒体乌头酸酶基因（ACO2）编码一种在三羧酸循环中催化柠檬酸转化为异柠檬酸的酶。ACO2中的双等位基因变异据称会引起两种不同的疾病：婴儿小脑-视网膜变性（ICRD），其特征是CNS异常，神经发育表型，视神经萎缩和视网膜变性。和视神经萎缩9（OPA9），其特征在于眼科表现型分离，包括视神经萎缩和低视力。但是，关于双等位基因ACO2变异是否会引起孤立的眼科表型，仍存在一些疑问。文献回顾显示，来自三个家庭的五个人携带双等位基因ACO2表型与OPA9一致的变体。在这里，我们描述了一个弟弟和妹妹与OPA9谁是新的错义复合杂合在多个变ACO2 ; c。[487G> T]; [1894G> A]，第[[Val163Leu）]; [[Val632Met）]。对致病性ACO2变异的审查显示，与OPA9相关的变异不同于与ICRD相关的变异。与OPA9或ICRD相关的错义变体不会聚集在不同的ACO2域中，因此仅凭位置就很难预测变体的严重性。我们得出的结论是，ACO2中的双等位基因变异可导致更温和的OPA9表型，并且迄今为止确定的与OPA9相关的ACO2变异与引起ICRD的变异不同。