背景:NARS2(MIM:612803)中的突变与联合氧化磷酸化缺陷24(COXPD24;MIM:616239)相关,后者是一种罕见的线粒体和多系统常染色体隐性遗传疾病。
目的:我们旨在检测两个患有进行性共济失调的兄弟姐妹的潜在遗传因素,癫痫,和严重到严重的听力障碍。
方法:在进行医学评估和相关测试(即,听觉脑干反应,纯音耳声发射试验,心脏检查,计算机断层扫描,和脑电图),由于临床和可能的遗传异质性,进行了全外显子组测序,通过Sanger测序证实了共分离分析。使用序列功能生物信息学工具评估了新变体的生物学影响。
结果:一个新的纯合错义变体,NM_024678.6:c.545T>A;p.(Ile182Lys),在两名患者中都发现了NARS2第5外显子,并通过Sanger测序进行了验证.在计算机分析中引入了这种变异作为致病性。二尖瓣脱垂伴轻度反流,短枝转移症,严重的外翻,据报道,棍状手指是与NARS2基因相关的新表现。通过文献综述,我们还强调了疾病表型的高度异质性.
结论:此处,我们报道了伊朗近亲COXPD24家族中两名女性患者的一些新表型和基因型特征,这是由NARS2-NM_024678.6的变异引起的:c.545T>A;p。(Ile182Lys)。此外,我们的数据扩大了NARS2相关疾病的表型和基因型谱,并证实了COXPD24中基因型-表型相关性的不可预知性.
BACKGROUND: Mutations in NARS2 (MIM: 612803) are associated with combined oxidative phosphorylation deficiency 24 (COXPD24; MIM: 616239) that is a rare mitochondrial and a multisystem autosomal recessive disorder.
OBJECTIVE: We aimed to detect the underlying genetic factors in two siblings with progressive ataxia, epilepsy, and severe-to-profound hearing impairment.
METHODS: After doing medical assessments and pertinent tests (i.e., auditory brainstem responses, pure tone otoacoustic emission test, cardiac examinations, computed tomography, and electroencephalogram), because of the clinical and probable genetic heterogeneity, whole-exome sequencing was performed, and co-segregation analysis was confirmed by Sanger sequencing. Biological impacts of the novel variant were evaluated using sequence-to-function bioinformatics tools.
RESULTS: A novel homozygous missense variant, NM_024678.6:c.545 T > A; p.(Ile182Lys), in exon 5 of NARS2 was identified in both patients and verified by Sanger sequencing. In silico analyses introduced this variant as pathogenic. Mitral valve prolapses with mild regurgitation,
brachymetatarsia, severe hallux valgus, and clubbed fingers were reported as novel manifestations in association with NARS2 gene. By doing a literature review, we also underscored the high heterogeneity of disease phenotype.
CONCLUSIONS: Herein, we report some novel phenotype and genotype features of two female patients in an Iranian consanguineous family with COXPD24, caused by a variant in NARS2-NM_024678.6: c.545 T > A; p.(Ile182Lys). Moreover, our data expanded the phenotype and genotype spectrum of NARS2-related disorder and confirmed an unpredictable nature of genotype-phenotype correlation in COXPD24.