• Mohammad Vafaee-Shahi, Mohammad Farhadi, Ehsan Razmara, Saeid Morovvati, Saeide Ghasemi, Seyedeh Sedigheh Abedini, Zohreh Bagher, Rafieh Alizadeh, and Masoumeh Falah.
• ENT and Head and Neck Research Center and Department, The Five Senses Health Institute, Hazrat Rasoul Akram Hospital, Iran University of Medical Sciences, Tehran, Iran.
• Ir J Med Sci. 2022 Aug 1; 191 (4): 187718901877-1890.

BackgroundMutations 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.AimsWe aimed to detect the underlying genetic factors in two siblings with progressive ataxia, epilepsy, and severe-to-profound hearing impairment.MethodsAfter 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.ResultsA 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.ConclusionsHerein, 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.© 2021. Royal Academy of Medicine in Ireland.

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