Whole‐exome sequencing identified novel variants in three Chinese Leigh syndrome pedigrees

Abstract

Leigh syndrome (LS), the most common mitochondrial disease in early childhood, usually manifests variable neurodegenerative symptoms and typical brain magnetic resonance imaging (MRI) lesions. To date, pathogenic variants in more than 80 genes have been identified. However, there are still many cases without molecular diagnoses, and thus more disease-causing variants need to be unveiled. Here, we presented three clinically suspected LS patients manifesting neurological symptoms including developmental delay, hypotonia, and epilepsy during the first year of age, along with symmetric brain lesions on MRI. We explored disease-associated variants in patients and their nonconsanguineous parents by whole-exome sequencing and subsequent Sanger sequencing verification. Sequencing data revealed three pairs of diseaseassociated compound heterozygous variants: c.1A>G (p.Met1?) and 409G>C (p. Asp137His) in SDHA, c.1253G>A (p.Arg418His) and 1300C>T (p.Leu434Phe) in NARS2, and c.5C>T (p.Ala2Val) and 773T>G (p.Leu258Trp) in ECHS1. Among them, the likely pathogenic variants c.409G>C (p.Asp137His) in SDHA, c.1300C>T (p. Leu434Phe) in NARS2, and c.773T>G (p.Leu258Trp) in ECHS1 were newly identified. Segregation analysis indicated the possible disease-causing nature of the novel variants. In silico prediction and three-dimensional protein modeling further suggested the potential pathogenicity of these variants. Our discovery of novel variants expands the gene variant spectrum of LS and provides novel evidence for genetic counseling.

Clinical and genetic analyses of premature mitochondrial encephalopathy with epilepsia partialis continua caused by novel biallelic NARS2 mutations

“…We searched 14 articles related to neural performance affected by NARS2 mutations ( Simon et al, 2015 ; Sofou et al, 2015 ; Vanlander et al, 2015 ; Mizuguchi et al, 2017 ; Souza et al, 2017 ; Seaver et al, 2018 ; Han et al, 2019 ; Lee et al, 2020 ; Štěrbová et al, 2021 ; Tanaka et al, 2022 ; Vafaee-Shahi et al, 2022 ; Yagasaki et al, 2022 ; Yang et al, 2022 ; Zhang et al, 2022 ). A total of 21 patients and 23 NARS2 mutations were reported in 16 families, most of which were missense mutations (91%, 21/23), followed by nonsense and frameshift mutations.…”

“…Most infants diagnosed with COXPD24 have sensorineural hearing loss in the early stage, followed by delayed neural development, intractable seizures, and hypotonia. MRI shows white matter lesions, mainly involving the frontal and parietal lobes and the deep white matter, and features of agenesis of the corpus callosum or diffuse brain atrophy ( Simon et al, 2015 ; Sofou et al, 2015 ; Vanlander et al, 2015 ; Mizuguchi et al, 2017 ; Souza et al, 2017 ; Seaver et al, 2018 ; Han et al, 2019 ; Lee et al, 2020 ; Štěrbová et al, 2021 ; Tanaka et al, 2022 ; Vafaee-Shahi et al, 2022 ; Yagasaki et al, 2022 ; Yang et al, 2022 ; Zhang et al, 2022 ). The characteristics of Leigh syndrome can be observed in some patients’ brain MRI or autopsy results, including symmetric long T2 abnormal signals in the brain stem or the putamen or atrophy of the corpus callosum with lamellar necrosis and vacuolization ( Simon et al, 2015 ; Tanaka et al, 2022 ).…”

Novel NARS2 variants in a patient with early-onset status epilepticus: case study and literature review

“…The number of reported cases related to NARS2 deficiency has been gradually increasing [3, 5-7, 9, 26-28]. Recently, more individuals of NARS2 variants have been reported [9,[22][23][24][25]. Data from this study was compared with 28 variants in NARS2 gene published studies.…”

Progressive Mitochondrial Encephalopathy Due to the Novel Compound Heterozygous Variants c.182C>T and c.446A>AG in NARS2: A Case Report

“…NARS2 variants cause a combined oxidative phosphorylation deficiency-24 (COXPD24) [3]. Biallelic variants in NARS2 cause mitochondrial disorders (MIDs) with a broad phenotypic spectrum [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18]. The following case report describes a patient with MID due to a novel compound heterozygous variant in NARS2 that phenotypically manifested only in the brain.…”