Wu Heyan, Zhou Min, Ye Xiaoting, Chen Huabao, Lin Hongxin, Wang Li, Nie Xing, Zhang Lidan
Pediatric Intensive Care Unit, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China.
Department of Pediatrics, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China.
Front Pediatr. 2025 Apr 8;13:1571426. doi: 10.3389/fped.2025.1571426. eCollection 2025.
Biallelic variants in that encodes the mitochondrial asparaginyl-tRNA synthetase are associated with a wide spectrum of clinical phenotypes. Herein, we report on two siblings carrying the same compound heterozygous missense variants in , to improve the understanding of the phenotypic heterogeneity of variants.
The two probands, a 3-year-old female (Patient 1) and a 16-month-old male (Patient 2), were clinically suspected of Combined oxidative phosphorylation deficiency 24 (COXPD24). Both presented with neurological manifestations, including refractory epilepsy, developmental delay and motor developmental regression, within the first year of life, accompanied by symmetrical brain lesions identified on magnetic resonance imaging (MRI). To elucidate the underlying genetic etiology, whole-exome sequencing (WES) was performed, followed by Sanger sequencing validation in the patients and their non-consanguineous parents. Genetic analysis revealed that both probands harbored identical compound heterozygous variants in the gene: c.1253G>A (p.Arg418His) and c.1163C>T (p.Thr388Met). Notably, the c.1163C>T (p.Thr388Met) variant in represents a novel finding, further expanding the genetic spectrum associated with this disorder.
Our findings expand the mutational spectrum of and highlight the associated phenotypic heterogeneity, underscoring the critical role of in epilepsy and neurodevelopmental processes. For pediatric patients with refractory epilepsy, early genetic testing is essential to improve diagnostic accuracy, refine prognostic stratification, and guide personalized treatment strategies. Additionally, mitochondrial drug cocktail therapy may be beneficial for epilepsy caused by NARS2 mutations.
编码线粒体天冬酰胺 - tRNA合成酶的基因中的双等位基因变异与广泛的临床表型相关。在此，我们报告了两名携带相同复合杂合错义变异的兄弟姐妹，以增进对该基因变异表型异质性的理解。
两名先证者，一名3岁女性（患者1）和一名16个月大男性（患者2），临床上疑似患有联合氧化磷酸化缺陷24（COXPD24）。两人在生命的第一年内均出现神经学表现，包括难治性癫痫、发育迟缓及运动发育倒退，并伴有磁共振成像（MRI）显示的对称性脑损伤。为阐明潜在的遗传病因，进行了全外显子测序（WES），随后对患者及其非近亲父母进行了桑格测序验证。基因分析显示，两名先证者在该基因中均携带相同的复合杂合变异：c.1253G>A（p.Arg418His）和c.1163C>T（p.Thr388Met）。值得注意的是，该基因中的c.1163C>T（p.Thr388Met）变异代表一项新发现，进一步扩展了与该疾病相关的遗传谱。
我们的发现扩展了该基因的突变谱，突出了相关的表型异质性，强调了该基因在癫痫和神经发育过程中的关键作用。对于难治性癫痫的儿科患者，早期基因检测对于提高诊断准确性、完善预后分层及指导个性化治疗策略至关重要。此外，线粒体药物联合疗法可能对由NARS2突变引起的癫痫有益。
