摘要目的:采用高通量测序技术，对一个综合征型耳聋家系的致病变异进行鉴定。方法:详细询问一综合征型耳聋家系的病史及家族史，绘制家系图。对该家系进行听力学检查，采用全外显子组测序及生物信息学分析，筛选疑似致病变异，使用Sanger测序进行变异共分离验证，并通过转录组测序探究内含子对剪切的影响。结果:该家系中先证者（男性，2岁2个月）患有听神经病，伴有发育缓慢、肌无力、癫痫发作等症状。患者携带 NARS2（NM_024678.6）c.［779A>C］；［372+3A>G］复合杂合变异，其中c.779A>C p.（Glu260Ala）遗传自父亲，c.372+3A>G遗传自母亲，两变异均未见文献报道或数据库收录。转录组测序结果表明c.372+3A>G变异会导致转录跳过第三个外显子。依据美国医学遗传学与基因组学学会（American College of Medical Genetics and Genomics，ACMG）相关指南将c.779A>C变异及c.372+3A>G变异评级为可能致病。基于患者表型及基因检测结果，该患者诊断为联合氧化磷酸化缺乏症24型。 结论:NARS2基因致病变异可能是该患者的致病原因，新变异的检出丰富了 NARS2基因的变异谱，为进一步明确 NARS2与联合氧化磷酸化缺乏症24型的关系提供了参考依据。

abstractsObjective:To investigate the pathogenic variants and function of a pedigree with syndromic hearing loss using high-throughput sequencing.Methods:Detailed medical history and pedigree history were inquired, and a pedigree chart was drawn. Hearing examinations were performed on this pedigree, and whole-exome sequencing and bioinformatics analysis were performed to screen for suspected pathogenic variants. Then, Sanger sequencing was used to test co-segregation in the family, and transcriptome sequencing was used to investigate the effect of a variant on splicing.Results:The proband has auditory neuropathy combined with symptoms such as development delay, muscle weakness, and seizure. The patient carries two variants in NARS2 (NM_024678.6), namely: c.779A>C (p.Glu260Ala) and c.372+3A>G (intronic variant), of which c.779A>C is inherited from the father and c.372+3A>G from the mother. Both variants have not been reported in the literature or included in any databases. Transcriptome sequencing results indicate that the c.372+3A>G variant leads to the skipping of the third exon during transcription. According to the American College of Medical Genetics and Genomics(ACMG) guidelines, the c.779A>C variant and c.372+3A>G are classified as likely pathogenic. Based on the patient′s phenotype and genetic testing results, the proband has been diagnosed with combined oxidative phosphorylation deficiency 24(COXPD24). Conclusions:The pathogenic variants in the NARS2 gene are the underlying cause of the patient′s disease. The identification of novel variants enriches the mutational spectrum of the NARS2 gene, providing evidence for further clarification of the relationship between NARS2 and COXPD24.