KARS1相关伴或不伴耳聋的婴儿期起病进行性白质脑病：一例新变异及表型扩展

文献信息

中文摘要

背景： KARS1基因编码赖氨酰-tRNA合成酶，其双等位基因变异可导致常染色体隐性遗传疾病，如伴或不伴耳聋的婴儿期起病进行性白质脑病（LEPID；OMIM #619147）及非综合征性听力损失（DFNB89）。LEPID的常见特征包括感音神经性听力损失、发育迟缓和白质脑病，但面容异常和心脏异常并不常被报道。本研究报道了伊朗首例有记录的LEPID病例，扩展了KARS1相关疾病的表型和遗传谱。方法：对一名来自非近亲结婚父母、无任何神经系统疾病阳性史的2岁伊朗男孩进行了全外显子组测序（WES）。所鉴定的变异通过Sanger测序验证，并进行了家系共分离分析。此外，对41例KARS1相关病例进行了文献复习，以比较临床和遗传学发现。结果：WES鉴定出两个复合杂合KARS1变异（NM_005548.3）：c.959G > A（p.Arg320His）和c.2T > C（p.Met1Thr），前者既往已有报道，后者为新变异，二者均根据美国医学遗传学与基因组学学会标准被归类为可能致病。该患者表现出典型的LEPID特征（感音神经性听力损失、发育迟缓、癫痫发作、白质脑病），同时伴有前所未有的面容异常（如连眉、尖三角形下巴）和心脏异常（肺动脉狭窄、房间隔缺损）。文献复习证实这些面容异常为新的发现，既往病例中未见，而心脏受累仅见于少数患者。结论：本研究强调了一个新的KARS1变异以及LEPID表型谱的扩展，突出了WES在诊断罕见疾病中的作用，即使在非近亲结婚的情况下也是如此。这些发现支持更广泛的表型识别和功能研究，以阐明KARS1在神经发育、颅面和心脏异常中的作用。

英文摘要

Biallelic variants in the KARS1 gene, encoding lysyl-tRNA synthetase, are responsible for autosomal recessive disorders such as infantile-onset progressive leukoencephalopathy with or without deafness (LEPID; OMIM #619147) and nonsyndromic hearing loss (DFNB89). Common features of LEPID include sensorineural hearing loss, developmental delay, and leukoencephalopathy, but dysmorphic facial features and cardiac anomalies are not commonly reported. This study presents the first documented LEPID case in Iran, expanding the phenotypic and genetic spectrum of KARS1-related disorders. Whole exome sequencing (WES) was performed on a two-year-old Iranian boy from non-consanguineous parents, without a positive history of any neurologic conditions. Identified variants were validated by Sanger sequencing, with familial segregation analysis. Moreover, a literature review of 41 KARS1-related cases was conducted to compare clinical and genetic findings. WES identified two compound heterozygous KARS1 variants (NM_005548.3): c.959G > A (p.Arg320His) and c.2T > C (p.Met1Thr), previously reported and novel, respectively, both of which were classified as likely pathogenic according to the American College of Medical Genetics and Genomics criteria. The patient exhibited typical LEPID features (sensorineural hearing loss, developmental delay, seizures, leukoencephalopathy) alongside unprecedented dysmorphic facial features (e.g., synophrys, pointed triangular chin) and cardiac anomalies (pulmonary stenosis, atrial septal defect). Literature review confirmed these dysmorphic features as novel, absent in prior cases, with cardiac involvement in a limited number of patients. This study highlights a novel KARS1 variant and an expanded phenotypic spectrum of LEPID, emphasizing the role of WES in diagnosing rare disorders even in non-consanguineous marriages. These findings advocate for broader phenotypic recognition and functional studies to elucidate KARS1's role in neurodevelopmental, craniofacial, and cardiac abnormalities.