Leung Marco L, Woodhull Whitney, Uggenti Carolina, Schord Shauna, Mato Raul Perez, Rodriguez Diana P, Ream Margie, Crow Yanick J, Mori Mari
The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA; Departments of Pathology, Departments of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA.
Division of Pediatric Neurology, Renown Children's Hospital, Reno, NV, USA; University of Nevada, Reno School of Medicine, Reno, NV, USA.
Eur J Med Genet. 2023 Apr;66(4):104731. doi: 10.1016/j.ejmg.2023.104731. Epub 2023 Feb 11.
Aicardi-Goutières syndrome (AGS) is a progressive multisystem disorder including encephalopathy with significant impacts on intellectual and physical abilities. An early diagnosis is becoming ever more crucial, as targeted therapies are emerging. A deep understanding of the molecular heterogeneity of AGS can help guide the early diagnosis and clinical management of patients, and inform recurrence risks. Here, we detail the diagnostic odyssey of a patient with an early presentation of AGS. Exome and genome sequencing detected an intronic RNASEH2B variant missed in a conventional leukodystrophy NGS gene panel. RNA studies demonstrated that a c.322-17 A > G variant affected splicing and caused 16-nucleotide intronic retention in the RNASEH2B transcript, introducing an out-of-frame early termination codon. RNASEH2B expression in the patient's blood was reduced when compared to controls. Our study highlights the pathogenicity of this intronic variant and the importance of its inclusion in variant assessment.
艾卡迪-古铁雷斯综合征（AGS）是一种进行性多系统疾病，包括脑病，对智力和身体能力有重大影响。随着靶向治疗的出现，早期诊断变得越来越关键。深入了解AGS的分子异质性有助于指导患者的早期诊断和临床管理，并告知复发风险。在此，我们详细介绍了一名早期表现为AGS的患者的诊断历程。外显子组和基因组测序检测到一个在传统脑白质营养不良二代测序基因panel中遗漏的内含子RNASEH2B变异。RNA研究表明，c.322-17 A>G变异影响剪接，并导致RNASEH2B转录本中16个核苷酸的内含子保留，引入了一个移码的早期终止密码子。与对照组相比，患者血液中RNASEH2B的表达降低。我们的研究突出了这个内含子变异的致病性及其纳入变异评估的重要性。
