Background Aicardi-Goutières syndrome (AGS) is a genetic inflammatory disorder that presents with early infantile encephalopathy. We report the clinical and molecular details of multiple members of a family with AGS secondary to a novel RNASEH2C mutation, highlighting the evolution of phenotypic abnormalities in AGS. Methods Between February 2018 and June 2019, a pedigree tree was constructed for 141 members of a family. The clinical and radiological details of 14 symptomatic children were chronicled and compared with the asymptomatic family members. Genetic analysis was performed on 23 individuals (six symptomatic). This involved whole exome sequencing for one patient and confirmation of the identified indel variant in other family members. Results The symptomatic children were diagnosed as AGS secondary to a novel indel variation in exon 2 of the RNASEH2C gene (chr11:65487843_65487846delinsGCCA). Clinically, between the ages of 2 and 6 months, the symptomatic children developed irritability (14/14), unexplained fever (9/14), chill blains (12/14), sleep irregularities (14/14) and developmental delay (14/14), with deterioration to vegetative state at a median (IQR) age of 10.5 months (9.25–11). In addition, chill blains were observed in 5/17 (29.4%) carrier individuals. Neuroimaging demonstrated a gradual progression of calcification involving basal ganglia, periventricular white matter and dentate nucleus. Three patients also demonstrated presence of subependymal germinolytic cysts. Conclusion This report highlights a novel founder RNASEH2C mutation and the phenotypic evolution of AGS. In addition, we report chill blains in one-third of RNASEH2C mutation carriers. Neuroradiologically, the report illustrates novel MRI findings and demonstrates a progression pattern of disease. These findings will aid in earlier suspicion and diagnosis of AGS.

中文翻译：

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一个大家族多个成员的新 RNASEH2C 突变：对 Aicardi-Goutières 综合征表型谱的洞察

背景 Aicardi-Goutières 综合征 (AGS) 是一种遗传性炎症性疾病，表现为早期婴儿脑病。我们报告了继发于新型 RNASEH2C 突变的 AGS 家族的多个成员的临床和分子细节，突出了 AGS 表型异常的演变。方法 2018 年 2 月至 2019 年 6 月，为一个家庭的 141 名成员构建谱系树。记录了 14 名有症状儿童的临床和放射学细节，并与无症状的家庭成员进行了比较。对 23 名个体（6 名有症状）进行了遗传分析。这涉及对一名患者进行全外显子组测序，并在其他家庭成员中确认已识别的 indel 变体。结果 有症状的儿童被诊断为继发于 RNASEH2C 基因外显子 2 中新的插入缺失变异 (chr11:65487843_65487846delinsGCCA) 的 AGS。临床上，在 2 至 6 个月大时，有症状的儿童出现易怒 (14/14)、不明原因发热 (9/14)、冷疹 (12/14)、睡眠不规律 (14/14) 和发育迟缓 (14 /14），在中位（IQR）年龄为 10.5 个月（9.25-11）时恶化为植物人。此外，在 5/17 (29.4%) 携带者个体中观察到冻疮。神经影像显示基底节、脑室周围白质和齿状核的钙化逐渐进展。三名患者还表现出室管膜下溶菌囊肿的存在。结论 本报告重点介绍了一种新的创始人 RNASEH2C 突变和 AGS 的表型进化。此外，我们在三分之一的 RNASEH2C 突变携带者中报告了冻疮。在神经放射学上，该报告说明了新的 MRI 发现并展示了疾病的进展模式。这些发现将有助于早期怀疑和诊断 AGS。