Novel RNASEH2C mutation in multiple members of a large family: insights into phenotypic spectrum of Aicardi-Goutières Syndrome

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.