Molecular Genetics and Interferon Signature in the Italian Aicardi Goutières Syndrome Cohort: Report of 12 New Cases and Literature Review

Abstract

Aicardi-Goutières syndrome (AGS) is a genetically determined early onset encephalopathy characterized by cerebral calcification, leukodystrophy, and increased expression of interferon-stimulated genes (ISGs). Up to now, seven genes (TREX1, RNASEH2B, RNASEH2C, RNASEH2A, ADAR1, SAMHD1, IFIH1) have been associated with an AGS phenotype. Next Generation Sequencing (NGS) analysis was performed on 51 AGS patients and interferon signature (IS) was investigated in 18 AGS patients and 31 healthy controls. NGS identified mutations in 48 of 51 subjects, with three patients demonstrating a typical AGS phenotype but not carrying mutations in known AGS-related genes. Five mutations, in RNASEH2B, SAMHD1 and IFIH1 gene, were not previously reported. Eleven patients were positive and seven negatives for the upregulation of interferon signaling (IS > 2.216). This work presents, for the first time, the genetic data of an Italian cohort of AGS patients, with a higher percentage of mutations in RNASEH2B and a lower frequency of mutations in TREX1 than those seen in international series. RNASEH2B mutated patients showed a prevalence of negative IS consistent with data reported in the literature. We also identified five novel pathogenic mutations that warrant further functional investigation. Exome/genome sequencing will be performed in future studies in patients without a mutation in AGS-related genes.

Case Report: Novel Compound Heterozygous RNASEH2B Mutations Cause Aicardi–Goutières Syndrome

“…Here we report the case of a child diagnosed with AGS caused by one previously described and one novel variant in RNASEH2B gene in a compound heterozygous state. RNASEH2B has been defined an AGS-causing gene in 2006 ( 11 ), and it is usually the most frequently mutated gene found in these patients ( 2 , 5 ). Patients mutated in RNASEH2B are more likely to retain some motor and communication abilities, and they usually develop later-onset forms of AGS with a longer life expectancy ( 6 ).…”

“…Mutations in nine genes have been described as causative of AGS ( 2 , 3 ), and they all lead to the pathological activation of the innate immune system usually observed in these patients ( 3 , 4 ). In the worldwide cohort of patients, as well as in the Italian one, the most frequently mutated gene is RNASEH2B ( 2 , 5 ). RNASEH2B encodes one of the three subunits of RNase H2, one of the major endonucleases in humans ( 6 ).…”

Dirty Fish Versus Squeaky Clean Mice: Dissecting Interspecies Differences Between Animal Models of Interferonopathy

“…In contrast, zebrafish are relatively outbred, leading to an accumulation of polymorphisms that vary from one animal to the next and perhaps more closely mimic the complex genetic make-up of humans than mice. The combined effect of these mutations may well act as a phenotypic modifier—resulting in intraspecies variability in pathology, as is seen in human AGS patients with mutations in the same gene ( 18 ). However, any increased variation in zebrafish models relative to mice still cannot account for the general trend towards greater neurological involvement in the fish compared to rodents.…”

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“…Here we report the case of a child diagnosed with AGS caused by one previously described and one novel variant in RNASEH2B gene in a compound heterozygous state. RNASEH2B has been defined an AGS-causing gene in 2006 (11), and it is usually the most frequently mutated gene found in these patients (2,5). Patients mutated in RNASEH2B are more likely to retain some motor and communication abilities, and they usually develop later-onset forms of AGS with a longer life expectancy (6).…”

“…Mutations in nine genes have been described as causative of AGS (2,3), and they all lead to the pathological activation of the innate immune system usually observed in these patients (3,4). In the worldwide cohort of patients, as well as in the Italian one, the most frequently mutated gene is RNASEH2B (2,5). RNASEH2B encodes one of the three subunits of RNase H2, one of the major endonucleases in humans (6).…”