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. 2019 May 26;8(5):750.
doi: 10.3390/jcm8050750.

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

Jessica Garau  1   2 , Vanessa Cavallera  3 , Marialuisa Valente  4 , Davide Tonduti  5 , Daisy Sproviero  6 , Susanna Zucca  7 , Domenica Battaglia  8 , Roberta Battini  9 , Enrico Bertini  10 , Silvia Cappanera  11 , Luisa Chiapparini  12 , Camilla Crasà  13 , Giovanni Crichiutti  14 , Elvio Dalla Giustina  15 , Stefano D'Arrigo  16 , Valentina De Giorgis  17 , Micaela De Simone  18 , Jessica Galli  19   20 , Roberta La Piana  21 , Tullio Messana  22 , Isabella Moroni  23 , Nardo Nardocci  24 , Celeste Panteghini  25 , Cecilia Parazzini  26 , Anna Pichiecchio  27   28 , Antonella Pini  29 , Federica Ricci  30 , Veronica Saletti  31 , Elisabetta Salvatici  32 , Filippo M Santorelli  33 , Stefano Sartori  34 , Francesca Tinelli  35 , Carla Uggetti  36 , Edvige Veneselli  37 , Giovanna Zorzi  38 , Barbara Garavaglia  39 , Elisa Fazzi  40   41 , Simona Orcesi  42   43 , Cristina Cereda  44
Affiliations

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

Jessica Garau et al. J Clin Med. .

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.

Keywords: Aicardi-Goutières Syndrome; Interferon signature; Next Generation Sequencing.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Numbers and percentages of patients with Aicardi–Goutières syndrome with or without mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1 and IFIH1 genes.
Figure 2
Figure 2
(A) Quantitative reverse transcription PCR of six ISGs IFI27, IFI44, IFIT1, ISG15, RSAD2 and SIGLEC1 in whole blood measured in 18 patients with Aicardi-Goutières syndrome and 31 controls. The threshold is calculated at 2.216: Higher values are considered positive, whereas lower scores are negative. (B) Interferon scores of 12 RNASEH2B mutated patients and 31 healthy controls. Scores above the threshold are positive whereas those below are negative. (C) Interferon signatures of 18 AGS patients.
Figure 2
Figure 2
(A) Quantitative reverse transcription PCR of six ISGs IFI27, IFI44, IFIT1, ISG15, RSAD2 and SIGLEC1 in whole blood measured in 18 patients with Aicardi-Goutières syndrome and 31 controls. The threshold is calculated at 2.216: Higher values are considered positive, whereas lower scores are negative. (B) Interferon scores of 12 RNASEH2B mutated patients and 31 healthy controls. Scores above the threshold are positive whereas those below are negative. (C) Interferon signatures of 18 AGS patients.
Figure 3
Figure 3
Median fold expression of six interferon-stimulated genes ISGs IFI27, IFI44, IFIT1, ISG15, RSAD and SIGLEC1 according to the genotype of 18 AGS patients and controls.
See this image and copyright information in PMC

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