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

• Main Authors: Jessica Garau, Vanessa Cavallera, Marialuisa Valente, Davide Tonduti, Daisy Sproviero, Susanna Zucca, Domenica Battaglia, Roberta Battini, Enrico Bertini, Silvia Cappanera, Luisa Chiapparini, Camilla Crasà, Giovanni Crichiutti, Elvio Dalla Giustina, Stefano D’Arrigo, Valentina De Giorgis, Micaela De Simone, Jessica Galli, Roberta La Piana, Tullio Messana, Isabella Moroni, Nardo Nardocci, Celeste Panteghini, Cecilia Parazzini, Anna Pichiecchio, Antonella Pini, Federica Ricci, Veronica Saletti, Elisabetta Salvatici, Filippo M. Santorelli, Stefano Sartori, Francesca Tinelli, Carla Uggetti, Edvige Veneselli, Giovanna Zorzi, Barbara Garavaglia, Elisa Fazzi, Simona Orcesi, Cristina Cereda
• Format: Article
• Language: English
• Published: MDPI AG 2019-05-01
• Series: Journal of Clinical Medicine
• Subjects: Aicardi-Goutières Syndrome; Next Generation Sequencing; Interferon signature
• Online Access: https://www.mdpi.com/2077-0383/8/5/750

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 (<i>TREX1, RNASEH2B, RNASEH2C, RNASEH2A, ADAR1, SAMHD1, IFIH1</i>) 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 <i>RNASEH2B</i>, <i>SAMHD1</i> and <i>IFIH1</i> gene, were not previously reported. Eleven patients were positive and seven negatives for the upregulation of interferon signaling (IS &gt; 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 <i>RNASEH2B</i> and a lower frequency of mutations in <i>TREX1</i> than those seen in international series. <i>RNASEH2B</i> 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.