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

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 MessanaIsabella 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

Research output: Contribution to journalArticle

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.

Original languageEnglish
JournalJournal of Clinical Medicine
Volume8
Issue number5
DOIs
Publication statusPublished - May 26 2019

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Aicardi Syndrome
Interferons
Molecular Biology
Mutation
Genes
Exome
Phenotype
Brain Diseases
Mutation Rate
Up-Regulation
Genome

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Molecular Genetics and Interferon Signature in the Italian Aicardi Goutières Syndrome Cohort : Report of 12 New Cases and Literature Review. / Garau, Jessica; Cavallera, Vanessa; Valente, Marialuisa; Tonduti, Davide; Sproviero, Daisy; Zucca, Susanna; Battaglia, Domenica; Battini, Roberta; Bertini, Enrico; Cappanera, Silvia; Chiapparini, Luisa; Crasà, Camilla; Crichiutti, Giovanni; Dalla Giustina, Elvio; D'Arrigo, Stefano; De Giorgis, Valentina; De Simone, Micaela; Galli, Jessica; La Piana, Roberta; Messana, Tullio; Moroni, Isabella; Nardocci, Nardo; Panteghini, Celeste; Parazzini, Cecilia; Pichiecchio, Anna; Pini, Antonella; Ricci, Federica; Saletti, Veronica; Salvatici, Elisabetta; Santorelli, Filippo M; Sartori, Stefano; Tinelli, Francesca; Uggetti, Carla; Veneselli, Edvige; Zorzi, Giovanna; Garavaglia, Barbara; Fazzi, Elisa; Orcesi, Simona; Cereda, Cristina.

In: Journal of Clinical Medicine, Vol. 8, No. 5, 26.05.2019.

Research output: Contribution to journalArticle

Garau, J, Cavallera, V, Valente, M, Tonduti, D, Sproviero, D, Zucca, S, Battaglia, D, Battini, R, Bertini, E, Cappanera, S, Chiapparini, L, Crasà, C, Crichiutti, G, Dalla Giustina, E, D'Arrigo, S, De Giorgis, V, De Simone, M, Galli, J, La Piana, R, Messana, T, Moroni, I, Nardocci, N, Panteghini, C, Parazzini, C, Pichiecchio, A, Pini, A, Ricci, F, Saletti, V, Salvatici, E, Santorelli, FM, Sartori, S, Tinelli, F, Uggetti, C, Veneselli, E, Zorzi, G, Garavaglia, B, Fazzi, E, Orcesi, S & Cereda, C 2019, 'Molecular Genetics and Interferon Signature in the Italian Aicardi Goutières Syndrome Cohort: Report of 12 New Cases and Literature Review', Journal of Clinical Medicine, vol. 8, no. 5. https://doi.org/10.3390/jcm8050750
Garau, Jessica ; Cavallera, Vanessa ; Valente, Marialuisa ; Tonduti, Davide ; Sproviero, Daisy ; Zucca, Susanna ; Battaglia, Domenica ; Battini, Roberta ; Bertini, Enrico ; Cappanera, Silvia ; Chiapparini, Luisa ; Crasà, Camilla ; Crichiutti, Giovanni ; Dalla Giustina, Elvio ; D'Arrigo, Stefano ; De Giorgis, Valentina ; De Simone, Micaela ; Galli, Jessica ; La Piana, Roberta ; Messana, Tullio ; Moroni, Isabella ; Nardocci, Nardo ; Panteghini, Celeste ; Parazzini, Cecilia ; Pichiecchio, Anna ; Pini, Antonella ; Ricci, Federica ; Saletti, Veronica ; Salvatici, Elisabetta ; Santorelli, Filippo M ; Sartori, Stefano ; Tinelli, Francesca ; Uggetti, Carla ; Veneselli, Edvige ; Zorzi, Giovanna ; Garavaglia, Barbara ; Fazzi, Elisa ; Orcesi, Simona ; Cereda, Cristina. / Molecular Genetics and Interferon Signature in the Italian Aicardi Goutières Syndrome Cohort : Report of 12 New Cases and Literature Review. In: Journal of Clinical Medicine. 2019 ; Vol. 8, No. 5.
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abstract = "Aicardi-Gouti{\`e}res 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.",
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T1 - Molecular Genetics and Interferon Signature in the Italian Aicardi Goutières Syndrome Cohort

T2 - Report of 12 New Cases and Literature Review

AU - Garau, Jessica

AU - Cavallera, Vanessa

AU - Valente, Marialuisa

AU - Tonduti, Davide

AU - Sproviero, Daisy

AU - Zucca, Susanna

AU - Battaglia, Domenica

AU - Battini, Roberta

AU - Bertini, Enrico

AU - Cappanera, Silvia

AU - Chiapparini, Luisa

AU - Crasà, Camilla

AU - Crichiutti, Giovanni

AU - Dalla Giustina, Elvio

AU - D'Arrigo, Stefano

AU - De Giorgis, Valentina

AU - De Simone, Micaela

AU - Galli, Jessica

AU - La Piana, Roberta

AU - Messana, Tullio

AU - Moroni, Isabella

AU - Nardocci, Nardo

AU - Panteghini, Celeste

AU - Parazzini, Cecilia

AU - Pichiecchio, Anna

AU - Pini, Antonella

AU - Ricci, Federica

AU - Saletti, Veronica

AU - Salvatici, Elisabetta

AU - Santorelli, Filippo M

AU - Sartori, Stefano

AU - Tinelli, Francesca

AU - Uggetti, Carla

AU - Veneselli, Edvige

AU - Zorzi, Giovanna

AU - Garavaglia, Barbara

AU - Fazzi, Elisa

AU - Orcesi, Simona

AU - Cereda, Cristina

PY - 2019/5/26

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N2 - 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.

AB - 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.

U2 - 10.3390/jcm8050750

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M3 - Article

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VL - 8

JO - Journal of Clinical Medicine

JF - Journal of Clinical Medicine

SN - 2077-0383

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