Dr. Jessica Garau is a postdoctoral researcher at IRCCS Mondino Foundation in Pavia, Italy. She has been working on Aicardi-Goutières Syndrome since 2015, first as an undergraduate and then as a PhD student. After obtaining a PhD in Biomedical Sciences in 2020, Dr Garau is now a researcher committed to genetic and molecular characterization of rare genetic neurological diseases.
Dr. Jessica Garau discussed her work with AGS.
Dr. Garau will spend the second half of 2022 exploring potential causes of the high degree of variability in AGS as awardee of our Rare Researcher ECR Grant (project title and summary provided below). Many families are aware that AGS can present with varying degrees of severity and symptoms, even between siblings that share the same AGS causing mutations. Using AGS patient samples and data already available at the Mondino Foundation, Dr. Garau will take a careful look at the genomes and gene expression profiles of AGS individuals that share identical RNASEH2B mutations in an effort to pinpoint additional genes or variations that contribute to the development of mild vs severe outcomes. Regardless of her findings, this important work will provide insights into the factors that give rise to AGS and help guide our efforts to anticipate needs and identify targets for new therapies. The AGSAA will hold an event towards the end of 2022, inviting Dr. Garau and our community to discuss her project and work. We wish her good luck and good science!
Transcriptome and Exome analysis of RNASEH2B patients with heterogeneous phenotypes
PI Name: Dr. Jessica Garau, PhD
Abstract/Summary of Project
Aicardi-Goutières syndrome (AGS) is a rare early-onset genetic neuroinflammatory disorder following recessive or dominant inheritance. AGS patients exhibit symptoms including acquired or congenital microcephaly, cerebral calcification, white matter abnormalities, and cerebral atrophy from birth or develop them within their first year of life. To date, mutations in nine genes have been discovered as pathogenic, all of which encode for proteins involved in nucleic acid-sensing and/or metabolism. AGS- associated mutations in these genes result in an accumulation of endogenous DNA, RNA:DNA hybrids, and/or double-stranded RNA (dsRNA) that are recognized as “foreign” and trigger type I interferon- mediated immune responses, analogous to anti-viral responses and led to classification as “primary type I interferonopathies”. Though defined by identical disease-causing mutations, clinical presentations of AGS patients can vary significantly, even within families. Thus, additional modifying molecular pathomechanisms are likely, including the coexistence of additional genomic variants or altered expression of coding and non-coding RNAs. However, scientific evidence for these hypotheses is currently lacking. In the study proposed, we aim to define molecular modifiers of disease in AGS patients with the p.A177T mutation in RNASEH2B, the most common variant seen in our group, but with different phenotypes (mild and severe). Molecular targets include: 1) Analysis of coding and non-coding RNAs by RNA-Seq or RT-qPCR 2) Analysis of patients’ exomes to identify possible digenic variants