Project 2: Improved Presymptomatic Diagnosis in Aicardi Goutieres Syndrome

Summary/Abstract for Project 2: Improved Presymptomatic Diagnosis in Aicardi Goutières Syndrome Aicardi Goutières Syndrome (AGS) is an inborn error in RNA and DNA metabolism resulting in an early-onset (neonatal or in first two years of life) leukodystrophy with extensive multisystemic disease and severe morbidity. Off-label use of bariciticib, a janus kinase inhibitor, is now considered standard of care in this disorder. There is a common prodromal period of systemic symptoms, although the diagnosis is typically made after neurologic regression. This results in delayed treatment and irreversible neurologic injury. Thus, there is an urgent, unmet need for newborn screening (NBS) to support early diagnosis and intervention to improve outcomes for children affected by AGS. We propose to define novel analytic approaches to detect IFN related proteins and identify the most sensitive and specific interferon signaling genes in retrospectively collected natal NBS cards from AGS patients. Aim 1 will establish immunoassay approaches for IFN-related protein detection as a NBS biomarker in AGS. Using AGS and control NBS card punches, we will perform iterative testing of 10 candidate antigens using commercially available ELISA antibodies. The antigen with the best sensitivity and specificity will then be developed into a first-tier newborn screening of AGS. Aim 2 will resolve elevation patterns of IFN-related genes in AGS NBS as a second tier screen. We already have extensive published experience in ISG use in post-natal AGS samples and the primary goal of this aim is to assess the appropriate cut-off points and genes of interest in a NBS sample. This will be done by evaluating ISG scores and mRNA profiles of at least 48 IFN response genes. Aim 3 will pilot the use of a two-tiered IFN protein/gene expression assay in a retrospective newborn cohort. This will entail 50,000 existing deidentified newborn screening blood spots as well as blinded positive controls undergoing the testing procedures as outlined in aims 1 and 2 as well as genetic testing. We anticipate that these aims will define the diagnostic workflow for AGS in the context of newborn screening: IFN-related protein measurement by immunoassay, then IFN-related RNA measurement via nanoString®, followed by genetic confirmation.