Emilia Cirillo ¹ Antonietta Tarallo ^1,2 Elisabetta Toriello ¹ Annamaria Carissimo ³ Giuliana Giardino ⁴ Antonio De Rosa ⁴ Carla Damiano ^2,5 Annarosa Soresina ⁶ Raffaele Badolato ⁶ Rosa Maria Dellepiane ⁷ Lucia A. Baselli ⁷ Maria Carrabba ⁸ Giovanna Fabio ⁸ Patrizia Bertolini ⁹ Davide Montin ¹⁰ Francesca Conti ¹¹ Roberta Romano ¹ Elisa Pozzi ¹² Giulio Ferrero ¹³ ROBERTA RONCARATI ¹⁴ Manuela Ferracin ¹⁵ Alfredo Brusco ^16,17 Giancarlo Parenti ^1,2 Claudio Pignata ^4*

• ¹ Department of Translational Medical Sciences, School of Medicine and Surgery, University of Naples Federico II, Naples, Campania, Italy
• ² Telethon Institute of Genetics and Medicine (TIGEM), Naples, Campania, Italy
• ³ Institute for Calculation Applications Mauro Picone, Department of Engineering, ICT and Technology for Energy and Transport, National Research Council (CNR), Rome, Lazio, Italy
• ⁴ Department of Translational Medical Sciences, Pediatric Section, Federico II University of Naples, Naples, Italy
• ⁵ Department of Pediatrics, University of Naples Federico II, Naples, Italy
• ⁶ Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Lombardy, Italy
• ⁷ Pediatric Area, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
• ⁸ Department of Internal Medicine, IRCCS Ca 'Granda Foundation Maggiore Policlinico Hospital, Milan, Lombardy, Italy
• ⁹ Department of Pediatric Oncohematology, University Hospital of Parma, Parma, Emilia-Romagna, Italy
• ¹⁰ Department of Public Health and Pediatric Sciences, School of Medicine, University of Turin, Turin, Piedmont, Italy
• ¹¹ Pediatric Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
• ¹² Centro Regionale di Biologia Molecolare – Arpa Piemonte, Torino, Italy
• ¹³ Department of Clinical and Biological Sciences, School of Medicine, University of Turin, Turin, Piedmont, Italy
• ¹⁴ Istituto di Genetica Molecolare - Consiglio Nazionale delle Ricerche (CNR), Bologna, Italy
• ¹⁵ Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
• ¹⁶ Department of Neuroscience Rita Levi Montalcini, University of Turin, Turin, Piedmont, Italy
• ¹⁷ Unità di Genetica Medica, AOU Città della Salute e della Scienza di Torino, Torino, Italy

Introduction: Ataxia Telangiectasia (AT) is a rare disorder characterized by neurodegeneration, combined immunodeficiency, a predisposition to malignancies and high clinical variability. Profiling of microRNAs (miRNAs) may offer insights into the underlying mechanisms of complex rare human diseases, as miRNA play a role in various biological functions including proliferation, differentiation, and DNA repair. In this study we investigate the differential expression of miRNAs in samples from AT patients with the aim of identifying miRNA patterns and to investigate how these patterns are related to the disease.We enrolled twenty AT patients (mean age 17.7+9.6 years old) and collected clinical and genetic data. We performed short non-coding RNA-seq analysis on peripheral blood mononuclear cells (PBMCs) and fibroblasts to compare the miRNA expression profile between AT patients and controls.We observed 42 differentially expressed (DE)-miRNAs in blood samples and 26 in fibroblasts samples. Among these, three were further validated in additional AT samples, confirming their dysregulation.We identified an AT-related miRNA signature in blood cells and fibroblast samples collected from a group of AT patients. We also predicted several dysregulated pathways, primarily related to cancer, immune system control or inflammatory processes. The findings suggest that miRNAs may provide insights into the pathophysiology and tumorigenesis of AT and have the potential to serve as useful biomarkers in cancer research.