Tuberous sclerosis complex (TSC) is a rare multi-system genetic disorder characterized by a high incidence of epilepsy and neuropsychiatric manifestations known as tuberous-sclerosis-associated neuropsychiatric disorders (TANDs), including autism spectrum disorder (ASD) and intellectual disability (ID). MicroRNAs (miRNAs) are small regulatory non-coding RNAs that regulate the expression of more than 60% of all protein-coding genes in humans and have been reported to be dysregulated in several diseases, including TSC. In the current study, RNA sequencing analysis was performed to define the miRNA and isoform (isomiR) expression patterns in serum. A Receiver Operating Characteristic (ROC) curve analysis was used to identify circulating molecular biomarkers, miRNAs, and isomiRs, able to discriminate the development of neuropsychiatric comorbidity, either ASD, ID, or ASD + ID, in patients with TSC. Part of our bioinformatics predictions was verified with RT-qPCR performed on RNA isolated from patients' serum. Our results support the notion that circulating miRNAs and isomiRs have the potential to aid standard clinical testing in the early risk assessment of ASD and ID development in TSC patients.

Chalfont Centre for Epilepsy Chalfont St Peter SL9 0RJ UK

Child Neurology and Psychiatry Unit Systems Medicine Department Tor Vergata University 00133 Rome Italy

Child Neurology Unit Neuroscience Department Bambino Gesù Children's Hospital IRCCS 00165 Rome Italy

Department of Child Neurology Brain Center University Medical Center Member of ERN EpiCare 3584 BA Utrecht The Netherlands

Department of Child Neurology Medical University of Warsaw 02 097 Warsaw Poland

Department of Clinical and Experimental Epilepsy UCL Queen Square Institute of Neurology London WC1E 6BT UK

Department of Development and Regeneration Section Pediatric Neurology University Hospitals KU Leuven 3000 Leuven Belgium

Department of Experimental Medicine Sapienza University of Rome 00161 Rome Italy

Department of Medicine Brigham and Women's Hospital Boston MA 02115 USA

Department of Neurology and Epileptology The Children's Memorial Health Institute 04 730 Warsaw Poland

Department of Neuropediatrics Charité University Medicine Berlin 13353 Berlin Germany

Department of Pathology Amsterdam Neuroscience Amsterdam UMC Location University of Amsterdam Meibergdreef 9 1105 AZ Amsterdam The Netherlands

Department of Pediatrics and Adolescent Medicine Medical University of Vienna Member of ERN EpiCARE 1090 Vienna Austria

Department of Translational Neurosciences University of Antwerp 2000 Antwerp Belgium

Diagnose und Behandlungszentrum für Kinder Vivantes Klinikum Neukölln 12351 Berlin Germany

Faculty of Medicine The University of Queensland Herston QLD 4029 Australia

Internal Medicine Erasmus MC 3015 GD Rotterdam The Netherlands

International Institute of Molecular and Cell Biology 02 109 Warsaw Poland

Motol University Hospital Charles University 15000 Prague Czech Republic

Neurosciences Unit Queensland Children's Hospital South Brisbane QLD 4101 Australia

Reference Centre for Rare Epilepsies Department of Pediatric Neurology Necker Enfants Malades University Hospital APHP Member of ERN EpiCARE Université de Paris 149 Rue de Sèvres 75015 Paris France

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