PURPOSE: To perform comprehensive genotyping of TSC1 and TSC2 in a cohort of 94 infants with tuberous sclerosis complex (TSC) and correlate with clinical manifestations. METHODS: Infants were enrolled at age <4 months, and subject to intensive clinical monitoring including electroencephalography (EEG), brain magnetic resonance imaging (MRI), and neuropsychological assessment. Targeted massively parallel sequencing (MPS), genome sequencing, and multiplex ligation-dependent probe amplification (MLPA) were used for variant detection in TSC1/TSC2. RESULTS: Pathogenic variants in TSC1 or TSC2 were identified in 93 of 94 (99%) subjects, with 23 in TSC1 and 70 in TSC2. Nine (10%) subjects had mosaicism. Eight of 24 clinical features assessed at age 2 years were significantly less frequent in those with TSC1 versus TSC2 variants including cortical tubers, hypomelanotic macules, facial angiofibroma, renal cysts, drug-resistant epilepsy, developmental delay, subependymal giant cell astrocytoma, and median seizure-free survival. Additionally, quantitative brain MRI analysis showed a marked difference in tuber and subependymal nodule/giant cell astrocytoma volume for TSC1 versus TSC2. CONCLUSION: TSC2 pathogenic variants are associated with a more severe clinical phenotype than mosaic TSC2 or TSC1 variants in TSC infants. Early assessment of gene variant status and mosaicism might have benefit for clinical management in infants and young children with TSC.

Amsterdam UMC University of Amsterdam Department of Pathology Amsterdam Neuroscience Amsterdam The Netherlands

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

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

Department of Child Neurology Brain Center University Medical Center Utrecht Utrecht The Netherlands

Department of Child Neurology Charité University Medicine Berlin Berlin Germany

Department of Child Neurology Medical University of Warsaw Warsaw Poland

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

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

Department of Molecular Genetics Institute of Bioorganic Chemistry Polish Academy of Sciences Poznan Poland

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

Department of Pediatric Neurology Reference Centre for Rare Epilepsies Necker Enfants Malades Hospital University Paris Descartes Imagine Institute Paris France

Department of Pediatrics and Adolescent Medicine Medical University of Vienna; Affiliated Partner of ERN EpiCARE Vienna Austria

Diagnose und Behandlungszentrum für Kinder Vivantes Klinikum Neukölln Berlin Germany

GenomeScan Leiden The Netherlands

Image Sciences Institute University Medical Center Utrecht Utrecht The Netherlands

International Institute of Molecular and Cell Biology Warsaw Poland

Motol University Hospital Charles University Prague Czech Republic

Neurosciences Unit Queensland Children's Hospital South Brisbane Queensland Australia School of Medicine University of Queensland St Lucia Queensland Australia

Pediatric Neurology Unit UZ Brussel Neurogenetics Research Group Vrije Universiteit Brussel Brussels Belgium

Stichting Epilepsie Instellingen Nederland Heemstede the Netherlands Utrecht The Netherlands

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