Barbara Ogórek1, Lana Hamieh1, Hanna M Hulshof2, Kathryn Lasseter1, Katarzyna Klonowska1, Hugo Kuijf3, Romina Moavero4,5, Christoph Hertzberg6, Bernhard Weschke7, Kate Riney8, Martha Feucht9, Theresa Scholl9, Pavel Krsek10, Rima Nabbout11, Anna C Jansen12, Barbora Benova10, Eleonora Aronica13,14, Lieven Lagae15, Paolo Curatolo4, Julita Borkowska16, Krzysztof Sadowski16, Dorota Domańska-Pakieła16, Stef Janson17, Piotr Kozlowski18, Malgorzata Urbanska16, Jacek Jaworski19, Sergiusz Jozwiak16,20, Floor E Jansen2, Katarzyna Kotulska16, David J Kwiatkowski21. 1. Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. 2. Department of Child Neurology, Brain Center University Medical Center Utrecht, Utrecht, The Netherlands. 3. Image Sciences Institute, University Medical Center Utrecht, Utrecht, The Netherlands. 4. Child Neurology and Psychiatry Unit, Systems Medicine Department, Tor Vergata University, Rome, Italy. 5. Child Neurology Unit, Neuroscience and Neurorehabilitation Department, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy. 6. Diagnose- und Behandlungszentrum für Kinder, Vivantes-Klinikum Neukölln, Berlin, Germany. 7. Department of Child Neurology, Charité University Medicine Berlin, Berlin, Germany. 8. Neurosciences Unit, Queensland Children's Hospital, South Brisbane, Queensland, Australia/School of Medicine, University of Queensland, St Lucia, Queensland, Australia. 9. Department of Pediatrics and Adolescent Medicine, Medical University of Vienna; "Affiliated Partner of ERN EpiCARE", Vienna, Austria. 10. Motol University Hospital, Charles University, Prague, Czech Republic. 11. Department of Pediatric Neurology, Reference Centre for Rare Epilepsies, Necker-Enfants Malades Hospital, University Paris Descartes, Imagine Institute, Paris, France. 12. Pediatric Neurology Unit, UZ Brussel, Neurogenetics Research Group, Vrije Universiteit Brussel, Brussels, Belgium. 13. Amsterdam UMC, University of Amsterdam, Department of (Neuro)Pathology, Amsterdam Neuroscience, Amsterdam, The Netherlands. 14. Stichting Epilepsie Instellingen Nederland (SEIN), Heemstede the Netherlands, Utrecht, The Netherlands. 15. Department of Development and Regeneration Section Pediatric Neurology, University Hospitals KU Leuven, Leuven, Belgium. 16. Department of Neurology and Epileptology, The Children's Memorial Health Institute, Warsaw, Poland. 17. GenomeScan, Leiden, The Netherlands. 18. Department of Molecular Genetics, Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan, Poland. 19. International Institute of Molecular and Cell Biology, Warsaw, Poland. 20. Department of Child Neurology, Medical University of Warsaw, Warsaw, Poland. 21. Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. dk@rics.bwh.harvard.edu.
Abstract
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.
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.
Authors: Katarzyna Klonowska; Joannes M Grevelink; Krinio Giannikou; Barbara A Ogorek; Zachary T Herbert; Aaron R Thorner; Thomas N Darling; Joel Moss; David J Kwiatkowski Journal: J Clin Invest Date: 2022-05-16 Impact factor: 19.456
Authors: Mark F Bennett; Michael S Hildebrand; Sayaka Kayumi; Mark A Corbett; Sachin Gupta; Zimeng Ye; Michael Krivanek; Rosemary Burgess; Olivia J Henry; John A Damiano; Amber Boys; Jozef Gécz; Melanie Bahlo; Ingrid E Scheffer; Samuel F Berkovic Journal: Neurol Genet Date: 2022-01-25
Authors: Jessie De Ridder; Mario Lavanga; Birgit Verhelle; Jan Vervisch; Katrien Lemmens; Katarzyna Kotulska; Romina Moavero; Paolo Curatolo; Bernhard Weschke; Kate Riney; Martha Feucht; Pavel Krsek; Rima Nabbout; Anna C Jansen; Konrad Wojdan; Dorota Domanska-Pakieła; Magdalena Kaczorowska-Frontczak; Christoph Hertzberg; Cyrille H Ferrier; Sharon Samueli; Barbora Benova; Eleonora Aronica; David J Kwiatkowski; Floor E Jansen; Sergiusz Jóźwiak; Sabine Van Huffel; Lieven Lagae Journal: Front Neurol Date: 2020-10-16 Impact factor: 4.003