Tariq Zaman1, Katherine L Helbig1,2, Jérôme Clatot1,2, Christopher H Thompson3, Seok Kyu Kang3, Katrien Stouffs4, Anna E Jansen5,6, Lieve Verstraete7, Adeline Jacquinet8, Elena Parrini9, Renzo Guerrini9, Yuh Fujiwara10, Satoko Miyatake11, Bruria Ben-Zeev12,13, Haim Bassan13,14, Orit Reish13,15, Daphna Marom13,15, Natalie Hauser16, Thuy-Anh Vu17, Sally Ackermann18, Careni E Spencer19, Natalie Lippa20, Shraddha Srinivasan21, Agnieszka Charzewska22, Dorota Hoffman-Zacharska22, David Fitzpatrick23, Victoria Harrison24, Pradeep Vasudevan25, Shelagh Joss26, Daniela T Pilz26,27, Katherine A Fawcett28, Ingo Helbig1,2,29,30, Naomichi Matsumoto11, Jennifer A Kearney3, Andrew E Fry27,31, Ethan M Goldberg1,2,29,32. 1. Division of Neurology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA. 2. Epilepsy NeuroGenetics Initiative, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA. 3. Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA. 4. Center for Medical Genetics/Research Center for Reproduction and Genetics, University Hospital Brussels, Free University of Brussels, Brussels, Belgium. 5. Pediatric Neurology Unit, Department of Pediatrics, University Hospital Brussels, Brussels, Belgium. 6. Neurogenetics Research Group, Free University of Brussels, Brussels, Belgium. 7. Child Neurology, Heilig Hart Hospital Lier, Lier, Belgium. 8. Human Genetics Service, Sart Tilman University Hospital Center, Liege, Belgium. 9. Pediatric Neurology, Neurogenetics, and Neurobiology Unit and Laboratories, Department of Neuroscience, A. Meyer Children's Hospital, University of Florence, Florence, Italy. 10. Department of Pediatrics, Yokohama City University Medical Center, Yokohama, Japan. 11. Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan. 12. Pediatric Neurology Unit, Edmond and Lili Safra Children's Hospital, Haim Sheba Medical Center, Ramat Gan, Israel. 13. Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. 14. Pediatric Neurology & Development Center, Shamir Medical Center (Assaf Harofe), Zerifin, Israel. 15. Genetics Institute, Shamir Medical Center (Assaf Harofe) Zerifin, Zerifin, Israel. 16. Inova Translational Medicine Institute, Inova Health System, Fairfax, Virginia, USA. 17. Department of Pediatric Neurology, Children's National Medical Center, Washington, District of Columbia, and Pediatric Specialists of Virginia, Fairfax, Virginia, USA. 18. Division of Paediatric Neurology, Department of Paediatrics and Child Health, Red Cross War Memorial Children's Hospital, University of Cape Town, Cape Town, South Africa. 19. Division of Human Genetics, Department of Medicine, University of Cape Town, South Africa and Groote Schuur Hospital, Cape Town, South Africa. 20. Institute for Genomic Medicine, Columbia University Medical Center, New York, New York, USA. 21. Department of Neurology, Columbia University Medical Center, New York, New York, USA. 22. Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland. 23. Medical Research Council Human Genetics Unit, Medical Research Council Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom. 24. Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, United Kingdom. 25. Department of Clinical Genetics, University Hospitals Leicester National Health Service Trust, Leicester, United Kingdom. 26. West of Scotland Clinical Genetics Service, Queen Elizabeth University Hospital, Glasgow, United Kingdom. 27. Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, United Kingdom. 28. Medical Research Council (MRC) Computational Genomics Analysis and Training Programme, MRC Centre for Computational Biology, MRC Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, United Kingdom. 29. Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. 30. Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA. 31. Institute of Medical Genetics, University Hospital of Wales, Cardiff, United Kingdom. 32. Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Abstract
OBJECTIVE: Pathogenic variants in SCN3A, encoding the voltage-gated sodium channel subunit Nav1.3, cause severe childhood onset epilepsy and malformation of cortical development. Here, we define the spectrum of clinical, genetic, and neuroimaging features of SCN3A-related neurodevelopmental disorder. METHODS: Patients were ascertained via an international collaborative network. We compared sodium channels containing wild-type versus variant Nav1.3 subunits coexpressed with β1 and β2 subunits using whole-cell voltage clamp electrophysiological recordings in a heterologous mammalian system (HEK-293T cells). RESULTS: Of 22 patients with pathogenic SCN3A variants, most had treatment-resistant epilepsy beginning in the first year of life (16/21, 76%; median onset, 2 weeks), with severe or profound developmental delay (15/20, 75%). Many, but not all (15/19, 79%), exhibited malformations of cortical development. Pathogenic variants clustered in transmembrane segments 4 to 6 of domains II to IV. Most pathogenic missense variants tested (10/11, 91%) displayed gain of channel function, with increased persistent current and/or a leftward shift in the voltage dependence of activation, and all variants associated with malformation of cortical development exhibited gain of channel function. One variant (p.Ile1468Arg) exhibited mixed effects, with gain and partial loss of function. Two variants demonstrated loss of channel function. INTERPRETATION: Our study defines SCN3A-related neurodevelopmental disorder along a spectrum of severity, but typically including epilepsy and severe or profound developmental delay/intellectual disability. Malformations of cortical development are a characteristic feature of this unusual channelopathy syndrome, present in >75% of affected individuals. Gain of function at the channel level in developing neurons is likely an important mechanism of disease pathogenesis. ANN NEUROL 2020;88:348-362.
OBJECTIVE: Pathogenic variants in SCN3A, encoding the voltage-gated sodium channel subunit Nav1.3, cause severe childhood onset epilepsy and malformation of cortical development. Here, we define the spectrum of clinical, genetic, and neuroimaging features of SCN3A-related neurodevelopmental disorder. METHODS: Patients were ascertained via an international collaborative network. We compared sodium channels containing wild-type versus variant Nav1.3 subunits coexpressed with β1 and β2 subunits using whole-cell voltage clamp electrophysiological recordings in a heterologous mammalian system (HEK-293T cells). RESULTS: Of 22 patients with pathogenic SCN3A variants, most had treatment-resistant epilepsy beginning in the first year of life (16/21, 76%; median onset, 2 weeks), with severe or profound developmental delay (15/20, 75%). Many, but not all (15/19, 79%), exhibited malformations of cortical development. Pathogenic variants clustered in transmembrane segments 4 to 6 of domains II to IV. Most pathogenic missense variants tested (10/11, 91%) displayed gain of channel function, with increased persistent current and/or a leftward shift in the voltage dependence of activation, and all variants associated with malformation of cortical development exhibited gain of channel function. One variant (p.Ile1468Arg) exhibited mixed effects, with gain and partial loss of function. Two variants demonstrated loss of channel function. INTERPRETATION: Our study defines SCN3A-related neurodevelopmental disorder along a spectrum of severity, but typically including epilepsy and severe or profound developmental delay/intellectual disability. Malformations of cortical development are a characteristic feature of this unusual channelopathy syndrome, present in >75% of affected individuals. Gain of function at the channel level in developing neurons is likely an important mechanism of disease pathogenesis. ANN NEUROL 2020;88:348-362.
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