Chiara Klöckner1, Heinrich Sticht2, Pia Zacher3, Bernt Popp1, Holly E Babcock4, Dewi P Bakker5, Katy Barwick6, Michaela V Bonfert7, Carsten G Bönnemann8, Eva H Brilstra9, Wendy K Chung10, Angus J Clarke11, Patrick Devine12, Sandra Donkervoort8, Jamie L Fraser13, Jennifer Friedman14,15, Alyssa Gates16, Jamal Ghoumid17, Emma Hobson18, Gabriella Horvath19, Jennifer Keller-Ramey20, Boris Keren21, Manju A Kurian6, Virgina Lee22, Kathleen A Leppig16, Johan Lundgren23, Marie T McDonald24, Heather M McLaughlin25, Amy McTague6, Heather C Mefford26, Cyril Mignot27, Mohamad A Mikati28, Caroline Nava29, F Lucy Raymond30,31, Julian R Sampson11, Alba Sanchis-Juan30,32, Vandana Shashi24, Joseph T C Shieh33,34, Marwan Shinawi35, Anne Slavotinek33, Tommy Stödberg36, Nicholas Stong37, Jennifer A Sullivan24, Ashley C Taylor38, Tomi L Toler35, Marie-José van den Boogaard9, Saskia N van der Crabben39, Koen L I van Gassen9, Richard H van Jaarsveld9, Jessica Van Ziffle12, Alexandrea F Wadley40, Matias Wagner41, Kristen Wigby42, Saskia B Wortmann43,44, Yuri A Zarate45, Rikke S Møller46,47, Johannes R Lemke1, Konrad Platzer48. 1. Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany. 2. Institute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany. 3. The Saxon Epilepsy Center Kleinwachau, Radeberg, Germany. 4. Rare Disease Institute, Children's National Hospital, Washington, DC, USA. 5. Department of Child Neurology, Amsterdam University Medical Centers, Amsterdam, The Netherlands. 6. Institute of Child Health, University Collge London, London, UK. 7. Department of Pediatric Neurology and Developmental Medicine and LMU Center for Children with Medical Complexity, Dr. von Hauner Children's Hospital, LMU - University Hospital, Ludwig-Maximilians-Universität, Munich, Germany. 8. Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA. 9. Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands. 10. Departments of Pediatrics and Medicine, Columbia University Medical Center, New York, NY, USA. 11. Division of Cancer & Genetics, School of Medicine, Cardiff University, Wales, UK. 12. Department of Pathology, University of California San Francisco, San Francisco, CA, USA. 13. Rare Disease Institute, Division of Genetics and Metabolism, Children's National Hospital, Washington, DC, USA. 14. Departments of Neurosciences and Pediatrics, University of California San Diego and Division of Neurology, Rady Children's Hospital, San Diego, CA, USA. 15. Rady Children's Institute for Genomic Medicine, San Diego, CA, USA. 16. Department of Genetic Services, Kaiser Permanente Washington, Seattle, WA, USA. 17. Service de Génétique Clinique, Hôpital Jeanne de Flandre, CHU Lille, Lille, France. 18. Yorkshire Clinical Genetics Service, Chapel Allerton Hospital, Leeds, UK. 19. Department of Pediatrics, Division of Biochemical Diseases, University of British Columbia, Vancouver, Canada. 20. GeneDx, Gaithersburg, MD, USA. 21. APHP, Département de Génétique, Groupe Hospitalier Pitié Salpêtrière, Paris, France. 22. Department of Neurology, University of California San Francisco, San Francisco, CA, USA. 23. Institute of Clinical Sciences, Skane University Hospital, Lund, Sweden. 24. Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA. 25. Invitae Corporation, San Francisco, CA, USA. 26. Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA, USA. 27. Département de Génétique, Centre de Référence Déficiences Intellectuelles de Causes Rares, Groupe Hospitalier Pitié Salpêtrière et Hôpital Trousseau, APHP, Sorbonne Université, Paris, France. 28. Division of Pediatric Neurology, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA. 29. Sorbonne University, Paris Brain Institute, Inserm U1127, CNRS UMR 7225, AP-HP, Pitié Salpêtrière Hospital, Department of Genetics, Paris, France. 30. NIHR BioResource, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK. 31. Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK. 32. Department of Haematology, University of Cambridge, NHS Blood and Transplant Centre, Cambridge, UK. 33. Division of Medical Genetics, University of California, San Francisco, San Francisco, CA, USA. 34. Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA. 35. Department of Pediatrics, Division of Genetics and Genomic Medicine, Washington University School of Medicine, St. Louis, MO, USA. 36. Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden. 37. Institute for Genomic Medicine, Columbia University, New York, NY, USA. 38. Section of Genetics, Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. 39. Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands. 40. University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. 41. Institute of Neurogenomics, Helmholtz Zentrum Munich, Neuherberg, Germany. 42. Department of Pediatrics, Division of Genetics, University of California, San Diego and Rady Children's Hospital-San Diego, San Diego, CA, USA. 43. Amalia Children's Hospital, Radboud University Nijmegen, Nijmegen, The Netherlands. 44. University Childrens Hospital, Paracelsus Medical University, Salzburg, Austria. 45. Section of Genetics and Metabolism, Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, USA. 46. Institute for Regional Health Services, University of Southern Denmark, Odense, Denmark. 47. Department of Epilepsy Genetics and Personalized Medicine, Danish Epilepsy Centre Filadelfia, Dianalund, Denmark. 48. Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany. konrad.platzer@medizin.uni-leipzig.de.
Abstract
PURPOSE: This study aims to provide a comprehensive description of the phenotypic and genotypic spectrum of SNAP25 developmental and epileptic encephalopathy (SNAP25-DEE) by reviewing newly identified and previously reported individuals. METHODS: Individuals harboring heterozygous missense or loss-of-function variants in SNAP25 were assembled through collaboration with international colleagues, matchmaking platforms, and literature review. For each individual, detailed phenotyping, classification, and structural modeling of the identified variant were performed. RESULTS: The cohort comprises 23 individuals with pathogenic or likely pathogenic de novo variants in SNAP25. Intellectual disability and early-onset epilepsy were identified as the core symptoms of SNAP25-DEE, with recurrent findings of movement disorders, cerebral visual impairment, and brain atrophy. Structural modeling for all variants predicted possible functional defects concerning SNAP25 or impaired interaction with other components of the SNARE complex. CONCLUSION: We provide a comprehensive description of SNAP25-DEE with intellectual disability and early-onset epilepsy mostly occurring before the age of two years. These core symptoms and additional recurrent phenotypes show an overlap to genes encoding other components or associated proteins of the SNARE complex such as STX1B, STXBP1, or VAMP2. Thus, these findings advance the concept of a group of neurodevelopmental disorders that may be termed "SNAREopathies."
PURPOSE: This study aims to provide a comprehensive description of the phenotypic and genotypic spectrum of SNAP25 developmental and epileptic encephalopathy (SNAP25-DEE) by reviewing newly identified and previously reported individuals. METHODS: Individuals harboring heterozygous missense or loss-of-function variants in SNAP25 were assembled through collaboration with international colleagues, matchmaking platforms, and literature review. For each individual, detailed phenotyping, classification, and structural modeling of the identified variant were performed. RESULTS: The cohort comprises 23 individuals with pathogenic or likely pathogenic de novo variants in SNAP25. Intellectual disability and early-onset epilepsy were identified as the core symptoms of SNAP25-DEE, with recurrent findings of movement disorders, cerebral visual impairment, and brain atrophy. Structural modeling for all variants predicted possible functional defects concerning SNAP25 or impaired interaction with other components of the SNARE complex. CONCLUSION: We provide a comprehensive description of SNAP25-DEE with intellectual disability and early-onset epilepsy mostly occurring before the age of two years. These core symptoms and additional recurrent phenotypes show an overlap to genes encoding other components or associated proteins of the SNARE complex such as STX1B, STXBP1, or VAMP2. Thus, these findings advance the concept of a group of neurodevelopmental disorders that may be termed "SNAREopathies."
Authors: Julian Schubert; Aleksandra Siekierska; Mélanie Langlois; Patrick May; Clément Huneau; Felicitas Becker; Hiltrud Muhle; Arvid Suls; Johannes R Lemke; Carolien G F de Kovel; Holger Thiele; Kathryn Konrad; Amit Kawalia; Mohammad R Toliat; Thomas Sander; Franz Rüschendorf; Almuth Caliebe; Inga Nagel; Bernard Kohl; Angela Kecskés; Maxime Jacmin; Katia Hardies; Sarah Weckhuysen; Erik Riesch; Thomas Dorn; Eva H Brilstra; Stephanie Baulac; Rikke S Møller; Helle Hjalgrim; Bobby P C Koeleman; Karin Jurkat-Rott; Frank Lehman-Horn; Jared C Roach; Gustavo Glusman; Leroy Hood; David J Galas; Benoit Martin; Peter A M de Witte; Saskia Biskup; Peter De Jonghe; Ingo Helbig; Rudi Balling; Peter Nürnberg; Alexander D Crawford; Camila V Esguerra; Yvonne G Weber; Holger Lerche Journal: Nat Genet Date: 2014-11-02 Impact factor: 38.330
Authors: Vincenzo Salpietro; Nancy T Malintan; Isabel Llano-Rivas; Christine G Spaeth; Stephanie Efthymiou; Pasquale Striano; Jana Vandrovcova; Maria C Cutrupi; Roberto Chimenz; Emanuele David; Gabriella Di Rosa; Anna Marce-Grau; Miquel Raspall-Chaure; Elena Martin-Hernandez; Federico Zara; Carlo Minetti; Oscar D Bello; Rita De Zorzi; Sara Fortuna; Andrew Dauber; Mariam Alkhawaja; Tipu Sultan; Kshitij Mankad; Antonio Vitobello; Quentin Thomas; Frederic Tran Mau-Them; Laurence Faivre; Francisco Martinez-Azorin; Carlos E Prada; Alfons Macaya; Dimitri M Kullmann; James E Rothman; Shyam S Krishnakumar; Henry Houlden Journal: Am J Hum Genet Date: 2019-03-28 Impact factor: 11.025
Authors: Eliyahu Perl; Padmapriyadarshini Ravisankar; Manu E Beerens; Lejla Mulahasanovic; Kelly Smallwood; Marion Bermúdez Sasso; Carina Wenzel; Thomas D Ryan; Matej Komár; Kevin E Bove; Calum A MacRae; K Nicole Weaver; Carlos E Prada; Joshua S Waxman Journal: HGG Adv Date: 2022-04-27
Authors: Giulia Spoto; Giulia Valentini; Maria Concetta Saia; Ambra Butera; Greta Amore; Vincenzo Salpietro; Antonio Gennaro Nicotera; Gabriella Di Rosa Journal: Front Neurol Date: 2022-03-08 Impact factor: 4.003
Authors: Julie Xian; Shridhar Parthasarathy; Sarah M Ruggiero; Ganna Balagura; Eryn Fitch; Katherine Helbig; Jing Gan; Shiva Ganesan; Michael C Kaufman; Colin A Ellis; David Lewis-Smith; Peter Galer; Kristin Cunningham; Margaret O'Brien; Mahgenn Cosico; Kate Baker; Alejandra Darling; Fernanda Veiga de Goes; Christelle M El Achkar; Jan Henje Doering; Francesca Furia; Ángeles García-Cazorla; Elena Gardella; Lisa Geertjens; Courtney Klein; Anna Kolesnik-Taylor; Hanna Lammertse; Jeehun Lee; Alexandra Mackie; Mala Misra-Isrie; Heather Olson; Emma Sexton; Beth Sheidley; Lacey Smith; Luiza Sotero; Hannah Stamberger; Steffen Syrbe; Kim Marie Thalwitzer; Annemiek van Berkel; Mieke van Haelst; Christopher Yuskaitis; Sarah Weckhuysen; Ben Prosser; Charlene Son Rigby; Scott Demarest; Samuel Pierce; Yuehua Zhang; Rikke S Møller; Hilgo Bruining; Annapurna Poduri; Federico Zara; Matthijs Verhage; Pasquale Striano; Ingo Helbig Journal: Brain Date: 2022-06-03 Impact factor: 15.255