Eric Lee1, Trang Le1, Ying Zhu1,2, George Elakis1, Anne Turner3, William Lo1, Hanka Venselaar4, Carol-Ann Verrenkamp3, Nicole Snow3, David Mowat3, Edwin Philip Kirk1,3, Rani Sachdev3, Janine Smith5, Natasha Jane Brown6, Mathew Wallis6, Chris Barnett7,8, Fiona McKenzie9, Mary-Louise Freckmann10, Felicity Collins5, Maya Chopra11, Nerine Gregersen12, Ian Hayes12, Sulekha Rajagopalan13, Tiong Yang Tan14,15,16, Zornitza Stark14,15, Ravi Savarirayan14,15,16, Alison Yeung14,15, Lesley Adès5, Michael Gattas17, Kate Gibson18, Michael Gabbett19, David John Amor14,15,16, Wanda Lattanzi20, Simeon Boyd21, Eric Haan7,8, Mark Gianoutsos22, Timothy Chilton Cox23, Michael Francis Buckley1, Tony Roscioli24,25. 1. Genetics Laboratory, NSW Health Pathology East, Sydney, Australia. 2. Newcastle GOLD Service, Hunter Genetics, Waratah, Australia. 3. Centre for Clinical Genetics, Sydney Children's Hospital, Randwick, Australia. 4. Centre for Molecular and Biomolecular Informatics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. 5. The Children's Hospital at Westmead, Sydney, Australia. 6. Department of Clinical Genetics, Austin Health, Melbourne, Australia. 7. South Australian Clinical Genetics Service, SA Pathology, Adelaide, Australia. 8. School of Medicine, The University of Adelaide, Adelaide, Australia. 9. King Edward Memorial Hospital, Perth, Australia. 10. Department of Clinical Genetics, Royal North Shore Hospital, Sydney, Australia. 11. Imagine Institute of Genetic Diseases, Paris, France. 12. Genetic Health Service New Zealand, Auckland, New Zealand. 13. Department of Clinical Genetics, Liverpool Hospital, Sydney, Australia. 14. Victorian Clinical Genetics Services, Melbourne, Australia. 15. Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Australia. 16. Department of Paediatrics, The University of Melbourne, Melbourne, Australia. 17. Brisbane Genetics, Brisbane, Australia. 18. Genetic Health Service New Zealand, Christchurch Hospital, Christchurch, New Zealand. 19. Royal Brisbane & Women's Hospital, Brisbane, Australia. 20. Institute of Anatomy and Cell Biology, Università Cattolica del Sacro Cuore, Rome, Italy. 21. Department of Pediatrics, School of Medicine UC Davis MIND Institute, Sacramento, USA. 22. Craniofacial Unit, Sydney Children's Hospital, Randwick, Australia. 23. Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington, USA. 24. Centre for Clinical Genetics, Sydney Children's Hospital, Randwick, Australia. tony.roscioli@health.nsw.gov.au. 25. Neuroscience Research Australia and Prince.of Wales Clinical School, University of New South Wales, Sydney, Australia. tony.roscioli@health.nsw.gov.au.
Abstract
PURPOSE: The craniosynostoses are characterized by premature fusion of one or more cranial sutures. The relative contribution of previously reported genes to craniosynostosis in large cohorts is unclear. Here we report on the use of a massively parallel sequencing panel in individuals with craniosynostosis without a prior molecular diagnosis. METHODS: A 20-gene panel was designed based on the genes' association with craniosynostosis, and clinically validated through retrospective testing of an Australian and New Zealand cohort of 233 individuals with craniosynostosis in whom previous testing had not identified a causative variant within FGFR1-3 hot-spot regions or the TWIST1 gene. An additional 76 individuals were tested prospectively. RESULTS: Pathogenic or likely pathogenic variants in non-FGFR genes were identified in 43 individuals, with diagnostic yields of 14% and 15% in retrospective and prospective cohorts, respectively. Variants were identified most frequently in TCF12 (N = 22) and EFNB1 (N = 8), typically in individuals with nonsyndromic coronal craniosynostosis or TWIST1-negative clinically suspected Saethre-Chotzen syndrome. Clinically significant variants were also identified in ALX4, EFNA4, ERF, and FGF10. CONCLUSION: These findings support the clinical utility of a massively parallel sequencing panel for craniosynostosis. TCF12 and EFNB1 should be included in genetic testing for nonsyndromic coronal craniosynostosis or clinically suspected Saethre-Chotzen syndrome.
PURPOSE: The craniosynostoses are characterized by premature fusion of one or more cranial sutures. The relative contribution of previously reported genes to craniosynostosis in large cohorts is unclear. Here we report on the use of a massively parallel sequencing panel in individuals with craniosynostosis without a prior molecular diagnosis. METHODS: A 20-gene panel was designed based on the genes' association with craniosynostosis, and clinically validated through retrospective testing of an Australian and New Zealand cohort of 233 individuals with craniosynostosis in whom previous testing had not identified a causative variant within FGFR1-3 hot-spot regions or the TWIST1 gene. An additional 76 individuals were tested prospectively. RESULTS: Pathogenic or likely pathogenic variants in non-FGFR genes were identified in 43 individuals, with diagnostic yields of 14% and 15% in retrospective and prospective cohorts, respectively. Variants were identified most frequently in TCF12 (N = 22) and EFNB1 (N = 8), typically in individuals with nonsyndromic coronal craniosynostosis or TWIST1-negative clinically suspected Saethre-Chotzen syndrome. Clinically significant variants were also identified in ALX4, EFNA4, ERF, and FGF10. CONCLUSION: These findings support the clinical utility of a massively parallel sequencing panel for craniosynostosis. TCF12 and EFNB1 should be included in genetic testing for nonsyndromic coronal craniosynostosis or clinically suspected Saethre-Chotzen syndrome.
Authors: Erica E Davis; Ravikumar Balasubramanian; Zachary A Kupchinsky; David L Keefe; Lacey Plummer; Kamal Khan; Blazej Meczekalski; Karen E Heath; Vanesa Lopez-Gonzalez; Mary J Ballesta-Martinez; Gomathi Margabanthu; Susan Price; James Greening; Raja Brauner; Irene Valenzuela; Ivon Cusco; Paula Fernandez-Alvarez; Margaret E Wierman; Taibo Li; Kasper Lage; Priscila Sales Barroso; Yee-Ming Chan; William F Crowley; Nicholas Katsanis Journal: Hum Mol Genet Date: 2020-08-11 Impact factor: 6.150
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Authors: Graeme E Glass; Justine O'Hara; Natalie Canham; Deirdre Cilliers; David Dunaway; Aimee L Fenwick; Noor-Owase Jeelani; David Johnson; Tracy Lester; Helen Lord; Jenny E V Morton; Hiroshi Nishikawa; Peter Noons; Kemmy Schwiebert; Caroleen Shipster; Alison Taylor-Beadling; Stephen R F Twigg; Pradeep Vasudevan; Steven A Wall; Andrew O M Wilkie; Louise C Wilson Journal: Am J Med Genet A Date: 2019-02-13 Impact factor: 2.802
Authors: Ram Singh; Ana S A Cohen; Cathryn Poulton; Tina Duelund Hjortshøj; Moe Akahira-Azuma; Geetu Mendiratta; Wahab A Khan; Dimitar N Azmanov; Karen J Woodward; Maria Kirchhoff; Lisong Shi; Lisa Edelmann; Gareth Baynam; Stuart A Scott; Ethylin Wang Jabs Journal: Cold Spring Harb Mol Case Stud Date: 2021-06-11
Authors: Tianyun Wang; Kendra Hoekzema; Davide Vecchio; Huidan Wu; Arvis Sulovari; Bradley P Coe; Madelyn A Gillentine; Amy B Wilfert; Luis A Perez-Jurado; Malin Kvarnung; Yoeri Sleyp; Rachel K Earl; Jill A Rosenfeld; Madeleine R Geisheker; Lin Han; Bing Du; Chris Barnett; Elizabeth Thompson; Marie Shaw; Renee Carroll; Kathryn Friend; Rachael Catford; Elizabeth E Palmer; Xiaobing Zou; Jianjun Ou; Honghui Li; Hui Guo; Jennifer Gerdts; Emanuela Avola; Giuseppe Calabrese; Maurizio Elia; Donatella Greco; Anna Lindstrand; Ann Nordgren; Britt-Marie Anderlid; Geert Vandeweyer; Anke Van Dijck; Nathalie Van der Aa; Brooke McKenna; Miroslava Hancarova; Sarka Bendova; Marketa Havlovicova; Giovanni Malerba; Bernardo Dalla Bernardina; Pierandrea Muglia; Arie van Haeringen; Mariette J V Hoffer; Barbara Franke; Gerarda Cappuccio; Martin Delatycki; Paul J Lockhart; Melanie A Manning; Pengfei Liu; Ingrid E Scheffer; Nicola Brunetti-Pierri; Nanda Rommelse; David G Amaral; Gijs W E Santen; Elisabetta Trabetti; Zdeněk Sedláček; Jacob J Michaelson; Karen Pierce; Eric Courchesne; R Frank Kooy; Magnus Nordenskjöld; Corrado Romano; Hilde Peeters; Raphael A Bernier; Jozef Gecz; Kun Xia; Evan E Eichler Journal: Nat Commun Date: 2020-10-01 Impact factor: 14.919