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Title: A craniosynostosis massively parallel sequencing panel study in 309 Australian and New Zealand patients: findings and recommendations
Austin Authors: Lee, Eric;Le, Trang;Zhu, Ying;Elakis, George;Turner, Anne;Lo, William;Venselaar, Hanka;Verrenkamp, Carol-Ann;Snow, Nicole;Mowat, David;Kirk, Edwin Philip;Sachdev, Rani;Smith, Janine;Brown, Natasha Jane;Wallis, Mathew;Barnett, Chris;McKenzie, Fiona;Freckmann, Mary-Louise;Collins, Felicity;Chopra, Maya;Gregersen, Nerine;Hayes, Ian;Rajagopalan, Sulekha;Tan, Tiong Yang;Stark, Zornitza;Savarirayan, Ravi;Yeung, Alison;Adès, Lesley;Gattas, Michael;Gibson, Kate;Gabbett, Michael;Amor, David John;Lattanzi, Wanda;Boyd, Simeon;Haan, Eric;Gianoutsos, Mark;Cox, Timothy Chilton;Buckley, Michael Francis;Roscioli, Tony
Affiliation: Craniofacial Unit, Sydney Children's Hospital, Randwick, Australia
The Children's Hospital at Westmead, Sydney, Australia
Department of Clinical Genetics, Austin Health, Heidelberg, Victoria, Australia
South Australian Clinical Genetics Service, SA Pathology, Adelaide, Australia
Department of Clinical Genetics, Royal North Shore Hospital, Sydney, Australia
Department of Clinical Genetics, Liverpool Hospital, Sydney, Australia
Victorian Clinical Genetics Services, Melbourne, Australia
Brisbane Genetics, Brisbane, Australia
Royal Brisbane & Women's Hospital, Brisbane, Australia
King Edward Memorial Hospital, Perth, Australia
Department of Pediatrics, School of Medicine UC Davis MIND Institute, Sacramento, California, USA
Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington, USA
Genetics Laboratory, NSW Health Pathology East, Sydney, Australia
Centre for Clinical Genetics, Sydney Children's Hospital, Randwick, Australia
Centre for Molecular and Biomolecular Informatics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Imagine Institute of Genetic Diseases, Paris, France.
Genetic Health Service New Zealand, Auckland, New Zealand.
Genetic Health Service New Zealand, Christchurch Hospital, Christchurch, New Zealand.
Institute of Anatomy and Cell Biology, Università Cattolica del Sacro Cuore, Rome, Italy.
Issue Date: 2018
Date: 2017-12-07
Publication information: Genetics in medicine : official journal of the American College of Medical Genetics 2018; 20(9): 1061-1068
Abstract: PurposeThe 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.MethodsA 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.ResultsPathogenic 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.ConclusionThese 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.
DOI: 10.1038/gim.2017.214
Journal: Genetics in medicine : official journal of the American College of Medical Genetics
PubMed URL: 29215649
PubMed URL:
Type: Journal Article
Appears in Collections:Journal articles

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