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Title: Pitfalls in genetic testing: the story of missed SCN1A mutations
Austin Authors: Djémié, Tania;Weckhuysen, Sarah;von Spiczak, Sarah;Carvill, Gemma L;Jaehn, Johanna;Anttonen, Anna-Kaisa;Brilstra, Eva;Caglayan, Hande S;de Kovel, Carolien G;Depienne, Christel;Gaily, Eija;Gennaro, Elena;Giraldez, Beatriz G;Gormley, Padhraig;Guerrero-López, Rosa;Guerrini, Renzo;Hämäläinen, Eija;Hartmann, Corinna;Hernandez-Hernandez, Laura;Hjalgrim, Helle;Koeleman, Bobby PC;Leguern, Eric;Lehesjoki, Anna-Elina;Lemke, Johannes;Leu, Costin;Marini, Carla;McMahon, Jacinta M;Mei, Davide;Møller, Rikke S;Muhle, Hiltrud;Myers, Candace T;Nava, Caroline;Serratosa, Jose M;Sisodiya, Sanjay M;Stephani, Ulrich;Striano, Pasquale;van Kempen, Marjan JA;Verbeek, Nienke E;Usluer, Sunay;Zara, Federico;Palotie, Aarno;Mefford, Heather C;Scheffer, Ingrid E ;De Jonghe, Peter;Helbig, Ingo;Suls, Arvid;EuroEPINOMICS‐RES Dravet working group
Affiliation: Austin Health, Heidelberg, Victoria, Australia
Neurogenetics group, Department of Molecular Genetics, VIB, Antwerp, Belgium
Laboratory of Neurogenetics Institute, Born-Bunge, University of Antwerp, Antwerp, Belgium
Sorbonne universités, UPMC université Paris, Paris, France
ICM, CNRS UMR 7225, Inserm U 1127, Paris, France
Centre de reference épilepsies rares, Epilepsy unit, AP-HP Groupe hospitalier Pitié-Salpêtrière, Paris, France
Department of Neuropediatrics, University Medical Center Schleswig-Holstein, Kiel, Germany
Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA, USA
Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland
Helsinki University Hospital, Helsinki, Finland
Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands
Department of Molecular Biology and Genetics, Bogaziçi University, Istanbul, Turkey
Département de génétique, AP-HP, hôpital Pitié-Salpêtrière, Paris, France
Department of Pediatric Neurology, Helsinki University Hospital, Helsinki, Finland
Laboratory of Genetics, E.O. Ospedali Galliera, Genova, Italy
Neurology Laboratory and Epilepsy Unit, Department of Neurology, Instituto de Investigatión Sanitaria-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Madrid, Spain
IIS-Fundación Jiménez Díaz and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain
Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
Wellcome Trust Sanger Institute, Hinxton, UK
Pediatric Neurology and Neurogenetics Unit and Laboratories, A. Meyer Children's Hospital-University of Florence, Florence, Italy
Institute for Molecular Medicine Finland FIMM, University of Helsinki, Helsinki, Finland
Department of Clinical and Experimental Epilepsy, NIHR University College London Hospitals Biomedical Research Centre, UCL Institute of Neurology, London, UK
The Epilepsy Society, Chalfont-St-Peter, Bucks, UK
Department of Neurology, Danish Epilepsy Centre, Dianalund, Denmark
Institute for Regional Health research, University of Southern Denmark, Odense, Denmark
Folkhälsan Institute of Genetics, Helsinki, Finland
Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland
Institute of Human Genetics, University of Leipzig, Leipzig, Germany
Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Victoria, Australia
Pediatric Neurology and Muscular Diseases Unit, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, and Maternal and Child Health, University of Genoa ‘G. Gaslini’ Institute, Genova, Italy
Laboratory of Neurogenetics, Department of Neurosciences, Giannina Gaslini Institute, Genova, Italy
Department of Paediatrics, University of Melbourne and Royal Children's Hospital, Parkville, Victoria, Australia
Florey Institute of Neuroscience and Mental Health, Melbourne, Victoria, Australia
Division of Neurology, Antwerp University Hospital, Antwerp, Belgium
Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USA
GENOMED, Center for Medical Genetics, University of Antwerp, Antwerp, Belgium
Issue Date: Jul-2016 2016-04
Publication information: Molecular Genetics & Genomic Medicine 2016; 14(4):457-464
Abstract: BACKGROUND: Sanger sequencing, still the standard technique for genetic testing in most diagnostic laboratories and until recently widely used in research, is gradually being complemented by next-generation sequencing (NGS). No single mutation detection technique is however perfect in identifying all mutations. Therefore, we wondered to what extent inconsistencies between Sanger sequencing and NGS affect the molecular diagnosis of patients. Since mutations in SCN1A, the major gene implicated in epilepsy, are found in the majority of Dravet syndrome (DS) patients, we focused on missed SCN1A mutations. METHODS: We sent out a survey to 16 genetic centers performing SCN1A testing. RESULTS: We collected data on 28 mutations initially missed using Sanger sequencing. All patients were falsely reported as SCN1A mutation-negative, both due to technical limitations and human errors. CONCLUSION: We illustrate the pitfalls of Sanger sequencing and most importantly provide evidence that SCN1A mutations are an even more frequent cause of DS than already anticipated.
DOI: 10.1002/mgg3.217
PubMed URL:
Type: Journal Article
Subjects: Dravet syndrome
Sanger sequencing
Genetic screening
Next‐generation sequencing
Appears in Collections:Journal articles

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