Journal
MOLECULAR GENETICS & GENOMIC MEDICINE
Volume 4, Issue 4, Pages 457-464Publisher
WILEY
DOI: 10.1002/mgg3.217
Keywords
Dravet syndrome; epilepsy; genetic screening; next-generation sequencing; Sanger sequencing
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Funding
- Assistance Publique des Hopitaux de Paris (AP-HP)
- Dravet Syndrome UK
- Katy Baggott Foundation
- Epilepsy Society
- International Coordination Action (ICA) [G0E8614N]
- EpiPGX (European Union 7th Framework Programme Grant) [279062]
- UK Department of Health's NIHR Biomedical Research Centres funding scheme
- Folkhalsan Research Foundation
- Eurocores program of the European Science Foundation P.D.J. [G.A.136.11.N, FWO/ESF-ECRP]
- TUBITAK [110S518]
- medical faculty of Kiel University, Germany
- French program Investissements d'avenir [ANR-10-IAIHU-06]
- [HE5415/3-1]
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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.
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