Pitfalls in genetic testing: the story of missed SCN1A mutations

Tania Djémié, Sarah Weckhuysen, Sarah von Spiczak, Gemma L Carvill, Johanna Jaehn, Anna-Kaisa Anttonen, Eva Brilstra, Hande S Caglayan, Carolien G de Kovel, Christel Depienne, Eija Gaily, Elena Gennaro, Beatriz G Giraldez, Padhraig Gormley, Rosa Guerrero-López, Renzo Guerrini, Eija Hämäläinen, Corinna Hartmann, Laura Hernandez-Hernandez, Helle HjalgrimBobby P C Koeleman, Eric Leguern, Anna-Elina Lehesjoki, Johannes R Lemke, Costin Leu, Carla Marini, Jacinta M McMahon, Davide Mei, Rikke Steensbjerre Møller, Hiltrud Muhle, Candace T Myers, Caroline Nava, Jose M Serratosa, Sanjay M Sisodiya, Ulrich Stephani, Pasquale Striano, Marjan J A van Kempen, Nienke E Verbeek, Sunay Usluer, Federico Zara, Aarno Palotie, Heather C Mefford, Ingrid E Scheffer, Peter De Jonghe, Ingo Helbig, Arvid Suls, EuroEPINOMICS‐RES Dravet working group

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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.

TidsskriftMolecular Genetics & Genomic Medicine
Udgave nummer4
Sider (fra-til)457-464
StatusUdgivet - jul. 2016

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