TY - JOUR
T1 - Pitfalls in genetic testing
T2 - The story of missed SCN1A mutations
AU - EuroEPINOMICS-RES Dravet working group
AU - Djémié, Tania
AU - Weckhuysen, Sarah
AU - Von Spiczak, Sarah
AU - Carvill, Gemma Louise
AU - Jaehn, Johanna
AU - Anttonen, Anna Kaisa
AU - Brilstra, Eva
AU - Caglayan, Hande S.
AU - De Kovel, Carolien G.
AU - Depienne, Christel
AU - Gaily, Eija
AU - Gennaro, Elena
AU - Giraldez, Beatriz G.
AU - Gormley, Padhraig
AU - López, Rosa Guerrero
AU - Guerrini, Renzo
AU - Hämäläinen, Eija
AU - Hartmann, Corinna
AU - Hernandez, Laura Hernandez
AU - Hjalgrim, Helle
AU - Koeleman, Bobby P.C.
AU - Leguern, Eric
AU - Lehesjoki, Anna Elina
AU - Lemke, Johannes R.
AU - Leu, Costin
AU - Marini, Carla
AU - McMahon, Jacinta M.
AU - Mei, Davide
AU - Møller, Rikke S.
AU - Muhle, Hiltrud
AU - Myers, Candace T.
AU - Nava, Caroline
AU - Serratosa, Jose M.
AU - Sisodiya, Sanjay M.
AU - Stephani, Ulrich
AU - Striano, Pasquale
AU - Van Kempen, Marjan J.A.
AU - Verbeek, Nienke E.
AU - Usluer, Sunay
AU - Zara, Federico
AU - Palotie, Aarno
AU - Mefford, Heather C.
AU - Scheffer, Ingrid E.
AU - De Jonghe, Peter
AU - Helbig, Ingo
AU - Suls, Arvid
N1 - Publisher Copyright:
© 2016 The Authors.
PY - 2016/7/1
Y1 - 2016/7/1
N2 - 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.
AB - 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.
KW - Dravet syndrome
KW - Epilepsy
KW - Genetic screening
KW - Next-generation sequencing
KW - Sanger sequencing
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U2 - 10.1002/mgg3.217
DO - 10.1002/mgg3.217
M3 - Article
C2 - 27465585
AN - SCOPUS:85013625371
VL - 4
SP - 457
EP - 464
JO - Molecular genetics & genomic medicine
JF - Molecular genetics & genomic medicine
SN - 2324-9269
IS - 4
ER -