De novo SCN1A mutations in Dravet syndrome and related epileptic encephalopathies are largely of paternal origin
- Sarah E Heron1,2,
- Ingrid E Scheffer3,4,
- Xenia Iona1,
- Sameer M Zuberi5,
- Rachael Birch6,
- Jacinta M McMahon3,
- Carla M Bruce3,
- Samuel F Berkovic3,
- John C Mulley1,2,7
- 1Epilepsy Program, SA Pathology at Women's and Children's Hospital, North Adelaide, South Australia, Australia
- 2School of Paediatrics and Reproductive Health, The University of Adelaide, Adelaide, South Australia, Australia
- 3Department of Medicine and Epilepsy Research Centre, The University of Melbourne, Austin Health, Heidelberg, Victoria, Australia
- 4Department of Paediatrics, The University of Melbourne, Royal Children's Hospital, Melbourne, Victoria, Australia
- 5Fraser of Allander Neurosciences Unit, Royal Hospital for Sick Children, Yorkhill, Glasgow, UK
- 6Duncan Guthrie Institute of Medical Genetics, Royal Hospital for Sick Children, Yorkhill, Glasgow, UK
- 7School of Molecular and Biomedical Sciences, The University of Adelaide, Adelaide, South Australia, Australia
- Correspondence to Sarah E Heron, SA Pathology, Women's and Children's Hospital, 72 King William Road, North Adelaide, SA 5006, Australia;
- Received 23 December 2008
- Revised 29 June 2009
- Accepted 30 June 2009
- Published Online First 8 July 2009
Background Dravet syndrome is a severe infantile epileptic encephalopathy caused in approximately 80% of cases by mutations in the voltage gated sodium channel subunit gene SCN1A. The majority of these mutations are de novo. The parental origin of de novo mutations varies widely among genetic disorders and the aim of this study was to determine this for Dravet syndrome.
Methods 91 patients with de novo SCN1A mutations and their parents were genotyped for single nucleotide polymorphisms (SNPs) in the region surrounding their mutation. Allele specific polymerase chain reaction (PCR) based on informative SNPs was used to separately amplify and sequence the paternal and maternal alleles to determine in which parental chromosome the mutation arose.
Results The parental origin of SCN1A mutations was established in 44 patients for whom both parents were available and SNPs were informative. The mutations were of paternal origin in 33 cases and of maternal origin in the remaining 11 cases. De novo mutation of SCN1A most commonly, but not exclusively, originates from the paternal chromosome. The average age of parents originating mutations did not differ from that of the general population.
Conclusions The greater frequency of paternally derived mutations in SCN1A is likely to be due to the greater chance of mutational events during the increased number of mitoses which occur during spermatogenesis compared to oogenesis, and the greater susceptibility to mutagenesis of the methylated DNA characteristic of sperm cells.
- Dravet syndrome
- molecular genetics
- epilepsy and seizures
Supplementary tables 1–3 are published online only at http://jmg.bmj.com/content/vol47/issue2
Funding National Health and Medical Research Council of Australia, GPO Box 1421, Canberra ACT 2601, Australia.
Competing interests None.
Ethics approval This study was conducted with the approval of the Human Research Ethics Committees of Austin Health and the Women's and Children's Hospital.
Provenance and peer review Not commissioned; externally peer reviewed.