Genetic analysis of PHOX2B in sudden unexpected death in epilepsy cases

Richard D Bagnall; Douglas E Crompton; Carina Cutmore; Brigid M Regan; Samuel F Berkovic; Ingrid E Scheffer; Christopher Semsarian

doi:10.1212/WNL.0000000000000781

Genetic analysis of PHOX2B in sudden unexpected death in epilepsy cases

Neurology. 2014 Sep 9;83(11):1018-21. doi: 10.1212/WNL.0000000000000781. Epub 2014 Aug 1.

Authors

Richard D Bagnall¹, Douglas E Crompton¹, Carina Cutmore¹, Brigid M Regan¹, Samuel F Berkovic¹, Ingrid E Scheffer¹, Christopher Semsarian²

Affiliations

¹ From the Agnes Ginges Centre for Molecular Cardiology (R.D.B., C.C., C.S.), Centenary Institute, Sydney; Sydney Medical School (R.D.B., C.S.), University of Sydney; Neurology Department (D.E.C., B.M.R.), Northern Health, Melbourne; Epilepsy Research Centre (D.E.C., S.F.B., I.E.S.), Department of Medicine, University of Melbourne, Austin Health, Melbourne; Florey Institute of Neurosciences and Mental Health (I.E.S.), Melbourne; Department of Paediatrics (I.E.S.), University of Melbourne, Royal Children's Hospital, Melbourne; and Department of Cardiology (C.S.), Royal Prince Alfred Hospital, Sydney, Australia.
² From the Agnes Ginges Centre for Molecular Cardiology (R.D.B., C.C., C.S.), Centenary Institute, Sydney; Sydney Medical School (R.D.B., C.S.), University of Sydney; Neurology Department (D.E.C., B.M.R.), Northern Health, Melbourne; Epilepsy Research Centre (D.E.C., S.F.B., I.E.S.), Department of Medicine, University of Melbourne, Austin Health, Melbourne; Florey Institute of Neurosciences and Mental Health (I.E.S.), Melbourne; Department of Paediatrics (I.E.S.), University of Melbourne, Royal Children's Hospital, Melbourne; and Department of Cardiology (C.S.), Royal Prince Alfred Hospital, Sydney, Australia. c.semsarian@centenary.org.au.

PMID: 25085640
DOI: 10.1212/WNL.0000000000000781

Abstract

Objective: To determine the contribution of sequence variations in PHOX2B to sudden unexpected death in epilepsy (SUDEP).

Methods: Patients who died of SUDEP were identified in 2 major Australian cohorts, the Epilepsy Genetics research program in Melbourne and postmortem cases at the Department of Forensic Medicine in Sydney. Coding exons of the PHOX2B gene were sequenced and a fluorescent sizing assay was used to measure the PHOX2B polyalanine repeat sequence.

Results: Sequencing of 68 cases of SUDEP identified a 15-nucleotide deletion in the PHOX2B polyalanine repeat region in one case, a 16-year-old adolescent with focal dyscognitive seizures from age 5 years. This deletion was verified using a fluorescent sizing assay. Two synonymous variants were identified in 4 cases, but no PHOX2B polyalanine repeat expansion alleles or point mutations were found.

Conclusions: The absence of PHOX2B polyalanine repeat expansion alleles or point mutations in 68 Australian cases of SUDEP, with one deletion of uncertain significance, shows that PHOX2B mutations are not a common risk factor for SUDEP.

Publication types

Multicenter Study
Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Aged
Aged, 80 and over
Alleles
Australia
Child
Death, Sudden*
Epilepsy / genetics*
Exons
Female
Genetic Predisposition to Disease
Homeodomain Proteins / genetics*
Humans
Male
Middle Aged
Peptides / genetics
Repetitive Sequences, Nucleic Acid
Risk Factors
Sequence Analysis, DNA
Sequence Deletion
Transcription Factors / genetics*
Young Adult

Substances

Homeodomain Proteins
NBPhox protein
Peptides
Transcription Factors
polyalanine