Andreas Brunklaus1, Rachael Ellis2, Helen Stewart3, Sarah Aylett4, Eleanor Reavey2, Ros Jefferson5, Rakesh Jain6, Supratik Chakraborty7, Sandeep Jayawant6, Sameer M Zuberi8. 1. The Paediatric Neurosciences Research Group, Royal Hospital for Sick Children, Glasgow, UK; Developmental Neurosciences Programme at UCL-ICH, Great Ormond Street Hospital for Sick Children, London, UK. 2. The Paediatric Neurosciences Research Group, Royal Hospital for Sick Children, Glasgow, UK; Molecular Diagnostics, West of Scotland Genetic Services, Southern General Hospital, Glasgow, UK. 3. Department of Clinical Genetics, Oxford Radcliffe Hospitals NHS Trust, Oxford, UK. 4. Developmental Neurosciences Programme at UCL-ICH, Great Ormond Street Hospital for Sick Children, London, UK. 5. Royal Berkshire NHS Foundation Trust, Reading, UK. 6. Department of Paediatric Neurology, Children's Hospital, Oxford, UK. 7. Coventry and Warwickshire Partnership NHS Trust, Coventry, UK. 8. The Paediatric Neurosciences Research Group, Royal Hospital for Sick Children, Glasgow, UK; School of Medicine, College of Medical, Veterinary & Life Sciences, University of Glasgow, UK. Electronic address: sameer.zuberi@nhs.net.
Abstract
BACKGROUND: Mutations in the gene encoding the alpha subunit of the voltage-gated sodium channel SCN1A are associated with several epilepsy syndromes. These range from severe phenotypes including Dravet syndrome to milder phenotypes such as genetic epilepsy with febrile seizures plus (GEFS+). To date the sequence variants identified have been heterozygous in nature as one would expect for a disorder that occurs de novo or is dominantly inherited. METHODS AND RESULTS: We report the association of two novel homozygous missense mutations of the SCN1A gene in four children with infantile epilepsies from two consanguineous pedigrees. We suggest that the nature and location of the identified amino acid changes allows heterozygous carriers to remain unaffected. However, having such changes on both alleles may have a cumulative and detrimental effect. CONCLUSION: The presented cases illustrate how better understanding of the nature and location of SCN1A missense mutations may aid the interpretation of genotype-phenotype associations. SCN1A related epilepsies should be considered in children with infantile onset epilepsies even when an autosomal recessive neurological disorder is suspected.
BACKGROUND: Mutations in the gene encoding the alpha subunit of the voltage-gated sodium channel SCN1A are associated with several epilepsy syndromes. These range from severe phenotypes including Dravet syndrome to milder phenotypes such as genetic epilepsy with febrile seizures plus (GEFS+). To date the sequence variants identified have been heterozygous in nature as one would expect for a disorder that occurs de novo or is dominantly inherited. METHODS AND RESULTS: We report the association of two novel homozygous missense mutations of the SCN1A gene in four children with infantile epilepsies from two consanguineous pedigrees. We suggest that the nature and location of the identified amino acid changes allows heterozygous carriers to remain unaffected. However, having such changes on both alleles may have a cumulative and detrimental effect. CONCLUSION: The presented cases illustrate how better understanding of the nature and location of SCN1A missense mutations may aid the interpretation of genotype-phenotype associations. SCN1A related epilepsies should be considered in children with infantile onset epilepsies even when an autosomal recessive neurological disorder is suspected.
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