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Whole genome sequencing identifies SCN2A mutation in monozygotic twins with O htahara syndrome and unique neuropathologic findings
Author(s) -
Touma Marlin,
Joshi Mugdha,
Connolly Meghan C.,
Ellen Grant P.,
Hansen Anne R.,
Khwaja Omar,
Berry Gerard T.,
Kinney Hannah C.,
Poduri Annapurna,
Agrawal Pankaj B.
Publication year - 2013
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/epi.12137
Subject(s) - epilepsy , dentate gyrus , cortical dysplasia , monozygotic twin , sanger sequencing , medicine , neuroscience , genetics , pathology , biology , mutation , gene , central nervous system
Summary Mutations in SCN2A gene cause a variety of epilepsy syndromes. We report a novel SCN2A ‐associated epilepsy phenotype in monozygotic twins with tonic seizures soon after birth and a suppression‐burst electroencephalography ( EEG ) pattern. We reviewed the medical records, EEG tracings, magnetic resonance imaging ( MRI ), and neuropathologic findings, and performed whole genome sequencing ( WGS ) on Twin B 's DNA and Sanger sequencing ( SS ) on candidate gene mutations. Extensive neurometabolic evaluation and early neuroimaging studies were normal. Twin A died of an iatrogenic cause at 2 weeks of life. His neuropathologic examination was remarkable for dentate‐olivary dysplasia and granule cell dispersion of the dentate gyrus. Twin B became seizure free at 8 months and was off antiepileptic drugs by 2 years. His brain MRI , normal at 2 months, revealed evolving brainstem and basal ganglia abnormalities at 8 and 15 months that resolved by 20 months. At 2.5 years, Twin B demonstrated significant developmental delay. Twin B 's WGS revealed a heterozygous variant c.788C>T predicted to cause p.Ala263Val change in SCN 2A and confirmed to be de novo in both twins by SS . In conclusion, we have identified a de novo SCN 2A mutation as the etiology for Ohtahara syndrome in monozygotic twins associated with a unique dentate‐olivary dysplasia in the deceased twin.