title: Whole genome sequencing identifies SCN2A mutation in monozygotic twins with Ohtahara syndrome and unique neuropathologic findings.
abstract: 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 SCN2A and confirmed to be de novo in both twins by SS. In conclusion, we have identified a de novo SCN2A mutation as the etiology for Ohtahara syndrome in monozygotic twins associated with a unique dentate-olivary dysplasia in the deceased twin.
authors.affiliation: Division of Newborn Medicine, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Marlin
authors.initials: M
authors.lastname: Touma
authors.forename: Mugdha
authors.initials: M
authors.lastname: Joshi
authors.forename: Meghan C
authors.initials: MC
authors.lastname: Connolly
authors.forename: P Ellen
authors.initials: PE
authors.lastname: Grant
authors.forename: Anne R
authors.initials: AR
authors.lastname: Hansen
authors.forename: Omar
authors.initials: O
authors.lastname: Khwaja
authors.forename: Gerard T
authors.initials: GT
authors.lastname: Berry
authors.forename: Hannah C
authors.initials: HC
authors.lastname: Kinney
authors.forename: Annapurna
authors.initials: A
authors.lastname: Poduri
authors.forename: Pankaj B
authors.initials: PB
authors.lastname: Agrawal
mesh_terms: D001921:Brain / Q000002:abnormalities*; D002675:Child, Preschool; D004200:Diseases in Twins / Q000235:genetics* / Q000473:pathology; D004569:Electroencephalography; D004827:Epilepsy / Q000235:genetics* / Q000473:pathology*; D015894:Genome, Human / Q000235:genetics*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D009154:Mutation / Q000235:genetics*; D062551:NAV1.2 Voltage-Gated Sodium Channel / Q000235:genetics*; D010641:Phenotype; D013577:Syndrome; D014430:Twins, Monozygotic / Q000235:genetics*
chemical_list: D062551:NAV1.2 Voltage-Gated Sodium Channel; C568251:SCN2A protein, human
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