title: SLC25A22 is a novel gene for migrating partial seizures in infancy.
abstract: OBJECTIVE
  To identify a genetic cause for migrating partial seizures in infancy (MPSI).
  
  
  METHODS
  We characterized a consanguineous pedigree with MPSI and obtained DNA from affected and unaffected family members. We analyzed single nucleotide polymorphism 500K data to identify regions with evidence of linkage. We performed whole exome sequencing and analyzed homozygous variants in regions of linkage to identify a candidate gene and performed functional studies of the candidate gene SLC25A22.
  
  
  RESULTS
  In a consanguineous pedigree with 2 individuals with MPSI, we identified 2 regions of linkage, chromosome 4p16.1-p16.3 and chromosome 11p15.4-pter. Using whole exome sequencing, we identified 8 novel homozygous variants in genes in these regions. Only 1 variant, SLC25A22 c.G328C, results in a change of a highly conserved amino acid (p.G110R) and was not present in control samples. SLC25A22 encodes a glutamate transporter with strong expression in the developing brain. We show that the specific G110R mutation, located in a transmembrane domain of the protein, disrupts mitochondrial glutamate transport.
  
  
  CONCLUSIONS
  We have shown that MPSI can be inherited and have identified a novel homozygous mutation in SLC25A22 in the affected individuals. Our data strongly suggest that SLC25A22 is responsible for MPSI, a severe condition with few known etiologies. We have demonstrated that a combination of linkage analysis and whole exome sequencing can be used for disease gene discovery. Finally, as SLC25A22 had been implicated in the distinct syndrome of neonatal epilepsy with suppression bursts on electroencephalogram, we have expanded the phenotypic spectrum associated with SLC25A22.
authors.forename: Annapurna
authors.initials: A
authors.lastname: Poduri
authors.forename: Erin L
authors.initials: EL
authors.lastname: Heinzen
authors.forename: Vida
authors.initials: V
authors.lastname: Chitsazzadeh
authors.forename: Francesco Massimo
authors.initials: FM
authors.lastname: Lasorsa
authors.forename: P Christina
authors.initials: PC
authors.lastname: Elhosary
authors.forename: Christopher M
authors.initials: CM
authors.lastname: LaCoursiere
authors.forename: Emilie
authors.initials: E
authors.lastname: Martin
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Yuskaitis
authors.forename: Robert Sean
authors.initials: RS
authors.lastname: Hill
authors.forename: Kutay Deniz
authors.initials: KD
authors.lastname: Atabay
authors.forename: Brenda
authors.initials: B
authors.lastname: Barry
authors.forename: Jennifer N
authors.initials: JN
authors.lastname: Partlow
authors.forename: Fahad A
authors.initials: FA
authors.lastname: Bashiri
authors.forename: Radwan M
authors.initials: RM
authors.lastname: Zeidan
authors.forename: Salah A
authors.initials: SA
authors.lastname: Elmalik
authors.forename: Mohammad M U
authors.initials: MM
authors.lastname: Kabiraj
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Kothare
authors.forename: Tommy
authors.initials: T
authors.lastname: Stödberg
authors.forename: Amy
authors.initials: A
authors.lastname: McTague
authors.forename: Manju A
authors.initials: MA
authors.lastname: Kurian
authors.forename: Ingrid E
authors.initials: IE
authors.lastname: Scheffer
authors.forename: A James
authors.initials: AJ
authors.lastname: Barkovich
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Palmieri
authors.forename: Mustafa A
authors.initials: MA
authors.lastname: Salih
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Walsh
mesh_terms: D000328:Adult; D003241:Consanguinity; D020936:Epilepsy, Benign Neonatal / Q000235:genetics* / Q000503:physiopathology; D059472:Exome / Q000235:genetics*; D005260:Female; D008040:Genetic Linkage / Q000235:genetics; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D033681:Mitochondrial Membrane Transport Proteins / Q000235:genetics*; D010375:Pedigree
chemical_list: D033681:Mitochondrial Membrane Transport Proteins; C499215:SLC25A22 protein, human