Journal
ANNALS OF NEUROLOGY
Volume 74, Issue 6, Pages 873-882Publisher
WILEY
DOI: 10.1002/ana.23998
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Funding
- NIH NINDS [K23NS069784, R37 NS35129, R01NS035129, R01NS035129S]
- Comitato Telethon Fondazione Onlus [GGP11139]
- Italian Human ProteomeNet [RBRN07BMCT_009]
- Deanship of Scientific Research at King Saud University, Riyadh, Saudi Arabia [301]
- NIH National Institute of Mental Health [NIMH1RC2MH089952]
- Manton Center for Orphan Disease Research
- Dubai Harvard Foundation for Medical Research
- Simons Foundation
- Nancy Lurie Marks Family Foundation
- Bryan Alzheimer's Disease Research Center [NIA P30 AG028377]
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ObjectiveTo identify a genetic cause for migrating partial seizures in infancy (MPSI). MethodsWe 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. ResultsIn 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. InterpretationWe 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. Ann Neurol 2013;74:873-882
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