About Us

Epilepsy is one of the most common neurological disorders in humans, with a prevalence of ~1% and a lifetime incidence of up to 3%. Epilepsy is characterized by recurrent seizures due to abnormal, synchronized neuronal firing in the brain. Although it has long been known that epilepsy has a strong genetic component, the epilepsy genes discovered to date explain only a small fraction of disease. In this project, we are working to identify novel genetic causes of the most severe forms of epilepsy, the epileptic encephalopathies. We use state-of-the-art technologies including array comparative genomic hybridization, exome sequencing and targeted candidate gene resequencing to find mutations that cause disease. Using this combination of genomic approaches, we hope to identify new genes and pathways important in brain development and epileptogenesis.

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Since the introduction of array CGH and SNP microarrays - technologies that allow genome-wide detection of copy number variants (CNVs) - the discovery of novel genomic disorders has increased rapidly. Between 2006-2009, at least 18 novel recurrent disorders have been described. These include rearrangements of 1q21, 15q13, 15q24, 16p13, 17q12 and 17q21. Interestingly, some genomic rearrangements are associated with a wide range of neurocognitive and neuropsychiatric conditions, ranging from mild learning disabilities to epilepsy to schizophrenia. We are interested in understanding the range of phenotypes associated with novel genomic disorders and studying the genetic and epigenetic modifiers that influence clinical outcome.

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The genomic technologies that our lab uses can be used to identify genetic causes of many different conditions. Our work focuses on congenital anomalies and other pediatric disorders. We have investigated a variety of conditions, including craniosynostosis (premature fusion of the skull bones), congenital diaphragmatic hernia, brain malformations, multiple congenital anomalies, and various prenatally detected birth defects.

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  • Myers CT, Mefford HC^ (2015) Advancing epilepsy genetics in the genomic era. Genome Medicine 7:91
  • Mefford HC^, Zemel M, Geraghty E, Cook J, Clayton PT, Paul K, Plecko B, Mills PB, Nordli DR, Gospe SM (2015) Intragenic deletions of ALDH7A1 in pyridoxine-dependent epilepsy caused by Alu-Alu recombination. Neurology (in press).
  • Carvill GL, Crompton DE, Regan BM, McMahon JM, Saykally J, Zemel M, Schneider AL, Dibbens L, Howell KB, Mandelstam S, Leventer FJ, Harvey AS, Mullen SA, Berkovic SF, Sullivan J, Scheffer IE, Mefford HC^ (2015) Epileptic spasms are a feature of DEPDC5 mTORopathy. Neurology: Genetics (in press).
  • Jones K, Schwarze U, Adam M, Byers PH, Mefford HC^ (2015) A homozygous B3GAT3 mutation causes a severe syndrome with multiple fractures, expanding the phenotype of linkeropathy syndromes. Am J Med Gen doi:10.1002/ajmg.a.37209 [Epub ahead of print].
  • Howell KB, McMahon JM, Carvill GL, Tambunan D, Mackay MT, Casero VR, Webster R, Clark D, Freeman JL, Calvert S, Olson HE, Mandelstam SA, Poduri A, Mefford HC, Harvey AS, Scheffer IE (2015) SCN2A encephalopathy: a major cause of epilepsy of infancy with migrating focal seizures. Neurology (in press).
  • Moller RS, Heron SE, Larsen LHG, Lim CX, Ricos MG, Bayly MA, van Kempen MJA, Klinkenberg S, Andrews I, Kelley K, Ronen GM, Callen D, McMahon JM, Yendle SC, Carvill GL, Mefford HC, Nabbout R, Poduri A, Striano P, Baglietto MG, Zara F, Smith NJ, Pridmore C, Gardella E, Nikanorova M, Dahl HA, Gellert P, Scheffer IE, Gunning B, Kargh-Olsen B, Dibbens LM (2015) Mutations in KCNT1 cause a spectrum of focal epilepsies. Epilepsia doi:10.1111/epi13701 [Epub ahead of print].
  • Bernier R, Steinman KJ, Reilly B, Wallace AS, Sherr EH, Pojman N, Mefford HC, Gerdts J, Earl R, Hanson E, Goin-Kochel RP, Berry L, Kanne S, Snyder LAG, Spence S, Ramocki MB, Evans DW, Spiro JE, Martin CL, Ledbetter DH, Chunk WK, Simons VIP Consortium (2015) Clinical phenotype of the recurrent 1q21.1 copy number variation. Genet Med doi: 10.1038/gim.2015.78 [epub ahead of print].
  • Carvill GL, McMahon JM, Schneider A, Zemel M, Myers CT, Saykally J, Nguyen J, Robbiano A, Zara F, Specchio N, Mecarelli O, Smith RL, Leventer RJ, Møller RS, Nikanorova M, Dimova P, Jordanova A, Petrou S, Euroepinomics RES, Helbig I, Striano P, Weckhuysen S, Berkovic SF, Scheffer IE, Mefford HC^. Mutations in the GABA transporter GAT-1 cause epilepsy with myoclonic astatic seizures. American Journal of Human Genetics 96:808-15.
  • Galizia EC#, Myers CT#, Leu C, de Kovel CGF, Afrikanova T, Cordero-Maldonado ML, Martins TG, Jacmin M, Drury S, Chinthapalli VK, Muhle H, Pendziwiat M, Sander T, Ruppert A-K. Moller RS, Thiele H, Krause R, Schubert J, Lehesjoki A-E, Nurnberg P, Lerche H, Palotie A, Coppola A, Striano S, Del Gaudio L, Boustred C, Schneider AL, Lench N, Jocic-Jakubi B, Covanis A, Capovilla G, Veggotti P, Piccioli M, Parisi P, Cantonetti L, Sadleir LG, Mullen SA, Berkovic SF, Stephani U, Helbig I, Crawford AD, Esguerra CV, Kasteleijn-Nolst Trenite DGA, Koeleman BPC, Mefford HC^, Scheffer IE, Sisodiya SM (2015) CHD2 variants are a risk factor for photosensitivity in epilepsy. Brain 138:1198-207.
  • Paemka L, Mahajan VB, Ehaideb SN, Skeie JM, Tan MC, Wu S, Cox AJ, Sowers LP, Gecz J, Jolly L, Ferguson PJ, Darbro B, Schneider A, Scheffer IE, Carvill GL, Mefford HC, El-Shanti H, Wood S, Manak JR, Bassuk AG (2015) Seizures are regulated by ubiquitin-specific peptidase 9 X-linked (USP9X), a de-ubiquitinase. PLoS Genetics 11:e1005022. PMCID PMC4357451.
  • Epi4K Consortium & Epilepsy Phenome/Genome Project (2015) CNV analysis from exome data in 349 patients with epileptic encephalopathy. Annals of Neurology 78:323-8.
  • van Bon BW, Coe BP, Bernier R, Green C, Gerdts J, Witherspoon K, Kleefstra T, Willemsen MH, Kumar R, Bosco P, Fichera M, Li D, Amaral D, Cristofoli F, Peeters H, Haan E, Romano C, Mefford HC, Scheffer I, Gecz J, de Vries BB, Eichler EE. Disruptive de novo mutations in DYRK1A lead to a syndromic form of autism and ID (2015) Mol Psych doi:10.1038/mp.2015.5 [Epub ahead of print].
  • Hartmann C, von Spiczak S, Suls A, Weckhuysen S, Buyse G, Vilain C, Van Bogaert P, De Jonghe P, Cook J, Muhle H, Stephani U, Helbig I, Mefford HC^ (2015) Investigating the genetic basis of fever-associated syndromic epilepsies using copy number variation analysis. Epilepsia doi:10.1111/epi.12920 [Epub ahead of print].
  • Thomas RH, Zhang LM, Carvill GL, Archer JS, Heavin SB, Mandelstam SA, Craiu D, EuroEPINOMICS-RES Consortium, Berkovic SF, Gill DS, Mefford HC, Scheffer IE (2015) CHD2 myoclonic encephalopathy is frequently associated with self-induced seizures. Neurology 84:951-8.
  • Larsen J, Carvill GL, Gardella E, Kluger G, Schmiedel G, Barisic N, Depienne C, Brilstra E, Mang Y, Nielsen JEK, Kirkpatrick M, Goudie D, Goldman R, Jähn JA, Jepsen B, Gill D, Döcker M, Biskup S, McMahon JM, Koeleman B, Harris M, Braun K, de Kovel CGF, Marini C, Specchio N, Djémié T, Weckhuysen S, Tommerup N, Troncoso M, Troncoso L, EuroEPINOMICS RES CRP, Bevot A, Wolff M, Hjalgrim H, Guerrini R, Scheffer IE, Mefford HC^, Møller RS (2015) The phenotypic spectrum of SCN8A encephalopathy. Neurology 84:480-9.
  • EuroEPINOMICS-RES Consortium, Epilepsy Phenome/Genome Project, and Epi4K Consortium (2014) De novo mutations in synaptic transmission genes including DNM1 cause epileptic encephalopathies. Am J Hum Genet 95:360-70. PMCID PMC4185114.
  • Coe BP, Witherspoon K, Rosenfeld JA, van Bon BW, Vulto-van Silfhout AT, Bosco P, Friend KL, Baker C, Buono S, Vissers LE, Schuurs-Hoeijmakers JH, Hoischen A, Pfundt R, Krumm N, Carvill GL, Li D, Amaral D, Brown N, Lockhart PJ, Scheffer IE, Alberti A, Shaw M, Pettinato R, Tervo R, de Leeuw N, Reijnders MR, Torchia BS, Peeters H, Thompson E, O'Roak BJ, Fichera M, Hehir-Kwa JY, Shendure J, Mefford HC, Haan E, Gécz J, de Vries BB, Romano C, Eichler EE. (2014) Refining analyses of copy number variation identifies specific genes associated with developmental delay. Nat Genet 46:1063-71. PMCID: PMC4177294.
  • Mefford HC^ (2014) CNVs in epilepsy. Current Genetic Medicine Reports. 2:162-7.
  • Bernier R, Golzio C, Xiong B, Stessman H, Coe BP, Penn O, Witherspoon K, Gerdts J, Baker C, Vulto-van Silfhout AT, Schuurs-Hoeijmakers JH, Fichera M, Bosco P, Buono S, Alberti A, Failla P, Peeters H, Steyaert J, Vissers LELM, Francescatto L, Mefford HC, Rosenfeld JA, Bakken T, O.Roak BJ, Pawlus M, Moon R, Shendure J, Amaral DG, Lein E, Rankin J, Romano C, de Vries BBA, Katsanis N, Eichler EE (2014) Disruptive CHD8 mutations define a subtype of autism early in development. Cell 158:263-76. PMCID: PMC4136921.