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Heinzen Lab

Research Summary

My lab focuses on the genetic and genomic basis of epilepsy disorders, including analyses of the role of germline mutations, somatic mutations, and how regulation of the cellular transcriptome influences the risk and presentation of seizures. In collaboration with a number of investigators in neurology, neuropathology, and neurosurgery, a major focus of my group is to study the role of somatic mutations in epilepsy and other neurological diseases. Unlike inherited variation or newly acquired mutations in parental gametes that present in the germline of offspring, mutations can also be acquired somatically at some point in development after fertilization. The burden and localization of a somatically acquired mutation depends on when each mutation arises. There is accumulating evidence that new mutations can lead to disease, and in some cases, severe tissue-specific disease. My lab currently has active research projects seeking to identify and molecularly characterize disease-causing somatic mutations in patients with brain malformations and in patients who have drug-resistant, non-lesional focal epilepsies. We also focus on the study of the transcriptome in brain tissue of epilepsy patients to better understand how regulation at this level may cause or contribute to the presentation of epilepsy. Making use of therapeutically excised tissue specimens from patients with a range of refractory epilepsies, we use a variety of experimental approaches to study the tissue and cellular transcriptome and subsequently relate transcriptional changes to pathological endpoints. Relevant changes are then studied in depth using a range of in vitro and in vivo models to determine how the associated transcriptional changes contribute to disease pathophysiology.

Current Projects

  • Identification and molecular characterization of somatic mutations in malformations of cortical development.
  • Discovery of novel molecular abnormalities underlying non-lesional focal epilepsy.
  • Exploratory genomic investigations of mesial temporal lobe epilepsy.

Lab Members

  • Gabi Griffin, Postdoctoral Scholar
  • Jinfeng Lu, Postdoctoral Scholar
  • Kate Stanley, Technician B

Collaborations

  • Discovery of novel molecular abnormalities underlying non-lesional focal epilepsy
  • Epi4K Consortium
  • Epilepsy Genetics Initiative
  • Epi25
  • Epigen Consortium
  • Pediatric Status Epilepticus Research Group
  • International Alternating Hemiplegia of Childhood Research Consortium

Selected Publications

  • Winawer MR, Griffin NG, Samanamud J, Baugh EH, Rathakrishnan D, Ramalingam S, Zagzag D, Schevon CA, Dugan P, Hegde M, Sheth SA, McKhann GM, Doyle WK, Grant GA, Porter BE, Mikati MA, Muh CR, Malone CD, Bergin AMR, Peters JM, McBrian DK, Pack AM, Akman CI, LaCoursiere CM, Keever KM, Madsen JR, Yang E, Lidov HGW, Shain C, Allen AS, Canoll P, Crino PB, Poduri AH, Heinzen EL. Somatic SLC35A2 variants in the brain are associated with intractable neocortical epilepsy.  Ann Neurol. 2018 Apr 20. doi: 10.1002/ana.25243. [Epub ahead of print] PMID: 29679388

  • Heinzen EL, O'Neill AC, Zhu X, Allen AS, Bahlo M, Chelly J, Dobyns WB, Freytag S, Guerrini R, Leventer RJ, Poduri A, Robertson SP, Walsh CA, Zhang M; Epi4K Consortium; Epilepsy Phenome/Genome Project. De novo and inherited private variants in MAP1B in periventricular nodular heterotopia. PLoS Genet. 2018 May 8;14(5):e1007281. doi: 10.1371/journal.pgen.1007281. [Epub ahead of print] PMID: 29738522

  • Myers CT, Stong N, Mountier EI, Helbig KL, Freytag S, Sullivan JE, Ben Zeev B, Nissenkorn A, Tzadok M, Heimer G, Shinde DN, Rezazadeh A, Regan BM, Oliver KL, Ernst ME, Lippa NC, Mulhern MS, Ren Z, Poduri A, Andrade DM, Bird LM, Bahlo M, Berkovic SF, Lowenstein DH, Scheffer IE, Sadleir LG, Goldstein DB, Mefford HC, Heinzen EL. De Novo Mutations in PPP3CA Cause Severe Neurodevelopmental Disease with Seizures. Am J Hum Genet. 2017 Oct 5;101(4):516-524. PMID: 28942967. PMCID: PMC5630160.

  • Griffin NG, Cronin KD, Walley NM, Hulette CM, Grant GA, Mikati MA, LaBreche HG, Rehder CW, Allen AS, Crino PB, Heinzen EL. Somatic uniparental disomy of Chromosome 16p in hemimegalencephaly. Cold Spring Harb Mol Case Stud. 2017 Sep 1;3(5). PubMed PMID: 28864461; PubMed Central PMCID: PMC5593155.

  • Hildebrand MS, Griffin NG, Damiano JA, Cops EJ, Burgess R, Ozturk E, Jones NC, Leventer RJ, Freeman JL, Harvey AS, Sadleir LG, Scheffer IE, Major H, Darbro BW, Allen AS, Goldstein DB, Kerrigan JF, Berkovic SF, Heinzen EL. Mutations of the sonic hedgehog pathway underlie hypothalamic hamartoma with gelastic epilepsy. Am J Hum Genet. 2016 in press.

  • Griffin NG, Wang Y, Hulette CM, Halvorsen M, Cronin KD, Walley NM5, Haglund MM, Rodney A. Radtke RA, Skene JHP, Sinha SR, Heinzen EL. Differential gene expression in dentate granule cells in mesial temporal lobe epilepsy with and without hippocampal sclerosis. Epilepsia. 2016, Mar 57(3):376-85.

  • EpiPM Consortium. A roadmap for precision medicine in the epilepsies. Lancet Neurology. 2015, Dec 14(12):1219-28.

  • Heinzen EL, Neale BM, Traynelis SF, Allen AS, Goldstein DB. Annu Rev Neurosci. 2015, Jul 8; 38:47-68.

  • EuroEPINOMICS-RES Consortium; Epilepsy Phenome/Genome Project; Epi4K Consortium. De Novo Mutations in Synaptic Transmission Genes Including DNM1 Cause Epileptic Encephalopathies. Am J Hum Genet. 2014, Oct 2;95(4):360-70.

  • Heinzen EL, Arzimanoglou A, Brashear A, Clapcote SJ, Gurrieri F, Goldstein DB, Jóhannesson SH, Mikati MA, Neville B, Nicole S, Ozelius LJ, Poulsen H, Schyns T, Sweadner KJ, van den Maagdenberg A, Vilsen B; ATP1A3 Working Group. Distinct neurological disorders with ATP1A3 mutations. Lancet Neurol. 2014, May;13(5):503-14. Review.

  • Epi4K Consortium and Epilepsy Phenome/Genome Project. De novo mutations in epileptic encephalopathies. Nature. 2013, Sept 12;501(7466):217-21.

  • Heinzen EL*, Swoboda KJ*, Hitomi Y*, Gurrieri F, Nicole S, de Vries B, Tiziano FD, Fontaine B, Walley NM, Heavin S, Panagiotakaki E; European Alternating Hemiplegia of Childhood (AHC) Genetics Consortium; Biobanca e Registro Clinico per l'Emiplegia Alternante (I.B.AHC) Consortium; European Network for Research on Alternating Hemiplegia (ENRAH) for Small and Medium-sized Enterpriese (SMEs) Consortium, Fiori S, Abiusi E, et al, Goldstein DB. De novo mutations in ATP1A3 cause alternating hemiplegia of childhood. Nat Genet. 2012, Sep;44(9):1030-4.

  • Poduri A, Evrony GD, Cai X, Elhosary PC, Hills L, Beroukhim R, Lehtinen MK, Heinzen EL, Hill A, Hill RS, Barry BJ, Bourgeois BFD, Riviello JJ, Barkovich AJ, Black PM, Ligon KL, Walsh CA. Somatic Activation of AKT3 Causes Hemispheric Developmental Brain Malformations. Neuron. 2012, Apr 12;74(1):41-8.

  • Heinzen EL, Depondt C, Cavalleri GL, Ruzzo EK, Walley NM, Need AC, Ge D, He M, Cirulli ET, Zhao Q, Cronin KD, Gumbs CE, Campbell CR, Hong LK, Maia JM, Shianna KV, McCormack M, O’Conner GD, Radtke RA, Mikati MA, Gallentine WB, Husain AM, Sinha SR, Chinthapalli K, Puranam RS, McNamara JO, Ottman R, Sisodiya SM, Norman Delanty*, Goldstein DB* Exome sequencing of idiopathic generalized epilepsy patients. Am J Hum Genet. 2012, Aug 10; 91(2):293-302.

  • Heinzen EL, Radtke RA, Urban TJ, Cavalleri GL, Depondt C, Need AC, Walley NM, Nicoletti P, Ge D, Catarino CB, Duncan JS, Kasperaviciūte D, Tate SK, Caboclo LO, Sander JW, Clayton L, Linney KN, Shianna KV, Gumbs CE, Smith J, Cronin KD, Maia JM, Doherty CP, Pandolfo M, Leppert D, Middleton LT, Gibson RA, Johnson MR, Matthews PM, Hosford D, Kälviäinen R, Eriksson K, Kantanen AM, Dorn T, Hansen J, Krämer G, Steinhoff BJ, Wieser HG, Zumsteg D, Ortega M, Wood NW, Huxley-Jones J, Mikati M, Gallentine WB, Husain AM, Buckley PG, Stallings RL, Podgoreanu MV, Delanty N, Sisodiya SM, Goldstein DB. Rare deletions at 16p13.11 predispose to a diverse spectrum of sporadic epilepsy syndromes. Am J Hum Genet. 2010, May 14;86(5):707-18.
  • Heinzen EL*, Ge D*, Cronin KD, Maia JM, Shianna KV, Gabriel WN, Welsh-Bohmer KA, Hulette CM, Denny TN, Goldstein DB. Tissue-specific genetic control of splicing: Implications for the study of complex traits. PLoS Biol. 2008, 6(12): e1000001.

Education

  • Pharm. D., University of North Carolina
  • Ph.D., Pharmacokinetics/Pharmacodynamics, University of North Carolina

Positions

  • Deputy Director of the Institute for Genomic Medicine
  • Assistant Professor, Department of Pathology & Cell Biology, Columbia University
  • Assistant Professor, Department of Medicine, Duke University