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MDC

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Molecular Diagnostics Core (NS090362)


Specific Aims and Tasks

Provide DNA sequencing and analysis of samples from individuals with epilepsy who have died prematurely or who have a high clinical risk of SUDEP
  1. Sample preparation, logging, and organization of human specimens and induced pluripotent stem cells (iPSCs) provided by Project 1 (Goldman, SUDEP cases) and Project 3 (Parent/IPSCs of Dravet Syndrome cases), and the Clinical Network. All submitted sampes will be prepared with optimal quality control, issued uniform identifiers, and submitted for sequencing.
  2. Genomic variant detection in DNA samples using multiple analysis platforms. This aim will enable research discovery of novel SUDEP genes and profiles.
  3. Variant consolidation, curation, and analysis. This step allows detection and profiling
  4. Detection of deleterious mutations in known SUDEP risk genes in living epilepsy patients. De novo mutations in known LQT genes linked to SUDEP will be translated into clinical practice by contacting the referring physician with advice to seek additional physician referral, CLIA approved testing, and genetic counseling where appropriate.
  5. Provide a web-based interface for secure interactive variant curation and data sharing. This will facilitate the discovery process and cohort refinement for planned studies to integrate research genomics data and clinical electrophysiological data by working with SRA project directors to develop a predictive risk assessment algorithm for epilepsy patients and their families, and precision molecular autopsy of SUDEP cases. This step will manage submission of all DNA sequence data and phenotype into NIH public repositories (dbGAP).

The Core will also assist the Administrative core to optimize case resource utilization and facilitate data exchange, analysis, and communication among the SRA projects, cores, and research stakeholders (NINDS, advocacy groups, and patients).

Principal Investigators



Core Personnel

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Eric Raap

Core Administrator

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Chad Shaw, PhD

Core Investigator



Publication Links

  • Lalani SR, Safiullah AM, Fernbach SD, Harutyunyan KG, Thaller C, Peterson LE, McPherson JD, Gibbs RA, White LD, Hefner M, Davenport SL, Graham JM, Bacino CA, Glass NL, Towbin JA, Craigen WJ, Neish SR, Lin AE, Belmont JW. Spectrum of CHD7 Mutations in 110 Individuals with CHARGE Syndrome and Genotype-Phenotype Correlation. PMID 16400610.
  • Altshuler D, Brooks LD, Chakravarti A, Collins FS, Daly MJ, Donnelly P; International HapMap Consortium. A haplotype map of the human genome. PMID 16255080.
  • Frazer KA, Ballinger DG, Cox DR et al: A second generation human haplotype map of over 3.1 million SNPs. PMID 17943122.
  • McBride, K.L., Zender, G.A., Fitzgerald-Butt, S.M., Koehler, D., Menesses-Diaz, A., Fernbach, S., Lee, K., Towbin, J.A., Leal, S. and Belmont, J.W. Linkage analysis of left ventricular outflow tract malformations (aortic valve stenosis, coarctation of the aorta, and hypoplastic left heart syndrome). PMID 19142209.
  • Prakash S, Lemaire SA, Bray M, Milewicz DM, Belmont JW. Large deletions and uniparental disomy detected by SNP arrays in adults with thoracic aortic aneurysms and dissections. PMID 20683997.
  • Prakash SK, LeMaire SA, Guo DC, Russell L, Regalado ES, Golabbakhsh H, Johnson RJ, Safi HJ, Estrera AL, Coselli JS, Bray MS, Leal SM, Milewicz DM, Belmont JW. Rare copy number variants disrupt genes regulating vascular smooth muscle cell adhesion and contractility in sporadic thoracic aortic aneurysms and dissections. PMID 21092924.
  • Bucasas KL, Franco LM, Shaw CA, Bray MS,4 Wells JM, Nino D, Arden N, Quarles JM,Couch RB, Belmont JW. Early Patterns of Gene Expression Correlate with the Humoral Immune Response to Influenza Vaccination in Humans, PMID 21357945.
  • Lemaire SA, McDonald ML, Guo DC, Russell L, Miller CC, 3rd, Johnson RJ, Bekheirnia MR, Franco LM, Nguyen M, Pyeritz RE, Bavaria JE, Devereux R, Maslen C, Holmes KW, Eagle K, Body SC, Seidman C, Seidman JG, Isselbacher EM, Bray M, Coselli JS, Estrera AL, Safi HJ, Belmont JW, Leal SM, Milewicz DM. Genome-wide association study identifies a susceptibility locus for thoracic aortic aneurysms and aortic dissections spanning FBN1 at 15q21.1. PMID 21909107.
  • Kuang SQ, Guo DC, Prakash SK, McDonald ML, Johnson RJ, Wang M, Regalado ES, Russell L, Cao JM, Kwartler C, Fraivillig K, Coselli JS, Safi HJ, Estrera AL, Leal SM, Lemaire SA, Belmont JW, Milewicz DM. Recurrent chromosome 16p13.1 duplications are a risk factor for aortic dissections. PMID 21698135.
  • French VM, van de Laar IM, Wessels MW, Rohe C, Roos-Hesselink JW, Wang G, Frohn-Mulder IM, Severijnen LA, de Graaf BM, Schot R, Breedveld G, Mientjes E, van Tienhoven M, Jadot E, Jiang Z, Verkerk A, Swagemakers S, Venselaar H, Rahimi Z, Najmabadi H, Meijers-Heijboer H, de Graaff E, Helbing WA, Willemsen R, Devriendt K, Belmont JW, Oostra BA, Amack JD, Bertoli-Avella AM. NPHP4 Variants Are Associated With Pleiotropic Heart Malformations. PMID 22550138.
  • Jiang Z, Zhu L, Hu L, Slesnick TC, Pautler RG, Justice MJ, Belmont JW. 2013. Zic3 is required in the extra-cardiac perinodal region of the lateral plate mesoderm for left-right patterning and heart development. PMID 23184148.
  • Lalani SR, Shaw C, Wang X, Patel A, Patterson LW, Kolodziejska K, Szafranski P, Ou Z, Tian Q, Kang SH, Jinnah A, Ali S, Malik A, Hixson P, Potocki L, Lupski JR, Stankiewicz P, Bacino CA, Dawson B, Beaudet AL, Boricha FM, Whittaker R, Li C, Ware SM, Cheung SW, Penny DJ, Jefferies JL, Belmont JW. 2013. Rare DNA copy number variants in cardiovascular malformations with extracardiac abnormalities. European journal of human genetics : PMID 22929023.
  • Lalani SR, Ware SM, Wang X, Zapata G, Tian Q, Franco LM, Jiang Z, Bucasas K, Scott DA, Campeau PM, Hanchard N, Umaña L, Cast A, Patel A, Cheung SW, McBride KL, Bray M, Craig Chinault A, Boggs BA, Huang M, Baker MR, Hamilton S, Towbin J, Jefferies JL, Fernbach SD, Potocki L, Belmont JW. MCTP2 is a dosage-sensitive gene required for cardiac outflow tract development. PMID 23773997.
  • Franco LM, Bucasas KL, Wells JM, Niño D, Wang X, Zapata GE, Arden N, Renwick A, Yu P, Quarles JM, Bray MS, Couch RB, Belmont JW, Shaw CA.Integrative genomic analysis of the human immune response to influenza vaccination. Elife. PMID 23878721.
  • Carvalho CM, Pehlivan D, Ramocki MB, Fang P, Alleva B, Franco LM, Belmont JW, Hastings PJ, Lupski JR.Replicative mechanisms for CNV formation are error prone. PMID 24056715.