Oleg Iartchouk

Publications (5)97.12 Total impact

• Source

  Available from: Stephan Ripke

  Article: A rare penetrant mutation in CFH confers high risk of age-related macular degeneration.

  Soumya Raychaudhuri, Oleg Iartchouk, Kimberly Chin, Perciliz L Tan, Albert K Tai, Stephan Ripke, Sivakumar Gowrisankar, Soumya Vemuri, Kate Montgomery, Yi Yu, Robyn Reynolds, Donald J Zack, Betsy Campochiaro, Peter Campochiaro, Nicholas Katsanis, Mark J Daly, Johanna M Seddon
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  ABSTRACT: Two common variants in the gene encoding complement factor H (CFH), the Y402H substitution (rs1061170, c.1204C>T)(1-4) and the intronic rs1410996 SNP(5,6), explain 17% of age-related macular degeneration (AMD) liability. However, proof for the involvement of CFH, as opposed to a neighboring transcript, and knowledge of the potential mechanism of susceptibility alleles are lacking. Assuming that rare functional variants might provide mechanistic insights, we used genotype data and high-throughput sequencing to discover a rare, high-risk CFH haplotype with a c.3628C>T mutation that resulted in an R1210C substitution. This allele has been implicated previously in atypical hemolytic uremic syndrome, and it abrogates C-terminal ligand binding(7,8). Genotyping R1210C in 2,423 AMD cases and 1,122 controls demonstrated high penetrance (present in 40 cases versus 1 control, P = 7.0 × 10(-6)) and an association with a 6-year-earlier onset of disease (P = 2.3 × 10(-6)). This result suggests that loss-of-function alleles at CFH are likely to drive AMD risk. This finding represents one of the first instances in which a common complex disease variant has led to the discovery of a rare penetrant mutation.
  Nature Genetics 12/2011; 43(12):1232-6. · 35.53 Impact Factor
• Article: Use of whole genome sequencing to estimate the mutation rate of Mycobacterium tuberculosis during latent infection.

  Christopher B Ford, Philana Ling Lin, Michael R Chase, Rupal R Shah, Oleg Iartchouk, James Galagan, Nilofar Mohaideen, Thomas R Ioerger, James C Sacchettini, Marc Lipsitch, JoAnne L Flynn, Sarah M Fortune
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  ABSTRACT: Tuberculosis poses a global health emergency, which has been compounded by the emergence of drug-resistant Mycobacterium tuberculosis (Mtb) strains. We used whole-genome sequencing to compare the accumulation of mutations in Mtb isolated from cynomolgus macaques with active, latent or reactivated disease. We sequenced 33 Mtb isolates from nine macaques with an average genome coverage of 93% and an average read depth of 117×. Based on the distribution of SNPs observed, we calculated the mutation rates for these disease states. We found a similar mutation rate during latency as during active disease or in a logarithmically growing culture over the same period of time. The pattern of polymorphisms suggests that the mutational burden in vivo is because of oxidative DNA damage. We show that Mtb continues to acquire mutations during disease latency, which may explain why isoniazid monotherapy for latent tuberculosis is a risk factor for the emergence of isoniazid resistance.
  Nature Genetics 05/2011; 43(5):482-6. · 35.53 Impact Factor
• Article: Evaluation of second-generation sequencing of 19 dilated cardiomyopathy genes for clinical applications.

  Sivakumar Gowrisankar, Jordan P Lerner-Ellis, Stephanie Cox, Emily T White, Megan Manion, Kevin LeVan, Jonathan Liu, Lisa M Farwell, Oleg Iartchouk, Heidi L Rehm, Birgit H Funke
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  ABSTRACT: Medical sequencing for diseases with locus and allelic heterogeneities has been limited by the high cost and low throughput of traditional sequencing technologies. "Second-generation" sequencing (SGS) technologies allow the parallel processing of a large number of genes and, therefore, offer great promise for medical sequencing; however, their use in clinical laboratories is still in its infancy. Our laboratory offers clinical resequencing for dilated cardiomyopathy (DCM) using an array-based platform that interrogates 19 of more than 30 genes known to cause DCM. We explored both the feasibility and cost effectiveness of using PCR amplification followed by SGS technology for sequencing these 19 genes in a set of five samples enriched for known sequence alterations (109 unique substitutions and 27 insertions and deletions). While the analytical sensitivity for substitutions was comparable to that of the DCM array (98%), SGS technology performed better than the DCM array for insertions and deletions (90.6% versus 58%). Overall, SGS performed substantially better than did the current array-based testing platform; however, the operational cost and projected turnaround time do not meet our current standards. Therefore, efficient capture methods and/or sample pooling strategies that shorten the turnaround time and decrease reagent and labor costs are needed before implementing this platform into routine clinical applications.
  The Journal of molecular diagnostics: JMD 11/2010; 12(6):818-27. · 3.48 Impact Factor
• Article: Filter-based hybridization capture of subgenomes enables resequencing and copy-number detection.

  Daniel S Herman, G Kees Hovingh, Oleg Iartchouk, Heidi L Rehm, Raju Kucherlapati, J G Seidman, Christine E Seidman
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  ABSTRACT: To exploit contemporary sequencing technologies for targeted genetic analyses, we developed a hybridization enrichment strategy for DNA capture that uses PCR products as subgenomic traps. We applied this strategy to 115 kilobases of the human genome encompassing 47 genes implicated in cardiovascular disease. Massively parallel sequencing of captured subgenomic libraries interrogated 99.8% of targeted nucleotides >or=20 times ( approximately 40,000-fold enrichment), enabling sensitive and specific detection of sequence variation and copy-number variation.
  Nature Methods 06/2009; 6(7):507-10. · 19.28 Impact Factor
• Article: SOS1 mutations are rare in human malignancies: implications for Noonan Syndrome patients.

  Kenneth D Swanson, Jordan M Winter, Marcelo Reis, Mohamed Bentires-Alj, Heidi Greulich, Rupinder Grewal, Ralph H Hruban, Charles J Yeo, Yosuf Yassin, Oleg Iartchouk, Kate Montgomery, Susan P Whitman, Michael A Caligiuri, Mignon L Loh, D Gary Gilliland, A Thomas Look, Raju Kucherlapati, Scott E Kern, Matthew Meyerson, Benjamin G Neel
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  ABSTRACT: Germ line gain-of-function mutations in several members of the RAS/ERK pathway, including PTPN11, KRAS, and RAF1, cause the autosomal dominant genetic disorder Noonan Syndrome (NS). NS patients are at increased risk of leukemia/myeloproliferative disease and possibly some solid tumors, such as neuroblastoma. Recently, SOS1 gain of function mutations have also been shown to cause NS. Somatic PTPN11, KRAS, and RAF1 mutations occur (although at different frequencies) in a variety of sporadic neoplasms, but whether SOS1 mutations are associated with human cancer has not been evaluated. We sequenced DNA from a total of 810 primary malignancies, including pancreatic, lung, breast, and colon carcinomas, and acute myelogenous leukemia, as well as several neuroblastoma cell lines. From this large, diverse series, missense SOS1 mutations were identified in a single pancreatic tumor, one lung adenocarcinoma, and a T-cell acute lymphoblastic leukemia cell line. Our findings suggest that SOS1 is not a significant human oncogene in most cancers. Furthermore, NS patients with SOS1 mutations may not be at increased risk of developing cancer.
  Genes Chromosomes and Cancer 04/2008; 47(3):253-9. · 3.31 Impact Factor