Researchers Search Results

BC Children's Hospital Research Institute
Room 3060
950 West 28th Avenue
Vancouver, BC  V5Z 4H4

Genomics and functional genomics of human diseases (intellectual disability, autism and reproductive disorders).

My laboratory studies genomic abnormalities as the cause of human diseases. We use genomic microarrays to detect tiny chromosomal microdeletions and microduplications in patients with intellectual disability, autism or reproductive disorders. Most recently, we started using next generation sequencing to identify even smaller abnormalities in the DNA from our patients. Our current interest includes finding the functional consequences of gene copy number or sequence changes in patient cells and in animal models (e.g. zebrafish or C.elegans). Our ultimate goal is to understand better the connection between the phenotypic abnormalities in our patients and the defects in their genes.

1. Genomics of intellectual disability 
   Intellectual disability (ID) is a diagnosis given to persons who have life-long cognitive and adaptive impairments that commence in early life. ID affects about 1-3 per cent of the population, and cause remains unknown in at least 40 per cent of all cases. We are using chromosome microarray technology (CMA) and next generation sequencing to detect small chromosomal and DNA changes in children with ID. We are also interested in understanding how these changes affect the gene function by assessing RNA and protein expression as well as gene-specific pathways. For more information see http://www.research-europe.com/magazine/healthcare2/hc22/index.html.
2. Genomic changes in human miscarriages and their functional consequences
   Pregnancy loss is a significant health concern as 15 per cent of clinically recognized pregnancies end in miscarriage, with the highest rate in the first trimester. Although finding the cause of pregnancy loss is essential for prognosis, recurrence risk counseling, and the management of all future pregnancies, the cause remains unknown in 30-50 per cent of all cases. Our studies focus on finding the genomic cause of abnormal human embryo development and miscarriage. We have shown show that 30% of sporadic and recurrent miscarriages have small and unique chromosomal gains and losses, detectable only by CMA. These genomic abnormalities are frequently inherited from one of the parents and could represent predisposing genetic factors for recurrent pregnancy loss (RPL). Functional follow-up of candidate miscarriage genes in the pregnancy loss as well as the use of next generation sequencing to identify pathogenic mutation are currently the main focus of this study (for more information see http://www.cihr-irsc.gc.ca/e/43150.html).

Qiao Y, Mondal K, Trapani V, Wen J, Carpenter G, Wildin R, Price EM, Gibbons, RJ, Eichmeyer J, Jiang R, Dupont B, Martell S, Lewis SM, Robinson WP, O'Driscoll M, Wolf FI, Zwick ME, Rajcan-Separovic E. Variant ATRX Syndrome with Dysfunction of ATRX and MAGT1 Genes. Hum Mutat. 2013 Oct 15. doi: 10.1002/humu.22465. [Epub ahead of print] PubMed PMID: 24130152.

Qiao Y, Badduke C, Mercier E, Lewis SM, Pavlidis P, Rajcan-Separovic E. miRNA and miRNA target genes in copy number variations occurring in individuals with intellectual disability. BMC Genomics. 2013 Aug 10;14:544. doi: 10.1186/1471-2164-14-544. PubMed PMID: 23937676; PubMed Central PMCID: PMC3750877.

Bessa C, Ylstra B, Lewis S, Isoherranen N, Maciel P, Rajcan-Separovic E. Phenotypic and functional consequences of haploinsufficiency of genes from exocyst and retinoic acid pathway due to a recurrent microdeletion of 2p13.2. Orphanet J Rare Dis. 2013 Jul 10;8:100. doi: 10.1186/1750-1172-8-100. PubMed PMID: 23837398; PubMed Central PMCID: PMC3710273.

Wang P, Carrion P, Qiao Y, Tyson C, Hrynchak M, Calli K, Lopez-Rangel E, Andrieux J, Delobel B, Duban-Bedu B, Thuresson AC, Annerén G, Liu X, Rajcan-Separovic E, Suzanne Lewis ME. Genotype-phenotype analysis of 18q12.1-q12.2 copy number variation in autism. Eur J Med Genet. 2013 Aug;56(8):420-5. doi: 10.1016/j.ejmg.2013.05.006. Epub 2013 May 29. PubMed PMID: 23727450.

Rassekh SR, Rajcan-Separovic E. Comparative genomic hybridization of Wilms'
tumor. Methods Mol Biol. 2013;973:249-65. doi: 10.1007/978-1-62703-281-0_16.
Review. PubMed PMID: 23412795.

Zufferey F, Sherr EH, Beckmann ND, Hanson E, Maillard AM, Hippolyte L, Macé A, Ferrari C, Kutalik Z, Andrieux J, Aylward E, Barker M, Bernier R, Bouquillon S, Conus P, Delobel B, Faucett WA, Goin-Kochel RP, Grant E, Harewood L, Hunter JV, Lebon S, Ledbetter DH, Martin CL, Männik K, Martinet D, Mukherjee P, Ramocki MB, Spence SJ, Steinman KJ, Tjernagel J, Spiro JE, Reymond A, Beckmann JS, Chung WK, Jacquemont S; Simons VIP Consortium; 16p11.2 European Consortium. A 600 kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders. J Med Genet. 2012 Oct;49(10):660-8. doi: 10.1136/jmedgenet-2012-101203. PubMed PMID: 23054248; PubMed Central PMCID: PMC3494011.

Rajcan-Separovic E. Chromosome microarrays in human reproduction. Hum Reprod Update. 2012 Sep-Oct;18(5):555-67. doi: 10.1093/humupd/dms023. Epub 2012 Jun 2. Review. PubMed PMID: 22661549.

Qiao Y, Tyson C, Hrynchak M, Lopez-Rangel E, Hildebrand J, Martell S, Fawcett C, Kasmara L, Calli K, Harvard C, Liu X, Holden JJ, Lewis SM, Rajcan-Separovic E. Clinical application of 2.7M Cytogenetics array for CNV detection in subjects with idiopathic autism and/or intellectual disability. Clin Genet. 2013 Feb;83(2):145-54. doi: 10.1111/j.1399-0004.2012.01860.x. Epub 2012 Apr 9. PubMed PMID: 22369279. 

Malenfant P, Liu X, Hudson ML, Qiao Y, Hrynchak M, Riendeau N, Hildebrand MJ, Cohen IL, Chudley AE, Forster-Gibson C, Mickelson EC, Rajcan-Separovic E, Lewis ME, Holden JJ. Association of GTF2i in the Williams-Beuren syndrome critical region with autism spectrum disorders. J Autism Dev Disord. 2012 Jul;42(7):1459-69. doi: 10.1007/s10803-011-1389-4. PubMed PMID: 22048961.

Jacquemont S, Reymond A, Zufferey F, Ndiaye NC, Nordgren A, Pasquier, L, Petit F, Pfundt R, Plessis G, Rajcan-Separovic E, Ramelli GP, Rauch A, Ravazzolo R, Reis A, Renieri A, Richart C, Ried JS, Rieubland C, Roberts W, Roetzer KM, Rooryck C, Rossi M, Saemundsen E, Satre V, Schurmann C, Sigurdsson E, Stavropoulos DJ, Stefansson H, Tengström C…Estivill X, Gusella, JF, Gustafsson O, Metspalu A, Scherer SW, Stefansson K, Blakemore AI, Beckmann, JS, Froguel P. Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus. Nature. 2011 Aug 31;478(7367):97-102. doi: 10.1038/nature10406. PubMed PMID: 21881559; PubMed Central PMCID: PMC3637175.

Harvard C, Strong E, Mercier E, Colnaghi R, Alcantara D, Chow E, Martell S, Tyson C, Hrynchak M, McGillivray B, Hamilton S, Marles S, Mhanni A, Dawson AJ, Pavlidis P, Qiao Y, Holden JJ, Lewis SM, O'Driscoll M, Rajcan-Separovic E. Understanding the impact of 1q21.1 copy number variant. Orphanet J Rare Dis. 2011 Aug 8;6:54. doi: 10.1186/1750-1172-6-54. PubMed PMID: 21824431; PubMed Central PMCID: PMC3180300.

Liu X, Malenfant P, Reesor C, Lee A, Hudson ML, Harvard C, Qiao Y, Persico, AM, Cohen IL, Chudley AE, Forster-Gibson C, Rajcan-Separovic E, Lewis ME, Holden, JJ. 2p15-p16.1 microdeletion syndrome: molecular characterization and association of the OTX1 and XPO1 genes with autism spectrum disorders. Eur J Hum Genet. 2011 Dec;19(12):1264-70. doi: 10.1038/ejhg.2011.112. Epub 2011 Jul 13. PubMed PMID: 21750575; PubMed Central PMCID: PMC3230356.

Rajcan-Separovic E, Diego-Alvarez D, Robinson WP, Tyson C, Qiao Y, Harvard C, Fawcett C, Kalousek D, Philipp T, Somerville MJ, Stephenson MD. Identification of copy number variants in miscarriages from couples with idiopathic recurrent pregnancy loss. Hum Reprod. 2010 Nov;25(11):2913-22. doi: 10.1093/humrep/deq202. Epub 2010 Sep 16. PubMed PMID: 20847186.

Qiao Y, Harvard C, Tyson C, Liu X, Fawcett C, Pavlidis P, Holden JJ, Lewis ME, Rajcan-Separovic E. Outcome of array CGH analysis for 255 subjects with intellectual disability and search for candidate genes using bioinformatics. Hum Genet. 2010 Aug;128(2):179-94. doi: 10.1007/s00439-010-0837-0. Epub 2010 May 29. PubMed PMID: 20512354.

Rajcan-Separovic E, Qiao Y, Tyson C, Harvard C, Fawcett C, Kalousek D, Stephenson M, Philipp T. Genomic changes detected by array CGH in human embryos with developmental defects. Mol Hum Reprod. 2010 Feb;16(2):125-34. doi: 10.1093/molehr/gap083. Epub 2009 Sep 23. PubMed PMID: 19778950.

Qiao Y, Riendeau N, Koochek M, Liu X, Harvard C, Hildebrand MJ, Holden JJ, Rajcan-Separovic E, Lewis ME. Phenomic determinants of genomic variation in autism spectrum disorders. J Med Genet. 2009 Oct;46(10):680-8. doi: 10.1136/jmg.2009.066795. Epub 2009 Jul 21. PubMed PMID: 19625284.

Rajcan-Separovic E, Harvard C, Liu X, McGillivray B, Hall JG, Qiao Y, Hurlburt J, Hildebrand J, Mickelson EC, Holden JJ, Lewis ME. Clinical and molecular cytogenetic characterisation of a newly recognised microdeletion syndrome involving 2p15-16.1. J Med Genet. 2007 Apr;44(4):269-76. Epub 2006 Sep 8. PubMed PMID: 16963482; PubMed Central PMCID: PMC2598046.

CIHR Clinical Investigatorship salary award - 2005-2009
Michael Smith Foundation for Health Research, Career Scholar Award, 2008-2014
Fellow of the Canadian College of Medical Genetics (subspecialty cytogenetics), 1998

• Dr Ying Qiao – Research Associate
• Dr Jiadi Wen – Postdoctoral Fellow
• Chansonette Harvard – PhD Student
• Hani Bagheri – PhD Student
• Jila Dastan – PhD Student
• Sally Martell – Research Assistant 
• Kristina Calli – Research Assistant
• Flamingo Tang – Undergraduate Academic Assistant
• Jane Hurburt – Genetic Counselor