Genetics

The Regional Genetics Program at CHEO conducts research in virtually all areas of clinical and laboratory genetics.

Areas of research include, but are not limited to:

  • Rare disease gene discovery
  • Describing new genetic conditions
  • Finding new clinical or laboratory characteristics of existing genetic conditions
  • Finding new ways to test for genetic conditions
  • Learning about the impact of genetic conditions on patients and families
  • Finding the best way to provide genetic counseling to patients and families

Research Projects

  1. Assessment of longitudinal bone growth in osteogenesis imperfecta using metacarpophalangeal pattern profiles

    27/07/2020

    COL1A1 and COL1A2 mutations affect bone growth not only by inducing fractures and bone deformities, but also through longitudinal growth deficits in bones that do not fracture or deform.

  2. Musculoskeletal phenotype in two unrelated individuals with a recurrent nonsense variant in SGMS2

    06/05/2020

    Bisphosphonates seem to be effective at treating SGMS2-associated osteoporosis.

  3. ALU transposition induces familial hypertrophic cardiomyopathy

    01/09/2019

    Our results demonstrate that haploinsufficiency resulting from MYBPC3 complete deletion, potentially mediated by Alu recombination, is an important disease mechanism in cardiomyopathy and emphasizes the importance of copy number variation analysis in patients clinically suspected of HCM.

  4. Mendelian bone fragility disorders

    01/09/2019

    Interestingly, large sequencing databases indicate that there are about 10 times more carriers of COL1A1/COL1A2 variants that should lead to OI than there are individuals with a diagnosis of OI.

  5. Salbutamol modifies the neuromuscular junction in a mouse model of ColQ myasthenic syndrome

    04/07/2019

    Motor neurons contact their target muscle fibres at highly specialised chemical synapses, neuromuscular junctions (NMJ).

  6. Adopting High-Resolution Allele Frequencies Substantially Expedites Variant Interpretation in Genetic Diagnostic Laboratories

    01/07/2019

    these data demonstrate that implementing FAF thresholds may considerably decrease the amount of variant interpretations and significantly reduce the cost of genetic testing for clinical genetic laboratories, without compromising the accuracy of genetic diagnostic services.

  7. Genetic Diagnostic Testing for Inherited Cardiomyopathies: Considerations for Offering Multi-Gene Tests in a Health Care Setting

    01/05/2019

    Our genetics diagnostic laboratory has been providing clinical diagnostic testing for ICs since 2012. We began by testing nine genes and expanded our panel by fivefold in 2015.

  8. Analyses of Adverse Drug Reactions-Nationwide Active Surveillance Network: Canadian Pharmacogenomics Network for Drug Safety Database

    04/03/2019

    Adverse drug reactions (ADRs) are a major problem in modern medicine, representing up to the fourth‐highest cause of mortality.

  9. A phase 3 randomized study evaluating sialic acid extended-release for GNE myopathy

    25/01/2019

    This study provides Class I evidence that for patients with GNE myopathy, Ace-ER does not improve muscle strength compared to placebo.

  10. Epilepsy genetics: Current knowledge, applications, and future directions

    01/07/2018

    Drug screening with in vitro and in vivo models of epilepsy can potentially facilitate new treatment strategies.

  11. Reinterpretation of sequence variants: one diagnostic laboratory’s experience, and the need for standard guidelines

    02/03/2018

    Ongoing variant reinterpretation is required to maintain the highest standards for delivering genetics laboratory services.

  12. Histone H3K36 mutations promote sarcomagenesis through altered histone methylation landscape

    30/06/2016

    We present evidence that the H3K36M mutation plays a driver role in the development of mesenchymal neoplasms through impaired differentiation of MPCs. Although H3.1 and H3.3 K36M are found at different genomic locations, they result in the same genome-wide changes in chromatin landscape, gene expression profile, and tumorigenic capacity. These data imply that the specific genomic locations of H3K36M-containing nucleosomes are relatively unimportant for K36M's function. While other non-mutually exclusive mechanisms may be involved (19), the dominant inhibition of H3K36 methyltransferases is a critical downstream event mediating H3K36M's differentiation-arresting potential. The concurrent inactivation of multiple methyltransferases via a single missense mutation in histone H3 provides an efficient means to "lock" cells into an aberrant chromatin state that, in the context of mesenchymal progenitors, promotes neoplastic transformation. Our study highlights an underappreciated role of intergenic H3K36 methylation in polycomb complex recruitment through the antagonization of H3K27me3 propagation (20, 21) and demonstrate that modest alterations to the intergenic to gene-associated H3K27me3 ratio can have profound outcomes on polycomb-mediated gene silencing. We speculate that similar mechanisms may underlie other human cancers where histone H3K27 and K36-directed enzymes are frequently dysregulated.

  13. Utility of whole‐exome sequencing for those near the end of the diagnostic odyssey: time to address gaps in care

    01/03/2016

    In the next decade we will witness a paradigm shift in the way we care for patients with rare genetic diseases, addressing a significant gap in the management of individuals with rare diseases. The diagnostic journey for patients will include clinical genomic sequencing, which in the not too distant future will be WGS as costs decrease with new platforms. The accessibility of WGS‐based diagnostics for patients will be central to understanding the complete compendium of human genetic pathology. Strategies and infrastructure should be put in place to facilitate discovery in clinical settings, and to further mine large phenotypic and genomic datasets for disease mechanisms. As we understand the etiology of more rare diseases, it is probable that we will increasingly implicate known genes and that the approach to the completion of the complete Mendelian dataset will be asymptotic. There will be a subset of rare diseases that are due to non‐coding mutations in regulatory regions that may be more readily identified with the imminent use of WGS and RNA sequencing, and to implicate and understand this type of variation will require large‐scale data sharing at an impressive level. Ultimately, such datasets will be instrumental in identifying modifiers of disease, providing insight into phenotypic variability, prognosis, and for a subset of diseases, identifying drug targets. Finally, NGS technologies are providing significant opportunities to implement personalized health strategies including prevention or early detection of disease, improved health maintenance, and development of tailored therapy for patients with rare genetic diseases.

  14. Novel WDR45 Mutation and Pathognomonic BPAN Imaging in a Young Female With Mild Cognitive Delay

    04/09/2015

    Pregnancy and birth history were unremarkable. Gross and fine motor developmental milestones were achieved at appropriate times during childhood; however, her mother reported a long-standing history of expressive and receptive language difficulties requiring speech language therapy until grade 8.

  15. Biallelic Mutations in BRCA1 Cause a New Fanconi Anemia Subtype

    01/08/2015

    The proband presented at birth with microsomia and dysmorphic features (Fig. 1A). Growth parameters were less than the 0.4 percentile at term (birth weight 1990g, height 40.5 cm, head circumference (HC) 27 cm), and subsequent catch-up growth was not evident at 25 years of age (weight 40 kg, −3.03 S.D.; 135 cm tall, −4.35 S.D.; HC 48.5 cm, approx.−4 to −5 S.D.). Additional congenital abnormalities included sparse hair, upslanted palpebral fissures, blepharophimosis, a narrow palate, dental malocclusion, a high-pitched and hoarse voice, hyper and hypopigmented skin lesions, duodenal stenosis and a slightly enlarged left kidney. She has proximally inserted thumbs (Fig. 1A), 2nd digit camptodactyly, 2–3 toe syndactyly and hyperextensible knees as well as a history of hip dislocation. Conductive hearing loss was diagnosed at 4 years of age. Bone age at 2y 3m was delayed (1y and 6m (−2S.D.)), but had normalized by 9 years. The patient also has mild intellectual disability with significantly delayed speech. At 23 years of age she was diagnosed with ductal breast carcinoma that was estrogen and progesterone receptor positive and Her2 negative. Mastectomy was performed followed by treatment with docetaxel, fluorouracil-epirubicin-cyclophosphamide and radiation therapy. A prophylactic mastectomy was performed on the contralateral breast at age 25. The patient did not experience unusual treatment associated toxicity and has not been diagnosed with bone marrow failure to date.

  16. Immunohistochemistry (IHC) Predicts High Risk Cytogenetics in Acute Myeloid Leukemia (AML)

    14/01/2015

    p53 Immunohistochemistry staining was performed on bone marrow clot and biopsy sections from AML patients diagnosed from January 2007-January 2009 and with successful cytogenetic analysis done by standard methods. 

  17. Evidence for Clinical, Genetic and Biochemical Variability in Spinal Muscular Atrophy With Progressive Myoclonic Epilepsy

    01/12/2014

    The results of the WES and the functional studies prompted an electromyography (EMG) study that showed evidence of motor neuron disease despite only mild proximal muscle weakness.

  18. Targeted therapies for congenital myasthenic syndromes: systematic review and steps towards a treatabolome

    We assess the strength and quality of the evidence and create a dataset that provides the foundation for a computer-aided system to enable clinicians to gain easier access to information about treatable variants and the evidence they need to consider.

Researchers

  1. Tommy Michel Alain

    Scientist, CHEO Research Institute

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  2. Kym M Boycott

    Senior Scientist, CHEO Research Institute

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  3. Melissa Carter

    Investigator, CHEO Research Institute

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  4. David A. Dyment

    Investigator, CHEO Research Institute

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  5. Olga Jarinova

    Investigator, CHEO Research Institute

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  6. Nathalie Lepage

    Investigator, CHEO Research Institute

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  7. Mira F Liebman

    Investigator, CHEO Research Institute

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  8. Hanns Lochmüller

    Senior Scientist, CHEO Research Institute

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  9. Michelle Long

    Investigator, CHEO Research Institute

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  10. Alex MacKenzie

    Senior Scientist, CHEO Research Institute

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  11. Jean McGowan-Jordan

    Investigator, CHEO Research Institute

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  12. Marie-Eve Robinson

    Investigator, CHEO Research Institute

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  13. Sarah Sawyer

    Investigator, CHEO Research Institute

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  14. Régis Vaillancourt

    Investigator, CHEO Research Institute

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  15. Jodi Warman

    Scientist, CHEO Research Institute

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Family Leaders

  1. Andrew McVey

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  2. Andy Statia

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  3. Anne Maloney

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  4. Barb Shantz

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  5. Bina Sharma

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  6. Bleadon Anderson

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  7. Carolyn Stiff

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  8. Christine Dalgleish

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  9. Claire Dawe-McCord

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  10. Ellen Song

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  11. Erin Fobert

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  12. Haishan Chen

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  13. Jaime Waitman

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  14. Jessica Hay

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  15. Kate Stevens

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  16. Keira Danson

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  17. Krista Byrne

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  18. Laurie Woodward

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  19. Leanne van der Zweep

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  20. Linda Lefebvre

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  21. Lisa Wadden

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  22. Madleen Zapata-Martinez

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  23. Mairead Green

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  24. Mariann Michael

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  25. Samantha Bellefeuille

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  26. Sheena Murphy

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  27. Shelley Frappier

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  28. Sophie Dagenais

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  29. Tysen Lefebvre

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