Article Text

PDF
MG-108 Beyond the ACMG 56: Parental choices and initial results from a comprehensive whole genome sequencing-based search for predictive genomic variants in children
  1. MStephen Meyn1,2,3,4,5,
  2. Nasim Monfared2,
  3. Christian R Marshall6,7,
  4. Daniele Merico1,6,
  5. Dimitri J Stavropoulos7,8,
  6. Robin Z Hayeems2,9,
  7. Michael Szego6,10,11,
  8. Rebekah Jobling4,
  9. Marta Girdea1,12,
  10. Gary D Bader3,13,
  11. Michael Brudno1,12,
  12. Ronald D Cohn1,2,3,4,
  13. Stephen W Scherer1,2,3,6,14,
  14. Randi Zlotnik Shaul5,10,15,
  15. Cheryl Shuman3,4,
  16. Peter N Ray1,2,3,6,7,
  17. Sarah Bowdin2,4,5
  1. 1Program in Genetics and Genome Biology, Hospital for Sick Children, Toronto, ON, Canada
  2. 2Centre for Genetic Medicine, The Hospital for Sick Children, Toronto, ON, Canada
  3. 3Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
  4. 4Division of Clinical and Metabolic Genetics, Department of Paediatrics, The Hospital for Sick Children, Toronto, ON, Canada
  5. 5Department of Paediatrics, University of Toronto, Toronto, ON, Canada
  6. 6The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON, Canada
  7. 7Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, ON, Canada
  8. 8Department of Laboratory Medicine and Pathology, University of Toronto, Toronto, ON, Canada
  9. 9Program in Child Health Evaluative Sciences, Hospital for Sick Children, Toronto, ON, Canada
  10. 10Joint Centre for Bioethics, University of Toronto, Toronto, ON, Canada
  11. 11Centre for Clinical Ethics, St. Joseph’s Health Centre, Toronto, ON, Canada
  12. 12Department of Computer Science, University of Toronto, Toronto, ON, Canada
  13. 13The Donnelly Centre, University of Toronto, Toronto, ON, Canada
  14. 14McLaughlin Centre, University of Toronto, Toronto, ON, Canada
  15. 15Department of Bioethics, The Hospital for Sick Children, Toronto, ON, Canada

Abstract

Objective The overall goal of the SickKids Genome Clinic is to pilot paediatric genomic medicine. To this end we have assessed parental interest in predictive secondary medically-actionable variants (MAVs) and used whole genome sequencing (WGS) to determine the frequency and nature of these MAVs in children.

Design The Genome Clinic conducts diagnostic WGS for 150+ children/year who are undergoing genetic evaluations. With parents’ permission, we search children’s genomes for predictive MAVs in 2800+ disease genes listed in the NIH Clinical Genomic Database.

Results Of 373 families approached to date, 56% agreed to participate. 58% of participants chose to learn their child’s secondary adult-onset MAVs. Among these parents, 79% decided to learn their own status for these variants. Bioinformatics analysis of the first 100 patient genomes yielded 2957 candidate variants in 1132 genes (~30 variants/genome). ~70% of candidates were listed in HGMD. However, subsequent manual assessment rejected >90% of variants for dominant diseases listed in HGMD as disease causing due to inadequate evidence of pathogenicity. After manual assessment, 33/100 children had at least one reportable predictive MAV. 9 MAVs occurred in a 2013 ACMG-guideline reportable gene. Expanding our search 50 fold to include 2800+ disease genes yielded 29 additional reportable predictive MAVs. Return of predictive MAVs and assessment of their penetrance is underway.

Conclusions Parental opinions vary widely regarding return of predictive MAVs and comprehensive genomic analysis can yield predictive MAVs in 1/3 of children, with the number of reportable predictive MAVs constrained by disease prevalence and imperfect variant interpretation.

Statistics from Altmetric.com

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.