Pharmacogenetic profiling via genome sequencing in children with medical complexity

Amy Pan; Sierra Scodellaro; Tayyaba Khan; Inna Ushcatz; Wendy Wu; Meredith Curtis; Eyal Cohen; Ronald D Cohn; Robin Z Hayeems; M Stephen Meyn; Julia Orkin; Jaskiran Otal; Miriam S Reuter; Susan Walker; Stephen W Scherer; Christian R Marshall; Iris Cohn; Gregory Costain

doi:10.1038/s41390-022-02313-3

Pharmacogenetic profiling via genome sequencing in children with medical complexity

Pediatr Res. 2023 Mar;93(4):905-910. doi: 10.1038/s41390-022-02313-3. Epub 2022 Sep 27.

Authors

Amy Pan¹, Sierra Scodellaro^{2

3}, Tayyaba Khan¹, Inna Ushcatz¹, Wendy Wu¹, Meredith Curtis¹, Eyal Cohen^{4

5

6

7

8}, Ronald D Cohn^{1

4

5

9

10}, Robin Z Hayeems^{6

7

11}, M Stephen Meyn^{4

9

10

11

12}, Julia Orkin^{4

5

6}, Jaskiran Otal⁵, Miriam S Reuter¹³, Susan Walker¹³, Stephen W Scherer^{1

10

11

13}, Christian R Marshall^{11

13

14

15}, Iris Cohn^{2

3}, Gregory Costain^{16

17

18

19}

Affiliations

¹ Genetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, ON, Canada.
² Program in Translational Medicine, The Hospital for Sick Children, Toronto, ON, Canada.
³ Division of Clinical Pharmacology and Toxicology, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
⁴ Department of Paediatrics, University of Toronto, Toronto, ON, Canada.
⁵ Division of Paediatric Medicine, The Hospital for Sick Children, Toronto, ON, Canada.
⁶ Child Health Evaluative Sciences, Research Institute, The Hospital for Sick Children, Toronto, ON, Canada.
⁷ Institute of Health Policy Management and Evaluation, University of Toronto, Toronto, ON, Canada.
⁸ Edwin S.H. Leong Centre for Healthy Children, University of Toronto, Toronto, ON, Canada.
⁹ Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON, Canada.
¹⁰ Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
¹¹ Centre for Genetic Medicine, The Hospital for Sick Children, Toronto, ON, Canada.
¹² Center for Human Genomics and Precision Medicine, University of Wisconsin, Madison, WI, USA.
¹³ The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON, Canada.
¹⁴ Genome Diagnostics, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, ON, Canada.
¹⁵ Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
¹⁶ Genetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, ON, Canada. gregory.costain@sickkids.ca.
¹⁷ Department of Paediatrics, University of Toronto, Toronto, ON, Canada. gregory.costain@sickkids.ca.
¹⁸ Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON, Canada. gregory.costain@sickkids.ca.
¹⁹ Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada. gregory.costain@sickkids.ca.

Abstract

Background: Children with medical complexity (CMC) are a priority pediatric population, with high resource use and associated costs. Genome-wide sequencing is increasingly organized for CMC early in life as a diagnostic test. Polypharmacy becomes common as CMC age. Clinically relevant pharmacogenetic (PGx) information can be extracted from existing genome sequencing (GS) data via GS-PGx profiling. The role of GS-PGx profiling in the CMC population is unclear.

Methods: Prescribed medications were extracted from care plans of 802 eligible CMC enrolled in a structured Complex Care Program over a 10-year period. Drug-gene associations were annotated using curated Clinical Pharmacogenetics Implementation Consortium data. GS-PGx profiling was then performed for a subset of 50 CMC.

Results: Overall, 546 CMC (68%) were prescribed at least one medication with an established PGx association. In the GS-PGx subgroup, 24 (48%) carried variants in pharmacogenes with drug-gene guidelines for one or more of their current medications. All had findings of potential relevance to some medications, including 32 (64%) with variants in CYP2C19 that could affect their metabolism of proton-pump inhibitors.

Conclusion: GS-PGx profiling at the time of diagnostics-focused genetic testing could be an efficient way to incorporate precision prescribing practices into the lifelong care of CMC.

Impact: Polypharmacy and genetic test utilization are both common in children with medical complexity. The role of repurposing genome sequencing data for pharmacogenetic profiling in children with medical complexity was previously unclear. We identified a high rate of medication use with clinically relevant drug-gene associations in this priority pediatric population and demonstrated that relevant pharmacogenetic information can be extracted from their existing genome sequencing data. Pharmacogenetic profiling at the time of diagnostics-focused genetic testing could be an efficient way to incorporate precision prescribing practices into the lifelong care of children with medical complexity.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Child
Chromosome Mapping
Genetic Testing*
Humans
Pharmacogenetics*