Precision Child Health – Comprehensive Sequencing for Childhood Life-long Disorders

Disorders of childhood are highly penetrant, heritable, often polygenic and have lifelong impact, especially as advances in medicine have resulted in improved survival into adulthood. These disorders engender a high burden on patients, families and healthcare resources across a lifetime. Early diagnosis is essential to inform preventive and pre-emptive management to reduce complications and improve survival and quality of life. The yield from conventional genetic testing is suboptimal in disorders with genetic heterogeneity. Whole genome sequencing (GS) provides comprehensive genetic characterization by exploring both rare and common alterations not only the protein-coding regions but also variants in the “dark matter” of the genome, complex structural variants, tandem repeat expansions, and regulatory variants in the noncoding genome. The goal of the Precision Child Health (PCH) – Comprehensive Sequencing for Childhood Life-long Onset disorders (PCHSeq) project is to leverage the power of genomics to enable early and more accurate diagnosis and prediction of health trajectory and identification of novel therapeutic targets to guide personalized care and improve outcomes. The backbone of these efforts is the generation of short-read GS on DNA samples from 9,500 participants (including family members) with a diversity of childhood onset disorders coupled with long read sequencing (LRS) in a subset of 800 “genotype-elusive” patients. With access to a highly diverse patient population with rare and complex disorders referred to SickKids from Ontario and across the country, the PCHSeq team has already enrolled 9,296 potentially eligible participants with childhood onset disorders into existing biobanks. The cohorts are clinically and geographically diverse, with sex and ethnic composition reflecting that of the larger Canadian population. In addition to these existing eligible participants, 3,500 new participants will be recruited using a targeted approach to invite patients from underserved communities to participate. Overall, this study will provide a rich genomic dataset linked to clinical phenotypes and other molecular/omics datasets that are representative of the ethnic and clinical diversity of Canadians across a spectrum of childhood-onset disorders that have life-long impact. Immediate clinical impact will be achieved through return of medically actionable findings to physicians and participants after review by SickKids Genome Board. Health technology assessment will be performed to assess patient and community perspectives on use of GS as a clinical diagnostic test. Industry collaborations will focus on development of targeted therapies. Our team has a long-track record in precision health research generating many of the first and largest publicly available GS datasets. We also believe investment in GS of paediatric cohorts and their families is most strategic because they encompass rare and common genetic disease, and the data will be of value across the lifespan.

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