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.
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