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At-Risk Genomic Findings for Pediatric-Onset Disorders From Genome Sequencing vs Medically Actionable Gene Panel in
Jorune Balciuniene1, Ruby Liu1, Lora Bean1
1PerkinElmer Genomics, PerkinElmer Inc, Pittsburgh, Pennsylvania.
Insights
Genome sequencing identified more pediatric disease risks in healthy children than gene panels. This proactive screening approach can guide early interventions for various high-penetrance conditions.
Area of Science:
- Genomics
- Pediatric Medicine
- Genetic Screening
Background:
- Clinical utility of genome sequencing is established for critically ill children.
- Proactive pediatric screening using genome sequencing is less explored.
- Medically actionable pediatric conditions require timely diagnosis and intervention.
Purpose of the Study:
- Compare genome sequencing with gene panels for proactive screening in healthy children.
- Evaluate molecular findings and disease risks identified by each method.
- Assess the utility of genome sequencing for early detection of pediatric disorders.
Main Methods:
- Case series of apparently healthy children undergoing genetic screening.
- Comparison between genome sequencing (n=562) and an exome-based gene panel (n=606).
- Analysis of molecular findings, including pathogenic variants and copy number variations.
Main Results:
- Genome sequencing identified 8.2% of children at risk for pediatric-onset disease, versus 2.1% with gene panels (P<.001).
- High-penetrance conditions were identified in 3.9% of children via genome sequencing.
- Pharmacogenomic variants were reported in 89.0% of the genome sequencing cohort.
Conclusions:
- Genome sequencing offers broader gene coverage and technical advantages over gene panels for proactive pediatric screening.
- Identifies a wider range of heterogeneous, high-penetrance pediatric conditions.
- Supports early intervention and medical management strategies for identified genetic risks.
Importance:
Although the clinical utility of genome sequencing for critically ill children is well recognized, its utility for proactive pediatric screening is not well explored.
Objective:
To evaluate molecular findings from screening ostensibly healthy children with genome sequencing compared with a gene panel for medically actionable pediatric conditions.
Design, Setting, And Participants:
This case series study was conducted among consecutive, apparently healthy children undergoing proactive genetic screening for pediatric disorders by genome sequencing (n = 562) or an exome-based panel of 268 genes (n = 606) from March 1, 2018, through July 31, 2022.
Exposures:
Genetic screening for pediatric-onset disorders using genome sequencing or an exome-based panel of 268 genes.
Main Outcomes And Measures:
Molecular findings indicative of genetic disease risk.
Results:
Of 562 apparently healthy children (286 girls [50.9%]; median age, 29 days [IQR, 9-117 days]) undergoing screening by genome sequencing, 46 (8.2%; 95% CI, 5.9%-10.5%) were found to be at risk for pediatric-onset disease, including 22 children (3.9%) at risk for high-penetrance disorders. Sequence analysis uncovered molecular diagnoses among 32 individuals (5.7%), while copy number variant analysis uncovered molecular diagnoses among 14 individuals (2.5%), including 4 individuals (0.7%) with chromosome scale abnormalities. Overall, there were 47 molecular diagnoses, with 1 individual receiving 2 diagnoses; of the 47 potential diagnoses, 22 (46.8%) were associated with high-penetrance conditions. Pathogenic variants in medically actionable pediatric genes were found in 6 individuals (1.1%), constituting 12.8% (6 of 47) of all diagnoses. At least 1 pharmacogenomic variant was reported for 89.0% (500 of 562) of the cohort. In contrast, of 606 children (293 girls [48.3%]; median age, 26 days [IQR, 10-67 days]) undergoing gene panel screening, only 13 (2.1%; 95% CI, 1.0%-3.3%) resulted in potential childhood-onset diagnoses, a significantly lower rate than those screened by genome sequencing (P < .001).
Conclusions And Relevance:
In this case series study, genome sequencing as a proactive screening approach for children, due to its unrestrictive gene content and technical advantages in comparison with an exome-based gene panel for medically actionable childhood conditions, uncovered a wide range of heterogeneous high-penetrance pediatric conditions that could guide early interventions and medical management.
