At-Risk Genomic Findings for Pediatric-Onset Disorders From Genome Sequencing vs Medically Actionable Gene Panel in Proactive Screening of Newborns and Children

• DOI: 10.1001/jamanetworkopen.2023.26445
• Publication Date: 2023-07-31T15:34:27Z
• Authors: Jorune Balciuniene; Ruby Liu; Lora Bean; Fen Guo; Babi Ramesh Reddy...; Naga Guruju; Xiangwen Chen-Deu...; Rizwan Yousaf; Kristina Fura; Ephrem Chin; Abhinav Mathur; Zeqiang Ma; Jonathan Carmichael; Cristina da Silva; Christin Collins; Madhuri Hegde
• Keywords: 0301 basic medicine; 03 medical and health sciences; Infant, Newborn; Humans; Female; Penetrance; Exome; Genetic Testing; Genomics; Child; Original Investigation

ImportanceAlthough the clinical utility of genome sequencing for critically ill children is well recognized, its utility for proactive pediatric screening is not well explored.ObjectiveTo evaluate molecular findings from screening ostensibly healthy children with genome sequencing compared with a gene panel for medically actionable pediatric conditions.Design, Setting, and ParticipantsThis 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.ExposuresGenetic screening for pediatric-onset disorders using genome sequencing or an exome-based panel of 268 genes.Main Outcomes and MeasuresMolecular findings indicative of genetic disease risk.ResultsOf 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 RelevanceIn 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.