In a recent study published in JAMA Network Open, a group of researchers compared the efficacy of proactive genome sequencing and a medically actionable gene panel in identifying potential risk for pediatric-onset disorders in healthy newborns and children.
Background
Genome sequencing is now common in healthcare, but its high cost prevents it from being widely accepted. It offers higher sensitivity than exome sequencing and microarrays by detecting variants, deletions, and copy number variants (CNV) across the genome. It also covers mitochondrial DNA (mtDNA), enabling the detection of low-heteroplasmy variants.
Several studies reported that genome sequencing has a 20% to 40% diagnostic yield for rare diseases. Its clinical utility has been demonstrated for critically ill pediatric patients, improving outcomes and saving costs.
Genome sequencing is entering preventive and precision medicine for disease risk screening, carrier testing, and pharmacogenomics. As sequencing costs drop, GS is now emerging as a feasible method for broad population screening, and it is gaining significant attention, specifically for newborn screening.
About the study
The present study was a retrospective case series investigation that utilized anonymized data obtained from a self-pay genetic testing service. Parents or guardians provided informed consent for the testing of their children.
The internal policy review board and the Western Institutional Review Board (WIRB), known as WIRB-Copernicus Group, approved the use of deidentified data for this study.
Healthy screenings were made available through the ViaCord service to families registered for cord blood or tissue banking. During their second or third routine trimester visits, parents were presented with cord blood or tissue banking services and two genetic screening options, genome sequencing or exome sequencing–based gene panel (ESGP).
This service was initiated by the parents or legal guardians and facilitated by an independent physician from Genome Medical. Test orders were processed after genetic counseling or after the birth of an infant, given the family had consented prior to delivery.
The genome sequencing screening examined over 22,000 genes, while the ESGP focused on 268 nuclear genes associated with medically actionable childhood-onset conditions. All assays were performed at the PerkinElmer Genomics laboratory in Pittsburgh, Pennsylvania.
The genomic deoxyribonucleic acid (DNA) for these screenings was extracted from a variety of sources, including whole blood, saliva, or dried blood spots (DBS).
The data collected was then stratified according to the age at testing, with individuals divided into various age groups. Categorical variables were summarized using proportions with 95% confidence intervals (Cis) where applicable, while continuous variables were calculated for median values.
The Fisher exact test and the X2 calculator were used to assess the significance of the differences observed in diagnostic results or the distribution of stratified data, with results deemed statistically significant at P < .01.
Study results
The study evaluated 562 children (276 boys [49.1%] and 286 girls [50.9%], median age 29 days) using genome sequencing proactive screening and 606 individuals (313 boys [51.7%] and 293 girls [48.3%], median age 26 days) using ESGP proactive screening. Neonates and infants formed the majority in both cohorts.
Most of the samples were DBS, with genome sequencing and ESGP capturing 94.1% and 99.0%, respectively. The results revealed that 11 samples failed, the turnaround time for genome sequencing was 1.5 times longer than ESGP (56 vs 37 days), and genome sequencing provided 50 times and ESGP 231 times sequencing coverage of target regions.
Genome sequencing screening identified potential diagnoses in 46 individuals (8.2%) with 47 at-risk genotypes. Sequence analysis contributed to 70.2% of these potential diagnoses, while CNV analysis provided 29.8%.
Notably, pathogenic mtDNA variants were found at a 7% heteroplasmy level in one individual, and 6 children had positive findings in the American College of Medical Genetics and Genomics secondary finding list version 3.1 (ACMG SF).
For ESGP screening, 13 individuals (2.1%) had positive findings, with 14 potential diagnoses involving different single-nucleotide variants or deletions or insertions in 11 genes. High-penetrance conditions were reported for 2 individuals, moderate-penetrance conditions for 7 of 11 individuals, and low-penetrance conditions for 5 of 11 individuals. There were no diagnoses from the CNV analysis.
Comparing diagnostic results from genome sequencing and ESGP proactive screening approaches revealed that genome sequencing would have provided at-risk findings in 2.8% of children, resembling the rate of findings in the real ESGP data set. Genome sequencing diagnoses uncovered by ESGP were only 36.2%, and the proportion was much lower for high-penetrance conditions (22.7%).