Genome Screening of Newborns: what can we find and what's next?
Laboratory Genetics and Genomics
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Primary Categories:
- Genomic Medicine
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Secondary Categories:
- Genomic Medicine
Introduction:
The early diagnosis of genetic diseases is critical for maximizing clinical outcomes and reducing healthcare costs. Genome sequencing (GS) has shown promise in rapidly diagnosing critically ill newborns and is gaining attention in nationwide initiatives exploring GS in newborn screening (GS for NBS). Investigating the genomic findings from GS for NBS and their impact on clinical outcomes and the psychosocial well-being of affected families is essential for designing effective GS for NBS programs.
We previously published at-risk genomic findings from a large cohort of ostensibly healthy newborns and children (N=1168) screened by GS (N=562) or an exome-based gene panel (ESGP, N=606) (Balciuniene et al., 2023). To further assess the clinical utility of proactive genomic screening in the pediatric population, we are conducting a follow-up study to gather additional data on children and their families identified as carrying unanticipated risks for pediatric genomic disorders.
Methods:
The screening cohort consists of families who voluntarily enrolled for out-of-pocket proactive screening offered through a commercial cord blood and tissue banking company. Proactive screening of the asymptomatic pediatric cohort was conducted using ESGP for actionable pediatric conditions (268 genes) or GS (~6000 genes). Illumina short-read sequencing was performed, followed by sequence and copy number (CN) analysis using a clinically validated bioinformatics pipeline. Only pathogenic or likely pathogenic variants consistent with the risk of developing pediatric-onset diseases were reported.
A single-arm follow-up study uses a structured questionnaire-based tool to gather clinical and psychosocial impact data on families with children who received positive GS findings.
Results:
GS screening revealed that 8.2% (46/562) of asymptomatic newborns and children are at risk for pediatric-onset conditions, compared to just 2.1% (13/606) of at-risk children identified by ESGP. The higher diagnostic utility of GS was anticipated due to the greater number of target genes. Sequence variants (SVs) constituted 70% (33/47) of diagnoses (G6PD, TNFRSF13B, SGCE, SLC39A5, COL4A3, COL11A1, ABCA4, CYP21A2, MEFV, PPM1D), while 21% (10/47) were CN variants (CNVs), including four microdeletions and four microduplications. Additionally, 9% (4/47) were chromosome-scale rearrangements (mosaic 12p triplication and unbalanced translocation associated with Wolf-Hirschhorn syndrome). Nearly half of these findings (22/47) represent high-penetrance conditions, with 77% of these potentially missed by ESGP.
We developed a structured questionnaire tool to follow up with families whose children were found to be positive for at-risk genomic findings. The questionnaire covers the respondents’ demographics, family reasons for choosing GS for NBS, family history, proband’s phenotype, and medical care received, cascade testing driven by screening results, and psychosocial impacts on family well-being after result return. We are in the process of re-contacting families that received screening results 2-5 years ago.
Conclusion:
We have already demonstrated the significant diagnostic utility of genome sequencing for pediatric-onset conditions among asymptomatic newborns. Follow-up studies to assess the long-term clinical and psychosocial impacts on families affected by the genomic discoveries are vital for gauging the clinical utility of GS for NBS programs which would inform cost-effective healthcare strategies and guide public health policy.
The early diagnosis of genetic diseases is critical for maximizing clinical outcomes and reducing healthcare costs. Genome sequencing (GS) has shown promise in rapidly diagnosing critically ill newborns and is gaining attention in nationwide initiatives exploring GS in newborn screening (GS for NBS). Investigating the genomic findings from GS for NBS and their impact on clinical outcomes and the psychosocial well-being of affected families is essential for designing effective GS for NBS programs.
We previously published at-risk genomic findings from a large cohort of ostensibly healthy newborns and children (N=1168) screened by GS (N=562) or an exome-based gene panel (ESGP, N=606) (Balciuniene et al., 2023). To further assess the clinical utility of proactive genomic screening in the pediatric population, we are conducting a follow-up study to gather additional data on children and their families identified as carrying unanticipated risks for pediatric genomic disorders.
Methods:
The screening cohort consists of families who voluntarily enrolled for out-of-pocket proactive screening offered through a commercial cord blood and tissue banking company. Proactive screening of the asymptomatic pediatric cohort was conducted using ESGP for actionable pediatric conditions (268 genes) or GS (~6000 genes). Illumina short-read sequencing was performed, followed by sequence and copy number (CN) analysis using a clinically validated bioinformatics pipeline. Only pathogenic or likely pathogenic variants consistent with the risk of developing pediatric-onset diseases were reported.
A single-arm follow-up study uses a structured questionnaire-based tool to gather clinical and psychosocial impact data on families with children who received positive GS findings.
Results:
GS screening revealed that 8.2% (46/562) of asymptomatic newborns and children are at risk for pediatric-onset conditions, compared to just 2.1% (13/606) of at-risk children identified by ESGP. The higher diagnostic utility of GS was anticipated due to the greater number of target genes. Sequence variants (SVs) constituted 70% (33/47) of diagnoses (G6PD, TNFRSF13B, SGCE, SLC39A5, COL4A3, COL11A1, ABCA4, CYP21A2, MEFV, PPM1D), while 21% (10/47) were CN variants (CNVs), including four microdeletions and four microduplications. Additionally, 9% (4/47) were chromosome-scale rearrangements (mosaic 12p triplication and unbalanced translocation associated with Wolf-Hirschhorn syndrome). Nearly half of these findings (22/47) represent high-penetrance conditions, with 77% of these potentially missed by ESGP.
We developed a structured questionnaire tool to follow up with families whose children were found to be positive for at-risk genomic findings. The questionnaire covers the respondents’ demographics, family reasons for choosing GS for NBS, family history, proband’s phenotype, and medical care received, cascade testing driven by screening results, and psychosocial impacts on family well-being after result return. We are in the process of re-contacting families that received screening results 2-5 years ago.
Conclusion:
We have already demonstrated the significant diagnostic utility of genome sequencing for pediatric-onset conditions among asymptomatic newborns. Follow-up studies to assess the long-term clinical and psychosocial impacts on families affected by the genomic discoveries are vital for gauging the clinical utility of GS for NBS programs which would inform cost-effective healthcare strategies and guide public health policy.