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WES-based screening of 7,000 newborns: A pilot study in Russia
Jekaterina Shubina1, Ekaterina Tolmacheva1, Dmitry Maslennikov1
1National Medical Research Center for Obstetrics, Gynecology, and Perinatology of the Ministry of Health of the Russian Federation, 117198 Moscow, Russia.
Insights
Next-generation sequencing (NGS) can screen thousands of genes in newborns, identifying rare genetic diseases and variants in healthy infants. This large-scale study highlights the potential and challenges of expanding newborn genetic screening.
Area of Science:
- Genetics
- Genomics
- Pediatrics
Background:
- Next-generation sequencing (NGS) costs are decreasing, enabling its use in newborn screening.
- Conventional newborn screening detects limited diseases, while NGS can screen thousands of genes.
- Ethical and interpretation challenges exist for screening healthy infants using NGS.
Purpose of the Study:
- To assess the feasibility and findings of large-scale NGS-based genetic screening in healthy newborns.
- To identify clinically significant variants in infants, including those with early-onset, adult-onset, and chromosomal conditions.
- To address variant interpretation issues in presumed healthy newborns.
Main Methods:
- Whole-exome and whole-genome sequencing were used for genetic screening.
- The study included 7,000 apparently healthy infants screened for variants in 2,350 genes.
- Variants associated with early-onset, adult-onset, and chromosomal abnormalities were analyzed.
Main Results:
- Clinically significant variants for early-onset treatable diseases were found in 0.9% of infants.
- Variants linked to adult-onset diseases were identified in 2.1% of newborns.
- Chromosomal abnormalities were detected in 0.3% of the screened infants.
Conclusions:
- Large-scale NGS newborn screening identifies a significant proportion of infants with actionable genetic findings.
- The study demonstrates the potential of NGS for expanding newborn screening beyond conventional methods.
- Further research is needed to address variant interpretation and clinical management strategies for identified variants in healthy infants.
Abstract:
The effective implementation of whole-exome sequencing- and whole-genome sequencing-based diagnostics in the management of children affected with genetic diseases and the rapid decrease in the cost of next-generation sequencing (NGS) enables the expansion of this method to newborn genetic screening programs. Such NGS-based screening greatly increases the number of diseases that can be detected compared to conventional newborn screening, as the latter is aimed at early detection of a limited number of inborn diseases. Moreover, genetic testing provides new possibilities for family members of the proband, as many variants responsible for adult-onset conditions are inherited from the parents. However, the idea of NGS-based screening in healthy children raises issues of medical and ethical integrity as well as technical questions, including interpretation of the observed variants. Pilot studies have shown that both parents and medical professionals have moved forward and are enthused about these new possibilities. However, either the number of participants or the number of genes studied in previous investigations thus far has been limited to a few hundred, restricting the scope of potential findings. Our current study (NCT05325749) includes 7,000 apparently healthy infants born at our center between February 2021 and May 2023, who were screened for pathogenic variants in 2,350 genes. Clinically significant variants associated with early-onset diseases that can be treated, prevented, or where symptoms can be alleviated with timely introduced symptomatic therapy, were observed in 0.9% of phenotypically normal infants, 2.1% of the screened newborns were found to carry variants associated with reduced penetrance or monogenic diseases of adult-onset and/or variable expressivity, and 0.3% had chromosomal abnormalities. Here, we report our results and address questions regarding the interpretation of variants in newborns who were presumed to be healthy.
