WES-based screening of 7,000 newborns: A pilot study in Russia

Abstract

The effective implementation of WES and WGS-based diagnostics in the management of children affected with genetic diseases and the rapid decrease in the cost of NGS enables the expansion of this method to the 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 being 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, so far has been limited to a few hundreds, 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 the 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 interpretation of variants in newborns who were presumed to be healthy.