1 Interpretation of Genomic Sequencing results in healthy and ill newborns: results from the BabySeq project (Ceyhan-Birsoy et al., 2019)

A randomized prospective pilot clinical trial was conducted (BabySeq Project) to investigate the clinical, psychological, and financial impact of nGS (Newborn Genomic Sequencing). This project analyzed childhood-onset and actionable adult-onset disease risk, carrier status, and pharmacogenomic variants in 159 newborns using nGS.

The study revealed that 15/159 newborns (9.4%) had a risk of childhood-onset diseases, none of which were anticipated based on the infant’s known clinical or family histories. The data revealed that 3/85 newborns (3.5%) had an actionable adult-onset disease. Carrier status was established for recessive diseases in 88% and pharmacogenomics variants were reported in 5% of newborns. This study, hence, corroborates the utility of nGS in efficiently identifying the risk and carrier status for several disorders that the current newborn screening assays are unable to predict.

2 Application of a next-generation sequencing (NGS) panel in newborn screening (NBS) efficiently identifies inborn disorders of neonates (Huang et al., 2022)

A newborn genetic sequencing panel based on multiplex PCR and NGS was utilized to analyze 134 genes of 74 inborn disorders. This panel was validated in 287 samples with previously known mutations. The panel was able to identify 154 variants from 287 samples with 100% accuracy. A retrospective cohort of 4,986 newborns was analyzed using this panel and the results were compared with their biochemical reports. Of these, 113 newborns were detected with biallelic/hemizygous mutations. Within these 113 newborns, 36 were positive for the same disorder by both newborn genetic sequencing panel and conventional NBS (C-NBS). This investigation revealed that NGS combined with C-NBS can provide early and accurate detection of inborn disorders in neonates.

3 Newborn screening with targeted sequencing: a multicenter investigation and a pilot clinical study in China (Hao et al., 2022)

A panel of 465 causative genes for 596 early-onset, relatively high incidence, and potentially actionable severe inherited conditions was formulated for the Newborn Screening with Targeted Sequencing (NESTS) program in China. A cohort of 11,484 babies was screened retrospectively from eight Women's and Children’s hospitals. The estimated clinical diagnosis rate in the program was observed to be ˜95% on average. NESTS was executed in a hospital to screen 3,923 newborns to assess its clinical application, turn-around-time, feasibility, and cost effectiveness of making it a potential first-tier NBS program.

4 The role of exome sequencing in newborn screening for inborn errors of metabolism (Adhikari et al., 2020)

This study represents the largest-to-date sequencing analysis of 4.5 million infants born in California between mid-2005 and 2013 and of some infants who screened positive for tandem mass spectrometry (MS/MS) but were unaffected upon follow-up testing. Conventionally, MS/MS had been performed for these infants to assess the presence of an inborn error of metabolism (IEM) but in the NBSeq (Newborn Sequencing) project, whole exome sequencing (WES) was done on the archived blood samples to evaluate it as an innovative strategy for NBS. The MS/MS has an overall sensitivity and specificity of 99.0% and 99.8%, whereas the WES has 88% and 98.4% respectively. A noteworthy point was that MS/MS had a low positive predictive value and outcomes were non-specific as well. Conclusively, the authors suggest that WES could become a secondary test for infants with an abnormal MS/MS as it could then decrease false positive results, facilitate punctual case resolution, and in specific cases, direct toward a more appropriate diagnosis.

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