Expanded Molecular Newborn Screening: Comparing Results of a 256 vs.1,518 Gene Panel
Clinical Genetics and Therapeutics
-
Primary Categories:
- Clinical- Pediatric
-
Secondary Categories:
- Clinical- Pediatric
Introduction:
There has been increased research on expanded molecular newborn screening (NBS). Standard state NBS is based predominantly on biochemical analytes, which limits the pediatric onset conditions screened for. Multiple NBS studies have been conducted using exome sequencing (ES) or genome sequencing (GS); these studies have identified varying diagnostic rates, usually below 10%. There have been fewer studies comparing small vs. large molecular NBS panels. It would be useful to ascertain whether a large panel may be able to identify additional newborns who have relevant findings compared to a smaller panel. This would help target the size a panel would need to be to have a comparable positivity rate to ES/GS for identifying newborns who are at risk to develop a genetic condition for which medical management could help alleviate or prevent symptoms.
Methods:
We performed a retrospective analysis of a 256-gene NBS panel analyzed at a commercial laboratory between 01/01/2019 and 10/02/2024 which was updated to 258 genes on 10/12/2023. We compared this to a NBS panel of 1,518 genes analyzed at the same commercial laboratory between 01/01/2024 and 10/02/2024. All of the genes from the smaller panel were included in the larger panel. Next-generation sequencing analysis was performed for sequencing variants and copy number variations. Only diagnostic pathogenic and likely pathogenic variants were reported. Carrier status was not reported. This test was a voluntary clinical test with informed consent and was not performed as part of a research study. The smaller-gene panel focused on metabolic and hematologic disorders. The larger panel included genes associated with metabolism, immunodeficiency, cardiology, oncology, hematology, epilepsy, and sensory deficits.
Results:
We analyzed 582 individuals with the smaller panel and identified 24 positive individuals for a 4.1% positivity rate. We analyzed 58 individuals with the 1,518-gene panel and identified 14 positives individuals for a positivity rate of 24.1%. We also identified an incidental finding of Trisomy 21 in one individual. Nine of the 1,518-gene panel positives were in genes with both autosomal dominant (AD) and autosomal recessive (AR) inheritance (AD/AR). Five AD conditions were identified and one AR condition. The smaller panel identified 12 AD/AR conditions, 1 AD, 7 X-linked (XL) conditions, and 4 AR conditions. Individuals with dual positives were identified twice on the smaller panel and once on the larger panel. Chi square of the small vs. large panel positivity rate is 34.33, which corresponds to a p-value of 4.65x10-9. Conditions not on State NBS included 75% of positives on the smaller panel and 71% on the larger panel.
Conclusion:
We identified a statistically significantly higher percentage of positive newborns using the larger 1,518-gene panel vs. the 256-gene panel. We identified a single heterozygous variant in multiple genes associated with AD/AR conditions, meaning the phenotype could be on the milder end of the spectrum for those conditions. Identifying these results in newborns can help the scientific community better understand the spectrum of disease when identifying it prior to symptom onset. These children can be monitored for symptom onset and treated promptly. This has the potential to lead to additional medical appointments and/or parental concern and anxiety. The possibly uncertain disease onset or symptom severity highlights the necessity of comprehensive consenting prior to ordering expanded NBS. The 1,518-gene panel data is preliminary and is from a small sample size; more individuals should be tested to determine whether the positivity rate stays equivalent, increases, or decreases. If it does stay equivalent to the current positivity rate, then this 1,518 gene panel could be an effective avenue for expanded NBS that could identify a higher percentage of children requiring medical evaluation and possible management than a smaller panel.
There has been increased research on expanded molecular newborn screening (NBS). Standard state NBS is based predominantly on biochemical analytes, which limits the pediatric onset conditions screened for. Multiple NBS studies have been conducted using exome sequencing (ES) or genome sequencing (GS); these studies have identified varying diagnostic rates, usually below 10%. There have been fewer studies comparing small vs. large molecular NBS panels. It would be useful to ascertain whether a large panel may be able to identify additional newborns who have relevant findings compared to a smaller panel. This would help target the size a panel would need to be to have a comparable positivity rate to ES/GS for identifying newborns who are at risk to develop a genetic condition for which medical management could help alleviate or prevent symptoms.
Methods:
We performed a retrospective analysis of a 256-gene NBS panel analyzed at a commercial laboratory between 01/01/2019 and 10/02/2024 which was updated to 258 genes on 10/12/2023. We compared this to a NBS panel of 1,518 genes analyzed at the same commercial laboratory between 01/01/2024 and 10/02/2024. All of the genes from the smaller panel were included in the larger panel. Next-generation sequencing analysis was performed for sequencing variants and copy number variations. Only diagnostic pathogenic and likely pathogenic variants were reported. Carrier status was not reported. This test was a voluntary clinical test with informed consent and was not performed as part of a research study. The smaller-gene panel focused on metabolic and hematologic disorders. The larger panel included genes associated with metabolism, immunodeficiency, cardiology, oncology, hematology, epilepsy, and sensory deficits.
Results:
We analyzed 582 individuals with the smaller panel and identified 24 positive individuals for a 4.1% positivity rate. We analyzed 58 individuals with the 1,518-gene panel and identified 14 positives individuals for a positivity rate of 24.1%. We also identified an incidental finding of Trisomy 21 in one individual. Nine of the 1,518-gene panel positives were in genes with both autosomal dominant (AD) and autosomal recessive (AR) inheritance (AD/AR). Five AD conditions were identified and one AR condition. The smaller panel identified 12 AD/AR conditions, 1 AD, 7 X-linked (XL) conditions, and 4 AR conditions. Individuals with dual positives were identified twice on the smaller panel and once on the larger panel. Chi square of the small vs. large panel positivity rate is 34.33, which corresponds to a p-value of 4.65x10-9. Conditions not on State NBS included 75% of positives on the smaller panel and 71% on the larger panel.
Conclusion:
We identified a statistically significantly higher percentage of positive newborns using the larger 1,518-gene panel vs. the 256-gene panel. We identified a single heterozygous variant in multiple genes associated with AD/AR conditions, meaning the phenotype could be on the milder end of the spectrum for those conditions. Identifying these results in newborns can help the scientific community better understand the spectrum of disease when identifying it prior to symptom onset. These children can be monitored for symptom onset and treated promptly. This has the potential to lead to additional medical appointments and/or parental concern and anxiety. The possibly uncertain disease onset or symptom severity highlights the necessity of comprehensive consenting prior to ordering expanded NBS. The 1,518-gene panel data is preliminary and is from a small sample size; more individuals should be tested to determine whether the positivity rate stays equivalent, increases, or decreases. If it does stay equivalent to the current positivity rate, then this 1,518 gene panel could be an effective avenue for expanded NBS that could identify a higher percentage of children requiring medical evaluation and possible management than a smaller panel.