First-Tier Next Generation Sequencing for Newborn Screening: An Important Role for Biochemical Second-Tier Testing

Area of Science:

• Genetics
• Genomic Medicine
• Biochemistry

Background:

• Expanding newborn screening (NBS) using genomic sequence data presents challenges in DNA variant interpretation.
• Population-level databases like gnomAD offer insights into variant frequencies but may not capture all global diversity.

Purpose of the Study:

• To estimate the number of newborns who would test positive via next-generation sequencing (NGS) for genetic diseases.
• To evaluate the impact of variants of unknown significance (VUS) on screening outcomes.
• To propose a strategy for managing NGS-positive results in NBS.

Main Methods:

• Analysis of the Genome Aggregation Database (gnomAD) to estimate variant frequencies.
• Calculation of expected NGS-positive newborns for a set of monogenic recessive diseases, including lysosomal storage diseases.
• Modeling the reduction in positive results by biochemically annotating high-frequency VUS.

Main Results:

• For lysosomal storage diseases, 100-600 NGS-positive newborns per disease per year are estimated in a large NBS laboratory, potentially rising to ~1000.
• Annotating the top 10 VUS as benign could decrease positive results 2.5- to 10-fold.
• The number of newborns identified as NGS positive is substantial, highlighting the need for efficient interpretation strategies.

Conclusions:

• Genomic sequencing in NBS generates a significant number of positive results, including VUS.
• A second-tier biochemical assay on dried blood spots is proposed as a filter to reduce the number of high-risk newborns requiring further investigation.
• This tiered approach can make genomic NBS more manageable and clinically actionable.