Genomic Augmentation of Newborn Screening. B. Solomon, D. Bodian, R. Iyer, K. Huddleston, R. Hastak, A. Chu, A. Black, G. Eley, J. Vockley, J. Niederhuber Division of Medical Genomics, Inova Translational Medicine Institute, Falls Church, VA.

   Newborn Screening (NBS) aims to efficiently and cost-effectively identify neonates with treatable diseases. By design, NBS yields relatively frequent false positives, often requiring repeat NBS and further work-up. We aimed to generate preliminary data that NBS can be augmented by performing parallel DNA sequencing. These data were generated through our trio-based (parents + newborn), IRB-approved whole-genome sequencing (WGS) studies of early childhood health, which have generated > 6,000 whole genomes on comprehensively phenotyped patients in ~3 years. We conducted pilot NBS analyses on the first 702 newborns enrolled in our preterm birth study, including both full-term (FT) and preterm (PT) neonates. We bioinformatically analyzed variants in 127 selected genes corresponding to all disorders currently/planned to be included in blood-based NBS, and compared results to standard NBS. Among these infants, a total of 966 standard NBS were performed, with 117 infants (17%) receiving 1 abnormal/invalid result. PT infants were 8x more likely than FT to receive an abnormal/invalid result from standard NBS (39% vs 4.7%, p<0.0001). WGS analysis revealed 2,216 distinct variants in the 127 genes, 229 annotated in HGMD as disease mutations and 128 as pathogenic in ClinVar. Other than hemoglobinopathies, no infants with abnormal standard NBS had a confirmed NBS disorder, concurrent with WGS results. WGS analysis ascertained individuals with glucose-6-phosphate dehydrogenase deficiency, a disorder not included in NBS in the state where the studies take place. As an example of WGS analysis helping rule-out false positives, 4 infants had a positive initial NBS for cystic fibrosis, though none received a confirmatory diagnosis. WGS detected 56 distinct, heterozygous CFTR variants (30 HGMD disease mutations) but no bi-allelic mutations. Since many NBS conditions are rare, we focused on sickle cell anemia to test the ability of WGS to reproduce positive standard NBS, and found complete agreement between standard NBS and WGS. We are now conducting blinded sequencing for known positives from >50 NBS conditions, as well as known negatives and carriers. We have also designed several custom platforms to perform parallel sequencing (in real-time) with standard NBS, and can easily add additional genes of interest. Among other ancillary benefits, these studies are enabling the construction of a unique genomic resource related to WGS-detected NBS variants.

You may contact the first author (during and after the meeting) at