Whole genome sequencing (WGS) for expanded newborn screening represents a frontier in precision medicine. Following our pilot study of 321 newborns, we now report comprehensive findings from 10,000 unselected newborns in Qingdao, China.
We performed whole-genome sequencing (WGS) at 65X mean depth on 9,992 newborns to analyze 245 inheritable and metabolic diseases. Screen-positive results were identified in 2.7% (274/9992) of newborns, while 40.7% carried at least one disease mutation. WGS validation of mass spectrometry screening confirmed 3 of 17 MS-positive cases and identified 43 additional cases.
In-depth genomic analysis of 7,140 consented newborns revealed 95.86 million variants, including 40,200 high-confidence protein-truncating variants (PTVs), diverse copy number variations (CNVs), and 3,845 pathogenic variants. Individual newborns carried 0-10 pathogenic variants (predominantly 3-6) and 7-22 likely pathogenic variants. We identified 1,281 unique rare variants of pathogenic or likely pathogenic significance across 328 genes among 713 high-evidence genes.
Microbiome analysis revealed cytomegalovirus in half of the newborns, with carriage rates varying by delivery route and birth season. Our stringent analysis found no consistent core bacteriome in human blood, while deep sequencing identified novel HPV and Anellovirus genomes.
Pharmacogenomic analysis of 257 genes revealed 593,206 variants, with 45.37% novel in East Asians and 96.06% rare. Newborns carried 9-30 actionable pharmacogenomic variants (median 18), with 97% having at least one potentially damaging variant.
Genome-wide association analysis of 42 metabolic markers in 6,631 newborns identified 4,145 significantly associated SNPs, including 1,326 novel associations. Six novel independent casual missense variants were identified, notably rs2229291 in CPT2. SKAT analysis revealed 19 genes significantly associated with metabolism.
This is by far the largest report on WGS screening in unselected newborns. Our results show that newborn genome screening can effectively identify genetic diseases. Newborn genome data also provide scientific insight into precision health.