Whole genome sequencing from dried blood spots for newborn screening of Menkes disease and 36 other actionable inherited neurometabolic disorders.

Tandem mass spectrometry is currently used by the Ohio Department of Health to screen newborn infants for 36 medically actionable inborn errors of metabolism. As a complementary test for infants with abnormal biochemical screens, whole genome sequencing (WGS) theoretically could reduce false-positive results, facilitate timely case resolution and, in some instances, indicate a more specific diagnosis than obtained initially. Menkes disease is a X-linked recessive disorder of human copper metabolism with a predicted minimum birth prevalence of 1 in 34,810 live male births. Recent progress in treatment options for Menkes heighten the importance of newborn screening (NBS) to identify this illness within the window of therapeutic opportunity, the first 4 to 6 weeks of life. We developed a DNA extraction protocol from dried blood spots that yielded high quality DNA for whole genome sequencing and studied 24 subjects with known ATP7A variants. Analysis was confined to genes (n = 55) for neurometabolic conditions currently screened for in Ohio (n = 36) plus ATP7A (Menkes disease). WGS detected all ATP7A variants including 7 missense, 5 splice site, 4 copy number variants, 4 nonsense, 3 indels, and 1 missense/splice site. WGS also detected 5 heterozygous pathogenic variants in 5 genes that encode conditions for which Ohio screens. Our results confirm the feasibility and reliability of this approach for early Menkes disease detection and to complement tandem mass spectroscopy for detection of other actionable inherited disorders.