Background: Duchenne muscular dystrophy (DMD), a progressive X-linked muscle wasting disorder, is not nationally recommended for newborn screening (NBS), despite its lethality, new treatments, and approved screening tests and implementation in four states. Female carriers of DMD are most commonly identified following diagnosis of an affected son and can have cardiomyopathies and variable weakness.
Objective: This study aims to demonstrate the utility of a two-step newborn screening algorithm, using an inclusive 97th percentile cutoff for CK, followed by targeted next generation sequencing (NGS) on a single dried bloodspot (DBS) sample collected in conjunction with existing newborn screening infrastructure.
Methods: 17,373 newborns were enrolled, from whom CK was measured on existing NBS DBS samples. 473 newborns (2.7%) with CK values greater than the manufacturer’s 97th percentile underwent targeted NGS testing of DMD.
Results: 99.7% of samples were collected between 24 to 48 hours of life. 2.7% of infants (238 males and 235 females) were referred for NGS, of whom 5 females (CK range 1048–1980 ng/mL) were found to have pathogenic mutations, three of whom had CK values above the 97th percentile, but below the 99.5th percentile. There were no males with DMD identified in this study. Other perinatal variables associated with elevated CK included oxytocin use, gestational age, and events that required assistive maneuvers and/or resuscitation.
Conclusions: Using a 97th percentile cutoff, female carriers were identified in the cohort (2.9 per 10,000 enrolled) at a higher prevalence than the current literature; however, no male cases were identified. We demonstrate the feasibility of measuring CK and performing NGS on a single DBS NBS sample using existing newborn screening infrastructures. HyperCKemia, independent of a dystrophinopathy, is associated with several labor & delivery-related factors. Further discussion of optimal cutoffs for secondary testing, how to manage female carriers, and what long-term outcomes may result from earlier disease detection remain warranted.