Implementation of population-based newborn screening reveals low incidence of spinal muscular atrophy

Abstract

Purpose

Spinal muscular atrophy (SMA) was added to the Recommended Uniform Screening Panel (RUSP) in July 2018, following FDA approval of the first effective SMA treatment, and demonstration of feasibility of high-throughput newborn screening using a primary molecular assay. SMA newborn screening was implemented in New York State (NYS) on 1 October 2018.

Methods

Screening was conducted using DNA extracted from dried blood spots with a multiplex real-time quantitative polymerase chain reaction (qPCR) assay targeting the recurrent SMN1 exon 7 gene deletion.

Results

During the first year, 225,093 infants were tested. Eight screened positive, were referred for follow-up, and confirmed to be homozygous for the deletion. Infants with two or three copies of the SMN2 gene, predicting more severe, earlier-onset SMA, were treated with antisense oligonucleotide and/or gene therapy. One infant with ≥4 copies SMN2 also received gene therapy.

Conclusion

Newborn screening permits presymptomatic SMA diagnosis, when treatment initiation is most beneficial. At 1 in 28,137 (95% confidence interval [CI]: 1 in 14,259 to 55,525), the NYS SMA incidence is 2.6- to 4.7-fold lower than expected. The low SMA incidence is likely attributable to imprecise and biased estimates, coupled with increased awareness, access to and uptake of carrier screening, genetic counseling, cascade testing, prenatal diagnosis, and advanced reproductive technologies.

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Acknowledgements

Funding for universal screening was provided by the Centers for Disease Control and Prevention (CDC) (6 NU88EH001319–01–01) and the New York State Department of Health. Funding for the SMA pilot study and validation of the assay for universal screening was provided by Biogen, Idec to Columbia University Medical Center and contracted to the Wadsworth Center. The funding bodies had no role in the design of the study, collection and analysis of data or decision to publish. The authors thank New York State Newborn Screening Program staff, especially Jason Isabelle, Allison Madole, Robert Sicko, and Erin Hughes for technical support and data collection; Neuromuscular Disease Specialty Care Center staff, especially Katherine Hogan, Natasha Kleiman, Jacqueline Gomez, Dr. Angela Pena, Chelsea Kois, Dr. Chin-To Fong, Theresa Harte, Debra Guntrum, and Dawn Dawson; and Erin Collins and Joan Mountain for administrative support.

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Correspondence to Denise M. Kay PhD.

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Disclosure

D.M.K.'s work has been funded by the CDC and Biogen, Idec. C.F.S.'s work has been funded by the CDC and Biogen, Idec. W.K.C.'s work has been funded by the NIH, Simons Foundation, JPB Foundation, and Biogen, Idec. She is on the scientific advisory board for the Regeneron Genetics Center. C.A.C. has received funding from Avexis, Biogen and Roche. She is a consultant (advisory board) for Cytokinetics, Avexis, Genentech, and Roche, and she is an educational speaker for Biogen. E.C. has received personal compensation for serving on advisory boards and/or as a consultant for Avexis, Biogen, Medscape, Pfizer, PTC Therapeutics, Sarepta Therapeutics, Ra Pharma, Wave, and Strongbridge Biopharma. She has received personal compensation for serving on a speaker’s bureau for Biogen and has received research and/or grant support from the CDC, CureSMA, Muscular Dystrophy Association, National Institutes of Health, the Patient-Centered Outcomes Research Institute, Parent Project Muscular Dystrophy, PTC Therapeutics, Santhera, Sarepta Therapeutics, Orphazyme, and the US Food and Drug Administration. She has received royalties from Oxford University Press and compensation from Medlink for editorial duties. B.H.L. receives research support from Sanofi Genzyme. A.S. has received compensation for advisory board consultation for Avexis, Biogen, PTC Therapeutics, and BioMarin. M.C.'s work has been funded by the CDC and Biogen, Idec. The other authors declare no conflicts of interest.

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Kay, D.M., Stevens, C.F., Parker, A. et al. Implementation of population-based newborn screening reveals low incidence of spinal muscular atrophy. Genet Med 22, 1296–1302 (2020). https://doi.org/10.1038/s41436-020-0824-3

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Key words

  • spinal muscular atrophy (SMA)
  • newborn screening (NBS)
  • Recommended Uniform Screening Panel (RUSP)
  • carrier screening
  • SMN1

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