Perspectives of Rare Disease Experts on Newborn Genome Sequencing

Author:

Gold Nina B.12,Adelson Sophia M.34,Shah Nidhi567,Williams Shardae34,Bick Sarah L.27,Zoltick Emilie S.389,Gold Jessica I.10,Strong Alanna1011,Ganetzky Rebecca1011,Roberts Amy E.212,Walker Melissa1314,Holtz Alexander M.7,Sankaran Vijay G.21516,Delmonte Ottavia17,Tan Weizhen218,Holm Ingrid A.2719,Thiagarajah Jay R.220,Kamihara Junne21516,Comander Jason2122,Place Emily2122,Wiggs Janey2122,Green Robert C.342324

Affiliation:

1. Division of Medical Genetics and Metabolism, Massachusetts General Hospital for Children, Boston

2. Department of Pediatrics, Harvard Medical School, Boston, Massachusetts

3. Division of Genetics, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts

4. Ariadne Labs, Boston, Massachusetts

5. Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire

6. Geisel School of Medicine, Hanover, New Hampshire

7. Division of Genetics and Genomics, Boston Children’s Hospital, Boston, Massachusetts

8. Center for Healthcare Research in Pediatrics, Department of Population Medicine, Harvard Pilgrim Health Care Institute, Boston, Massachusetts

9. Department of Population Medicine, Harvard Medical School, Boston, Massachusetts

10. Division of Human Genetics, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania

11. Perelman School of Medicine, University of Pennsylvania, Philadelphia

12. Department of Cardiology and Division of Genetics and Genomics, Department of Pediatrics, Boston Children’s Hospital, Boston, Massachusetts

13. Division of Pediatric Neurology, Massachusetts General Hospital for Children, Boston

14. Department of Neurology, Harvard Medical School, Boston, Massachusetts

15. Division of Hematology/Oncology, Boston Children’s Hospital, Boston, Massachusetts

16. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts

17. Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland

18. Division of Pediatric Nephrology, Massachusetts General Hospital for Children, Boston

19. Manton Center for Orphan Diseases Research, Boston Children’s Hospital, Boston, Massachusetts

20. Division of Gastroenterology, Hepatology and Nutrition, Boston Children’s Hospital, Boston, Massachusetts

21. Department of Ophthalmology, Massachusetts Eye and Ear, Boston

22. Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts

23. Department of Medicine, Harvard Medical School, Boston, Massachusetts

24. Broad Institute, Boston, Massachusetts

Abstract

ImportanceNewborn genome sequencing (NBSeq) can detect infants at risk for treatable disorders currently undetected by conventional newborn screening. Despite broad stakeholder support for NBSeq, the perspectives of rare disease experts regarding which diseases should be screened have not been ascertained.ObjectiveTo query rare disease experts about their perspectives on NBSeq and which gene-disease pairs they consider appropriate to evaluate in apparently healthy newborns.Design, Setting, and ParticipantsThis survey study, designed between November 2, 2021, and February 11, 2022, assessed experts’ perspectives on 6 statements related to NBSeq. Experts were also asked to indicate whether they would recommend including each of 649 gene-disease pairs associated with potentially treatable conditions in NBSeq. The survey was administered between February 11 and September 23, 2022, to 386 experts, including all 144 directors of accredited medical and laboratory genetics training programs in the US.ExposuresExpert perspectives on newborn screening using genome sequencing.Main Outcomes and MeasuresThe proportion of experts indicating agreement or disagreement with each survey statement and those who selected inclusion of each gene-disease pair were tabulated. Exploratory analyses of responses by gender and age were conducted using t and χ2 tests.ResultsOf 386 experts invited, 238 (61.7%) responded (mean [SD] age, 52.6 [12.8] years [range 27-93 years]; 126 [52.9%] women and 112 [47.1%] men). Among the experts who responded, 161 (87.9%) agreed that NBSeq for monogenic treatable disorders should be made available to all newborns; 107 (58.5%) agreed that NBSeq should include genes associated with treatable disorders, even if those conditions were low penetrance; 68 (37.2%) agreed that actionable adult-onset conditions should be sequenced in newborns to facilitate cascade testing in parents, and 51 (27.9%) agreed that NBSeq should include screening for conditions with no established therapies or management guidelines. The following 25 genes were recommended by 85% or more of the experts: OTC, G6PC, SLC37A4, CYP11B1, ARSB, F8, F9, SLC2A1, CYP17A1, RB1, IDS, GUSB, DMD, GLUD1, CYP11A1, GALNS, CPS1, PLPBP, ALDH7A1, SLC26A3, SLC25A15, SMPD1, GATM, SLC7A7, and NAGS. Including these, 42 gene-disease pairs were endorsed by at least 80% of experts, and 432 genes were endorsed by at least 50% of experts.Conclusions and RelevanceIn this survey study, rare disease experts broadly supported NBSeq for treatable conditions and demonstrated substantial concordance regarding the inclusion of a specific subset of genes in NBSeq.

Publisher

American Medical Association (AMA)

Subject

General Medicine

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