Molecular testing in newborn screening: VUS burden among true positives and secondary reproductive limitations via expanded carrier screening panels

Sabina Cook; Emily Dunn; Jenna Kornish; Laurel Calderwood; MaryAnn Campion; Kristina P Cusmano-Ozog; Christina G Tise

doi:10.1016/j.gim.2023.101055

Molecular testing in newborn screening: VUS burden among true positives and secondary reproductive limitations via expanded carrier screening panels

Genet Med. 2024 Apr;26(4):101055. doi: 10.1016/j.gim.2023.101055. Epub 2023 Dec 23.

Authors

Sabina Cook¹, Emily Dunn², Jenna Kornish³, Laurel Calderwood⁴, MaryAnn Campion¹, Kristina P Cusmano-Ozog⁵, Christina G Tise⁶

Affiliations

¹ Masters Program in Human Genetics and Genetic Counseling, Stanford University, Stanford, CA.
² Division of Medical Genetics, Department of Pediatrics, Stanford University, Stanford, CA. Electronic address: erdunn@stanford.edu.
³ Lucile Packard Children's Hospital, Stanford, CA.
⁴ Division of Medical Genetics, Department of Pediatrics, Stanford University, Stanford, CA; Lucile Packard Children's Hospital, Stanford, CA.
⁵ Department of Pathology, Stanford University, Stanford, CA.
⁶ Division of Medical Genetics, Department of Pediatrics, Stanford University, Stanford, CA.

PMID: 38146699
DOI: 10.1016/j.gim.2023.101055

Abstract

Purpose: Expanded carrier screening (ECS) gene panels have several limitations, including variable content, current knowledge of disease-causing variants, and differing reporting policies. This study evaluated if the disease-associated variants identified in affected neonates who screened positive by California newborn screening (NBS) for an inherited metabolic disorder (IMD) by tandem mass spectrometry (MS/MS) would likely be reported by ECS gene panels.

Methods: Retrospective review of neonates referred by the California Department of Public Health for a positive NBS by multianalyte MS/MS from January 1, 2020 through June 30, 2021.

Results: One hundred thirty-six neonates screened positive for ≥1 NBS MS/MS indication. Nineteen neonates (14%) were ultimately diagnosed with an IMD, all of whom had abnormal biochemical testing. Eighteen of the 19 underwent molecular testing; 10 (56%) neonates had ≥1 variants of uncertain significance, 9 of whom were of non-White ancestry. ECS panels would have been negative for 56% (20/36) of parents with an affected neonate, 85% (17/20) of whom were of non-White ancestry.

Conclusion: The number of variants of uncertain significance identified in this cohort highlights the need for more diversified variant databases. Due in part to the lack of diversity in currently sequenced populations, genomic sequencing cannot replace biochemical testing for the diagnosis of an IMD.

Keywords: Ancestry-based health disparities; Expanded carrier screening; Genomic diversity; Newborn screening; Variant of uncertain significance.

MeSH terms

Humans
Infant, Newborn
Metabolic Diseases* / diagnosis
Molecular Diagnostic Techniques
Neonatal Screening* / methods
Reproduction
Tandem Mass Spectrometry