Newborn Sequencing Publications

Genome-based newborn screening for severe childhood genetic diseases has high positive predictive value and sensitivity in a NICU pilot trial

  • Kingsmore SF, Wright M, Olsen L, Schultz B, Protopsaltis L, Averbuj D, Blincow E, Carroll J, Caylor S, Defay T, Ellsworth K, Feigenbaum A, Gover M, Guidugli L, Hansen C, Van Der Kraan L, Kunard CM, Kwon H, Madhavrao L, Leipzig J, Liang Y, Mardach R, Mowrey WR, Nguyen H, Niemi AK, Oh D, Saad M, Scharer G, Schleit J, Mehtalia SS, Sanford E, Smith LD, Willis MJ, Wigby K, Reimers R. Genome-based newborn screening for severe childhood genetic diseases has high positive predictive value and sensitivity in a NICU pilot trial. Am J Hum Genet. 2024 Dec 5  

Am J Hum Genet. 2024 Dec 5;111(12):2643-2667. doi: 10.1016/j.ajhg.2024.10.020.

ABSTRACT

Large prospective clinical trials are underway or planned that examine the clinical utility and cost effectiveness of genome-based newborn screening (gNBS). One gNBS platform, BeginNGS, currently screens 53,575 variants for 412 severe childhood genetic diseases with 1,603 efficacious therapies. Retrospective evaluation of BeginNGS in 618,290 subjects suggests adequate sensitivity and positive predictive value (PPV) to proceed to prospective studies. To inform pivotal clinical trial design, we undertook a pilot clinical trial. We enrolled 120 infants in a regional neonatal intensive care unit (NICU) who were not under consideration for rapid diagnostic genome sequencing (RDGS). Each enrollee received BeginNGS and two index tests (California state NBS and RDGS). California NBS identified 4 of 4 true positive (TP) findings (TP rate 3.6%, sensitivity 100%) and 11 false positive (FP) findings (PPV 27%). RDGS identified 41 diagnostic findings in 36 neonates (diagnostic rate 30%). BeginNGS identified 5 of 6 on-target TP disorders (TP rate 4.2%, 95% confidence interval 1%-8%, sensitivity 83%) and no FPs (PPV 100%). Changes in management were anticipated following the return of 27 RDGS results in 25 enrollees (clinical utility [CU] 21%), 3 of 4 NBS TPs (CU 2.7%), and all BeginNGS TPs (CU 4.2%). The incidence of actionable genetic diseases in NICU infants not being considered for RDGS suggests (1) performance of RDGS in ∼20% of admissions misses many genetic diagnoses, (2) NICU enrollment in gNBS trials will greatly increase power to test endpoints, and (3) NICUs may be attractive for early implementation of consented BeginNGS screening.

PMID:39642868 | DOI:10.1016/j.ajhg.2024.10.020

Prequalification of genome-based newborn screening for severe childhood genetic diseases through federated training based on purifying hyperselection

  • Kingsmore SF, Wright M, Smith LD, Liang Y, Mowrey WR, Protopsaltis L, Bainbridge M, Baker M, Batalov S, Blincow E, Cao B, Caylor S, Chambers C, Ellsworth K, Feigenbaum A, Frise E, Guidugli L, Hall KP, Hansen C, Kiel M, Van Der Kraan L, Krilow C, Kwon H, Madhavrao L, Lefebvre S, Leipzig J, Mardach R, Moore B, Oh D, Olsen L, Ontiveros E, Owen MJ, Reimers R, Scharer G, Schleit J, Shelnutt S, Mehtalia SS, Oriol A, Sanford E, Schwartz S, Wigby K, Willis MJ, Yandell M, Kunard CM, Defay T. Prequalification of genome-based newborn screening for severe childhood genetic diseases through federated training based on purifying hyperselection. Am J Hum Genet. 2024 Dec 5    

Am J Hum Genet. 2024 Dec 5;111(12):2618-2642. doi: 10.1016/j.ajhg.2024.10.021.

ABSTRACT

Genome-sequence-based newborn screening (gNBS) has substantial potential to improve outcomes in hundreds of severe childhood genetic disorders (SCGDs). However, a major impediment to gNBS is imprecision due to variants classified as pathogenic (P) or likely pathogenic (LP) that are not SCGD causal. gNBS with 53,855 P/LP variants, 342 genes, 412 SCGDs, and 1,603 therapies was positive in 74% of UK Biobank (UKB470K) adults, suggesting 97% false positives. We used the phenomenon of purifying hyperselection, which acts to decrease the frequency of SCGD causal diplotypes, to reduce false positives. Training of gene-disease-inheritance mode-diplotype tetrads in 618,290 control and affected subjects identified 293 variants or haplotypes and seven genes with variable inheritance contributing higher positive diplotype counts than consistent with purifying hyperselection and with little or no evidence of SCGD causality. With these changes, 2.0% of UKB470K adults were positive. In contrast, gNBS was positive in 7.2% of 3,118 critically ill children with suspected SCGDs and 7.9% of 705 infant deaths. When compared with rapid diagnostic genome sequencing (RDGS), gNBS had 99.1% recall. In eight true-positive children, gNBS was projected to decrease time to diagnosis by a median of 121 days and avoid life-threatening disease presentations in four children, organ damage in six children, ∼$1.25 million in healthcare cost, and ten (1.4%) infant deaths. Federated training predicated on purifying hyperselection provides a general framework to attain high precision in population screening. Federated training across many biobanks and clinical trials can provide a privacy-preserving mechanism for qualification of gNBS in diverse genetic ancestries.

PMID:39642867 | DOI:10.1016/j.ajhg.2024.10.021

NBSTRN Tools to Advance Newborn Screening Research and Support Newborn Screening Stakeholders

  • Chan K, Hu Z, Bush LW, Cope H, Holm IA, Kingsmore SF, Wilhelm K, Scharfe C, Brower A.

Int J Neonatal Screen. 2023 Oct 30;9(4):63. doi: 10.3390/ijns9040063.

ABSTRACT

Rapid advances in the screening, diagnosis, and treatment of genetic disorders have increased the number of conditions that can be detected through universal newborn screening (NBS). However, the addition of conditions to the Recommended Uniform Screening Panel (RUSP) and the implementation of nationwide screening has been a slow process taking several years to accomplish for individual conditions. Here, we describe web-based tools and resources developed and implemented by the newborn screening translational research network (NBSTRN) to advance newborn screening research and support NBS stakeholders worldwide. The NBSTRN’s tools include the Longitudinal Pediatric Data Resource (LPDR), the NBS Condition Resource (NBS-CR), the NBS Virtual Repository (NBS-VR), and the Ethical, Legal, and Social Issues (ELSI) Advantage. Research programs, including the Inborn Errors of Metabolism Information System (IBEM-IS), BabySeq, EarlyCheck, and Family Narratives Use Cases, have utilized NBSTRN’s tools and, in turn, contributed research data to further expand and refine these resources. Additionally, we discuss ongoing tool development to facilitate the expansion of genetic disease screening in increasingly diverse populations. In conclusion, NBSTRN’s tools and resources provide a trusted platform to enable NBS stakeholders to advance NBS research and improve clinical care for patients and their families.

PMID:37987476 | DOI:10.3390/ijns9040063

The Promise and Perils of Next-Generation DNA Sequencing at Birth: Proceedings of a Workshop–in Brief

National Academies of Sciences, Engineering, and Medicine. 2023. The Promise and Perils of Next-Generation DNA Sequencing at Birth: Proceedings of a Workshop–in Brief. Washington, DC: The National Academies Press. https://doi.org/10.17226/2724

Pilot programs are employing whole genome sequencing and whole exome sequencing during the newborn phase both within the United States and internationally. While sequencing offers the opportunity to screen for treatable but not clinically evident conditions early in a child’s life, it raises a host of ethical, legal, and social questions for experts, including parents, to consider. The National Academies Roundtable on Genomics and Precision Health hosted experts from health care, industry, academia, the federal and state governments, and patient and consumer advocacy groups for a June 2023 workshop. Participants, including RCIGM investigator Nathaly Sweeney, explored the potential benefits and harms, data security, and health equity considerations for the widespread utilization of newborn genome sequencing in the U.S. This publication summarizes the presentation and discussion of the workshop.

Assessing Diversity in Newborn Genomic Sequencing Research Recruitment: Race/Ethnicity and Primary Spoken Language Variation in Eligibility, Enrollment, and Reasons for Declining

  • Cakici JA, Dimmock D, Caylor S, Gaughran M, Clarke C, Triplett C, Clark MM, Kingsmore SF, Bloss CS.

Clin Ther. 2023 Jul 8:S0149-2918(23)00220-5. doi: 10.1016/j.clinthera.2023.06.014. Online ahead of print.

ABSTRACT

PURPOSE: Diagnostic genomic research has the potential to directly benefit participants. This study sought to identify barriers to equitable enrollment of acutely ill newborns into a diagnostic genomic sequencing research study.

METHODS: We reviewed the 16-month recruitment process of a diagnostic genomic research study enrolling newborns admitted to the neonatal intensive care unit at a regional pediatric hospital that primarily serves English- and Spanish-speaking families. Differences in eligibility, enrollment, and reasons for not enrolling were examined as functions of race/ethnicity and primary spoken language.

FINDINGS: Of the 1248 newborns admitted to the neonatal intensive care unit, 46% (n = 580) were eligible, and 17% (n = 213) were enrolled. Of the 16 languages represented among the newborns’ families, 4 (25%) had translated consent documents. Speaking a language other than English or Spanish increased a newborn’s likelihood of being ineligible by 5.9 times (P < 0.001) after controlling for race/ethnicity. The main reason for ineligibility was documented as the clinical team declined having their patient recruited (41% [51 of 125]). This reason significantly affected families who spoke languages other than English or Spanish and was able to be remediated with training of the research staff. Stress (20% [18 of 90]) and the study intervention(s) (20% [18 of 90]) were the main reasons given for not enrolling.

IMPLICATIONS: This analysis of eligibility, enrollment, and reasons for not enrolling in a diagnostic genomic research study found that recruitment generally did not differ as a function of a newborn’s race/ethnicity. However, differences were observed depending on the parent’s primary spoken language. Regular monitoring and training can improve equitable enrollment into diagnostic genomic research. There are also opportunities at the federal level to improve access to those with limited English proficiency and thus decrease disparities in representation in research participation.

PMID:37429778 DOI:10.1016/j.clinthera.2023.06.014

Response to Grosse et al

  • Kingsmore SF, Smith LD, Kunard CM, Bainbridge M, Batalov S, Benson W, Blincow E, Caylor S, Chambers C, Del Angel G, Dimmock DP, Ding Y, Ellsworth K, Feigenbaum A, Frise E, Green RC, Guidugli L, Hall KP, Hansen C, Hobbs CA, Kahn SD, Kiel M, Van Der Kraan L, Krilow C, Kwon YH, Madhavrao L, Le J, Lefebvre S, Mardach R, Mowrey WR, Oh D, Owen MJ, Powley G, Scharer G, Shelnutt S, Tokita M, Mehtalia SS, Oriol A, Papadopoulos S, Perry J, Rosales E, Sanford E, Schwartz S, Tran D, Reese MG, Wright M, Veeraraghavan N, Wigby K, Willis MJ, Wolen AR, Defay T.

Am J Hum Genet. 2023 Jun 1;110(6):1017. doi: 10.1016/j.ajhg.2023.05.004.

NO ABSTRACT

PMID:37267897 DOI:10.1016/j.ajhg.2023.05.004

Scalable, high quality, whole genome sequencing from archived, newborn, dried blood spots

  • Ding Y, Owen M, Le J, Batalov S, Chau K, Kwon YH, Van Der Kraan L, Bezares-Orin Z, Zhu Z, Veeraraghavan N, Nahas S, Bainbridge M, Gleeson J, Baer RJ, Bandoli G, Chambers C, Kingsmore SF. 

NPJ Genom Med. 2023 Feb 14;8(1):5. doi: 10.1038/s41525-023-00349-w.

ABSTRACT

Universal newborn screening (NBS) is a highly successful public health intervention. Archived dried bloodspots (DBS) collected for NBS represent a rich resource for population genomic studies. To fully harness this resource in such studies, DBS must yield high-quality genomic DNA (gDNA) for whole genome sequencing (WGS). In this pilot study, we hypothesized that gDNA of sufficient quality and quantity for WGS could be extracted from archived DBS up to 20 years old without PCR (Polymerase Chain Reaction) amplification. We describe simple methods for gDNA extraction and WGS library preparation from several types of DBS. We tested these methods in DBS from 25 individuals who had previously undergone diagnostic, clinical WGS and 29 randomly selected DBS cards collected for NBS from the California State Biobank. While gDNA from DBS had significantly less yield than from EDTA blood from the same individuals, it was of sufficient quality and quantity for WGS without PCR. All samples DBS yielded WGS that met quality control metrics for high-confidence variant calling. Twenty-eight variants of various types that had been reported clinically in 19 samples were recapitulated in WGS from DBS. There were no significant effects of age or paper type on WGS quality. Archived DBS appear to be a suitable sample type for WGS in population genomic studies.

PMID:36788231 DOI:10.1038/s41525-023-00349-w

Dispatches from Biotech beginning BeginNGS: Rapid newborn genome sequencing to end the diagnostic and therapeutic odyssey

  • Kingsmore SF, The BeginNGS Consortium. 

Am J Med Genet C Semin Med Genet. 2022 Oct 11. doi: 10.1002/ajmg.c.32005. Online ahead of print.

ABSTRACT

In this Dispatch from Biotech, we briefly review the urgent need for extensive expansion of newborn screening (NBS) by genomic sequencing, and the reasons why early attempts had limited success. During the next decade transformative developments will continue in society and in the pharmaceutical, biotechnology, informatics, and medical sectors that enable prompt addition of genetic disorders to NBS by rapid whole genome sequencing (rWGS) upon introduction of new therapies that qualify them according to the Wilson and Jungner criteria (Wilson, J. M. G., & Jungner, G., World Health Organization. (1968). Principles and Practice of Screening for Disease. World Health Organization. Retrieved from https://apps.who.int/iris/handle/10665/37650). Herein we describe plans, progress, and clinical trial designs for BeginNGS (Newborn Genome Sequencing to end the diagnostic and therapeutic odyssey), a new international, pre-competitive, public-private consortium that proposes to implement a self-learning healthcare delivery system for screening all newborns for over 400 hundred genetic diseases, diagnostic confirmation, implementation of effective treatment, and acceleration of orphan drug development. We invite investigators and stakeholders worldwide to join the consortium in a prospective, multi-center, international trial of the clinical utility and cost effectiveness of BeginNGS.

PMID:36218021 DOI:10.1002/ajmg.c.32005

A genome sequencing system for universal newborn screening, diagnosis, and precision medicine for severe genetic diseases

  • Kingsmore SF, Smith LD, Kunard CM, Bainbridge M, Batalov S, Benson W, Blincow E, Caylor S, Chambers C, Del Angel G, Dimmock DP, Ding Y, Ellsworth K, Feigenbaum A, Frise E, Green RC, Guidugli L, Hall KP, Hansen C, Hobbs CA, Kahn SD, Kiel M, Van Der Kraan L, Krilow C, Kwon YH, Madhavrao L, Le J, Lefebvre S, Mardach R, Mowrey WR, Oh D, Owen MJ, Powley G, Scharer G, Shelnutt S, Tokita M, Mehtalia SS, Oriol A, Papadopoulos S, Perry J, Rosales E, Sanford E, Schwartz S, Tran D, Reese MG, Wright M, Veeraraghavan N, Wigby K, Willis MJ, Wolen AR, Defay T.

Am J Hum Genet. 2022 Aug 18:S0002-9297(22)00355-X. doi: 10.1016/j.ajhg.2022.08.003. Online ahead of print.

ABSTRACT

Newborn screening (NBS) dramatically improves outcomes in severe childhood disorders by treatment before symptom onset. In many genetic diseases, however, outcomes remain poor because NBS has lagged behind drug development. Rapid whole-genome sequencing (rWGS) is attractive for comprehensive NBS because it concomitantly examines almost all genetic diseases and is gaining acceptance for genetic disease diagnosis in ill newborns. We describe prototypic methods for scalable, parentally consented, feedback-informed NBS and diagnosis of genetic diseases by rWGS and virtual, acute management guidance (NBS-rWGS). Using established criteria and the Delphi method, we reviewed 457 genetic diseases for NBS-rWGS, retaining 388 (85%) with effective treatments. Simulated NBS-rWGS in 454,707 UK Biobank subjects with 29,865 pathogenic or likely pathogenic variants associated with 388 disorders had a true negative rate (specificity) of 99.7% following root cause analysis. In 2,208 critically ill children with suspected genetic disorders and 2,168 of their parents, simulated NBS-rWGS for 388 disorders identified 104 (87%) of 119 diagnoses previously made by rWGS and 15 findings not previously reported (NBS-rWGS negative predictive value 99.6%, true positive rate [sensitivity] 88.8%). Retrospective NBS-rWGS diagnosed 15 children with disorders that had been undetected by conventional NBS. In 43 of the 104 children, had NBS-rWGS-based interventions been started on day of life 5, the Delphi consensus was that symptoms could have been avoided completely in seven critically ill children, mostly in 21, and partially in 13. We invite groups worldwide to refine these NBS-rWGS conditions and join us to prospectively examine clinical utility and cost effectiveness.

PMID:36007526 | DOI:10.1016/j.ajhg.2022.08.003

An automated 13.5 hour system for scalable diagnosis and acute management guidance for genetic diseases

  • Mallory J. Owen, Sebastien Lefebvre, Christian Hansen, Chris M. Kunard, David P. Dimmock, Laurie D. Smith, Gunter Scharer, Rebecca Mardach, Mary J. Willis, Annette Feigenbaum, Anna-Kaisa Niemi, Yan Ding, Luca Van Der Kraan, Katarzyna Ellsworth, Lucia Guidugli, Bryan R. Lajoie, Timothy K. McPhail, Shyamal S. Mehtalia, Kevin K. Chau, Yong H. Kwon, Zhanyang Zhu, Sergey Batalov, Shimul Chowdhury, Seema Rego, James Perry, Mark Speziale, Mark Nespeca, Meredith S. Wright, Martin G. Reese, Francisco M. De La Vega, Joe Azure, Erwin Frise, Charlene Son Rigby, Sandy White, Charlotte A. Hobbs, Sheldon Gilmer, Gail Knight, Albert Oriol, Jerica Lenberg, Shareef A. Nahas, Kate Perofsky, Kyu Kim, Jeanne Carroll, Nicole G. Coufal, Erica Sanford, Kristen Wigby, Jacqueline Weir, Vicki S. Thomson, Louise Fraser, Seka S. Lazare, Yoon H. Shin, Haiying Grunenwald, Richard Lee, David Jones, Duke Tran, Andrew Gross, Patrick Daigle, Anne Case, Marisa Lue, James A. Richardson, John Reynders, Thomas Defay, Kevin P. Hall, Narayanan Veeraraghavan & Stephen F. Kingsmore

Nat Commun. 2022 Jul 26;13(1):4057. doi: 10.1038/s41467-022-31446-6.

While many genetic diseases have effective treatments, they frequently progress rapidly to severe morbidity or mortality if those treatments are not implemented immediately. Since front-line physicians frequently lack familiarity with these diseases, timely molecular diagnosis may not improve outcomes. Herein we describe Genome-to-Treatment, an automated, virtual system for genetic disease diagnosis and acute management guidance. Diagnosis is achieved in 13.5 h by expedited whole genome sequencing, with superior analytic performance for structural and copy number variants. An expert panel adjudicated the indications, contraindications, efficacy, and evidence-of-efficacy of 9911 drug, device, dietary, and surgical interventions for 563 severe, childhood, genetic diseases. The 421 (75%) diseases and 1527 (15%) effective interventions retained are integrated with 13 genetic disease information resources and appended to diagnostic reports (https://gtrx.radygenomiclab.com). This system provided correct diagnoses in four retrospectively and two prospectively tested infants. The Genome-to-Treatment system facilitates optimal outcomes in children with rapidly progressive genetic diseases.

PMID:35882841 | DOI:10.1038/s41467-022-31446-6

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