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

Consortium, The BeginNGS

doi:10.1002/ajmg.c.32005

Cited by 19 publications

(17 citation statements)

References 52 publications

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“…A future, alternative, and comprehensive approach to avoid underdiagnosis of the approximately 600 genetic diseases with current, effective treatments may be newborn screening (NBS) by automated WGS. 34,35 Such WGS-based NBS is envisaged to be in addition to, and not a replacement for, traditional NBS or indication-based rapid diagnostic WGS. 34,35 We identified several attributes of genetic diseases associated with infant death.…”

Section: Discussionmentioning

confidence: 99%

Reclassification of the Etiology of Infant Mortality With Whole-Genome Sequencing

et al. 2023

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ImportanceUnderstanding the causes of infant mortality shapes public health, surveillance, and research investments. However, the association of single-locus (mendelian) genetic diseases with infant mortality is poorly understood.ObjectiveTo determine the association of genetic diseases with infant mortality.Design, Setting, and ParticipantsThis cohort study was conducted at a large pediatric hospital system in San Diego County (California) and included 546 infants (112 infant deaths [20.5%] and 434 infants [79.5%] with acute illness who survived; age, 0 to 1 year) who underwent diagnostic whole-genome sequencing (WGS) between January 2015 and December 2020. Data analysis was conducted between 2015 and 2022.ExposureInfants underwent WGS either premortem or postmortem with semiautomated phenotyping and diagnostic interpretation.Main Outcomes and MeasuresProportion of infant deaths associated with single-locus genetic diseases.ResultsAmong 112 infant deaths (54 girls [48.2%]; 8 [7.1%] African American or Black, 1 [0.9%] American Indian or Alaska Native, 8 [7.1%] Asian, 48 [42.9%] Hispanic, 1 [0.9%] Native Hawaiian or Pacific Islander, and 34 [30.4%] White infants) in San Diego County between 2015 and 2020, single-locus genetic diseases were the most common identifiable cause of infant mortality, with 47 genetic diseases identified in 46 infants (41%). Thirty-nine (83%) of these diseases had been previously reported to be associated with childhood mortality. Twenty-eight death certificates (62%) for 45 of the 46 infants did not mention a genetic etiology. Treatments that can improve outcomes were available for 14 (30%) of the genetic diseases. In 5 of 7 infants in whom genetic diseases were identified postmortem, death might have been avoided had rapid, diagnostic WGS been performed at time of symptom onset or regional intensive care unit admission.Conclusions and RelevanceIn this cohort study of 112 infant deaths, the association of genetic diseases with infant mortality was higher than previously recognized. Strategies to increase neonatal diagnosis of genetic diseases and immediately implement treatment may decrease infant mortality. Additional study is required to explore the generalizability of these findings and measure reduction in infant mortality.

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Section: Discussionmentioning

confidence: 99%

Reclassification of the Etiology of Infant Mortality With Whole-Genome Sequencing

et al. 2023

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“…Those methods are compatible with the WGS from DBS described herein 33 . Thus, autonomous, expanded newborn screening by WGS of DBS is conceivable 32 , 33 . In screening mode, WGS interpretation would be limited to known pathogenic and likely pathogenic variants, which could be detected without the need for trio sequencing—confirmatory testing could incorporate parental samples if warranted, as is done currently 32 , 33 .…”

Section: Discussionmentioning

confidence: 99%

“…Thus, autonomous, expanded newborn screening by WGS of DBS is conceivable 32 , 33 . In screening mode, WGS interpretation would be limited to known pathogenic and likely pathogenic variants, which could be detected without the need for trio sequencing—confirmatory testing could incorporate parental samples if warranted, as is done currently 32 , 33 . Adding new conditions to the recommended uniform screening panel is costly, and each additional assay requires independent state or federal legislative approval 35 .…”

Section: Discussionmentioning

confidence: 99%

“…In California, 84 conditions are currently screened and 1 in 600 newborns has a positive NBS result 11 . In contrast, WGS has the potential to screen for known pathogenic and likely pathogenic variants in over 7200 disorders at once, including those that can cause sudden infant death 14 , 15 , 32 – 34 . There are many rare genetic diseases, such as pyridoxine-dependent epilepsy, which may have effective treatments and meet the Wilson and Junger criteria for inclusion in newborn screening 33 , 36 – 39 .…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, WGS has the potential to screen for known pathogenic and likely pathogenic variants in over 7200 disorders at once, including those that can cause sudden infant death 14 , 15 , 32 – 34 . There are many rare genetic diseases, such as pyridoxine-dependent epilepsy, which may have effective treatments and meet the Wilson and Junger criteria for inclusion in newborn screening 33 , 36 – 39 . Newborn screening by WGS has potential to reduce morbidity and mortality associated with these conditions.…”

Section: Discussionmentioning

confidence: 99%

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

Ding

Owen

et al. 2023

npj Genom. Med.

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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.

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

Consortium¹

2022

American J of Med Genetics Pt C

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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.

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

Cited by 19 publications

References 52 publications

Reclassification of the Etiology of Infant Mortality With Whole-Genome Sequencing

Reclassification of the Etiology of Infant Mortality With Whole-Genome Sequencing

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

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

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