Actionability of commercial laboratory sequencing panels for newborn screening and the importance of transparency for parental decision-making

DeCristo, Daniela M.; Milko, Laura V.; O’Daniel, Julianne; Foreman, Ann Katherine M.; Mollison, Lonna; Powell, Bradford C.; Powell, Cynthia M.; Berg, Jonathan S.

doi:10.1186/s13073-021-00867-1

Cited by 23 publications

(31 citation statements)

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“…These were collated into 4 categories, as detailed in the Table and summarized in what follows. 14,15,[17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51]…”

Section: Resultsmentioning

confidence: 99%

“…These were collated into 4 categories, as detailed in the Table and summarized in what follows. 14 , 15 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 …”

Section: Resultsmentioning

confidence: 99%

“…They then used this metric to assess the suitability of direct-to-consumer gNBS. 35 In contrast, the BabySeq group 32 started by scoring evidence around gene-disease association and then assessed genes by age of onset and available penetrance data. This resulted in 3 categories for analysis: “Category A: genes included in the Newborn Genomic Sequencing Report (NGSR) with definitive or strong evidence to cause a highly penetrant childhood-onset disorder.…”

Section: Discussionmentioning

confidence: 99%

“…Summary of Included Studies (continued)DeCristo et al,35 2021 United States 309 Genes from 4 gNBS gene lists Evaluated the overlap of the 4 panels and found overall 82 genes thought to be inappropriate for gNBS and 249 genes deemed to be suitable for gNBS were missing.Ko et al,36 2018 Korea 20 Infants with metabolic disease and/or abnormal NBS resultsConcluded gNBS would complement tNBS by providing earlier and more accurate diagnosis. Limitation was looking at an affected cohort; therefore, the study does not provide information on utility for a whole population or those who screen negative on tNBS.Lee et al,37 2019 Korea 48 Babies in intensive care units Overall, 25 genetic variants were identified in 19 infants, with only 1 definitive diagnosis made.…”

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Principles of Genomic Newborn Screening Programs

et al. 2021

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IMPORTANCE Genomic newborn screening (gNBS) may optimize the health and well-being of children and families. Screening programs are required to be evidence based, acceptable, and beneficial. OBJECTIVES To identify what has been discovered following the reporting of the first gNBS pilot projects and to provide a summary of key points for the design of gNBS. EVIDENCE REVIEW A systematic literature review was performed on April 14, 2021, identifying 36 articles that addressed the following questions: (1) what is the interest in and what would be the uptake of gNBS? (2) what diseases and genes should be included? (3) what is the validity and utility of gNBS? and ( 4) what are the ethical, legal, and social implications? Articles were only included if they generated new evidence; all opinion pieces were excluded. FINDINGS In the 36 articles included, there was high concordance, except for gene disease inclusion, which was highly variable. Key findings were the need for equitable access, appropriate educational materials, and informed and flexible consent. The process for selecting genes for testing should be transparent and reflect that parents value the certainty of prediction over actionability.Data should be analyzed in a way that minimizes uncertainty and incidental findings. The expansion of traditional newborn screening (tNBS) to identify more life-threatening and treatable diseases needs to be balanced against the complexity of consenting parents of newborns for genomic testing as well as the risk that overall uptake of tNBS may decline. The literature reflected that the right of a child to self-determination should be valued more than the possibility of the whole family benefiting from a newborn genomic test. CONCLUSIONS AND RELEVANCEThe findings of this systematic review suggest that implementing gNBS will require a nuanced approach. There are gaps in our knowledge, such as the views of diverse populations, the capabilities of health systems, and health economic implications. It will be essential to rigorously evaluate outcomes and ensure programs can evolve to maximize benefit.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Principles of Genomic Newborn Screening Programs

et al. 2021

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“…The growing interest in newborn sequencing and differences in the genes included in panels used [25] means that estimating the background distribution of likely benign variants identified by panel-based genomic analysis is essential both for appropriate gene selection and interpretation of the results. While panel-based analysis is an efficient way of identifying possibly pathogenic variants in known monogenic genes, many of the variants prioritised by such approaches will not be disease causing and as the genomic footprint of the panel increases, so too will the number of prioritised variants.…”

Section: Discussionmentioning

confidence: 99%

Estimating diagnostic noise in panel-based genomic analysis

Beaumont

Wright

2022

Preprint

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Background: Gene panels with a series of strict variant filtering rules are often used for clinical analysis of exomes and genomes. Panels vary in size, which affects the sensitivity and specificity of the test. We sought to investigate the background rate of candidate diagnostic variants in a population setting using gene panels developed to diagnose a range of heterogeneous monogenic diseases. Methods: We used the Genotype-2-Phenotype database with the Variant Effect Predictor plugin to identify rare non-synonymous variants in exome sequence data from 200,643 individuals in UK Biobank. We evaluated five clinically curated gene panels: developmental disorders (DD; 1708 genes), heritable eye disease (536 genes), skin disorders (293 genes), cancer syndromes (91 genes) and cardiac conditions (49 genes). We further tested the DD panel in 9,860 proband-parent trios from the Deciphering Developmental Disorders (DDD) study. Results: As expected, bigger gene panels resulted in more variants being prioritised, varying from an average of ~0.3 per person in the smallest panels, to ~3.5 variants per person using the largest panel. The number of individuals with prioritised variants varied linearly with coding sequence length for monoallelic disease genes (~300 individuals per 1000 base pairs) and quadratically for biallelic disease genes, with some notable outliers. Based on cancer registry data from UK Biobank, there was no detectable difference between cases and controls in the number of individuals with prioritised variants using the cancer panel, presumably due to the predominance of sporadic disease. However, we observed a marked increase in the number of prioritised variants in the DD panel in the DDD study (~5 variants per proband). Phasing of compound heterozygotes in biallelic genes resulted in a modest reduction in the number of prioritised variants. Conclusions: Although large gene panels may be the best strategy to maximize diagnostic yield in genetically heterogeneous diseases, they will frequently prioritise false positive candidate variants potentially requiring additional clinical follow-up. Most individuals will have at least one rare nonsynonymous variant in panels containing >500 monogenic disease genes. Extreme caution should therefore be applied when interpreting potentially pathogenic variants found in the absence of relevant phenotypes.

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Perspectives of Rare Disease Experts on Newborn Genome Sequencing

et al. 2023

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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.

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Actionability of commercial laboratory sequencing panels for newborn screening and the importance of transparency for parental decision-making

Cited by 23 publications

References 38 publications

Principles of Genomic Newborn Screening Programs

Principles of Genomic Newborn Screening Programs

Estimating diagnostic noise in panel-based genomic analysis

Perspectives of Rare Disease Experts on Newborn Genome Sequencing

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