Translating Molecular Technologies into Routine Newborn Screening Practice

Furnier, Sarah M; Durkin, Maureen S.; Baker, Mei W.

doi:10.3390/ijns6040080

Cited by 23 publications

(29 citation statements)

References 44 publications

(25 reference statements)

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“…In an attempt to further refine newborn screening for CF, some investigators have explored the use of next generation sequencing (NGS) technologies given their increased ease and affordability compared with other methods of DNA analysis such as Sanger sequencing [52,118]. For example, hoping "to address the shortcomings" of the IRT/DNA algorithm used in the Wisconsin NBS program, which targeted the 23 ACMG-recommended CFTR mutations, investigators carried out a retrospective study to evaluate an NGS assay capable of identifying 162 CFTR variants "for which clinical consequences have been described" [119].…”

Section: Discussionmentioning

confidence: 99%

Addressing Uncertainty: The Emergence of the CRMS/CFSPID Diagnostic Category Following Newborn Screening for Cystic Fibrosis

LaBonte¹

2021

obm genet

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This article uses cystic fibrosis as a case study to examine how physicians and scientists have navigated uncertainty following newborn screening. Despite the many benefits of newborn screening, including earlier diagnosis, therapeutic intervention, and a reduced diagnostic odyssey, this public health approach also comes with challenges. For example, physicians began to document infants with indeterminate diagnoses - those with a positive screen who did not clearly fit into the cystic fibrosis or “normal” categories - by the early twenty first century. As a means of addressing this uncertainty and to facilitate long-term follow up of such infants, the U.S. Cystic Fibrosis Foundation recommended in 2009 that a new diagnostic term, CFTR-related metabolic syndrome (CRMS), be used. However, the CRMS label was not favored in Europe and a different term, cystic fibrosis screen positive, inconclusive diagnosis (CFSPID), was adopted in 2015 instead. Efforts to address the uncertainty associated with indeterminate diagnoses have been complicated, as stakeholders have held differing views about whether the screening algorithms should aim to maximize or minimize CRMS/CFSPID cases. Many who favor the identification of babies with CRMS/CFSPID note that they are at increased risk of developing symptoms and signs consistent with a cystic fibrosis diagnosis. In contrast, those who support algorithms that reduce CRMS/CFSPID cases point to iatrogenic harms associated with the medicalization of children who may remain healthy into adulthood. Furthermore, investigators have grappled with how best to ensure equity in newborn screening among different racialized groups while concomitantly attempting to minimize false positive results. These issues are applicable beyond the context of cystic fibrosis, especially as programs contemplate the incorporation or expanded use of next generation sequencing in algorithms for a wide range of diseases, and this history highlights how efforts to reduce uncertainty in one setting can lead to new and persistent sources of uncertainty in other areas.

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Section: Discussionmentioning

confidence: 99%

Addressing Uncertainty: The Emergence of the CRMS/CFSPID Diagnostic Category Following Newborn Screening for Cystic Fibrosis

LaBonte¹

2021

obm genet

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“…The above are examples of situations where an entire disease or a subgroup of children with a certain disease type may be molecular genetically filtered away and not reported, possibly reducing harm. However, for such strategy we need to have an in-depth knowledge about how the molecular pathology is related to clinical manifestations or the lack of these [4]. Such knowledge is not always available [7], and we need to collect more molecular genetic data into generally available variant databases together with clinical data.…”

Section: Molecular Genetic Studies May Filter Diseases and Disease Subtypesmentioning

confidence: 99%

“…For confirmation of the screening positive samples, further biochemical methods are commonly used together with molecular genetic studies using new samples from the child. In recent years, molecular genetic studies have been introduced as second-tier testing before contacting the family for confirmative evaluation [1,[4][5][6][7]; even the use of molecular genetic studies as first-tier analyses has been introduced when screening for spinal muscular atrophy (SMA) and severe combined immunodeficiency (SCID) [4], and further use of molecular genetics as a first-tier procedure in NBS is being discussed. In Denmark, we have recently introduced molecular genetic analyses for SCID (though, strictly speaking, not a variant analysis) as first-tier screening, and SMA has also been accepted for addition to the routine screening panel with the use of first-tier molecular genetic analyses.…”

Section: Introductionmentioning

confidence: 99%

Use of Molecular Genetic Analyses in Danish Routine Newborn Screening

Lund

Wibrand

Skogstrand

et al. 2021

IJNS

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Historically, the analyses used for newborn screening (NBS) were biochemical, but increasingly, molecular genetic analyses are being introduced in the workflow. We describe the application of molecular genetic analyses in the Danish NBS programme and show that second-tier molecular genetic testing is useful to reduce the false positive rate while simultaneously providing information about the precise molecular genetic variant and thus informing therapeutic strategy and easing providing information to parents. When molecular genetic analyses are applied as second-tier testing, valuable functional data from biochemical methods are available and in our view, such targeted NGS technology should be implemented when possible in the NBS workflow. First-tier NGS technology may be a promising future possibility for disorders without a reliable biomarker and as a general approach to increase the adaptability of NBS for a broader range of genetic diseases, which is important in the current landscape of quickly evolving new therapeutic possibilities. However, studies on feasibility, sensitivity, and specificity are needed as well as more insight into what views the general population has towards using genetic analyses in NBS. This may be sensitive to some and could have potentially negative consequences for the NBS programme.

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“…In 2005, Chan and Puck published a seminal paper describing the measurement of T-cell receptor excision circles isolated from NBS dried blood spots as a potential population-based approach to identifying infants with SCID [ 3 ]. In 2008, the Wisconsin NBS program was the first to implement a molecular screening assay for SCID using optimized DNA isolation techniques and RT-PCR for TRECs [ 4 , 5 , 6 , 7 , 8 ]. Between 2008 and 2010, three additional states began NBS SCID screening: Massachusetts in 2009 and California and New York in 2010 [ 9 , 10 , 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

Newborn Screening for Severe Combined Immunodeficiency: Do Preterm Infants Require Special Consideration?

Atkins¹,

Cogley²,

Baker

2021

IJNS

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The Wisconsin Newborn Screening (NBS) Program began screening for severe combined immunodeficiency (SCID) in 2008, using real-time PCR to quantitate T-cell receptor excision circles (TRECs) in DNA isolated from dried blood NBS specimens. Prompted by the observation that there were disproportionately more screening-positive cases in premature infants, we performed a study to assess whether there is a difference in TRECs between full-term and preterm newborns. Based on de-identified SCID data from 1 January to 30 June 2008, we evaluated the TRECs from 2510 preterm newborns (gestational age, 23–36 weeks) whose specimens were collected ≤72 h after birth. The TRECs from 5020 full-term newborns were included as controls. The relationship between TRECs and gestational age in weeks was estimated using linear regression analysis. The estimated increase in TRECs for every additional week of gestation is 9.60%. The 95% confidence interval is 8.95% to 10.25% (p ≤ 0.0001). Our data suggest that TRECs increase at a steady rate as gestational age increases. These results provide rationale for Wisconsin’s existing premature infant screening procedure of recommending repeat NBS following an SCID screening positive in a premature infant instead of the flow cytometry confirmatory testing for SCID screening positives in full-term infants.

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Translating Molecular Technologies into Routine Newborn Screening Practice

Cited by 23 publications

References 44 publications

Addressing Uncertainty: The Emergence of the CRMS/CFSPID Diagnostic Category Following Newborn Screening for Cystic Fibrosis

Addressing Uncertainty: The Emergence of the CRMS/CFSPID Diagnostic Category Following Newborn Screening for Cystic Fibrosis

Use of Molecular Genetic Analyses in Danish Routine Newborn Screening

Newborn Screening for Severe Combined Immunodeficiency: Do Preterm Infants Require Special Consideration?

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