Newborn Screening for Cystic Fibrosis in California

Kharrazi, Martin; Yang, Juan; Bishop, Tracey; Lessing, S.; Young, Suzanne; Graham, Simon; Pearl, Michelle; Chow, H.; Ho, Tammy Szu-Yu; Currier, Robert; Gaffney, L.; Feuchtbaum, Lisa

doi:10.1542/peds.2015-0811

Cited by 129 publications

(138 citation statements)

References 30 publications

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“…With the California CF NBS algorithm, hypertrypsinogenemic newborns (top 1.6%) are considered screen positive either when two CFTR mutations are detected by a panel of 40 CF-causing mutations (CF40 mut ) or 1 by the panel and ‡1 by subsequent DNA sequencing (Kharrazi et al, 2015). If on sequencing CFTR (IVS8)-(TG)m-(T)n, poly T status revealed a 5T, TG tract length was reported (Strom et al, 2003;Kammesheidt et al, 2006;Keiles et al, 2012).…”

Section: Methodsmentioning

confidence: 99%

Phenotypes of California CF Newborn Screen-Positive Children with CFTR 5T Allele by TG Repeat Length

Salinas

Azen

Young

et al. 2016

Genetic Testing and Molecular Biomarkers

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Background: At the cystic fibrosis transmembrane conductance regulator (CFTR) gene (IVS8)-(TG)m(T)n locus, a lower number of thymidines (legacy names 9T vs. 7T vs. 5T) and a higher number of (TG) repeats (TG-11 vs. 12 vs. 13) are associated with decreasing translation of functional CFTR protein in vitro. Methods: Retrospective cohort study comparing phenotypes of California CF newborn screen-positive children (followed 2-8 years) who had two CF-causing mutations (diagnosed as CF) with those who had one mutation from a panel of 40 CF-causing mutations (CF40 mut ) and one (IVS8)-(TG)11, 12, or 13-5T mutation detected by sequencing (diagnosed as CFTR-related metabolic syndrome [cRMS]). Results: The study included 428 children, of which 234 had two CF-causing mutations, and were used to compare with the other 194 children with one CF-causing mutation and one isolated 5T allele [CF40 mut /(TG)13-5T = 21, CF40 mut /(TG)12-5T = 85, and CF40 mut /(TG)11-5T = 88]. Among children with CF40 mut /(TG)13-5T, 38% were diagnosed with CF by 8 years, based on sweat chloride results and clinical presentation. Six percent of those with CF40 mut /(TG)12-5T, and none with CF40 mut /(TG)11-5T, reached diagnostic criteria. Conclusions: CFTR (IVS8)-(TG)m-5T allele (TG) tract length determination provides valuable information in predicting the risk of developing a CF phenotype. Of the three types of 5T alleles evaluated, screen-positive children with genotype CF40 mut /(TG)13-5T progressed from CRMS to CF at a high rate, while there was little evidence of clinical disease in those with CF40 mut /(TG)11-5T. Additional data from longer follow-up intervals are needed to fully understand the natural history of individuals with a CF40 mut /(TG)m-5T genotype.

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Section: Methodsmentioning

confidence: 99%

Phenotypes of California CF Newborn Screen-Positive Children with CFTR 5T Allele by TG Repeat Length

Salinas

Azen

Young

et al. 2016

Genetic Testing and Molecular Biomarkers

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“…Another approach to SCID screening would be to detect DNA sequence variants in known SCID disease genes; these sequence variations could be either previously defined, or as‐yet unreported mutations predicted to be deleterious. Increasingly, NBS laboratories that include cystic fibrosis in their screening test panel currently use DNA mutation arrays, with genomic sequencing as a second‐tier test to detect further mutations . However, gene sequencing is not currently suitable for primary screening for SCID because new pathogenic SCID mutations continue to be discovered .…”

Section: Justification For Newborn Screening For Scid With the Trec Testmentioning

confidence: 99%

Newborn screening for severe combined immunodeficiency and T‐cell lymphopenia

Puck

2018

Immunological Reviews

134

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Summary The development of a T cell receptor excision circle (TREC) assay utilizing dried blood spots made possible universal newborn screening (NBS) for severe combined immunodeficiency (SCID) as a public health measure. Upon being flagged by an abnormal screening test in a SCID screening program, an infant can receive further diagnostic testing for SCID in the neonatal period, prior to onset of infectious complications, to pemit immediate institution of protective measures and definitive, life-saving treatment to establish a functional immune system. SCID screening is now the accepted standard of care in state public health departments across the USA, and it is being adopted in many countries. It has proven effective, with infants having this otherwise inapparent but serious, rare disorder achieving survival and immune reconstitution. In addition to bringing to attention infants with the primary screening target diseases, typical SCID and leaky SCID (due to hypomorphic mutations in known SCID genes), the newborn screening assay for insufficient TRECs in dried blood spots also reveals infants with non-SCID T lymphopenic conditions. Experience has accumulated regarding the range and limitations of diagnoses of newborns with low TRECs and low T cells. Previously unknown immune defects have been discovered, as well as conditions not formerly recognized to have low T cells in the neonatal period.

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“…One example is California’s use of sequencing to follow up a positive screen for Cystic Fibrosis, by sequencing the full CFTR gene. 64 Furthermore, some genetic conditions are not revealed by tandem mass spectrometry, the currently dominant technology.…”

Section: Targeted But Not Whole Exome/genome Sequencing Could Assist mentioning

confidence: 99%

Sequencing Newborns:A Call for Nuanced Use of Genomic Technologies

Johnston¹,

Lantos²,

Goldenberg³

et al. 2018

Hastings Center Report

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Many scientists and doctors hope that affordable genome sequencing will lead to more personalized medical care and improve public health in ways that will benefit children, families, and society more broadly. One hope in particular is that all newborns could be sequenced at birth, thereby setting the stage for a lifetime of medical care and self-directed preventive actions tailored to each child's genome. Indeed, commentators often suggest that universal genome sequencing is inevitable. Such optimism can come with the presumption that discussing the potential limits, cost, and downsides of widespread application of genomic technologies is pointless, excessively pessimistic, or overly cautious. We disagree. Given the pragmatic challenges associated with determining what sequencing data mean for the health of individuals, the economic costs associated with interpreting and acting on such data, and the psychosocial costs of predicting one's own or one's child's future life plans based on uncertain testing results, we think this hope and optimism deserve to be tempered. In the analysis that follows, we distinguish between two reasons for using sequencing: to diagnose individual infants who have been identified as sick and to screen populations of infants who appear to be healthy. We also distinguish among three contexts in which sequencing for either diagnosis or screening could be deployed: in clinical medicine, in public health programs, and as a direct-to-consumer service. Each of these contexts comes with different professional norms, policy considerations, and public expectations. Finally, we distinguish between two main types of genome sequencing: targeted sequencing, where only specific genes are sequenced or analyzed, and whole-exome or whole-genome sequencing, where all the DNA or all the coding segments of all genes are sequenced and analyzed. In a symptomatic newborn, targeted or genome-wide sequencing can help guide other tests for diagnosis or for specific treatment that is urgently needed. Clinicians use the infant's symptoms (or phenotype) to interrogate the sequencing data. These same complexities and uncertainties, however, limit the usefulness of genome-wide sequencing as a population screening tool. While we recognize considerable benefit in using targeted sequencing to screen for or detect specific conditions that meet the criteria for inclusion in newborn screening panels, use of genome-wide sequencing as a sole screening tool for newborns is at best premature. We conclude that sequencing technology can be beneficially used in newborns when that use is nuanced and attentive to context.

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Newborn Screening for Cystic Fibrosis in California

Cited by 129 publications

References 30 publications

Phenotypes of California CF Newborn Screen-Positive Children with CFTR 5T Allele by TG Repeat Length

Phenotypes of California CF Newborn Screen-Positive Children with CFTR 5T Allele by TG Repeat Length

Newborn screening for severe combined immunodeficiency and T‐cell lymphopenia

Sequencing Newborns:A Call for Nuanced Use of Genomic Technologies

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