Next Generation Sequencing in Newborn Screening in the United Kingdom National Health Service

Campen, Julia C. van; Sollars, Elizabeth; Thomas, Rebecca C.; Bartlett, Clare; Milano, Antonio; Parker, Matthew; Dawe, Jennifer; Winship, Peter R.; Peck, Gerrard; Grafham, Darren; Kirk, Richard; Bonham, James R.; Goodeve, Anne; Dalton, Ann

doi:10.3390/ijns5040040

Cited by 28 publications

(28 citation statements)

References 79 publications

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“…This work confirms that targeted NGS as a first-tier DNA based test in NBS represents an approach by which the molecular bases of multiple medically-actionable diseases, including Menkes disease, can be assessed rapidly in a single efficient assay [ 47 ]. Reduced health care costs could be realized by avoiding the illnesses and diagnostic odysseys of unrecognized affected infants, as well as removing the need for later molecular testing for diagnostic confirmation of biochemically screened genetic disorders.…”

Section: Discussionsupporting

confidence: 66%

Targeted next generation sequencing for newborn screening of Menkes disease

Parad

Kaler

Mauceli

et al. 2020

Molecular Genetics and Metabolism Reports

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Purpose Population-based newborn screening (NBS) allows early detection and treatment of inherited disorders. For certain medically-actionable conditions, however, NBS is limited by the absence of reliable biochemical signatures amenable to detection by current platforms. We sought to assess the analytic validity of an ATP7A targeted next generation DNA sequencing assay as a potential newborn screen for one such disorder, Menkes disease. Methods Dried blood spots from control or Menkes disease subjects ( n = 22) were blindly analyzed for pathogenic variants in the copper transport gene, ATP7A. The analytical method was optimized to minimize cost and provide rapid turnaround time . Results The algorithm correctly identified pathogenic ATP7A variants, including missense, nonsense, small insertions/deletions, and large copy number variants, in 21/22 (95.5%) of subjects, one of whom had inconclusive diagnostic sequencing previously. For one false negative that also had not been detected by commercial molecular laboratories, we identified a deep intronic variant that impaired ATP7A mRNA splicing. Conclusions Our results support proof-of-concept that primary DNA-based NBS would accurately detect Menkes disease, a disorder that fulfills Wilson and Jungner screening criteria and for which biochemical NBS is unavailable. Targeted next generation sequencing for NBS would enable improved Menkes disease clinical outcomes, establish a platform for early identification of other unscreened disorders, and complement current NBS by providing immediate data for molecular confirmation of numerous biochemically screened condition.

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Section: Discussionsupporting

confidence: 66%

Targeted next generation sequencing for newborn screening of Menkes disease

Parad

Kaler

Mauceli

et al. 2020

Molecular Genetics and Metabolism Reports

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“…Thus it is fitting for the International Journal of Neonatal Screening ( IJNS ) to devote this issue to ethical and psychosocial issues of NBS. These issues include the diagnostic and prognostic dilemmas of variant interpretation, how to handle the identification of carriers, identifying benign variants with the inevitable uncertainty and anxiety that this produces, unnecessary treatment, the potential for very large additional medical costs of confirmatory testing and unnecessary treatment, the identification of late-onset disorders with the need for continuous follow-up and uncertainty of early therapy, the need for informed consent and the difficulty of providing the correct information for appropriate consenting, the potential for adverse long-term consequences of insurance for the family as well as the infant, the need for additional geneticists and other specialists to handle, educate, and treat these newly-detected newborns, and the dreaded possibility that standard NBS for PKU, congenital hypothyroidism, and other well-established screening might be threatened [ 17 , 18 , 19 ]. All of these and many more issues must be carefully examined [ 20 , 21 ], as they will be in this special issue of the IJNS .…”

Section: Ethical and Psychosocial Implicationsmentioning

confidence: 99%

Ethical and Psychosocial Implications of Genomic Newborn Screening

Levy

2021

IJNS

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The potential for genomic screening of the newborn, specifically adding genomic screening to current newborn screening (NBS), raises very significant ethical issues. Regardless of whether NBS of this type would include entire genomes or only the coding region of the genome (exome screening) or even sequencing specific genes, the ethical issues raised would be enormous. These issues include the limitations of bioinformatic interpretation of identified variants in terms of pathogenicity and accurate prognosis, the potential for substantial uncertainty about appropriate diagnosis, therapy, and follow-up, the possibility of much anxiety among providers and parents, the potential for unnecessary treatment and “medicalizing” normal children, the possibility of adding large medical costs for otherwise unnecessary follow-up and testing, the potential for negatively impacting medical and life insurance, and the almost impossible task of obtaining truly-informed consent. Moreover, the potentially-negative consequences of adding genomic sequencing to NBS might jeopardize all of NBS which has been and continues to be so beneficial for thousands of children and their families throughout the world.

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“…Nonetheless, attempts to expand the use of DNA sequencing in NBS have been carried out using customized NGS panels targeting few relevant genes or alternatively using a WES approach and bioinformatics analysis ad hoc [ 74 , 75 ]. On the other hand, genotyping-based NBS seems the better solution for high-risk neonates admitted to the neonatal intensive care unit (NICU), or for those disorders with no existing biochemical marker [ 76 , 77 ].…”

Section: Opportunities and Challenges For Genomics In Lsdsmentioning

confidence: 99%

Highlights on Genomics Applications for Lysosomal Storage Diseases

Cognata

Guarnaccia

Polizzi

et al. 2020

Cells

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Lysosomal storage diseases (LSDs) are a heterogeneous group of rare multisystem genetic disorders occurring mostly in infancy and childhood, characterized by a gradual accumulation of non-degraded substrates inside the lysosome. Although the cellular pathogenesis of LSDs is complex and still not fully understood, the approval of disease-specific therapies and the rapid emergence of novel diagnostic methods led to the implementation of extensive national newborn screening (NBS) programs in several countries. In the near future, this will help the development of standardized workflows aimed to more timely diagnose these conditions. Hereby, we report an overview of LSD diagnostic process and treatment strategies, provide an update on the worldwide NBS programs, and discuss the opportunities and challenges arising from genomics applications in screening, diagnosis, and research.

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Next Generation Sequencing in Newborn Screening in the United Kingdom National Health Service

Cited by 28 publications

References 79 publications

Targeted next generation sequencing for newborn screening of Menkes disease

Targeted next generation sequencing for newborn screening of Menkes disease

Ethical and Psychosocial Implications of Genomic Newborn Screening

Highlights on Genomics Applications for Lysosomal Storage Diseases

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