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Genomic newborn screening: public health policy considerations and recommendations Friedman, Jan M; Cornel, Martina C; Goldenberg, Aaron J; Lister, Karla J; Sénécal, Karine; Vears, Danya F Feb 21, 2017

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RESEARCH ARTICLE Open AccessGenomic newborn screening: publichealth policy considerations andrecommendationsJan M. Friedman1,2*, Martina C. Cornel3,4, Aaron J. Goldenberg5, Karla J. Lister6, Karine Sénécal7, Danya F. Vears8,the Global Alliance for Genomics and Health Regulatory and Ethics Working Group Paediatric Task TeamAbstractBackground: The use of genome-wide (whole genome or exome) sequencing for population-based newbornscreening presents an opportunity to detect and treat or prevent many more serious early-onset health conditionsthan is possible today.Methods: The Paediatric Task Team of the Global Alliance for Genomics and Health’s Regulatory and EthicsWorking Group reviewed current understanding and concerns regarding the use of genomic technologies forpopulation-based newborn screening and developed, by consensus, eight recommendations for clinicians, clinicallaboratory scientists, and policy makers.Results: Before genome-wide sequencing can be implemented in newborn screening programs, its clinical utilityand cost-effectiveness must be demonstrated, and the ability to distinguish disease-causing and benign variants ofall genes screened must be established. In addition, each jurisdiction needs to resolve ethical and policy issuesregarding the disclosure of incidental or secondary findings to families and ownership, appropriate storage andsharing of genomic data.Conclusion: The best interests of children should be the basis for all decisions regarding the implementation ofgenomic newborn screening.Keywords: Newborn Screening, Whole Genome Sequencing, Exome Sequencing, Public Policy, Ethics,Public Health GeneticsBackgroundThe Global Alliance for Genomics and Health is an inter-national collaboration of more than 400 healthcare, re-search, disease advocacy, life science, and informationtechnology institutions working together to promotehuman health through sharing of genomic and clinical data[http://genomicsandhealth.org/]. Within this remit, thePaediatric Task Team of the Global Alliance’s Regulatoryand Ethics Working Group [http://genomicsandhealth.org/working-groups/regulatory-and-ethics-working-group] wasestablished to address issues of particular relevance tochild health.Recent research has demonstrated that genomictechnology, and particularly genome-wide (whole gen-ome or exome) sequencing, can identify genetic causesof rare paediatric diseases much more effectively thanconventional clinical and laboratory methods [1, 2].Furthermore, genome-wide sequencing could, at least intheory, be used in newborn screening to identify manymore serious health conditions than is possible today[3–8]. This possibility interests some parents [9–11],commercial testing laboratories [12], and the USNational Institutes of Health [http://www.nih.gov/news-events/news-releases/nih-program-explores-use-gen-omic-sequencing-newborn-healthcare], but it also raisesserious ethical and public policy concerns [3–5, 13–20].* Correspondence: jan.friedman@ubc.ca1Department of Medical Genetics, University of British Columbia, Vancouver,Canada2Child & Family Research Institute, Vancouver, CanadaFull list of author information is available at the end of the article© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Friedman et al. BMC Medical Genomics  (2017) 10:9 DOI 10.1186/s12920-017-0247-4MethodsThe Global Alliance Paediatric Task Team developed therecommendations shown in Table 1 for clinicians, clinicallaboratory scientists, and policy makers regarding ourcurrent understanding, concerns and consensus regardingthe use of genomic technologies for population-basednewborn screening. This document and its recommenda-tions were reviewed and approved by the Paediatric TaskTeam in December 2015. These recommendations shouldbe reconsidered in the future as our knowledge in theseareas improves.Following a brief overview of current programs andpublic health policies regarding newborn screening byother means, we describe the genomic technologies thatcould be used for newborn screening and discuss howgenomic newborn screening might differ from conven-tional newborn screening. We then consider issues ofconcern related to genomic newborn screening and pro-vide justification for each of our recommendations. Weconclude by considering the public health opportunitygenomic newborn screening offers and highlight theneed for more research in this area.ResultsNewborn screening todayNewborn screening is the process by which infants aretested for conditions that can cause death, serious life-long disability or chronic disease if not treated shortlyafter birth. The purpose of newborn screening is to iden-tify conditions for which effective therapy is availableand to provide this treatment early enough to prevent orameliorate the disease, so that affected children can livehealthier lives.Newborn screening began in the early 1960s for in-born errors of metabolism such as phenylketonuria(PKU) and is now routinely performed for a variety ofconditions on almost all infants in many countries.Given this history and wide acceptance, the essential ele-ments of population-based newborn screening programshave become well understood. At their heart, they areorganized approaches to early detection, through whichasymptomatic individuals in a specific population aresystematically tested for a set of conditions or for bio-markers of the conditions. The programs aim to identifythese conditions at an early stage, generally prior to theonset of symptoms. Screening must usually be followedby a more definitive diagnostic process for the condition.Once a serious condition is identified in a newborn in-fant, treatment or management designed to ameliorateor prevent the onset of symptoms must be initiated.Newborn screening programs vary greatly from juris-diction to jurisdiction with respect to which conditionsand how many diseases are tested for. Most newbornscreening is performed on a small blood sample ob-tained by heel prick from each baby. Testing this sampleby tandem mass spectrometry, a method of identifyingand quantitating many metabolites simultaneously, per-mits recognition of about 50 potentially treatable inbornerrors of metabolism, although most jurisdictions thatdo population-based newborn screening test for only asubset of these conditions.Only genetic abnormalities that are associated withmajor alterations of biochemicals in the blood can bedetected by tandem mass spectrometry, but other treat-able conditions, such as congenital hypothyroidism, cysticfibrosis, sickle cell disease, and severe combined immuno-deficiency, can be screened in the blood spot with otherkinds of tests. A few additional disorders, such as congeni-tal hearing loss and critical congenital heart disease, maybe screened by methods that require physical measure-ments directly on the infant rather than analysis of a bloodsample.Newborn screening and early diagnosis of serious diseasemight seem to be advantageous under all circumstances.Table 1 Recommendations1. Newborn screening by any method, including genomic testing, ifadopted as a public health program should be equally available andaccessible to every infant born in the jurisdiction.2. Interpretation of genomic newborn screening results requiresextensive knowledge of the normal (benign) variants, as well as ofpathogenic variants, of every gene tested. Genomic newbornscreening programs should, therefore, make population-specific allelefrequencies of every gene included in the program publicly availablein a freely-accessible database. The functional consequences (benign,pathogenic, or undetermined) of each allele should also be madeavailable, along with the evidence supporting functionalinterpretations.3. Publicly-funded universal newborn screening by genomic methodsshould be limited to diseases that can be diagnosed in the newbornperiod and effectively treated or prevented in childhood.4. If population-based genomic newborn screening is introduced, it shouldonly be offered as part of a comprehensive public health program thatincludes appropriate confirmatory testing, therapeutic interventions,clinical follow-up, genetic counselling, quality assurance, public andprofessional education, and governance and oversight.5. Newborn screening by next-generation sequencing or other genomicmethods should only be considered as an add-on to current first tierscreening programs.6. Current newborn screening should not be replaced by nextgeneration sequencing or other genomic methods for any diseaseunless the genomic technology has been shown to have equal orbetter sensitivity and specificity for the disease.7. At the present time, our understanding of, and ability to interpretgenomic variants does not justify use of genome-wide (whole genomeor exome) sequencing in population-based newborn screening. Researchis needed to demonstrate the clinical utility and cost-effectiveness ofgenome-wide sequencing and to resolve outstanding health policy andethical issues before genome-wide sequencing is implemented fornewborn screening within a jurisdiction.8. At the present time, our understanding of, and ability to interpretgenomic variants does not justify sequencing large multigene(physical or bioinformatic) panels for population-based newbornscreening. Research is needed to demonstrate the clinical utility andcost-effectiveness of sequencing large multigene panels forpopulation-based newborn screening and to resolve outstandinghealth policy and ethical issues before the use of large sequencingpanels is implemented for newborn screening within a jurisdiction.Friedman et al. BMC Medical Genomics  (2017) 10:9 Page 2 of 13However, there are several countervailing factors that mustalso be considered. These include the implications of falsepositive and false negative screening results; of parentalstress and anxiety about when, whether and how the dis-ease will appear; of the often uncertain utility of availabletreatments; and of the social and personal cost of the entireprogram of screening and management of early or asymp-tomatic disease.In 1968, under the auspices of the World HealthOrganization, Wilson and Jungner [21] developed cri-teria to assess the value of potential screening programsas public health interventions (Table 2). Almost 50 yearslater, the Wilson and Jungner criteria still provide auseful framework for assessing the value and appropri-ateness of newborn screening programs, although someof the criteria have been criticized and modificationsproposed in light of more recent scientific developmentsand circumstances [22, 23].Newborn screening programs follow defined protocolsto produce population-level benefits through reductionsin mortality and morbidity related to the conditionsscreened. The system generally includes most, if not all,of the following elements: Informing the family of thetesting, obtaining (or presuming) their consent, obtainingthe sample, performing the test, interpreting it, informingthe child’s physician or parents of “screen-positive” (or“screen-negative”) results, arranging and performing con-firmatory diagnostic testing, and initiating preventativemanagement or treatment, when indicated. The successfuldelivery of a screening program is dependent upon effi-cient and timely activities at each stage, delivered in linewith established policies, protocols, administration andgovernance. Additional components of a successfulscreening program are continuous quality management,monitoring and evaluation. These are necessary todemonstrate to funders, clinicians and the public thatthe program is achieving its objectives, justifying thecontinued investment of public resources.Ethical and public policy issues raised by currentnewborn screening practicesPopulation-based newborn screening with treatment orprevention of the serious conditions identified is one ofthe most successful public health interventions ever de-vised [24–26]. Almost every baby in most developedcountries and many developing countries currently under-goes newborn screening for various serious early-onsetdiseases [27]. Introduction of genomic technology mayprovide an opportunity to identify more infants for whomearly interventions can prevent serious illnesses, majorhandicaps or death. However, precautions must be takento ensure that genomic technology is used in a mannerthat does not compromise the effectiveness or societalsupport of current screening programs. In order to be suc-cessful, genomic newborn screening must learn from theexperience of conventional newborn screening over thepast 50 years. These lessons are briefly reviewed here.Consent for newborn screeningOne of the most problematic issues in population-basednewborn screening is whether parents should be askedfor permission before testing takes place. While someprograms do obtain explicit parental consent for new-born screening, most presume consent unless the par-ents express an objection. Such implicit consent isjustified by the belief that newborn screening is in thechild’s best interest. Newborn screening has been estab-lished as compulsory in some jurisdictions under a pub-lic health mandate, but even mandatory programsusually allow parents to “opt out” if they hold religiousor other beliefs that are contrary to screening.As programs have expanded to include conditions withwider phenotypic variability, unclear risk associations, andmore invasive or less effective treatments, there are con-cerns that the justification for implicit consent ormandatory screening has been compromised [13, 28, 29].Alternative suggestions include specific parent consent(i.e., “opting in”) for all newborn screening or a tiered ap-proach in which some tests would require explicit parentalconsent while others would not. The tiered approachwould be designed to maintain the benefits of universalscreening for conditions where it is essential for the bene-fit of the child while allowing parents to choose whetheror not to screen for conditions that do not meet thestandards for compulsory population-wide screening.Unfortunately, however, a number of studies have foundpoor understanding of newborn screening among parents[13, 30–32]. This may prevent them from makinginformed choices about screening if options are madeavailable. In addition, keeping track of and modifying thereporting in response to varying parental requests wouldgreatly increase the administrative complexity and thusthe cost of a newborn screening program.Table 2 Wilson and Jungner [21] Criteria1. The condition sought should be an important health problem.2. There should be an accepted treatment for patients with recognizeddisease.3. Facilities for diagnosis and treatment should be available.4. There should be a recognizable latent or early symptomatic stage.5. There should be a suitable test or examination.6. The test should be acceptable to the population.7. The natural history of the condition, including development fromlatent to declared disease, should be adequately understood.8. There should be an agreed policy on whom to treat as patients.9. The cost of case-finding (including diagnosis and treatment ofpatients diagnosed) should be economically balanced in relation topossible expenditure on medical care as a whole.10. Case-finding should be a continuing process and not a “once andfor all” project.Friedman et al. BMC Medical Genomics  (2017) 10:9 Page 3 of 13What conditions should be screened for?In accordance with the Wilson and Jungner criteria,newborn screening began in all jurisdictions with condi-tions that are life-threatening or could cause severe dis-ability, are easy to screen for, and have an effectivetreatment. In their landmark paper supporting compul-sory PKU screening, Faden, Holtzman and Chwalow[33] highlighted the harm that would likely occur in anewborn infant who was not screened and argued thatthis greatly outweighs the benefit of permitting parentalchoice about screening. As it became possible to screenfor other conditions, similar criteria were required foradditions to the screening panel. The association of dis-ease severity and treatability in all of the conditionstested for provided the moral justification for makingnewborn screening mandatory in many jurisdictions.While the Wilson and Jungner criteria have generallybeen used to assess the benefits and harms of addingconditions to the screening panel, programs may inter-pret these criteria differently and may also be subject todifferent political or public pressures to add certain con-ditions to the panel. As a consequence, different pro-grams often screen for different conditions [34–36].Some jurisdictions screen for fewer than ten conditions,and others screen for more than fifty.The potential to screen for such a large number ofconditions was made possible by the introduction of tan-dem mass spectrometry, which permits the addition ofnew screening targets to an existing metabolic panel atalmost no cost by simply adjusting the analytical soft-ware. As a result, the kinds of conditions that have beenproposed and added to newborn screening panels insome jurisdictions have begun to challenge conventionalethical norms. Some of the newly added conditions arenot completely penetrant – not all infants who have thepathogenic biomarker develop the disease. In other in-stances, those who develop the disease may do so at awide range of ages, from early childhood to adulthood,or may exhibit a wide range of disease severity or re-sponse to treatment. In such cases, some infants whoscreen positive may endure unnecessary diagnostic pro-cedures and treatments, and their families may sufferincreased stress and anxiety as they deal with future un-certainty. This could place a substantial burden on thehealth care system, with potentially negative effects [4].These issues are amplified if the available treatment isexpensive or associated with serious risks of adverse ef-fects, as occurs with hematopoietic stem cell transplant-ation, for example.The benefits of newborn screeningConcerns have also been raised about the kinds of bene-fits expanded newborn screening programs provide [37].Treatment has traditionally been defined in terms ofpreventing the occurrence of symptoms related to a con-dition or substantially ameliorating those symptoms ifthey do occur. In recent years, however, the concept of“treatable” has been expanded to include reducing symp-toms to some degree, prolonging life, or avoiding longdiagnostic quests once symptoms appear [38]. Further-more, some advocates have pointed out that interventionswhich have not been proven to be effective in reducingmorbidity or mortality might, nevertheless, benefit somechildren or their families [23]. Families may also value theopportunity to participate in disease-related research.Cystic fibrosis, which is now screened for in manyNorth American, European and Australian jurisdictions,provides an excellent example. Infants with cystic fibro-sis rarely die or suffer irreversible damage in the new-born period, but moderate clinical benefits have beendemonstrated in children with cystic fibrosis who areidentified by newborn screening and receive earlierdietary and respiratory management in comparison tochildren who are not diagnosed until they become symp-tomatic [39–41].At its core, newborn screening is intended to benefitindividual infants, but the justification for adding somenew conditions to the screening panel has been toprovide benefits beyond the infants to their families orsociety. For example, providing families informationabout an infant’s carrier status for a recessive geneticdisorder such as cystic fibrosis or sickle cell disease,while of no immediate clinical benefit to the child, mayallow the parents to make future reproductive choicesthat would not otherwise be available to them [42, 43].Some have argued that reporting such findings should beavoided because doing so increases the cost of reportingand follow up in the screening program and has not beenshown to be beneficial [42, 44]. Others advocate informingfamilies of such results, which are produced incidentallyby screening for primary targets with methods like tandemmass spectrometry or high-performance liquid chroma-tography of hemoglobin [45–47]. While expanding thescope of benefits considered may not be unethical, it doesrepresent a shift in the goals of newborn screening thatnecessitates re-examination of its ethical justification.Secondary use of newborn screening blood spotsAnother issue that has raised controversy in severaljurisdictions is retention and secondary use of leftoverdried blood spots after newborn screening is complete.Residual blood spots are routinely used for internallaboratory quality assurance purposes and confirmationof original results [48]. In addition, the residual bloodspots may be used to refine current methodologies andto develop new newborn screening tests [49]. These usesare generally accepted because they are related to theprimary purpose of the blood collection [50, 51].Friedman et al. BMC Medical Genomics  (2017) 10:9 Page 4 of 13As blood spots are collected from almost all childrenat the time of birth, these samples also represent aunique population-based resource for biomedical re-search, public health surveillance, and forensic uses,such as the identification of disaster victims [52–55].Biomedical and public health research using storedblood spots has contributed to our understanding in sev-eral important areas [56], including the development ofchildhood leukemia [57] and whether pregnant womenare eating fish that contain excessive amounts of mer-cury [55]. However, the lack of consent from the parentsfor such uses is problematic, especially for programs thatdo not obtain consent for screening itself. As a conse-quence, policies regarding the retention and secondaryuse of newborn screening blood spots vary greatlyworldwide [54, 55, 58–60] and secondary use of suchblood spots has been the subject of several lawsuits inthe United States and Canada [54].Genetic testing in newborn screeningTesting for mutations of individual genes and sets of genesMany potentially treatable conditions cannot be detectedin infants using current newborn screening methods[61]. Most of these disorders result from genetic muta-tions (either inherited from one or both of the parentsor arising de novo in the child) and could, in principle,be diagnosed shortly after birth by means of availablegenomic technologies [4, 62, 63]. Examples includemany early-onset seizure disorders, cardiac arrhythmias,cardiomyopathies, diseases of the blood or bone marrow,liver diseases and kidney disorders.Clinical laboratories currently employ molecular gen-etic technologies for a variety of purposes, including theidentification of bacteria or viruses involved in a pa-tient’s infection and matching tissue antigens between adonor organ and a patient who requires organ trans-plantation. In addition, genetic testing is routinely per-formed by clinical labs in circumstances other thannewborn screening – for example, to screen pregnantwomen for fetal Down syndrome [64–66] or in criticallyill intensive care unit patients suspected of having a gen-etic disease. The latter approach has been successfullyapplied to newborn infants [67, 68], but it is importantto distinguish this use of genome-wide sequencing forrapid diagnosis in a small number of critically ill infantsfrom population-based newborn screening, where almostall babies, including those who are completely healthy,are tested [69].There are several different kinds of genetic tests thatcould be used in newborn screening. Some employconventional technologies; other tests are performedwith massively-parallel (“next-generation”) sequencingmachines, which, in comparison to the sequencers usedin the Human Genome Project, produce 8,000,000 timesmore data 24,000 times faster at a cost that is 3,000,000times lower [70–72]. Genetic tests include:1. Molecular genetic testing by methods that do notinvolve sequencing, e.g., PCR of specific genetictargets. Such methods have been used in diagnostictesting for many years and are the clinical standardfor rapid identification of infectious agents [73, 74].A PCR-based technique has recently been adoptedin some jurisdictions to screen newborn infants forsevere combined immunodeficiency disease [75], agroup of genetic disorders causing recurrent andeventually lethal infections that can be effectivelytreated by early stem cell transplantation. Simplemolecular analytic technologies are also used toidentify disease-causing germ-line mutations forconfirmatory testing in some newborn screeningprograms [4] and even for primary screening in afew instances in which one or two specific mutationsare responsible for almost all cases of a diseasewithin a particular population. One example isnewborn screening for glutaric acidemia type 1 causedby homozygosity for the GCDH, IVS1, G-T, +5mutation in the Canadian province of Manitoba [76].2. Sequencing individual genes. For more than 25 years,clinical laboratories have offered sequencing ofindividual genes, such as those for cystic fibrosis(CFTR) or Duchenne muscular dystrophy (DMD), toprovide a molecular diagnosis in affected individuals.This testing is usually done by conventional (Sanger)sequencing of PCR-amplified coding regions of thegene. Individual gene sequencing is useful for clinicaldiagnosis in patients of any age, including newborninfants, but is too expensive and not sufficientlyautomatable to use for population-based screening.However, sequencing individual genes is used insome newborn screening programs for secondary orconfirmatory testing of screen-positive infants [77–79].3. Gene panels. Gene panels are sets of genes that aresequenced as a group. The group is selected becausemutations of any of the included genes can produceclinically similar disease or, more broadly, diseases ofthe same class. The first panels offered for clinicaldiagnosis were small – three genes (F8, F9 andVWF) for a coagulation disorder, for example – inessence just a few single gene tests done together.More recently, larger and larger gene panels havebeen developed, and it is now possible to obtainpanels that test simultaneously for mutations inhundreds of genes associated with epilepsy orintellectual disability, or even for any of more than3000 genes associated with mendelian diseases [80].As the panels have grown larger, the technologyemployed has changed, with larger panels usingFriedman et al. BMC Medical Genomics  (2017) 10:9 Page 5 of 13higher through-put methods to capture the codingsegments of the genes that are being tested, nextgeneration methods for sequencing, and additionalstudies to look for mutations like genomic copynumber changes that are difficult to identify bysequencing. Some laboratories offer “bioinformaticpanels” that involve sequencing the coding regionsof all genes (exome sequencing) but analyzing andreporting on only a selected subset of those genes.Genome-wide (Whole genome or exome) sequencingWith the development of next-generation DNA sequen-cing technology and its substantial reduction in costover recent years, sequencing all of the DNA (the wholegenome) or the coding segments of all of the genes (theexome) in the cells of an individual all at once hasemerged as a robust method of identifying mutationsthat cause treatment-resistant cancer [81, 82] or any ofthousands of serious genetic conditions in patients withpreviously undiagnosed diseases [1, 83–88].Most clinical laboratories currently utilize a differentmethod, usually Sanger sequencing, to confirm patho-genic variants identified by genome-wide sequencing.However, clinical validity – whether recognizing disease-associated variants by sequencing (e.g., of the CFTRlocus) predicts the disease (e.g., cystic fibrosis) – is oftena more difficult question to resolve than analytical valid-ity. No systematic studies of the clinical validity ofgenome-wide sequencing are available, but false positiveand false negative reports of pathogenic variants areknown to occur [1, 89, 90]. Such errors are more likelyin circumstances like newborn screening, where the apriori chance that an individual will have any particularrare genetic disease is vanishingly small. Moreover, rigor-ous genotype-phenotype correlation, which is critical forclinical interpretation of genomic variants [91, 92], isimpossible in most existing screening programs becauseinformation about illness or birth defects in the infantsis not available to the screening laboratory.Novel ethical and policy issues raised by genome-widesequencingAll of the ethical and public policy issues associated withcurrent newborn screening practices apply to genome-wide sequencing as well, and many of these issues areexacerbated by the fact that genome-wide sequencingproduces much more information about the individualthan conventional testing does. For example, it is moredifficult (or impossible) to justify mandatory screening,even if families have the ability to opt out, if many add-itional screening targets are added, especially if the bene-fits of screening for some of these additional targets areuncertain. At the very least, genomic newborn screeningwould require ensuring that parents have sufficient,clearly-understandable information available about thescreening program and that the entire population hasaccess to confirmatory diagnostic and treatment services,including genetic counselling. Maintaining effective gov-ernance and efficient administration of population-basedgenomic newborn screening programs would also beessential to avoid losing the high participation ratesand widespread public support that these programscurrently enjoy.Interpretation of genomic newborn screening resultsThe biggest challenge to using genome-wide sequencingto diagnose genetic disease is interpretation of the results[91, 93, 94]. The pathogenicity of genetic variants is oftendifficult to infer, especially if they are very rare or novel, asmay often occur in general population screening. Rigorouscriteria have been developed to define pathogenicity forclinical diagnostic labs, and the interpretation of variantsis greatly aided by the accumulation of large databases ofestablished pathogenic or benign variants [95, 96]. Never-theless, some variants cannot be classified as either patho-genic or benign and must be reported as variants ofuncertain significance (VUS), which can cause concern(often, but not always, unnecessarily) for individuals orfamilies. In sick children who undergo diagnostic sequen-cing, the clinical phenotype can be used to help determinewhether a variant is likely to be pathogenic by comparingthe child’s phenotype to that expected if the variant werepathogenic. In contrast, the purpose of newborn screeningis to identify infants with serious disorders before they be-come clinically apparent, and if the phenotype has not yetdeveloped, it cannot be used to determine the pathogen-icity of a genetic variant [1].Return of genome-wide sequencing results The uncer-tainty about interpretation raises questions regardingwhich variants laboratories should report back to cliniciansand, in turn, to what extent there is an obligation to com-municate these findings back to the patient [20, 97–100].The resources required to investigate and communicatethese findings may be a substantial burden on the healthcare system [3]. Other concerns include the potential forpsychological harm to patients and their families, and thelegal implications for laboratories and clinicians [101].An additional complexity with genomic newbornscreening relates to the fact that the testing is performedon infants who are legally incompetent when screenedbut who will gain competence when they grow older.This situation is not limited to newborn screening, ofcourse – infants and young children are incompetent tomake any decision regarding medical treatment orhealth screening. However, genomic newborn screeningcould detect diseases or predispositions to disease thatdo not have onset until middle or late adulthood, andFriedman et al. BMC Medical Genomics  (2017) 10:9 Page 6 of 13we know that many adults choose not to have genetictesting for such conditions when it is offered [102–105].Allowing substitute decision makers (usually the par-ents) to make decisions about such testing in infantsraises issues relating to respect for future autonomy andprivacy protection.Genomic incidental findings A major consideration ifgenome-wide (or large gene panel) sequencing were to beused for newborn screening is the frequent occurrence of“incidental findings” – genetic variants of potential im-portance to the child or family that are unrelated to thediseases for which the testing is performed [17, 106–110].The use of the term “incidental” to describe these findingssuggests that they are inadvertently found during the ana-lysis of genomic data. This can and does happen, but it isalso possible to look actively for genomic variants beyondthose for which the screening is being performed. Variantsof such secondary targets are sometimes called “secondaryfindings”. Others have used the terms “unsolicited”,“unanticipated”, or “adventitious” to describe incidentaland/or secondary findings.The frequency with which incidental or secondaryfindings are encountered can range from a few percentof patients to every single individual tested, dependingon how the data are analyzed and what kinds of findingsthe testing laboratory reports. Even at the lowest fre-quency reported for genome-wide sequencing, incidentalfindings would be expected to occur more frequentlythan true positive results for disease-causing mutationsassociated with any of the rare genetic diseases testedfor by conventional newborn screening.Return of incidental findings that arise in diagnosticgenome-wide sequencing is a contentious issue, and onethat has elicited a number of sometimes-conflicting pol-icy recommendations [4, 9, 17, 56, 97, 98, 101, 111, 112].Areas of concern include the kinds of incidental or sec-ondary findings that should be returned – should theseonly include “actionable” findings (i.e., those diagnosticof a condition for which an effective preventative ortherapeutic intervention is available) or should findingsthat cannot be effectively prevented or treated also bereturned? What about findings related to small or mod-erately increased risks of diseases that are common inthe general population, or findings that may or may notbe of value, depending on circumstances (e.g., pharma-cogenetic variants or carrier status for recessive dis-eases)? Should patients be able to obtain results that areirrelevant medically but may have social importance(e.g., ancestry, potential for athletic performance, or gen-etic sex that differs from gender)?Controversy has also arisen over which considerationsshould be prioritized with respect to the return of re-sults. Should the focus be on returning any finding thatcould possibly be of benefit to an individual patient, orshould incidental findings never be returned to maximizethe cost-effectiveness of diagnosing serious diseases in thepopulation as a whole? Should incidental findings only bereturned if specifically requested by the patient (or theirparents, if the patient is a child), or should such findingsalways be returned unless specifically declined? Return ofinformation that is of no immediate benefit to a child butmay be of benefit to other family members (e.g., the pres-ence of pathogenic BRCA1 mutation for hereditary breastand ovarian cancer in a little boy so that his mother canbe tested for the mutation) is particularly contentious be-cause it violates a core ethical principle that medical pro-cedures in children are only justifiable if they directlybenefit the child [101, 113].In the context of population screening of infants, theethical and policy concerns raised by return of incidentalgenomic findings are, if anything, even greater than fordiagnostic genome-wide sequencing. Some have evenquestioned whether decisions about return of genomic in-formation uncovered during newborn screening should bemade by public health officials or policy-makers at all,arguing that all genomic data belong to the child, and thatthe parents, who are presumed to act most effectively inthe child’s best interests, should decide what is of import-ance and what is not [114–117].Storage of personal genomic data As previously men-tioned, storage and secondary use of infant blood spotsobtained for population-based newborn screening is con-tentious, and similar issues arise for DNA samples isolatedfrom these blood spots for genomic testing. Moreover,genome-wide sequencing would produce a large amountof information on each infant that is both potentially iden-tifying and revealing of important medical or social issues.What should be done with these data once the newbornscreening has been completed has generated substantialdiscussion. Some argue that a child could benefit from thisinformation being stored in his or her electronic patientrecord for tailoring medical treatments to particular dis-eases that may arise later in life [3, 17]. These data wouldalso provide very valuable research opportunities in areassuch as population genetics, genome-wide associationstudies, penetrance of genetic disorders, and genotype-phenotype correlations [99].The cost, risks and benefits of long-term storage ofgenomic data depend greatly on what is being storedand how it is stored. At one extreme, only the highestlevel results of newborn screening might be stored, e.g.,“no cystic fibrosis-associated CFTR allele found”, whileat the other extreme a complete list of all variants oreach individual’s entire exome or whole genomesequence might be stored. The former does not differfrom the storage of any other medical result in a healthFriedman et al. BMC Medical Genomics  (2017) 10:9 Page 7 of 13record, while the latter provides the greatest amount ofboth potentially beneficial and potentially harmful infor-mation. Moreover, storage of raw genome sequencewould be of very little value without the ability to extractuseful clinical information from it as needed and to re-turn this information to the patient, family or physicianin an appropriate manner. The cost of doing this is likelyto remain far greater than the cost of data storage forthe foreseeable future [16].Others argue that the cost of secure storage and stew-ardship of these data over the lifetime of the child mayexceed the cost of repeating the genomic testing in thefuture if the information becomes necessary [17]. Thepossibility of misusing this information for discrimin-atory purposes, for example, with regard to employmentor insurance, is particularly concerning and must be pre-vented [3, 4, 118]. The balance struck between the bene-fits, risks and costs of storing individual data obtainedthrough any genomic newborn screening program islikely to vary among jurisdictions in response to societaland political forces as well as factors like cost and avail-able public health infrastructure.DiscussionRecommendations – further improving public healthGenomic technology provides an opportunity to improvenewborn screening by identifying more infants for whomearly interventions can prevent serious illnesses, majorhandicaps or death. However, to be successful, genomicnewborn screening must avoid compromising the effect-iveness of current screening programs or inadvertentlyharming children and their families. We, therefore, makeeight recommendations regarding the use of genomictechnologies for population-based newborn screening.We consider Recommendations 1-4 to be fundamentaland independent of the specific genomic technologyused. Recommendations 5-8 are precautionary and relateto the current state of available genomic testingmethods. These recommendations should be reconsid-ered from time to time in the future as our knowledgeimproves.Recommendation 1: Newborn screening by any method,including genomic testing, if adopted as a public healthprogram should be equally available and accessible toevery infant born in the jurisdiction.The success of current newborn screening programs islargely a reflection of their provision to all, or nearly all,infants. This population-based coverage, which will alsobe essential for effective genomic newborn screening, re-quires universal access for all babies. This is a principleof public health as well as a matter of justice.Recommendation 2: Interpretation of genomic newbornscreening results requires extensive knowledge of the nor-mal (benign) variants, as well as of pathogenic variants,of every gene tested. Genomic newborn screening programsshould, therefore, make population-specific allele fre-quencies of every gene included in the program publiclyavailable in a freely-accessible database. The functionalconsequences (benign, pathogenic, or undetermined) ofeach allele should also be made available, along with theevidence supporting functional interpretations.Because the diseases that are screened for in newbornsare rare (or extremely rare) and because the frequenciesof benign polymorphisms, VUS, and disease-causingmutations differ in different ethnic, cultural or geo-graphic populations, sharing information on the patho-genicity of variants internationally in a freely-accessibledatabase will be essential for interpretation of genomicscreening results [119, 120]. This must, of course, bedone in a way that protects the privacy of individual in-fants and their families appropriately [121]. Privacy pro-tection is easily managed for common benign variants,which only need to be reported as frequencies (e.g., “327per 10,000 in Southern Han Chinese populations”) butmay be more difficult for disease-causing variants thatare so rare that their occurrence in a particular popula-tion is limited to one individual or family. In suchinstances, the individual’s or family’s consent may benecessary for posting the information in a publicly-accessible database, but we believe that most affectedfamilies will agree to this to benefit other affectedfamilies.Recommendation 3: Publicly-funded universal newbornscreening by genomic methods should be limited todiseases that can be diagnosed in the newborn periodand effectively treated or prevented in childhood.In public health programs, limited funding is availableand prioritization is required. Unless the screening processfor a condition is robust and cost effective, its inclusion ina newborn screening program is more likely to be harmfulthan beneficial to the performance of the program as awhole. The cost of genome sequencing has fallen dramat-ically over past 15 years and is likely to continue to fall asa result of ongoing technical advances. Nevertheless, thecost of genome-wide (whole genome or exome) sequen-cing remains at least 10-100 times greater than anycurrent publicly-funded newborn screening program.Moreover, the sensitivity and specificity of sequencingtechnology and analytical pipelines have not been shownto be (and are currently probably not) sufficiently high foruse in population-based screening [7].Unless an effective preventative or therapeutic inter-vention is available to all children who are diagnosedwith a condition that is screened for, the program is un-likely to benefit the infants who are being screened in amanner that can be demonstrated to funding agencies.Publicly-funded newborn screening programs, like allpublic health programs, are held to a high standard ofFriedman et al. BMC Medical Genomics  (2017) 10:9 Page 8 of 13accountability, and if genomic newborn screening com-promised the cost-benefit calculation for the screeningprogram as a whole, current newborn screening activ-ities, which have been highly beneficial to many children,could be jeopardized.Recommendation 4: If population-based genomic new-born screening is introduced, it should only be offered aspart of a comprehensive public health program that in-cludes appropriate confirmatory testing, therapeutic inter-ventions, clinical follow-up, genetic counselling, qualityassurance, public and professional education, and govern-ance and oversight.As discussed above, the success of current newbornscreening programs depends on systematic screening,diagnosis, and management of affected infants throughestablished policies and protocols. Efficient administrationand effective governance are also necessary, along withongoing monitoring and evaluation. Genomic newbornscreening would probably be more complex than currentscreening programs and would, therefore, need to buildon the strengths of current programs and operate as acomprehensive system that is available to every infant.Recommendation 5: Newborn screening by next-generation sequencing or other genomic methods shouldonly be considered as an add-on to current first-tierscreening programs.Recommendation 6: Current newborn screening shouldnot be replaced by next generation sequencing or othergenomic methods for any disease unless the genomic tech-nology has been shown to have equal or better sensitivityand specificity for the disease.These recommendations are consistent with theWilson and Jungner criteria (Table 2) and more recentanalyses of their application to genome screening at itscurrent state of development for clinical testing [22, 122].Some conditions for which newborn screening is widelyperformed cannot be identified effectively by any methodof genetic or genomic testing because many cases do nothave a genetic cause. For example, congenital hypo-thyroidism may be caused by maternal dietary iodine defi-ciency or transfer of maternal anti-thyroid antibodiesacross the placenta. In other circumstances, even thoughgenetic factors usually cause the condition, genetic hetero-geneity and complexity make it unlikely that genetic test-ing will be as sensitive or as specific as current screeningmethods. Newborn screening for congenital hearing lossby testing otoacoustic emissions provides a clear example.Substituting genomic methods for the methods that arecurrently used to screen for such conditions wouldjeopardize the health or development of some children whoare identified by current newborn screening programs.Even for conditions in which genetic heterogeneityand complexity are of less concern, genomic testing maynot currently be the most robust method for population-based newborn screening. Bodian and associates studied1696 infants who had undergone whole genome sequen-cing and conventional newborn screening in a state-sponsored program [7]. Whole genome sequencing datafrom these infants were analysed for possible disease-causing variants of 163 genes involved in diseases thateither are routinely tested or are being considered fortesting in American newborn screening programs. Theaverage infant in this study carried one variant detectedby sequencing that was annotated as pathogenic(median = 1, range 0-6). The state newborn screeningprogram identified 4 of 5 infants with a currentlytargeted disease, while whole genome sequencing identi-fied only 2 of these 5 infants. Among the 27 diseases(associated with 65 genes) tested for in the state newbornscreen program, there were fewer false positive results butmore results of uncertain clinical significance with wholegenome sequencing.Genomic methods such as next-generation sequencingcould, at least in theory, detect some infants with poten-tially treatable early-onset genetic conditions that are notcurrently being identified by newborn screening [3–8].The addition of such conditions to the newborn screeningpanel may be beneficial and cost-effective, but research isrequired to demonstrate that this is true.Recommendation 7: At the present time, our under-standing of, and ability to interpret genomic variantsdoes not justify use of genome-wide (whole genome orexome) sequencing in population-based newborn screening.Research is needed to demonstrate the clinical utility andcost-effectiveness of genome-wide sequencing and to resolveoutstanding health policy and ethical issues beforegenome-wide sequencing is implemented for newbornscreening within a jurisdiction.The diploid human genome consists of more than6,000,000 base pairs of DNA, and every person has mil-lions of differences in comparison to the human refer-ence sequence. Some of these variants are known to bebenign, occurring as frequent polymorphisms in healthyindividuals. Other variants are known or very likely tocause genetic disease. Many other variants cannot beclassified as being benign or disease-causing; genome-wide sequencing identifies many such VUS in every indi-vidual [123, 124]. A typical exome from a person whodoes not have a mendelian disease includes more than100 novel or rare variants that are predicted to alterprotein function [123, 124]. Clinical diagnosis of a geneticdisease from genome-wide sequencing data requiresrecognition of the one or two variants that actually causethe disease in this large background of other variants thatare present but have nothing to do with the condition.As discussed above, interpretation of genomic sequen-cing results is the biggest practical problem in using thismethodology for population screening of newbornFriedman et al. BMC Medical Genomics  (2017) 10:9 Page 9 of 13infants [91, 93, 94]. The high-throughput sequencingand bioinformatics infrastructure and expertise requiredto interpret exome or whole genome data from manythousands of infants each year are beyond the capacityof current publicly-funded programs and would be verycostly to put into place. Moreover, even when a genomicvariant can be interpreted with certainty as pathogenic,predicting the resulting phenotype may be difficult.Different mutations of a single genetic locus can causedifferent diseases, and identical mutations in differentindividuals can cause disease manifestations of strikinglydifferent severity.It is often difficult to obtain the evidence of cost-effectiveness and therapeutic efficacy needed to justifythe addition of one condition to the newborn screeningpanel. The rarity of genetic diseases in infants frequentlyconfounds rigorous cost-benefit analysis and makes ran-domized controlled trials of the efficacy of therapeuticinterventions infeasible. It is hard to imagine how suchdata could be collected for all genetic diseases thatmight be identified by genome-wide sequencing, andobtaining these data just for the conditions covered by alarge gene panel would pose immense problems.Thorough assessment of the success of initial efforts atpopulation-based genomic newborn sequencing willcertainly be necessary.Recommendation 8: At the present time, our under-standing of, and ability to interpret genomic variantsdoes not justify sequencing large multigene (physical orbioinformatic) panels for population-based newbornscreening. Research is needed to demonstrate the clinicalutility and cost-effectiveness of sequencing large multi-gene panels for population-based newborn screening andto resolve outstanding health policy and ethical issuesbefore the use of large sequencing panels is implementedfor newborn screening within a jurisdiction.Most current suggestions for expanding newbornscreening through sequencing of disease genes proposeto do so by using targeted panels [17, 125]. Interpret-ation of variants found on gene panels with respect topathogenicity presents the same difficulties as interpret-ation of the variants found by sequencing individualgenes but multiplies these problems by as many genes asthere are on the panel. Although sequencing a smallpanel of genes is much less likely than genome-widesequencing to produce incidental findings or VUS, theseissues are unlikely to be completely resolved, and theadvantages are lost as the gene panel becomes larger[4, 99]. The more genes included in the panel, the largerthe proportion of variants for which the association withdisease is uncertain. The penetrance, variability andnatural history of disease caused by particular mutationsbecome more uncertain as the number of genes on apanel increases, and the frequency and distribution ofbenign polymorphisms in various populations is moreoften unknown.In any case, we do not currently know enough aboutthe pathogenic consequences of the full populationspectrum of variants for any disease gene, and much lessfor a panel of disease genes, to justify the use of such se-quencing as a primary method of newborn screening.More research in this area is needed.ConclusionsThe inclusion of genomic sequencing in newbornscreening presents a major opportunity to detect and ef-fectively treat or prevent many more serious child healthconditions than is possible today. However, before gen-omic sequencing can be implemented in a newbornscreening program, clinical utility and cost-effectivenessmust be demonstrated [37, 110, 111]. A key issue is theneed to improve the interpretation of genomic data topermit robust recognition of both disease-causing andbenign variants of all genes screened in every child inthe population. In addition, a consensus needs to bedeveloped within each jurisdiction on ethical and policycontroversies such as the disclosure of genomic VUSand incidental findings to families, ownership of thedata, and appropriate data storage and sharing. Revisionof our recommendations will be needed as more infor-mation becomes available.The best interests of children should remain theguiding principle in newborn screening and the basis fordecisions regarding the implementation of genomicnewborn screening.AbbreviationsPKU: Phenylketonuria; VUS: Variants of uncertain significanceAcknowledgementsThese recommendations were developed by consensus of the Global Alliancefor Genomics and Health Regulatory and Ethics Working Group Paediatric TaskTeam. The members of this task team are Jan M. Friedman (co-chair), Martina C.Cornel (co-chair), Khalid Al-Thihli (Sultan Qaboos University), Pascal Borry(University of Leuven), David Flannery (American College of Medical Geneticsand Genomics), Aaron Goldenberg (Case Western Reserve University), AnneJunker (British Columbia Children’s Hospital), Stephen Kingsmore (Rady PediatricGenomic and Systems Medicine Institute), Nigel G. Laing (University of WesternAustralia), Erick Scott (Scripps Translational Science Institute), and AmbroiseWonkam (University of Cape Town). We are grateful to Bartha Knoppers(McGill University) and Heidi Howard (Uppsala University), who provided helpfulcomments on the manuscript.FundingThis work was supported by Genome Canada; Genome Quebec; GenomeBritish Columbia; the National Human Genome Research Institute, NationalInstitutes of Health (USA), 2P50-HG-003390-06; Research Fund Flanders(Belgium); Ministère de l'Économie, de l'Innovation et des Eportations duQuébec, PSR-SIIRI-850 (Canada); and the Brocher Foundation (Switzerland).Availability of data and materialsNot applicable.Friedman et al. BMC Medical Genomics  (2017) 10:9 Page 10 of 13Authors’ contributionsThis manuscript was drafted by JMF, MCC, AJG, KJL, KS and DFV afterdiscussion among members of the Paediatric Task Team of the GlobalAlliance for Genomics and Health’s Regulatory and Ethics Working Group.The draft was reviewed, discussed, and revised by the writing group, and therevised version was sent to the Paediatric Task Team as whole. After furtherreview and discussion, additional revisions were made by JMF and MCC.All authors read and approved the final manuscript.Competing interestsThe authors have no financial, personal or professional interests that couldbe construed to have influenced this work.Consent for publicationNot applicable.Ethics approval and consent to participateNot applicable.Author details1Department of Medical Genetics, University of British Columbia, Vancouver,Canada. 2Child & Family Research Institute, Vancouver, Canada. 3SectionClinical Genetics, Department of Clinical Genetics, VU University MedicalCenter, Amsterdam, Holland. 4EMGO Institute for Health and Care Research,VU University Medical Center, Amsterdam, Holland. 5The Center for GeneticResearch Ethics and Law, Department of Bioethics, Case Western ReserveUniversity, Cleveland, OH, USA. 6Office of Population Health Genomics, PublicHealth Division, Department of Health, Government of Western Australia,Perth, Australia. 7Centre of Genomics and Policy, Department of HumanGenetics, McGill University, Montreal, Canada. 8Centre for Biomedical Ethicsand Law, Department of Public Health and Primary Care, KU Leuven, Leuven,Belgium.Received: 20 January 2016 Accepted: 14 February 2017References1. 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