Table. Summary of Included Studies.

Source	Country	Sample size and study population	Key results
Parental interest and uptake
Bombard et al,17 2014	Canada	1213 Adults from the general population	Parents felt less responsibility to have testing using gNBS compared with tNBS. Parents were less likely to participate in screening compared with tNBS (80% vs 94%). Study concluded that offer could reduce uptake of tNBS.
DeLuca,18 2018	United States	88 Families in pediatrician waiting rooms	Overall, 76% knew very little about NBS; 78% wanted face-to-face consent; 97% wanted to screen for as many conditions as possible; and 84% thought screening should be offered for untreatable disorders.
Goldenberg et al,19 2014	United States	1539 Parents	Overall, 74% of parents were somewhat or definitely interested. Most preferred the offer be made by a pediatrician. The most important factors were accuracy of the test and potential for preventing or decreasing a child’s chance of developing disease.
Joseph et al,20 2016	United States	26 Pregnant woman and 5 parents of children with an immune disorder	Participants agreed that parents should be informed and involved in gNBS decisions, potentially prenatally, when they are more likely to be engaged. Mixed views about scope of results. Concern among parents about expansion and consent decreasing uptake of tNBS.
Kerruish,21 2016	New Zealand	15 Parents whose child had screened as high risk for type 1 diabetes in a previous study	Very low level of worry or impact on parenting from previous testing. Concern about gNBS and the timing; consensus about not being in newborn period. Participants suggested that parents have choice around scope of gNBS.
Lewis et al,22 2016	United States	33 Couples pregnant or with a newborn were interviewed, and 1289 parents of children <5 y were included in a DCE	Interview data helped to inform a decision aid and shared parental tool. DCE showed that likelihood of developing disease was most important to parents when choosing diseases to test.
Paquin et al,23 2018	United States	1000 Women pregnant or planning pregnancy	Randomized to education only or education plus values clarification exercise. Those who did the values clarification exercise were more deeply engaged and had stronger intentions to consent to gNBS.
Tarini et al,24 2009	United States	1342 Adults	One-third thought conditions should be screened for only if treatment was available, one-third thought conditions should be screened for even without available treatment, and remainder had no opinion. The Hispanic population was more in favor of testing with no treatment available.
Ulm et al,25 2015	United States	113 Genetic health professionals	Overall, 85% felt gNBS should not be used currently; 76% believed it will be used in this setting in the future; 87% felt parents should be able to choose subsets of results; and 94% felt there needed to be active consent.
Waisbren et al,26 2015	United States	514 Parents within 48 h of birth	Parents reported being not at all (6%), a little (11%), somewhat (37%), very (28%), or extremely (18%) interested in gNBS. Parents were less interested if any health concerns were raised for baby.
Waisbren et al,27 2016	United States	663 Parents completed follow-up surveys from previous study21	At a 2-28 mo follow-up, 76% still had some interest; those interested had higher stress ratings on the Parenting Stress Index. There was more interest if any health concerns had been raised for baby.
Etchegary et al,28 2012	Canada	648 Individuals from the general population and prenatal classes	Results from first section of survey (ie, attitudes toward expansion for 3 conditions and reasons): 80% interested in the gNBS, 95% thought it should be offered even if they would decline. Attitudes toward expanded screening were positive, but slightly less positive in parents compared with general population.
Etchegary et al,29 2012	Canada	648 Individuals from the general population and prenatal classes	Results of second section of survey (ie, open questions about inclusion of conditions, risk and benefits): 93% agreed that informed consent was required; accuracy of gNBS was deemed important by 50%; most thought everything should be offered, 38% only if treatment were available, and 24% only if life-threatening condition.
Genetti et al,30 2019	United States	3860 Families of healthy and unwell newborns	Examination of cohort that declined participation in gNBS. Overall, 10% discharged prior to responding to offer, 80% declined at initial approach for involvement in research, and 10% accepted genetic counseling appointment. Of those who attended counseling, 67% (n = 268) enrolled. Study logistics followed by feeling overwhelmed were top reasons for declining participation.
Downie et al,15 2020	Australia	106 Parents of newborns with congenital deafness	Offered gNBS, and 68% wanted additional information (27%, treatable conditions only; 41%, all information possible). Very low decisional regret among all groups. Less decisional conflict and intolerance of uncertainty in those who chose more information. Feeling overwhelmed most common reason for declining additional information.
Gene and disease selection
Berg et al,31 2016	United States	Random sample of 1000 genes	Metric addressed 5 points: (1) severity of disease, (2) likelihood of disease (penetrance), (3) efficacy of intervention, (4) burden of intervention, and (5) knowledge base. Metric was a transparent and effective tool to assesses actionability of a gene disease pair.
Ceyhan-Birsoy et al,32 2017	United States	1514 Genes	954 Genes met reporting criteria after being assessed for validity of gene-disease association, age of onset, penetrance, and mode of inheritance. Reportable genes were those that cause childhood-onset disease with strong evidence and high penetrance, childhood-onset disease with moderate evidence or penetrance but for which there is actionability, pharmacogenomics association, and carrier status.
Milko et al,33 2019	United States	822 Genes	Combined actionability score34 with age of onset and intervention to identify 292 genes that met reporting criteria for gNBS and 125 genes for optional disclosure. Reportable genes for gNBS were those that were pediatric onset with high actionability, optional disclosure genes were those that were pediatric onset with low actionability, adult-onset conditions with actionability, and carrier status.
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.
Validity and utility
Ko et al,36 2018	Korea	20 Infants with metabolic disease and/or abnormal NBS results	Concluded 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. Concluded that gNBS complements tNBS by reducing follow-up investigations and clarifying diagnoses earlier and faster.
Narravula et al,38 2017	United States	Genomics results over a 10-y period in 3 disorders from a single laboratory	17 VUS results were reclassified as a result of new information in the literature or in public databases. Many of these could have been classified more accurately with biochemical data. Concluded that avoiding VUS results in gNBS will occur from close liaison with clinical team and biochemical and molecular laboratories.
Pavey et al,39 2017	United States	1349 Newborn-parent trios recruited prenatally	A total of 5 infants were computer-predicted to have immunodeficiency compared with 1 geneticist prediction. Overall, 29 children had features of immunodeficiency, of whom 3 had pathogenic variants. Screening for immunodeficiency would be augmented using gNBS.
Bhattacharjee et al,40 2015	United States	36 Samples from infants known to have a condition detected by tNBS	Genomics accurately identified 27 of 36 conditions (75%) using automated approach and 32 (89%) after manual clinical input was added. Targeted panel had benefit of higher coverage and faster turn-around time.
Bodian et al,41 2016	United States	1696 Neonates with NBS data, correlating genomic data	Overall, 89% (35) true positives and 99% (>45 000) true negatives were correctly called by both technologies. There were 513 results in disagreement (409 due to VUS variant). Concluded the technologies are complementary: no result was uncertain by both methods. A total of 3 cases were missed by genomics.
Ceyhan-Birsoy et al,14 2019	United States	159 Neonates well and unwell, plus 85 parents.	Overall, 10 well and 5 unwell infants had a returnable result, and 3 of 85 parents had cancer predisposition result returned. Difficulty in interpretation of variants in early infancy with no phenotype. Reporting of genes with incomplete penetrance. Detected 3 conditions missed by tNBS.
Solomon et al,42 2012	United States	3 Newborns with normal NBS with clinical diagnosis of VACTERL association	All 3 participants had carrier results identified. No genomics diagnoses made.
Yeh et al,43 2021	United States	Model of gNBS for cancer predisposition syndromes	Concluded that population-based gNBS for cancer predisposition syndromes would reduce pediatric mortality and is likely to be cost-effective.
Wojcik et al,44 2021	United States	159 Neonates in BabySeq project	gNBS results were compared with tNBS results. The technologies were found to be complementary.
Ethical, legal, and social implications
Bunnik et al,45 2013	Netherlands	Expert recommendations	Emphasized importance of informed consent. Child’s right to self-determination means that only childhood-onset disorders should be considered and direct-to-consumer tests should not be available to children. Recommend generic but categorized or differentiated consent for different disease types.
Frankel et al,46 2016	United States	Empirical evidence of psychosocial impact	Domains identified: child vulnerability; parent-child bonding; self and partner blame. Outlined how these will be evaluated in the BabySeq study.
Friedman et al,47 2017	Canada	Global Alliance Pediatric Task Team recommendations	Summary of recommendations: equal access; public data sharing for accurate interpretation of variants; only newborn treatable disease; all appropriate follow-up available; offered in addition to current screening; only replaced if proven increased specificity and sensitivity; and clinical utility and cost-effectiveness must be demonstrated
Golden-Grant et al,48 2015	United States	2 Case reports of population screening identifying adult-onset Pompe disease	Issues identified and discussed: child’s loss of decision-making capacity, potential stress of knowledge, and equity of care and access.
King and Smith,49 2016	United States	Analysis of current laws and application to gNBS	Suggests 3 options for introducing gNBS: use as second tier or report very targeted results and discard the rest; offer parents 1 y to have raw data transferred; or offer opt in analysis.
Holm et al,50 2019	United States	Change in protocol of BabySeq study	Best interests of child vs best interests of family.
Ross and Clayton,51 2019	United States	Discussion of family benefit	Refutes interests of family as a reason to expand newborn screening results.

Abbreviations: DCE, discrete choice experiment; gNBS, genomic newborn screening; tNBS, traditional newborn screening; VACTERL, vertebral anomalies, anal atresia, cardiac defects, tracheoesphegal fistula, renal anomalies, and limb abnormalities; VUS, variant of uncertain significance.