Experts were asked to indicate whether they agreed with 6 statements regarding the types of disorders that should be included in newborn genome sequencing.
Among 649 gene-disease pairs in the survey, each was endorsed by at least 11.8% of experts. Overall, 25 gene-disease pairs were endorsed by 85% or more of the experts.
eTable 1. Response Rates Computed According to AAPOR Standard Definitions
eAppendix. Complete PDF of Survey
eFigure. Methods and Results of Survey
eTable 2. All Genes Included in Survey, in Order of Concordance
eTable 3. Description of Characteristics of Genes Included in Survey
eTable 4. Demographic Information of the Respondents
eTable 5. Additional Genes Suggested for Inclusion by Respondents
Data Sharing Statement
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Gold NB, Adelson SM, Shah N, et al. Perspectives of Rare Disease Experts on Newborn Genome Sequencing. JAMA Netw Open. 2023;6(5):e2312231. doi:10.1001/jamanetworkopen.2023.12231
Do rare disease experts endorse genome sequencing of newborns to screen for treatable genetic diseases, and do they agree on which genes to include?
In this survey study of 238 rare disease experts, 87.9% agreed that genomic sequencing for monogenic treatable conditions should be available to all newborns. A total of 42 gene-disease pairs were endorsed by more than 80% of the experts.
In this study, rare disease experts broadly endorsed screening of newborns with genome sequencing, and there was substantial concordance on a limited number of specific gene-disease pairs for prioritization.
Newborn genome sequencing (NBSeq) can detect infants at risk for treatable disorders currently undetected by conventional newborn screening. Despite broad stakeholder support for NBSeq, the perspectives of rare disease experts regarding which diseases should be screened have not been ascertained.
To query rare disease experts about their perspectives on NBSeq and which gene-disease pairs they consider appropriate to evaluate in apparently healthy newborns.
Design, Setting, and Participants
This survey study, designed between November 2, 2021, and February 11, 2022, assessed experts’ perspectives on 6 statements related to NBSeq. Experts were also asked to indicate whether they would recommend including each of 649 gene-disease pairs associated with potentially treatable conditions in NBSeq. The survey was administered between February 11 and September 23, 2022, to 386 experts, including all 144 directors of accredited medical and laboratory genetics training programs in the US.
Expert perspectives on newborn screening using genome sequencing.
Main Outcomes and Measures
The proportion of experts indicating agreement or disagreement with each survey statement and those who selected inclusion of each gene-disease pair were tabulated. Exploratory analyses of responses by gender and age were conducted using t and χ2 tests.
Of 386 experts invited, 238 (61.7%) responded (mean [SD] age, 52.6 [12.8] years [range 27-93 years]; 126 [52.9%] women and 112 [47.1%] men). Among the experts who responded, 161 (87.9%) agreed that NBSeq for monogenic treatable disorders should be made available to all newborns; 107 (58.5%) agreed that NBSeq should include genes associated with treatable disorders, even if those conditions were low penetrance; 68 (37.2%) agreed that actionable adult-onset conditions should be sequenced in newborns to facilitate cascade testing in parents, and 51 (27.9%) agreed that NBSeq should include screening for conditions with no established therapies or management guidelines. The following 25 genes were recommended by 85% or more of the experts: OTC, G6PC, SLC37A4, CYP11B1, ARSB, F8, F9, SLC2A1, CYP17A1, RB1, IDS, GUSB, DMD, GLUD1, CYP11A1, GALNS, CPS1, PLPBP, ALDH7A1, SLC26A3, SLC25A15, SMPD1, GATM, SLC7A7, and NAGS. Including these, 42 gene-disease pairs were endorsed by at least 80% of experts, and 432 genes were endorsed by at least 50% of experts.
Conclusions and Relevance
In this survey study, rare disease experts broadly supported NBSeq for treatable conditions and demonstrated substantial concordance regarding the inclusion of a specific subset of genes in NBSeq.
Newborn screening is a successful, state-mandated public health program that primarily uses mass spectrometry to identify and direct the initial treatment of infants at risk for rare, childhood-onset disorders that are amenable to early treatment.1,2 As sequencing technologies have advanced and their costs have dropped in recent decades, interest in expanding newborn screening through newborn genome sequencing (NBSeq) has grown.3-8 Many states use genetic testing as part of newborn screening for conditions without biochemical markers, such as spinal muscular atrophy, or as a second-tier test for infants with abnormal biochemical laboratory results.9-12 Newborn genome sequencing has the potential to simultaneously evaluate risk for thousands of genetic disorders not amenable to current laboratory assays. Lack of data regarding downstream medical, psychosocial, and economic effects of NBSeq, however, has contributed to concerns regarding its feasibility, cost, clinical utility, and associations with patient autonomy, privacy, and distress.6,8,13-21
Studies have indicated that a high proportion of individuals, particularly parents, are interested in expanding the number of disorders included in newborn screening,22-25 including through NBSeq.26-30 Surveys of pediatricians31 and genetic counselors32 have revealed more nuanced perspectives but still largely positive attitudes toward NBSeq. Discussions among laboratory directors, patient advocates, and pharmaceutical companies have suggested that systemic changes would be required to integrate genomic sequencing into newborn screening.33,34 To date, however, the opinions of medical geneticists and other rare disease experts, who likely would be responsible for implementing NBSeq and managing the care of children with positive findings, have not been systematically elicited.
Diverse approaches have been used to nominate gene and disease candidates for NBSeq. In 2017, the BabySeq Project team evaluated 1514 gene-disease pairs and deemed 954 to be well established, childhood onset, and highly penetrant.35 In 2019, the North Carolina Newborn Exome Sequencing for Universal Screening study classified 466 gene-disease pairs as having plausible early intervention and benefit.36 The Rx-Genes database, which became publicly available in 2021, delineated 633 genes associated with treatable disorders.37 In the context of indication-based diagnosis, but relevant to NBSeq, Owen et al38 described a system in which 5 clinical and biochemical geneticists curated interventions for 358 genes. Concurrently, several commercial laboratories have launched expanded newborn screening panels ranging from 109 to 275 genes without clear explanation of their rationale.39 This study aimed to assess the perspectives of medical geneticists and other rare disease experts on key questions about NBSeq and to measure concordance regarding specific gene-disease pair candidates for NBSeq.
This survey study was developed to assess the perspectives of rare disease experts on NBSeq, which included (1) 6 questions regarding characteristics of potential disorders for NBSeq, (2) a list of potential gene-disease pairs for NBSeq, and (3) demographic characteristics of respondents. The survey was designed between November 2, 2021, and February 11, 2022, and administered between February 11, 2022, and September 23, 2022. A preliminary version of the survey was developed by a subset of the investigators (N.B.G., S.M.A., N.S., S.W., S.B., and R.C.G.). A pilot survey was conducted with 8 medical geneticists for comprehension and revised to reflect their recommendations. The study was approved by the Mass General Brigham institutional review board. A recruitment email that contained the necessary components of consent was used in lieu of a formal informed consent process. Experts who completed the survey were offered a $50 gift card. The study followed the American Association for Public Opinion Research (AAPOR) reporting guideline40 (eTable 1 in Supplement 1).
Six questions with responses measured on a 5-point Likert scale were used to elicit experts’ perspectives on NBSeq (eAppendix in Supplement 1). A list of gene-disease pairs was designed using data from multiple sources (eFigure in Supplement 1), including Rx-Genes37; Treatable ID41,42; and gene lists from publications describing commercial offerings of expanded genetic panels for childhood disorders,39 genetic disorders treatable by hematopoietic stem cell transplant,43 and a model for screening childhood cancer predisposition syndromes.44 From this aggregated list of 743 gene-disease pairs, we removed 92 pairs either associated with a core condition or designated as a secondary condition (ie, disorders that share biomarkers with core conditions and may be incidentally ascertained by newborn screening) on the US Department of Health and Human Services Recommended Uniform Screening Panel (RUSP).45 The remaining list of 651 genes was included in the final survey (eTable 2 in Supplement 1).
Gene-disease pairs were sorted into the following clinical areas: cardiovascular (17 genes), endocrinology (95 genes), gastroenterology (14 genes), hematology (90 genes), immunology (167 genes), metabolic (137 genes), nephrology (24 genes), neurology (83 genes), oncology (18 genes), ophthalmology (4 genes), and pulmonology (2 genes). For each gene, experts were asked whether they would recommend that pathogenic and likely pathogenic variants be screened in newborns. Experts were invited to assess all genes or to select the clinical area with which they were most familiar. They indicated their responses using radio buttons labeled yes, no, or unsure. Two genes (SLC19A3 and SLC35C1) were paired on the survey with the incorrect disease and were subsequently deleted from analyses.
Experts were asked for their age, gender (female, male, nonbinary, or other), race, ethnicity, state of residence, years in practice, primary practice setting, and the patient population they serve. Options for race (American Indian or Alaska Native, Asian, Black or African American, Native Hawaiian or Pacific Islander, White, or other) and ethnicity (Hispanic, Latino, or Spanish origin) were self-selected from a list46 and included to investigate whether respondents were representative of the field of medical geneticists. Missing demographic information on nonresponding experts, specifically age and gender, was supplemented from publicly available resources.
From February 11, 2022, through September 23, 2022, 386 experts were invited to participate. All 142 program directors of genetics and genomics programs accredited by the Accreditation Council for Graduate Medical Education were invited. Included in this group were directors of programs in molecular genetic pathology (n = 37), medical genetics and genomics (MGG) (n = 40), medical biochemical genetics (n = 7), clinical biochemical genetics (n = 11), internal medicine and MGG (n = 4), maternal fetal medicine and MGG (n = 7), laboratory genetics and genomics (n = 20), reproductive endocrinology and MGG (n = 3), and global molecular biology/genetics programs (n = 13).
Thirteen clinical champions, a group of individuals with expertise in each clinical area as demonstrated by recent scholarship and involvement in the care of patients with rare disease, were asked to complete the survey. This group included experts in pediatric cardiovascular disease (A.R.), endocrinology (I.H.), gastroenterology (J.R.T.), hematology (V.G.S.), immunology (O.D.), metabolism (R.G.), nephrology (W.T.), neurology (M.W.), oncology (J.K.), ophthalmology (J.C., E.P., and J.W.), and pulmonology (A.M.H.). They then provided the names of a total of 81 content area experts in their fields to participate in the survey. These content area experts were selected at the discretion of the clinical champions but broadly represented rare disease experts who were clinically active; had done scholarly and/or advocacy work related to newborn screening; and represented demographic, geographic, and gender diversity. An additional 150 individuals, including 138 clinicians and academicians and 12 employees of pharmaceutical companies, were identified as experts by the investigators based on their knowledge of an area of pediatric genetic disease and were invited to participate.
We emailed each prospective respondent a maximum of 7 times over the data collection period. Two weeks before closing the survey, a study team member called each individual who had not yet responded to the survey.
To explore whether there were patterns in the 649 gene-disease pairs selected, we created a table recording the inheritance pattern, prevalence, age of onset, disease symptoms, orthogonal tests (nonmolecular tests that can be used to confirm a diagnosis), intervention, age of intervention implementation, and specialist leading the intervention for each (eTable 3 in Supplement 1). The table, which was not shared with survey invitees, was reviewed and finalized by each of the 13 clinical champions.
Descriptive statistics, including means with SDs and counts with percentages, were reported for basic demographic characteristics. The age and gender distribution of respondents were compared with nonrespondents using a t test and χ2 test, respectively. The Likert scale responses to perspectives on NBSeq were dichotomized into agree (combining agree and somewhat agree) vs do not agree (combining all other responses). Multivariable logistic regression analyses were conducted to examine agreement with each perspective by age (reported per 10-year increase) and sex (female vs male), as well as by participant type (program director vs all other experts), reporting adjusted odds ratios (ORs) and 95% CIs. Responses regarding experts’ recommendation for each genetic disorder were tabulated, and rates of concordance were calculated and expressed as percentages. All statistical tests were 2-sided, with P < .05 considered statistically significant. Data were analyzed using SAS Studio, version 3.7 statistical software (SAS Institute Inc).
Of 386 experts to whom the survey was sent, 238 (61.7%) responded (eTable 4 in Supplement 1). Respondents included 64 of 142 (45.1%) program directors, all 13 (100%) clinical champions, 50 of 81 (61.7%) content area experts, and 111 of 150 (74.0%) additional rare disease experts. There were no statistically significant differences between respondents and nonrespondents in age (mean [SD], 52.6 [12.8] vs 54.8 [9.5] years, respectively; P = .07) or gender (126 [52.9%] women and 112 [47.1%] men vs 65 [43.9%] women and 83 [56.1%] men, respectively; P = .09). Respondents’ race was self-reported as Asian (26 [10.9%]), Native Hawaiian or Pacific Islander (2 [0.8%]), White (141 [59.2%]), multiracial (4 [1.7%]), other (5 [2.1%]), and unknown (60 [25.2%]). Respondent ethnicity was self-reported as Hispanic (7 [2.9%]), non-Hispanic (169 [71.0%]), and unknown (62 [26.1%]).
Figure 1 summarizes the experts’ perspectives regarding the types of disorders that should be included on NBSeq. Younger experts were significantly more likely to agree that genomic sequencing for treatable genetic conditions that are not currently on the RUSP should be made available for all newborns (OR, 0.67 per 10-year increase in age; 95% CI, 0.48-0.95; P = .02). Agreement with all other questions did not significantly differ by age or gender. Program directors had lower percentages of agreement with most of the questions compared with all other experts. However, after adjusting for age and gender, the only statistically significant finding was that program directors were less likely to agree with the statement that “genomic sequencing in newborns should include childhood-onset conditions like developmental delay for which there are no established targeted therapies or expert management guidelines for surveillance” compared with other experts (OR, 0.36; 95% CI, 0.15-0.89; P = .03).
Experts were invited to offer text responses throughout the survey, including suggestions for additional genes to be included in NBSeq (eTable 5 in Supplement 1) and to provide unstructured responses to the survey (Table 1). Several themes emerged in the text responses, including concern about the low prevalence of some of the disorders included in the survey; an emphasis on prioritizing treatable disorders; and mixed reactions to disorders that range in their age of onset, including those with attenuated adolescent or adult-onset forms.
Among the experts who responded, 161 (87.9%) agreed that NBSeq for monogenic treatable disorders should be made available to all newborns, 107 (58.5%) agreed that NBSeq should include genes associated with treatable disorders even if those conditions were low penetrance, 68 (37.2%) agreed that actionable adult-onset conditions should be sequenced in newborns to facilitate cascade testing in parents, and 51 (27.9%) agreed that NBSeq should include screening for conditions with no established therapies or management guidelines. Among the 649 gene-disease pairs presented in the survey, each was endorsed by at least 11.8% of experts. Overall, 25 gene-disease pairs (OTC-ornithine transcarbamylase deficiency [OCT]; G6PC-glycogen storage disease Ia; SLC37A4-glycogen storage disease Ib; CYP11B1-congenital adrenal hyperplasia due to 11-β-hydroxylase deficiency; ARSB-mucopolysaccharidosis type VI; F8-hemophilia A; F9-hemophilia B; SLC2A1-GLUT1 deficiency syndrome 1; CYP17A1-17-α-hydroxylase/17,20-lyase deficiency; RB1-retinoblastoma [hereditary]; IDS-mucopolysaccharidosis II; GUSB-mucopolysaccharidosis type VII; DMD-Duchenne muscular dystrophy and other dystrophinopathies; GLUD1-hyperinsulinism-hyperammonemia syndrome; CYP11A1-adrenal insufficiency, congenital, with 46XY sex reversal, partial or complete; GALNS-mucopolysaccharidosis IVA; CPS1-carbamoyl phosphate synthetase I deficiency; PLPBP-vitamin B6–dependent epilepsy; ALDH7A1-pyridoxine-dependent epilepsy; SLC26A3-congenital secretory chloride diarrhea; SLC25A15-hyperornithinemia-hyperammonemia-homocitrullinuria syndrome; SMPD1-Niemann-Pick disease, type A and type B; GATM-cerebral creatine deficiency syndrome 3; SLC7A7-lysinuric protein intolerance; and NAGS-N-acetylglutamate synthase deficiency) were endorsed by 85% or more of the experts (Table 2). The first of these 8 gene-disease pairs were endorsed by at least 90% of experts (Figure 2). Among 42 gene-disease pairs with 80% or higher concordance, 25 (60%) were metabolic disorders, 5 (12%) were endocrinologic disorders, 3 (7%) were neurologic disorders, 3 (7%) were hematologic disorders, 2 (5%) were gastroenterologic disorders, 2 (5%) were hereditary cancer predisposition syndromes, 1 (2%) was a renal disorder, and 1 (2%) was an immunologic disorder. A total of 432 genes were endorsed by 50% or more experts.
Because each clinical area included a different number of genes, we also tabulated the percentage of gene-disease pairs per area endorsed by experts. The highest percentage of genes that reached 80% or higher concordance were related to metabolic disorders (25 of 135 [18.5%]). Additionally, genes related to gastroenterology (2 of 14 [14.3%]), hereditary cancer syndromes (2 of 18 [11.1%]), endocrinology (5 of 95 [5.3%]), nephrology (1 of 24 [4.2%]), neurology (3 of 83 [3.6%]), hematology (3 of 90 [3.3%]), and immunology (1 of 167 [0.6%]) reached 80% or higher concordance. The gene-disease pair with the highest concordance was OTC, which is associated with OTC deficiency (62 of 63 [98.4%]). None of the cardiovascular, ophthalmology, or pulmonology genes reached 80% or higher concordance.
Newborn genome sequencing presents an opportunity to expand the reach of newborn screening by identifying more infants at risk for treatable genetic disorders, with the goal of improving childhood health and mortality. Here we present, to our knowledge, the first survey of rare disease experts on NBSeq, the results of which suggest that rare disease experts support the implementation of NBSeq with substantial agreement regarding which gene-disease pairs should be screened. In particular, we identified 25 gene-disease pairs with 85% or higher concordance that span several clinical areas and may be strong candidates for future inclusion in clinical and research NBSeq programs.
Many of the gene-disease pairs with high concordance are clinically similar to disorders currently included on the RUSP, but our results highlight the role of NBSeq as an adjunct screening modality. Concordance was highest among metabolic and endocrinologic disorders, clinical areas that are already well represented in current newborn screening. In particular, OTC deficiency, a condition with high morbidity and mortality in male infants, was recommended for inclusion in NBSeq by nearly all experts who evaluated it. Although some state programs currently screen for OTC deficiency using a glutamate/citrulline ratio, such biochemical measurements are sensitive to sample handling and may result in both false-positive and false-negative results,47,48 whereas NBSeq may more accurately identify children at risk for disease. Experts demonstrated high concordance regarding the inclusion of other treatable, infant-onset metabolic conditions that have no stable or pathognomonic biochemical screening biomarker and that could easily be assayed on a population level, such as glycogen storage diseases, types Ia and Ib; hyperinsulinism-hyperammonemia syndrome; and hereditary fructose intolerance. Additionally, 2 additional forms of congenital adrenal hyperplasia that are not ascertained by current newborn screening were highly endorsed. Our findings suggest that NBSeq could be used as a tool to further the long-standing goals of newborn screening by identifying infants at risk for additional severe, treatable, childhood-onset disorders in clinical areas that have already been deemed appropriate for screening but are not amenable to detection by current methodologies.
Experts also showed high concordance regarding the inclusion of disorders with newly developed and emerging pharmacologic therapies, such as Niemann-Pick disease, types A and B, for which enzyme replacement therapy (olipudase alfa) became clinically available in March 2022,49-51 and Duchenne muscular dystrophy, for which several exon-skipping therapies have emerged in addition to standard steroid therapy52,53 and for which trials of gene therapy are ongoing.54,55 Whereas current newborn screening programs often require the use of new biochemical methods to identify additional disorders, NBSeq provides a resource that can be repeatedly queried as treatments or clinical trials become available.
Our findings suggest that experts also support the inclusion of gene-disease pairs in clinical areas that have not previously been included in screening, such as childhood-onset cancer predisposition conditions and bleeding disorders. For example, RB1, which is associated with hereditary retinoblastoma, was endorsed for screening by 50 of 56 experts (89.3%). Early detection of retinoblastoma improves outcomes, affects ocular salvage, and leads to enhanced preservation of vision.56 Hemophilia A and B, which lead to symptoms ranging from severe intracranial bleeding in infancy to mild bleeding episodes in the setting of surgery or trauma, were also highly endorsed by experts. It has been previously suggested that screening F8 variants may be of limited value because results would not be available until after the first 7 days of life, the period of greatest risk for intracranial hemorrhage. However, the turnaround time for diagnostic genomic testing has significantly shortened in some settings, often within 1 to 2 days, signaling that the technical capabilities for rapid turnaround times are not far off.57-60 Furthermore, ascertainment of individuals at risk for hemophilia may improve surveillance and management of future bleeding episodes in less severe forms of disease. Our survey findings highlight a growing shift away from the historical goals of newborn screening and toward a more expansive view of the uses of genomic information to include not only conditions that require imminent treatment but possibly also those that may prompt changes in long-term risk ascertainment and outcomes.61,62
Ethical, legal, and social implications scholars have highlighted concerns in applying NBSeq to apparently healthy infants, including the uncertainties of variant interpretation, variable expressivity of disease phenotypes, and our nascent knowledge of genomics.14,20,63,64 Our results suggest that rare disease experts are largely supportive of NBSeq as a means for detecting additional disorders in newborns. Of note, younger experts were significantly more likely than older experts to agree with the statement that NBSeq should be integrated into newborn screening, suggesting that clinical experts who trained more recently are more open to the use of molecular screening tools in apparently healthy newborns.
This study has several limitations. The experts were primarily US based and not necessarily representative of the rare disease field. There were at least 2 types of selection bias: experts invited by the research team may be biased in favor of promoting NBSeq, and those invited may have been more likely to respond to the survey if they were in favor of NBSeq. Nonresponder bias was not quantified. The experts did not interact or participate in a process that would constitute formal consensus building. Some experts may not have been familiar with diagnostic or therapeutic developments for all gene-disease pairs that they responded to, leading them to indicate responses of “unsure,” thereby lowering rates of concordance. Survey respondents were not asked about practical considerations that would be necessary to actually implement NBSeq, such as cost, consent, and the relative scarcity of medical geneticists and other rare disease experts.65,66 For infants with positive results on NBSeq, standard operating procedures would need to be developed to facilitate appropriate care coordination between general pediatricians and specialists. Future studies will be needed to determine whether NBSeq is cost-effective and positively contributes to short- and long-term outcomes.
Our findings in this survey study suggest that rare disease experts support expanding the number of genetic disorders included in newborn screening through NBSeq. The greatest degree of consensus occurred within clinical areas that are already included on the RUSP, such as metabolic and endocrine disorders, for which experts support using NBSeq to screen for disorders that lack other accurate or efficient biomarkers. Our findings also indicate a growing awareness that other types of disorders could be screened with NBSeq in healthy newborns to facilitate early diagnosis and surveillance. The genes with the highest concordance in this study may be used in future genome-first studies to screen research participants or other apparently healthy individuals. Over time, the gene list may need to be revisited due to the increasing number of therapies available for genetic conditions. Eventually, with appropriate infrastructure, NBSeq may be an efficient modality to keep pace with the growing number of emerging pharmacologic and gene-based therapies for rare disorders by identifying infants who would benefit from presymptomatic and early treatments.
Accepted for Publication: March 23, 2023.
Published: May 8, 2023. doi:10.1001/jamanetworkopen.2023.12231
Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2023 Gold NB et al. JAMA Network Open.
Corresponding Author: Nina B. Gold, MD, Division of Medical Genetics and Metabolism, Mass General Hospital for Children, 175 Cambridge St, Boston, MA 02114 (firstname.lastname@example.org).
Author Contributions: Dr N. B. Gold had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: N. B. Gold, Adelson, Bick, J. I. Gold, Ganetzky, Roberts, Sankaran, Green.
Acquisition, analysis, or interpretation of data: N. B. Gold, Adelson, Shah, Williams, Bick, Zoltick, J. I. Gold, Strong, Ganetzky, Walker, Holtz, Sankaran, Delmonte, Tan, Holm, Thiagarajah, Kamihara, Comander, Place, Wiggs, Green.
Drafting of the manuscript: N. B. Gold, Adelson, Williams, Sankaran, Green.
Critical revision of the manuscript for important intellectual content: N. B. Gold, Adelson, Shah, Bick, Zoltick, J. I. Gold, Strong, Ganetzky, Roberts, Walker, Holtz, Sankaran, Delmonte, Tan, Holm, Thiagarajah, Kamihara, Comander, Place, Wiggs, Green.
Statistical analysis: N. B. Gold, Adelson, Shah, Zoltick.
Administrative, technical, or material support: Adelson, Williams, Strong, Ganetzky, Sankaran, Delmonte, Tan, Holm.
Supervision: N. B. Gold, Ganetzky, Roberts, Green.
Contributed thoughts on content, connected authors with other experts in the field, reviewed and compiled subsets of data: Walker.
Conflict of Interest Disclosures: Dr N. B. Gold reported receiving personal fees from Newspring Capital, Pfizer, and RCG Consulting; grants from the National Institutes of Health (NIH) and Greenwall Foundation; and an Eleanor and Miles Shore faculty development award outside the submitted work. Dr Shah reported serving as a scientific advisor for the Neuberg Center for Genomic Medicine. Dr Ganetzky reported receiving personal fees from Nurture Genomics during the conduct of the study and personal fees from Minovia Therapeutics outside the submitted work. Dr Walker reported receiving grant U01 HG007690 from the National Human Genome Research Institute; serving as a consortium co-investigator for the NIH Undiagnosed Disease Network, which has been supported by this U01 within the past 36 months outside the submitted work; having a patent pending (US Provisional Patent Application 63/034,740, Methods of Detecting Mitochondrial Diseases; The General Hospital Corporation, Children’s Medical Center Corporation, President and Fellows of Harvard College, The Broad Institute, and Massachusetts Institute of Technology [applicants] filed June 4, 2020); and receiving an honorarium in the past 3 years for writing board review questions for the American Academy of Neurolgoy. Dr Sankaran reported consulting fees from Novartis, Branch Biosciences, and Ensoma outside the submitted work. Dr Tan reported membership on an advisory board for Horizon Pharmaceuticals outside the submitted work. Dr Kamihara reported her spouse receiving consulting fees from ROME Therapeutics, Tekla Capital, Moderna, Ikena Oncology, Foundation Medicine, NanoString Technologies, and Pfizer; being a founder and having equity in ROME Therapeutics, PanTher Therapeutics, and TellBio; and receiving research support from ACD-Biotechne, PureTech Health, Ribon Therapeutics, and Incyte outside the submitted work. Dr Comander reported receiving research funding and consulting fees from companies studying inherited retinal disease genes for work not relevant to the topic of this article. Dr Wiggs reported receiving consulting fees from Editas outside the submitted work. Dr Green reported receiving consulting fees from AIA, Allelica, Atria, Fabric, Genome Web, Genomic Life, Verily, and VinBigData and being co-founder of Genome Medical and Nurture Genomics outside the submitted work. No other disclosures were reported.
Funding/Support: No funding was obtained specifically for this study. This research was supported by grants TR003201, K08 HG012811, and HG008685 from the NIH (Dr N. B. Gold); K08 NS117889 from the National Institute of Neurological Disorders and Stroke (Dr Walker); 5T32GM007748-44 from the National Institute of General Medical Science (Dr Holtz). R01 DK103794, R01 CA265726, and R01 HL146500 from the NIH (National Institute of Diabetes and Digestive and Kidney Diseases [NIDDK], National Cancer Institute, and National Heart, Lung, and Blood Institute) (Dr Sankaran); ZIA AI001270 from the NIH Intramural Research Program (Dr Delmonte); RC2 DK118640 from the NIDDK (Dr Thiagarajah); R01 EY031036 from the National Eye Institute (Dr Comander); 5U24 HG009650-06 from the National Human Genome Research Institute (Dr Wiggs); and TR003201, OD026553, HD090019, HG009922, HL143295, and HG008685 from the NIH (Dr Green).
Role of Funder/Sponsor: The funders had no role in the design and conduct of the study; the collection, management, analysis, or interpretation of the data; the preparation, review, or approval of the manuscript; and the decision to submit the manuscript for publication.
Data Sharing Statement: See Supplement 2.
Additional Contributions: The authors thank Joe Meiring, BFA (Ariadne Labs), for his assistance with the design of the tables and figures in the manuscript. The authors also thank undergraduate research assistants Nia Scott and Jacob Borgida (Division of Genetics, Department of Medicine, Brigham and Women’s Hospital) for their assistance researching the characteristics of the genes included in this survey (eTable 3 in Supplement 1). Mr Meiring, Ms Scott, and Mr Borgida were not compensated for their contributions.