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1.
Nat Med ; 25(8): 1198-1204, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31388181

RESUMO

While genetic testing may be the gateway to the future of medicine, it also poses challenges for individuals, especially in terms of differentiated treatments on the basis of their genetic characteristics. The fear of unwanted disclosure to insurers and the possibility of genetic discrimination can hamper the recruitment of individuals for clinical research that involves genetic testing. Precision medicine initiatives, such as All of Us, are proliferating in the United States. In order to succeed, however, they must ensure that the millions of Americans recruited to share their genetic data are not penalized with regard to life, disability and long-term insurance coverage. In this Perspective, we discuss several initiatives adopted by countries around the world, such as the United Kingdom and France, that better balance the interests of insurers and research subjects, and explain how the United States might learn from them. We call for regulatory and industry leadership to come together to establish a voluntary moratorium on insurance pricing with the aim of protecting research participants.

2.
Transfusion ; 59(10): 3253-3263, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31392742

RESUMO

BACKGROUND: Genotyping has expanded the number red blood cell (RBC) and platelet (PLT) antigens that can readily be typed, but often represents an additional testing cost. The analysis of existing genomic data offers a cost-effective approach. We recently developed automated software (bloodTyper) for determination of RBC and PLT antigens from whole genome sequencing. Here we extend the algorithm to whole exome sequencing (WES). STUDY DESIGN AND METHODS: Whole exome sequencing was performed on samples from 75 individuals. WES-based bloodTyper RBC and PLT typing was compared to conventional polymerase chain reaction (PCR) RHD zygosity testing and serologic and single-nucleotide polymorphism (SNP) typing for 38 RBC antigens in 12 systems (17 serologic and 35 SNPs) and 22 PLT antigens (22 SNPs). Samples from the first 20 individuals were used to modify bloodTyper to interpret WES followed by blinded typing of 55 samples. RESULTS: Over the first 20 samples, discordances were noted for C, M, and N antigens, which were due to WES-specific biases. After modification, bloodTyper was 100% accurate on blinded evaluation of the last 55 samples and outperformed both serologic (99.67% accurate) and SNP typing (99.97% accurate) reflected by two Fyb and one N serologic typing errors and one undetected SNP encoding a Jknull phenotype. RHD zygosity testing by bloodTyper was 100% concordant with a combination of hybrid Rhesus box PCR and PCR-restriction fragment length polymorphism for all samples. CONCLUSION: The automated bloodTyper software was modified for WES biases to allow for accurate RBC and PLT antigen typing. Such analysis could become a routing part of future WES efforts.

3.
Am J Hum Genet ; 105(1): 177-188, 2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31256874

RESUMO

Although genome sequencing is increasingly available in clinical and research settings, many questions remain about the interpretation of sequencing data. In the MedSeq Project, we explored how much effort is required to evaluate and report on more than 4,500 genes reportedly associated with monogenic conditions, as well as pharmacogenomic (PGx) markers, blood antigen serotyping, and polygenic risk scores in 100 individuals (50 with cardiomyopathy and 50 healthy) randomized to the sequencing arm. We defined the quality thresholds for determining the need for Sanger confirmation. Finally, we examined the effort needed and new findings revealed by reanalyzing each genome (6-23 months after initial analysis; mean 13 months). Monogenic disease risk and carrier status were reported in 21% and 94% of participants, respectively. Only two participants had no monogenic disease risk or carrier status identified. For the PGx results (18 genotypes in six genes for five drugs), the identified diplotypes prompted recommendation for non-standard dosing of at least one of the analyzed drugs in 95% of participants. For blood antigen studies, we found that 31% of participants had a rare blood antigen genotype. In the cardiomyopathy cohort, an explanation for disease was identified in 48% of individuals. Over the course of the study, 14 variants were reclassified and, upon reanalysis, 18 new variants met criteria for reporting. These findings highlight the quantity of medically relevant findings from a broad analysis of genomic sequencing data as well as the need for periodic reinterpretation and reanalysis of data for both diagnostic indications and secondary findings.

4.
Genet Med ; 2019 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-31189963

RESUMO

PURPOSE: As exome and genome sequencing (ES/GS) enters the clinic, there is an urgent need to understand the psychological effects of test result disclosure. Through a Clinical Sequencing Exploratory Research (CSER), phase 1 (CSER1) Consortium collaboration, we evaluated participants' psychological outcomes across multiple clinical settings. METHODS: We conducted a random effects meta-analysis of state anxiety (Hospital Anxiety and Depression Scale [HADS]/Generalized Anxiety Disorder 7-item), depressive symptoms (HADS/Personal Health Questionnaire 9-item), and multidimensional impact (i.e., test-related distress, uncertainty and positive impact: modified Multidimensional Impact of Cancer Risk Assessment/Feelings About Genomic Testing Results scale). RESULTS: Anxiety and depression did not increase significantly following test result disclosure. Meta-analyses examining mean differences from pre- to postdisclosure revealed an overall trend for a decrease in participants' anxiety. We observed low levels of test-related distress and perceptions of uncertainty in some populations (e.g., pediatric patients) and a wide range of positive responses. CONCLUSION: Our findings across multiple clinical settings suggest no clinically significant psychological harms from the return of ES/GS results. Some populations may experience low levels of test-related distress or greater positive psychological effects. Future research should further investigate the reasons for test-related psychological response variation.

5.
Genome Med ; 11(1): 10, 2019 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-30808425

RESUMO

BACKGROUND: Increasing numbers of healthy individuals are undergoing predispositional personal genome sequencing. Here we describe the design and early outcomes of the PeopleSeq Consortium, a multi-cohort collaboration of predispositional genome sequencing projects, which is examining the medical, behavioral, and economic outcomes of returning genomic sequencing information to healthy individuals. METHODS: Apparently healthy adults who participated in four of the sequencing projects in the Consortium were included. Web-based surveys were administered before and after genomic results disclosure, or in some cases only after results disclosure. Surveys inquired about sociodemographic characteristics, motivations and concerns, behavioral and medical responses to sequencing results, and perceived utility. RESULTS: Among 1395 eligible individuals, 658 enrolled in the Consortium when contacted and 543 have completed a survey after receiving their genomic results thus far (mean age 53.0 years, 61.4% male, 91.7% white, 95.5% college graduates). Most participants (98.1%) were motivated to undergo sequencing because of curiosity about their genetic make-up. The most commonly reported concerns prior to pursuing sequencing included how well the results would predict future risk (59.2%) and the complexity of genetic variant interpretation (56.8%), while 47.8% of participants were concerned about the privacy of their genetic information. Half of participants reported discussing their genomic results with a healthcare provider during a median of 8.0 months after receiving the results; 13.5% reported making an additional appointment with a healthcare provider specifically because of their results. Few participants (< 10%) reported making changes to their diet, exercise habits, or insurance coverage because of their results. Many participants (39.5%) reported learning something new to improve their health that they did not know before. Reporting regret or harm from the decision to undergo sequencing was rare (< 3.0%). CONCLUSIONS: Healthy individuals who underwent predispositional sequencing expressed some concern around privacy prior to pursuing sequencing, but were enthusiastic about their experience and not distressed by their results. While reporting value in their health-related results, few participants reported making medical or lifestyle changes.


Assuntos
Predisposição Genética para Doença/psicologia , Testes Genéticos , Conhecimentos, Atitudes e Prática em Saúde , Medicina de Precisão/psicologia , Sequenciamento Completo do Genoma , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Motivação , Inquéritos e Questionários
7.
Mayo Clin Proc ; 94(1): 103-109, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30611438

RESUMO

Opportunistic genomic screening is becoming increasingly common as laboratories adopt recommendations to report secondary genomic findings. In parallel, interest in using genome sequencing as a population screening test has grown rapidly. We consider here 3 potential applications of genome sequencing for preventive medicine: (1) provider-ordered predispositional testing in healthy adults, (2) indication-based testing with opportunistic screening of secondary results, and (3) population screening in the public health context. We conclude that despite superficial similarities, there are important and fundamental differences in the way medical risks and benefits can be addressed in these 3 contexts. Recommendations to report secondary genomic findings should not be interpreted as an endorsement of population genomic screening. Ongoing work is developing the evidence that will be needed to fully justify current and future initiatives in population genomic screening. Ongoing work is developing the evidence that will be needed to fully justify current and future initiatives in population genomic screening.


Assuntos
Testes Genéticos/métodos , Genômica/métodos , Programas de Rastreamento/métodos , Saúde Pública , Humanos
8.
Am J Hum Genet ; 104(1): 76-93, 2019 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-30609409

RESUMO

Genomic sequencing provides many opportunities in newborn clinical care, but the challenges of interpreting and reporting newborn genomic sequencing (nGS) results need to be addressed for its broader and effective application. The BabySeq Project is a pilot randomized clinical trial that explores the medical, behavioral, and economic impacts of nGS in well newborns and those admitted to a neonatal intensive care unit (NICU). Here we present childhood-onset and actionable adult-onset disease risk, carrier status, and pharmacogenomics findings from nGS of 159 newborns in the BabySeq Project. nGS revealed a risk of childhood-onset disease in 15/159 (9.4%) newborns; none of the disease risks were anticipated based on the infants' known clinical or family histories. nGS also revealed actionable adult-onset disease risk in 3/85 (3.5%) newborns whose parents consented to receive this information. Carrier status for recessive diseases and pharmacogenomics variants were reported in 88% and 5% of newborns, respectively. Additional indication-based analyses were performed in 29/32 (91%) NICU newborns and 6/127 (5%) healthy newborns who later had presentations that prompted a diagnostic analysis. No variants that sufficiently explained the reason for the indications were identified; however, suspicious but uncertain results were reported in five newborns. Testing parental samples contributed to the interpretation and reporting of results in 13/159 (8%) newborns. Our results suggest that nGS can effectively detect risk and carrier status for a wide range of disorders that are not detectable by current newborn screening assays or predicted based on the infant's known clinical or family history, and the interpretation of results can substantially benefit from parental testing.

9.
Pediatrics ; 143(Suppl 1): S6-S13, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30600265

RESUMO

BACKGROUND AND OBJECTIVES: There is interest in applying genomic sequencing (GS) to newborns' clinical care. Here we explore parents' and clinicians' attitudes toward and perceptions of the risks, benefits, and utility of newborn GS compared with newborn screening (NBS) prior to receiving study results. METHODS: The BabySeq Project is a randomized controlled trial used to explore the impact of integrating GS into the clinical care of newborns. Parents (n = 493) of enrolled infants (n = 309) and clinicians (n = 144) completed a baseline survey at enrollment. We examined between-group differences in perceived utility and attitudes toward NBS and GS. Open-ended responses about risks and benefits of each technology were categorized by theme. RESULTS: The majority of parents (71%) and clinicians (51%) agreed that there are health benefits of GS, although parents and clinicians agreed more that there are risks associated with GS (35%, 70%) than with NBS (19%, 39%; all P < .05). Parents perceived more benefit and less risk of GS than did clinicians. Clinicians endorsed concerns about privacy and discrimination related to genomic information more strongly than did parents, and parents anticipated benefits of GS that clinicians did not. CONCLUSIONS: Parents and clinicians are less confident in GS than NBS, but parents perceive a more favorable risk/benefit ratio of GS than do clinicians. Clinicians should be aware that parents' optimism may stem from their perceived benefits beyond clinical utility.

10.
Pediatrics ; 143(Suppl 1): S27-S32, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30600268

RESUMO

The authors of current professional guidelines generally do not support the return of information about genetic carrier status for infants and children because of a perceived lack of immediate benefit and an abundance of caution regarding potential harm and desire to protect the children's future autonomy. The advent of genomic sequencing, used either as a diagnostic or a screening tool, and the increasing use of this technology in childhood creates the potential for the identification of carrier status in the pediatric period. As part of the BabySeq Project, researchers are exploring the implications of genomic sequencing in both newborns who are healthy and newborns who are sick and developing policies and procedures for the return of carrier status information to the parents and physicians of newborns. In this commentary, we review the history of carrier testing in children and explore the potential benefits, risks, and challenges of returning such results both for the children, their parents, and potential future siblings.

11.
Pediatrics ; 143(Suppl 1): S37-S43, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30600270

RESUMO

The return of information from genomic sequencing in children, especially in early life, brings up complex issues around parental autonomy, the child's future autonomy, the best interest standard, and the best interests of the family. These issues are particularly important in considering the return of genomic results for adult-onset-only conditions in children. The BabySeq Project is a randomized trial used to explore the medical, behavioral, and economic impacts of integrating genomic sequencing into the care of newborns who are healthy or sick. We discuss a case in which a variant in a gene for an actionable, adult-onset-only condition was detected, highlighting the ethical issues surrounding the return of such finding in a newborn to the newborn's parents.

12.
Transfusion ; 59(3): 908-915, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30592300

RESUMO

BACKGROUND: Although P1 and Xga are known to be associated with the A4GALT and XG genes, respectively, the genetic basis of antigen expression has been elusive. Recent reports link both P1 and Xga expression with nucleotide changes in the promotor regions and with antigen-negative phenotypes due to disruption of transcription factor binding. STUDY DESIGN AND METHODS: Whole genome sequencing was performed on 113 individuals as part of the MedSeq Project with serologic RBC antigen typing for P1 (n = 77) and Xga (n = 15). Genomic data were analyzed by two approaches, nucleotide frequency correlation and serologic correlation, to find A4GALT and XG changes associated with P1 and Xga expression. RESULTS: For P1, the frequency approach identified 29 possible associated nucleotide changes, and the serologic approach revealed four among them correlating with the P1+/P1- phenotype: chr22:43,115,523_43,115,520AAAG/delAAAG (rs66781836); chr 22:43,114,551C/T (rs8138197); chr22:43,114,020 T/G (rs2143918); and chr22:43,113,793G/T (rs5751348). For Xga , the frequency approach identified 82 possible associated nucleotide changes, and among these the serologic approach revealed one correlating with the Xg(a+)/Xg(a-) phenotype: chrX:2,666,384G/C (rs311103). CONCLUSION: A bioinformatics analysis pipeline was created to identify genetic changes responsible for RBC antigen expression. This study, in progress before the recently published reports, independently confirms the basis for P1 and Xga . Although this enabled molecular typing of these antigens, the Y chromosome PAR1 region interfered with Xga typing in males. This approach could be used to identify and confirm the genetic basis of antigens, potentially replacing the historical approach using family pedigrees as genomic sequencing becomes commonplace.

13.
Patient Educ Couns ; 102(5): 976-983, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30558852

RESUMO

OBJECTIVE: To investigate the effect of providing comprehensive personalized risk information on concern for chronic disease development. METHODS: Unaffected first-degree relatives (FDRs) of rheumatoid arthritis (RA) patients (n = 238) were randomly allocated to: 1) disclosure of RA risk personalized to demographics, genetics, biomarkers, and behaviors using a web-based tool (PRE-RA arm, n = 78); 2) PRE-RA with interpretation by a health educator (PRE-RA Plus arm, n = 80); and 3) standard RA education (Comparison arm, n = 80). Concern for developing RA was assessed at baseline and immediately, 6 weeks, 6 months, and 12 months post-intervention. RESULTS: FDRs randomized to PRE-RA arms were less concerned about developing RA than the Comparison arm at all post-intervention assessments (p < 0.05). Among those concerned about RA risk at baseline, the PRE-RA (OR = 4.7, 95%CI 1.5-14.4) and PRE-RA Plus (OR = 5.2, 95%CI 1.6-17.3) arms were more likely to have reassurance 6 months post-intervention than the Comparison arm. CONCLUSION: A comprehensive tool provided reassurance to those at risk for developing a chronic disease, with or without interpretation from a health educator, compared to standard education. PRACTICE IMPLICATIONS: Individuals may be more likely to be reassured using a personalized chronic disease risk disclosure tool than a standard non-personalized approach.

14.
J Health Commun ; 23(8): 807-814, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30325721

RESUMO

The objective of this study was to identify how features of Alzheimer's disease (AD) genetic risk disclosure communication relate to patient and visit companion satisfaction. We conducted secondary analyses of 79 session recordings from the fourth REVEAL Study, a randomized-controlled trial of AD genetic risk disclosure among patients with mild cognitive impairment. Patient and companion satisfaction were ascertained from postdisclosure surveys. The Roter Interaction Analysis System (RIAS) was used to code triadic communication between the counselor, patient, and companion. High satisfaction was evident for 24% of patients (N = 19) and 48% of companions (N = 38). Multivariate logistic regressions showed that high patient satisfaction was associated with patients' expression of emotions (OR = 1.1, 95% CI: 1.0-1.1) and companions' questions about psychosocial and lifestyle topics (OR = 1.8, 95% CI: 1.1-2.8). High companion satisfaction was positively related to the RIAS overall patient-centeredness score for the session (OR = 4.0, 95% CI: 1.0-15.6) (all p-values <0.05). Communication predictors of patient and companion satisfaction reflect specific or summary indicators of patient-centeredness. Findings also suggest that visit companions positively influence patient satisfaction. The study results support the growing literature and policy attention directed toward delivering family-centered care.

15.
Alzheimers Dement ; 2018 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-30321505

RESUMO

INTRODUCTION: The overall goal of the Alzheimer's Disease Neuroimaging Initiative (ADNI) is to validate biomarkers for Alzheimer's disease (AD) clinical trials. ADNI is a multisite, longitudinal, observational study that has collected many biomarkers since 2004. Recent publications highlight the multifactorial nature of late-onset AD. We discuss selected topics that provide insights into AD progression and outline how this knowledge may improve clinical trials. METHODS: We used standard methods to identify nearly 600 publications using ADNI data from 2016 and 2017 (listed in Supplementary Material and searchable at http://adni.loni.usc.edu/news-publications/publications/). RESULTS: (1) Data-driven AD progression models supported multifactorial interactions rather than a linear cascade of events. (2) ß-Amyloid (Aß) deposition occurred concurrently with functional connectivity changes within the default mode network in preclinical subjects and was followed by specific and progressive disconnection of functional and anatomical networks. (3) Changes in functional connectivity, volumetric measures, regional hypometabolism, and cognition were detectable at subthreshold levels of Aß deposition. 4. Tau positron emission tomography imaging studies detailed a specific temporal and spatial pattern of tau pathology dependent on prior Aß deposition, and related to subsequent cognitive decline. 5. Clustering studies using a wide range of modalities consistently identified a "typical AD" subgroup and a second subgroup characterized by executive impairment and widespread cortical atrophy in preclinical and prodromal subjects. 6. Vascular pathology burden may act through both Aß dependent and independent mechanisms to exacerbate AD progression. 7. The APOE ε4 allele interacted with cerebrovascular disease to impede Aß clearance mechanisms. 8. Genetic approaches identified novel genetic risk factors involving a wide range of processes, and demonstrated shared genetic risk for AD and vascular disorders, as well as the temporal and regional pathological associations of established AD risk alleles. 9. Knowledge of early pathological changes guided the development of novel prognostic biomarkers for preclinical subjects. 10. Placebo populations of randomized controlled clinical trials had highly variable trajectories of cognitive change, underscoring the importance of subject selection and monitoring. 11. Selection criteria based on Aß positivity, hippocampal volume, baseline cognitive/functional measures, and APOE ε4 status in combination with improved cognitive outcome measures were projected to decrease clinical trial duration and cost. 12. Multiple concurrent therapies targeting vascular health and other AD pathology in addition to Aß may be more effective than single therapies. DISCUSSION: ADNI publications from 2016 and 2017 supported the idea of AD as a multifactorial disease and provided insights into the complexities of AD disease progression. These findings guided the development of novel biomarkers and suggested that subject selection on the basis of multiple factors may lower AD clinical trial costs and duration. The use of multiple concurrent therapies in these trials may prove more effective in reversing AD disease progression.

16.
Genet Med ; 2018 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-30287922

RESUMO

PURPOSE: Clinical sequencing emerging in health care may result in secondary findings (SFs). METHODS: Seventy-four of 6240 (1.2%) participants who underwent genome or exome sequencing through the Clinical Sequencing Exploratory Research (CSER) Consortium received one or more SFs from the original American College of Medical Genetics and Genomics (ACMG) recommended 56 gene-condition pair list; we assessed clinical and psychosocial actions. RESULTS: The overall adjusted prevalence of SFs in the ACMG 56 genes across the CSER consortium was 1.7%. Initially 32% of the family histories were positive, and post disclosure, this increased to 48%. The average cost of follow-up medical actions per finding up to a 1-year period was $128 (observed, range: $0-$678) and $421 (recommended, range: $141-$1114). Case reports revealed variability in the frequency of and follow-up on medical recommendations patients received associated with each SF gene-condition pair. Participants did not report adverse psychosocial impact associated with receiving SFs; this was corroborated by 18 participant (or parent) interviews. All interviewed participants shared findings with relatives and reported that relatives did not pursue additional testing or care. CONCLUSION: Our results suggest that disclosure of SFs shows little to no adverse impact on participants and adds only modestly to near-term health-care costs; additional studies are needed to confirm these findings.

17.
Value Health ; 21(9): 1054-1061, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30224109

RESUMO

OBJECTIVE: To summarize lessons learned while analyzing the costs of integrating whole genome sequencing into the care of cardiology and primary care patients in the MedSeq Project by conducting the first randomized controlled trial of whole genome sequencing in general and specialty medicine. METHODS: Case study that describes key methodological and data challenges that were encountered or are likely to emerge in future work, describes the pros and cons of approaches considered by the study team, and summarizes the solutions that were implemented. RESULTS: Major methodological challenges included defining whole genome sequencing, structuring an appropriate comparator, measuring downstream costs, and examining clinical outcomes. Discussions about solutions addressed conceptual and practical issues that arose because of definitions and analyses around the cost of genomic sequencing in trial-based studies. CONCLUSIONS: The MedSeq Project provides an instructive example of how to conduct a cost analysis of whole genome sequencing that feasibly incorporates best practices while being sensitive to the varied applications and diversity of results it may produce. Findings provide guidance for researchers to consider when conducting or analyzing economic analyses of whole genome sequencing and other next-generation sequencing tests, particularly regarding costs.


Assuntos
Genômica/métodos , Sequenciamento Completo do Genoma/economia , Serviço Hospitalar de Cardiologia/normas , Análise Custo-Benefício , Genômica/instrumentação , Genômica/tendências , Humanos , Atenção Primária à Saúde/normas , Sequenciamento Completo do Genoma/normas
18.
Genet Med ; 2018 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-30209271

RESUMO

PURPOSE: Newborn genomic sequencing (nGS) has great potential to improve pediatric care. Parental interest and concerns about genomics are relatively unexplored. Understanding why parents decline research consent for nGS may reveal implementation barriers. METHODS: We evaluated parental interest in a randomized trial of nGS in well-baby and intensive care unit nursery settings. Interested families attended an informational enrollment session (ES) with a genetic counselor prior to consenting. Reason(s) for declining participation and sociodemographic associations were analyzed. RESULTS: Of 3860 eligible approached families, 10% attended ES, 67% of whom enrolled. Of 1760 families queried for decline reasons, 58% were uninterested in research. Among 499 families considering research, principal reasons for decline prior to ES included burdensome study logistics (48%), feeling overwhelmed postpartum (17%), and lack of interest/discomfort with genetic testing (17%). Decliners after ES more often cited concerns about privacy/insurability (41%) and uncertain/unfavorable results (23%). CONCLUSION: Low interest in research and study logistics were major initial barriers to postpartum enrollment and are likely generic to many postpartum research efforts. Concerns over privacy and result implications were most commonly cited in decliners after ES. Understanding parental concerns around research nGS may inform future integration of nGS into newborn screening, predictive testing, and pediatric diagnostics.

20.
NPJ Genom Med ; 3: 21, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30131872

RESUMO

Despite major progress in defining the genetic basis of Mendelian disorders, the molecular etiology of many cases remains unknown. Patients with these undiagnosed disorders often have complex presentations and require treatment by multiple health care specialists. Here, we describe an integrated clinical diagnostic and research program using whole-exome and whole-genome sequencing (WES/WGS) for Mendelian disease gene discovery. This program employs specific case ascertainment parameters, a WES/WGS computational analysis pipeline that is optimized for Mendelian disease gene discovery with variant callers tuned to specific inheritance modes, an interdisciplinary crowdsourcing strategy for genomic sequence analysis, matchmaking for additional cases, and integration of the findings regarding gene causality with the clinical management plan. The interdisciplinary gene discovery team includes clinical, computational, and experimental biomedical specialists who interact to identify the genetic etiology of the disease, and when so warranted, to devise improved or novel treatments for affected patients. This program effectively integrates the clinical and research missions of an academic medical center and affords both diagnostic and therapeutic options for patients suffering from genetic disease. It may therefore be germane to other academic medical institutions engaged in implementing genomic medicine programs.

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