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1.
J Adolesc Health ; 66(3): 288-295, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31685375

RESUMO

PURPOSE: Adolescents will increasingly be involved in decisions about the return of genomic results. We examined adolescents' and parents' decisions about learning actual genomic research results for the adolescent and whether choices were associated with participants' demographic factors. METHODS: Adolescents aged between 13 and 17 years and a parent (dyads) were recruited through flyers, social media, employee emails, and clinic visits at a pediatric hospital. Dyads used a decision tool to independently choose the categories of conditions they wanted to learn about the adolescent. They then came together to discuss their independent decisions and make final joint decisions. Conditions were categorized by preventability, treatability, adult-onset conditions, and carrier status. Participants could make granular choices by including or excluding conditions in each category. Categorical choices were collapsed into the "aggregate choice" to learn all or not all results. RESULTS: Study visits were completed by 163 dyads. Adolescents were less likely than their parents to independently choose to learn all results (64.4% vs. 76.1%; p = .0056). Parents were less likely to independently choose to learn all results for their daughters than their sons (odds ratio = .41, 95% confidence interval .18-.96; p = .032). Black adolescents were less likely to independently choose to learn all results than white adolescents (odds ratio = .22; 95% confidence interval .08-.55; p = .0015). After making joint decisions, 70.6% of dyads chose to learn all results. CONCLUSIONS: Adolescents independently wanted to learn less genomic information than their parents. Although adolescents cannot legally make genomic testing decisions without parental permission, adolescents' should be engaged in decisions about the return of genomic results.

2.
Clin Genet ; 97(2): 312-320, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31654527

RESUMO

Genomic testing of adolescents is increasing yet engaging them in decision-making is not routine. We assessed decisional conflict in adolescents and a parent making independent decisions about actual genomic testing results and factors that influenced their choices. We enrolled 163 dyads consisting of an adolescent (13-17 years) not selected based on a specific clinical indication and one parent. After independently choosing categories of conditions to learn for the adolescent, participants completed the validated Decisional Conflict Scale and a survey assessing factors influencing their respective choices. Adolescents had higher decisional conflict scores than parents (15.6 [IQR:4.7-25.6] vs 9.4 [IQR:1.6-21.9]; P = .0007). Adolescents with clinically significant decisional conflict were less likely to choose to learn all results than adolescents with lower decisional conflict (19.6% vs 80.4%; P < .0001) and less likely to report their choices were influenced by actionability of results (33.3% vs 18.9%; P = .044) and feeling confident they can deal with the results (71.2% vs 91.9%; P = .0005). Our findings suggest higher decisional conflict in adolescents may influence the type and amount of genomic results they wish to learn. Additional research assessing decisional conflict and factors influencing testing choices among adolescents in clinical settings are required.

3.
Front Genet ; 10: 1059, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31737042

RESUMO

Genomic knowledge is being translated into clinical care. To fully realize the value, it is critical to place credible information in the hands of clinicians in time to support clinical decision making. The electronic health record is an essential component of clinician workflow. Utilizing the electronic health record to present information to support the use of genomic medicine in clinical care to improve outcomes represents a tremendous opportunity. However, there are numerous barriers that prevent the effective use of the electronic health record for this purpose. The electronic health record working groups of the Electronic Medical Records and Genomics (eMERGE) Network and the Clinical Genome Resource (ClinGen) project, along with other groups, have been defining these barriers, to allow the development of solutions that can be tested using implementation pilots. In this paper, we present "lessons learned" from these efforts to inform future efforts leading to the development of effective and sustainable solutions that will support the realization of genomic medicine.

4.
Mol Genet Genomic Med ; 7(11): e969, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31493347

RESUMO

BACKGROUND: The bone morphogenetic protein (BMP) pathway is known to play an imperative role in bone, cartilage, and cardiac tissue formation. Truncating, heterozygous variants, and deletions of one of the essential receptors in this pathway, Bone Morphogenetic Protein Receptor Type1A (BMPR1A), have been associated with autosomal dominant juvenile polyposis. Heterozygous deletions have also been associated with cardiac and minor skeletal anomalies. Populations with atrioventricular septal defects are enriched for rare missense BMPR1A variants. METHODS: We report on a patient with a homozygous missense variant in BMPR1A causing skeletal abnormalities, growth failure a large atrial septal defect, severe subglottic stenosis, laryngomalacia, facial dysmorphisms, and developmental delays. RESULTS: Functional analysis of this variant shows increased chondrocyte death for cells with the mutated receptor, increased phosphorylated R-Smads1/5/8, and loss of Sox9 expression mediated by decreased phosphorylation of p38. CONCLUSION: This homozygous missense variant in BMPR1A appears to cause a distinct clinical phenotype.

5.
J Clin Psychiatry ; 80(5)2019 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-31390496

RESUMO

OBJECTIVE: To determine the prevalence of abnormal thyroid-stimulating hormone (TSH) measures in youth with severe mood and anxiety disorders and to examine clinical and demographic predictors of abnormal TSH measures. METHODS: We retrospectively examined screening TSH concentrations in psychiatrically hospitalized children and adolescents (3-19 years) with mood/anxiety disorders (DSM-IV and DSM-5 criteria) at a large, urban, pediatric hospital between September 2013 and April 2017. Symptoms were extracted from the medical record using adaptive natural language processing algorithms, and the utility of demographic, clinical, and treatment variables as predictors of abnormal TSH measures was evaluated using logistic regression. RESULTS: In this sample (N = 1,017, mean ± SD age = 14.7 ± 2.24 years), 62 patients had a TSH concentration > 3.74 µIU/mL (5.3% [n = 6] of patients < 12 years of age and 6.2% [n = 56] of patients ≥ 12 years of age), and 7 patients had a TSH concentration < 0.36 µIU/mL. Elevated TSH concentrations were associated with a recent weight gain (odds ratio [OR] = 3.60; 95% CI, 1.13-9.61; P = .017), a history of thyroid disease (OR = 6.88; 95% CI, 2.37-10.7; P ≤ .0001), abnormal menstrual bleeding/menometrorrhagia (OR = 2.03; CI, 1.04-3.63; P = .024), and benzodiazepine treatment (OR = 2.29; 95% CI, 1.07-4.52; P = .02). No association was observed for sex, age, or body mass index z score. Among patients with elevated TSH measures, 12.9% (n = 8, mean ± SD age = 16.5 ± 1.5 years, 87.5% female) had an abnormal free/total thyroxine (T4) level or other biochemical findings consistent with thyroid disease. Patients with thyroid disease (compared to those patients with elevated TSH and normal active thyroid hormone concentrations) were older (16.5 ± 1.5 vs 14.6 ± 2.3 years, P = .020) but did not differ in sex distribution (87.5% vs 63.6% female, P = .444). CONCLUSIONS: TSH concentrations are abnormal in approximately 6% of psychiatrically hospitalized youth, although thyroid disease was present in < 1% of the total sample. Targeted screening should focus on patients with recent weight gain, those treated with benzodiazepines, and girls with a history of abnormal uterine bleeding/menometrorrhagia.

6.
Genet Med ; 21(11): 2422-2430, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31110330

RESUMO

Historically, medical geneticists and genetic counselors have provided the majority of genetic services. Advances in technology, reduction in testing costs, and increased public awareness have led to a growing demand for genetic services in both clinical and direct-to-consumer spaces. Recent and anticipated changes in the workforce of genetic counselors and medical geneticists require a reexamination of the way we educate health-care providers and the means by which we provide access to genetic services. The time is ripe for rapid growth of genetic and genomic services, but to capitalize on these opportunities, we need to consider a variety of educational mechanisms to reach providers both within and beyond the traditional genetic counseling and medical genetics sectors, including nurses, physician assistants, and nongenetics physicians. This article summarizes the educational efforts underway in each of these professions.

7.
Genet Med ; 21(10): 2255-2263, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-30894703

RESUMO

PURPOSE: A number of institutions have clinically implemented CYP2D6 genotyping to guide drug prescribing. We compared implementation strategies of early adopters of CYP2D6 testing, barriers faced by both early adopters and institutions in the process of implementing CYP2D6 testing, and approaches taken to overcome these barriers. METHODS: We surveyed eight early adopters of CYP2D6 genotyping and eight institutions in the process of adoption. Data were collected on testing approaches, return of results procedures, applications of genotype results, challenges faced, and lessons learned. RESULTS: Among early adopters, CYP2D6 testing was most commonly ordered to assist with opioid and antidepressant prescribing. Key differences among programs included test ordering and genotyping approaches, result reporting, and clinical decision support. However, all sites tested for copy-number variation and nine common variants, and reported results in the medical record. Most sites provided automatic consultation and had designated personnel to assist with genotype-informed therapy recommendations. Primary challenges were related to stakeholder support, CYP2D6 gene complexity, phenotype assignment, and sustainability. CONCLUSION: There are specific challenges unique to CYP2D6 testing given the complexity of the gene and its relevance to multiple medications. Consensus lessons learned may guide those interested in pursuing similar clinical pharmacogenetic programs.

8.
Front Pharmacol ; 10: 99, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30837874

RESUMO

In pediatric patients, the selective serotonin reuptake inhibitors (SSRIs) escitalopram and citalopram (es/citalopram) are commonly prescribed for anxiety and depressive disorders. However, pharmacogenetic studies examining CYP2C19 metabolizer status and es/citalopram treatment outcomes have largely focused on adults. We report a retrospective study of electronic medical record data from 263 youth < 19 years of age with anxiety and/or depressive disorders prescribed escitalopram or citalopram who underwent routine clinical CYP2C19 genotyping. Slower CYP2C19 metabolizers experienced more untoward effects than faster metabolizers (p = 0.015), including activation symptoms (p = 0.029) and had more rapid weight gain (p = 0.018). A larger proportion of slower metabolizers discontinued treatment with es/citalopram than normal metabolizers (p = 0.007). Meanwhile, faster metabolizers responded more quickly to es/citalopram (p = 0.005) and trended toward less time spent in subsequent hospitalizations (p = 0.06). These results highlight a disparity in treatment outcomes with es/citalopram treatment in youth with anxiety and/or depressive disorders when standardized dosing strategies were used without consideration of CYP2C19 metabolizer status. Larger, prospective trials are warranted to assess whether tailored dosing of es/citalopram based on CYP2C19 metabolizer status improves treatment outcomes in this patient population.

11.
Genesis ; 57(1): e23259, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30375152

RESUMO

A recent convergence of technological innovations has re-energized the ability to apply genetics to research in human craniofacial development. Next-generation exome and whole genome sequencing have significantly dropped in price, making it relatively trivial to sequence and analyze patients and families with congenital craniofacial anomalies. A concurrent revolution in genome editing with the use of the CRISPR-Cas9 system enables the rapid generation of animal models, including mouse, which can precisely recapitulate human variants. Here, we summarize the choices currently available to the research community. We illustrate this approach with the study of a family with a novel craniofacial syndrome with dominant inheritance pattern. The genomic analysis suggested a causal variant in AMOTL1 which we modeled in mice. We also made a novel deletion allele of Amotl1. Our results indicate that Amotl1 is not required in the mouse for survival to weaning. Mice carrying the variant identified in the human sequencing studies, however, do not survive to weaning in normal ratios. The cause of death is not understood for these mice complicating our conclusions about the pathogenicity in the index patient. Thus, we highlight some of the powerful opportunities and confounding factors confronting current craniofacial genetic research.


Assuntos
Anormalidades Craniofaciais/genética , Modelos Animais de Doenças , Proteínas de Membrana/genética , Adulto , Animais , Anormalidades Craniofaciais/patologia , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mutação , Análise de Sequência de DNA/métodos
12.
Genet Med ; 21(4): 965-971, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30369597

RESUMO

PURPOSE: The American College of Medical Genetics and Genomics supports parents' opting in or out of secondary analysis of 59 genes when their child has clinical exome/genome sequencing. We explored the reasons adolescents choose to learn certain types of results and the reasons they want to involve or not involve parents in decision-making. METHODS: Adolescents recruited without clinical indication were offered independent, followed by joint choices with a parent to learn genomic results. After making independent choices, adolescent/parent dyads were interviewed to explore the reasons for their choices. Interviews were audio-recorded and transcribed. The constant comparative method was used to analyze 64 purposefully selected transcripts that included 31 from adolescents who excluded some or all potential results. RESULTS: Three major themes informed adolescents' choices: (1) actionability of information, (2) knowledge seeking, and (3) psychological impact. Of adolescents who independently excluded some conditions (n=31), 58% changed their initial choices during the joint interview due to parental influence or improved understanding. Nearly all adolescents (98%) wanted to be involved in the decision-making process, and 53% wanted to make choices independently. CONCLUSIONS: Our findings contribute empirical evidence to support the refinement of professional guidelines for adolescents' engagement and preferences in genetic testing decisions.


Assuntos
Comportamento de Escolha , Tomada de Decisões , Testes Genéticos/tendências , Consentimento Livre e Esclarecido/psicologia , Adolescente , Criança , Exoma/genética , Feminino , Humanos , Masculino , Pais/psicologia , Inquéritos e Questionários , Sequenciamento Completo do Exoma
14.
J Empir Res Hum Res Ethics ; 13(4): 371-382, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29806518

RESUMO

Opportunities to participate in genomic sequencing studies, as well as recommendations to screen for variants in 59 medically actionable genes anytime clinical genomic sequencing is performed, indicate adolescents will increasingly be involved in decisions about learning secondary findings from genome sequencing. However, how adolescents want to be involved in such decisions is unknown. We conducted five focus groups with adolescents (2) and parents (3) to learn their decisional preferences about return of genomic research results to adolescents. Discussions about decisional preferences centered around three themes: feelings about receiving genomic risk information, adolescent involvement and capacity to participate in decision-making, and recommendations for parental versus collaborative decision-making. We address the contested space between parental duties to act in their children's best interests when choosing which results to return and adolescents' desires to make autonomous decisions. A collaborative decision-making approach is recommended for obtaining consent from adolescents and their parents for genome sequencing research.


Assuntos
Tomada de Decisões , Pesquisa em Genética , Testes Genéticos , Genômica , Consentimento Livre e Esclarecido , Pais , Preferência do Paciente , Adolescente , Comportamento do Adolescente , Adulto , Comportamento Cooperativo , Revelação , Feminino , Grupos Focais , Predisposição Genética para Doença , Humanos , Consentimento Informado por Menores , Masculino , Pessoa de Meia-Idade , Sujeitos da Pesquisa , Risco
15.
J Med Ethics ; 44(6): 389-391, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29463693

RESUMO

OBJECTIVE: Having failed to achieve adequate influenza vaccination rates among employees through voluntary programmes, healthcare organisations have adopted mandatory ones. Some programmes permit religious exemptions, but little is known about who requests religious objections or why. METHODS: Content analysis of applications for religious exemptions from influenza vaccination at a free-standing children's hospital in Cincinnati, Ohio, USA during the 2014-2015 influenza season. RESULTS: Twelve of 15 260 (0.08%) employees submitted applications requesting religious exemptions. Requestors included both clinical and non-clinical employees. All requestors voluntarily identified their religious affiliation, and most were Christian (n=9). Content analysis identified six categories of reasons used to justify an exemption: risks/benefits, ethical/political, lack of direct patient contact, providence, purity and sanctity of life. Individuals articulated reasons in 1-5 (mean 2.6) categories. The most frequently cited category (n=9) was purity; the vaccine and/or its mode of administration were impure, or receiving the vaccine would make the individual impure. Two individuals asserted that the vaccine contained cells derived from aborted human fetuses. Individuals (n=6) also volunteered information supporting the sincerity of their beliefs including distress over previous vaccination and examples of behaviour consistent with their specific objection or their general religious commitment. All requests were approved. CONCLUSIONS: Less than 0.1% of employees requested religious exemptions. Partnering with religious leaders and carefully correcting erroneous information may help address requestors' concerns.

16.
J Pers Med ; 8(1)2018 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-29301385

RESUMO

We examined the Institutional Review Board (IRB) process at 9 academic institutions in the electronic Medical Records and Genomics (eMERGE) Network, for proposed electronic health record-based genomic medicine studies, to identify common questions and concerns. Sequencing of 109 disease related genes and genotyping of 14 actionable variants is being performed in ~28,100 participants from the 9 sites. Pathogenic/likely pathogenic variants in actionable genes are being returned to study participants. We examined each site's research protocols, informed-consent materials, and interactions with IRB staff. Research staff at each site completed questionnaires regarding their IRB interactions. The time to prepare protocols for IRB submission, number of revisions and time to approval ranged from 10-261 days, 0-11, and 11-90 days, respectively. IRB recommendations related to the readability of informed consent materials, specifying the full range of potential risks, providing options for receiving limited results or withdrawal, sharing of information with family members, and establishing the mechanisms to answer participant questions. IRBs reviewing studies that involve the return of results from genomic sequencing have a diverse array of concerns, and anticipating these concerns can help investigators to more effectively engage IRBs.

17.
Hum Mol Genet ; 26(24): 4836-4848, 2017 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-29036432

RESUMO

Primary microcephaly is a congenital brain malformation characterized by a head circumference less than three standard deviations below the mean for age and sex and results in moderate to severe mental deficiencies and decreased lifespan. We recently studied two children with primary microcephaly in an otherwise unaffected family. Exome sequencing identified an autosomal recessive mutation leading to an amino acid substitution in a WD40 domain of the highly conserved Coatomer Protein Complex, Subunit Beta 2 (COPB2). To study the role of Copb2 in neural development, we utilized genome-editing technology to generate an allelic series in the mouse. Two independent null alleles revealed that Copb2 is essential for early stages of embryogenesis. Mice homozygous for the patient variant (Copb2R254C/R254C) appear to have a grossly normal phenotype, likely due to differences in corticogenesis between the two species. Strikingly, mice heterozygous for the patient mutation and a null allele (Copb2R254C/Zfn) show a severe perinatal phenotype including low neonatal weight, significantly increased apoptosis in the brain, and death within the first week of life. Immunostaining of the Copb2R254C/Zfnbrain revealed a reduction in layer V (CTIP2+) neurons, while the overall cell density of the cortex is unchanged. Moreover, neurospheres derived from animals with Copb2 variants grew less than control. These results identify a general requirement for COPB2 in embryogenesis and a specific role in corticogenesis. We further demonstrate the utility of CRISPR-Cas9 generated mouse models in the study of potential pathogenicity of variants of potential clinical interest.


Assuntos
Proteína Coatomer/genética , Microcefalia/genética , Animais , Criança , Modelos Animais de Doenças , Desenvolvimento Embrionário/genética , Feminino , Frequência do Gene , Heterozigoto , Homozigoto , Humanos , Deficiência Intelectual/genética , Masculino , Camundongos , Mutação , Linhagem , Repetições WD40 , Sequenciamento Completo do Exoma
18.
Pharmacogenomics ; 18(13): 1199-1213, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28745549

RESUMO

AIM: To determine parents' use of their children's CYP2D6 research result. We hypothesized that perceived utility, likelihood of sharing and actual sharing of results would differ between parents with children previously exposed (cases) or unexposed (controls) to opioids. METHODS: We returned results by phone (baseline). We surveyed parents about perceived utility and likelihood of sharing their child's research result at baseline, and actual sharing at 3 and 12 months. RESULTS: Cases were more likely than controls to agree that they (p = 0.022) and the doctors (p = 0.041) could use the results to care for their child, to report higher likelihood of sharing (p = 0.042) and to actually share results with the child's doctor (p = 0.026). CONCLUSION: Prior opioid exposure influenced perceived clinical utility and sharing behaviors.


Assuntos
Analgésicos Opioides/efeitos adversos , Citocromo P-450 CYP2D6/genética , Adolescente , Adulto , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pais , Percepção/fisiologia , Inquéritos e Questionários
19.
Pharmacogenomics ; 18(10): 1013-1025, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28639489

RESUMO

Ten organizations within the Electronic Medical Records and Genomics Network developed programs to implement pharmacogenomic sequencing and clinical decision support into clinical settings. Recognizing the importance of informed prescribers, a variety of strategies were used to incorporate provider education to support implementation. Education experiences with pharmacogenomics are described within the context of each organization's prior involvement, including the scope and scale of implementation specific to their Electronic Medical Records and Genomics projects. We describe common and distinct education strategies, provide exemplars and share challenges. Lessons learned inform future perspectives. Future pharmacogenomics clinical implementation initiatives need to include funding toward implementing provider education and evaluating outcomes.


Assuntos
Sistemas de Apoio a Decisões Clínicas/organização & administração , Registros Eletrônicos de Saúde/organização & administração , Pessoal de Saúde/educação , Farmacogenética/educação , Medicina de Precisão/métodos , Sistemas de Apoio a Decisões Clínicas/normas , Registros Eletrônicos de Saúde/normas , Medicina de Precisão/normas , Estados Unidos
20.
J Mol Diagn ; 19(4): 561-566, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28502727

RESUMO

There has been extensive debate about both the necessity of orthogonal confirmation of next-generation sequencing (NGS) results in Clinical Laboratory Improvement Amendments-approved laboratories and return of research NGS results to participants enrolled in research studies. In eMERGE-PGx, subjects underwent research NGS using PGRNseq and orthogonal targeted genotyping in clinical laboratories, which prompted a comparison of genotyping results between platforms. Concordance (percentage agreement) was reported for 4077 samples tested across nine combinations of research and clinical laboratories. Retesting was possible on a subset of 1792 samples, and local laboratory directors determined sources of genotype discrepancy. Research NGS and orthogonal clinical genotyping had an overall per sample concordance rate of 0.972 and per variant concordance rate of 0.997. Genotype discrepancies attributed to research NGS were because of sample switching (preanalytical errors), whereas the majority of genotype discrepancies (92.3%) attributed to clinical genotyping were because of allele dropout as a result of rare variants interfering with primer hybridization (analytical errors). These results highlight the analytical quality of clinically significant pharmacogenetic variants derived from NGS and reveal important areas for research and clinical laboratories to address with quality management programs.


Assuntos
Técnicas de Genotipagem/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Testes Farmacogenômicos/métodos , Alelos , Genótipo , Humanos , Farmacogenética , Polimorfismo Genético , Análise de Sequência de DNA/métodos
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