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2.
J Hum Genet ; 64(11): 1091-1095, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31451714

RESUMO

This study aimed to obtain a quantitative assessment of the occurrence of contradictory evidence in functional classification of genetic variation, according to the American College of Medical Genetics and Genomics (ACMG) guidelines. We analyzed 140,883 genetic variation in the Human Gene Mutation Database (HGMD). The 2014 release of the HGMD dataset before the publication of the ACMG guidelines was used for its independence from the ACMG guidelines. Evidence for benign classification, BS2 (0.37%), was identified among variants classified as pathogenic. For likely pathogenic variation, BP1 (2.99%) and BS2 (0.37%) were identified. PM1 is commonly observed among variants classified as benign (28.45%), while PM2 and PM1 are commonly identified among variants classified as likely benign (48.91% and 42.95%, respectively). Taken together, these observations will inform better approaches to apply the ACMG guidelines.


Assuntos
Bases de Dados Genéticas , Testes Genéticos , Variação Genética/genética , Genômica , Genética Médica/tendências , Humanos , Mutação , Estados Unidos
4.
Genet Med ; 21(9): 1916-1926, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30842646

RESUMO

There is no question that the advent of massively parallel ("next-generation") DNA sequencing has thrust Medical Genetics and Molecular Diagnostics into a new era, availing practitioners and patients of a form of genetic testing unprecedented in its scope and comprehensiveness. It has produced impressive diagnostic yield, ended the "diagnostic odyssey" for many patients and families, expanded the known phenotypes of countless disorders, and led to almost weekly new disease gene discoveries. Nevertheless, it still fails to identify the molecular cause of many patients who clearly exhibit genetic/syndromic conditions, while at the same time unmasking other sequence changes of uncertain significance or unexpected consequences. With over six years' experience in the clinical application of NGS, this seems an opportune time to take stock and face up honestly to how much we still do not know about genome action and, indeed, the DNA molecule itself. This review and assessment examines a number of residual deficiencies and misconceptions in clinical genomics, while daring to predict its future incorporation of other "-omics" approaches and even quantum phenomena in our unending quest to understand the heredity of Homo sapiens.


Assuntos
Doenças Genéticas Inatas/genética , Predisposição Genética para Doença , Genética Médica/tendências , Genômica , Doenças Genéticas Inatas/terapia , Testes Genéticos , Genoma Humano/genética , Sequenciamento de Nucleotídeos em Larga Escala/tendências , Humanos , Patologia Molecular
5.
Clin Sci (Lond) ; 133(5): 697-708, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30837331

RESUMO

Advances in genetic technology are having a major impact in the clinic, and mean that many perceptions of the role and scope of genetic testing are having to change. Genomic testing brings with it a greater opportunity for diagnosis, or predictions of future diagnoses, but also an increased chance of uncertain or unexpected findings, many of which may have impacts for multiple members of a person's family. In the past, genetic testing was rarely able to provide rapid results, but the increasing speed and availability of genomic testing is changing this, meaning that genomic information is increasingly influencing decisions around patient care in the acute inpatient setting. The landscape of treatment options for genetic conditions is shifting, which has evolving implications for clinical discussions around previously untreatable disorders. Furthermore, the point of access to testing is changing with increasing provision direct to the consumer outside the formal healthcare setting. This review outlines the ways in which genetic medicine is developing in light of technological advances.


Assuntos
Testes Genéticos/tendências , Terapia Genética/tendências , Genética Médica/tendências , Genômica/tendências , Animais , Difusão de Inovações , Predisposição Genética para Doença , Humanos , Farmacogenética/tendências , Fenótipo , Medicina de Precisão/tendências , Valor Preditivo dos Testes
6.
Genet Med ; 21(4): 772-789, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30659246

RESUMO

PURPOSE: Glycogen storage disease (GSD) types VI and IX are rare diseases of variable clinical severity affecting primarily the liver. GSD VI is caused by deficient activity of hepatic glycogen phosphorylase, an enzyme encoded by the PYGL gene. GSD IX is caused by deficient activity of phosphorylase kinase (PhK), the enzyme subunits of which are encoded by various genes: ɑ (PHKA1, PHKA2), ß (PHKB), É£ (PHKG1, PHKG2), and δ (CALM1, CALM2, CALM3). Glycogen storage disease types VI and IX have a wide spectrum of clinical manifestations and often cannot be distinguished from each other, or from other liver GSDs, on clinical presentation alone. Individuals with GSDs VI and IX can present with hepatomegaly with elevated serum transaminases, ketotic hypoglycemia, hyperlipidemia, and poor growth. This guideline for the management of GSDs VI and IX was developed as an educational resource for health-care providers to facilitate prompt and accurate diagnosis and appropriate management of patients. METHODS: A national group of experts in various aspects of GSDs VI and IX met to review the limited evidence base from the scientific literature and provided their expert opinions. Consensus was developed in each area of diagnosis, treatment, and management. Evidence bases for these rare disorders are largely based on expert opinion, particularly when targeted therapeutics that have to clear the US Food and Drug Administration (FDA) remain unavailable. RESULTS: This management guideline specifically addresses evaluation and diagnosis across multiple organ systems involved in GSDs VI and IX. Conditions to consider in a differential diagnosis stemming from presenting features and diagnostic algorithms are discussed. Aspects of diagnostic evaluation and nutritional and medical management, including care coordination, genetic counseling, and prenatal diagnosis are addressed. CONCLUSION: A guideline that will facilitate the accurate diagnosis and optimal management of patients with GSDs VI and IX was developed. This guideline will help health-care providers recognize patients with GSDs VI and IX, expedite diagnosis, and minimize adverse sequelae from delayed diagnosis and inappropriate management. It will also help identify gaps in scientific knowledge that exist today and suggest future studies.


Assuntos
Genômica , Doença de Depósito de Glicogênio/genética , Hipoglicemia/genética , Fosforilase Quinase/genética , Gerenciamento Clínico , Genética Médica/tendências , Glicogênio/genética , Glicogênio/metabolismo , Doença de Depósito de Glicogênio/diagnóstico , Doença de Depósito de Glicogênio/epidemiologia , Doença de Depósito de Glicogênio/terapia , Guias como Assunto , Humanos , Hipoglicemia/metabolismo , Hipoglicemia/terapia , Fígado/metabolismo , Fígado/patologia , Mutação , Fosforilase Quinase/química , Estados Unidos/epidemiologia
7.
Genet Med ; 21(8): 1874-1877, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30686822

RESUMO

PURPOSE: This study of current conditions in medical genetics practice is designed to inform public policy development and present possible solutions for improving access to genetic services. METHODS: Using the American College of Medical Genetics and Genomics Member Directory, membership directories from regional collaborative partners, listservs from national partners, and social media, a 16-question survey was electronically distributed in 2015. RESULTS: The responses of 924 genetics professionals and related providers present a snapshot of current practice and an assessment of workforce needs. More than 92% of the respondents (837/910) are involved in clinical care. Among geneticists, 60% spend more than 51% of their time in clinical care. Geneticists reported an average of 10.2 new patients per week and 7.8 follow-up visits per week. More than 62% of geneticists said that their practices were nearly full; 9.4% said that they were not taking new patients. The survey identified more than 100 geneticists and 200 genetic counselor job vacancies. Fewer than 18% of respondents reported use of telemedicine. CONCLUSION: When compared with previously published workforce studies, these data show that wait times and average new patient caseloads have increased, while the number of geneticists has not.


Assuntos
Aconselhamento Genético/tendências , Serviços em Genética , Genética Médica/tendências , Humanos , Médicos/tendências , Mídias Sociais , Inquéritos e Questionários , Estados Unidos/epidemiologia
8.
Am J Hum Genet ; 104(1): 13-20, 2019 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-30609404

RESUMO

Genomic sequencing is rapidly transitioning into clinical practice, and implementation into healthcare systems has been supported by substantial government investment, totaling over US$4 billion, in at least 14 countries. These national genomic-medicine initiatives are driving transformative change under real-life conditions while simultaneously addressing barriers to implementation and gathering evidence for wider adoption. We review the diversity of approaches and current progress made by national genomic-medicine initiatives in the UK, France, Australia, and US and provide a roadmap for sharing strategies, standards, and data internationally to accelerate implementation.


Assuntos
Assistência à Saúde/métodos , Assistência à Saúde/organização & administração , Genética Médica/métodos , Genética Médica/organização & administração , Genômica/tendências , Cooperação Internacional , Austrália , Assistência à Saúde/economia , Assistência à Saúde/tendências , Medicina Baseada em Evidências , França , Genética Médica/economia , Genética Médica/tendências , Genômica/economia , Humanos , Disseminação de Informação , Setor Privado , Reino Unido , Estados Unidos
10.
11.
Genet Med ; 21(6): 1457-1461, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30327540

RESUMO

PURPOSE: We analyzed the patients served by the University of Washington Adult Genetic Medicine Clinic (UWAGMC) over a 42-year period to determine how clinical services have changed and to evaluate the contributing factors. METHODS: We conducted a retrospective survey of patients seen by UWAGMC that included patients seen from 1975 to 2016. Variables considered included referral indication, disease status, and clinic visit date. Indications for referral were then binned into clinical categories for descriptive analysis. RESULTS: Of 30,780 patient visits during the 39 years for which data were available, 57.3% occurred in the last decade. Referrals for breast/ovarian cancer or colon/endometrial cancer account for 74.8% of cancer referrals since 1998. Huntington disease patients made up 46% of neurological referral indications. Telephone screening implemented in 2013 has reduced the number of referrals for hypermobile Ehlers-Danlos syndrome. CONCLUSION: Referral indications increased with clinical testing availability and because of the academic programs of UWAGMC providers. With increased public awareness of heritable conditions, prescreening self-referrals were used to allocate limited resources. These trends demonstrate the need for more geneticists in adult medicine to expand centers of excellence for rare diseases and to serve the increasing numbers of adult patients with genetic conditions.


Assuntos
Assistência Ambulatorial/tendências , Assistência à Saúde/tendências , Genética Médica/tendências , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Encaminhamento e Consulta , Estudos Retrospectivos , Inquéritos e Questionários , Revisão da Utilização de Recursos de Saúde/métodos , Washington/epidemiologia
12.
Genet Med ; 21(4): 987-993, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30181607

RESUMO

The Clinical Genome Resource (ClinGen) is supported by the National Institutes of Health (NIH) to develop expertly curated and freely accessible resources defining the clinical relevance of genes and variants for use in precision medicine and research. To facilitate expert input, ClinGen has formed Clinical Domain Working Groups (CDWGs) to leverage the collective knowledge of clinicians, laboratory diagnosticians, and researchers. In the initial phase of ClinGen, CDWGs were launched in the cardiovascular, hereditary cancer, and inborn errors of metabolism clinical fields. These early CDWGs established the infrastructure necessary to implement standardized processes developed or adopted by ClinGen working groups for the interpretation of gene-disease associations and variant pathogenicity, and provided a sustainable model for the formation of future disease-focused curation groups. The establishment of CDWGs requires recruitment of international experts to broadly represent the interests of their field and ensure that assertions made are reliable and widely accepted. Building on the successes, challenges, and trade-offs made in establishing the original CDWGs, ClinGen has developed standard operating procedures for the development of CDWGs in new clinical domains, while maximizing efforts to scale up curation and facilitate involvement of external groups who wish to utilize ClinGen methods and infrastructure for expert curation.


Assuntos
Bases de Dados Genéticas , Genética Médica/tendências , Genoma Humano/genética , Genômica/tendências , Variação Genética/genética , Humanos , Disseminação de Informação , Medicina de Precisão
13.
Genet Med ; 21(7): 1534-1540, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30467402

RESUMO

PURPOSE: Research on genomic medicine integration has focused on applications at the individual level, with less attention paid to implementation within clinical settings. Therefore, we conducted a qualitative study using the Consolidated Framework for Implementation Research (CFIR) to identify system-level factors that played a role in implementation of genomic medicine within Implementing GeNomics In PracTicE (IGNITE) Network projects. METHODS: Up to four study personnel, including principal investigators and study coordinators from each of six IGNITE projects, were interviewed using a semistructured interview guide that asked interviewees to describe study site(s), progress at each site, and factors facilitating or impeding project implementation. Interviews were coded following CFIR inner-setting constructs. RESULTS: Key barriers included (1) limitations in integrating genomic data and clinical decision support tools into electronic health records, (2) physician reluctance toward genomic research participation and clinical implementation due to a limited evidence base, (3) inadequate reimbursement for genomic medicine, (4) communication among and between investigators and clinicians, and (5) lack of clinical and leadership engagement. CONCLUSION: Implementation of genomic medicine is hindered by several system-level barriers to both research and practice. Addressing these barriers may serve as important facilitators for studying and implementing genomics in practice.


Assuntos
Genética Médica , Genômica , Atitude Frente a Saúde , Registros Eletrônicos de Saúde , Genética Médica/tendências , Genômica/tendências , Humanos , Ciência da Implementação , Aceitação pelo Paciente de Cuidados de Saúde , Pesquisa Qualitativa
14.
J Biochem ; 165(2): 139-158, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30452759

RESUMO

Personalized healthcare (PHC) based on an individual's genetic make-up is one of the most advanced, yet feasible, forms of medical care. The Tohoku Medical Megabank (TMM) Project aims to combine population genomics, medical genetics and prospective cohort studies to develop a critical infrastructure for the establishment of PHC. To date, a TMM CommCohort (adult general population) and a TMM BirThree Cohort (birth+three-generation families) have conducted recruitments and baseline surveys. Genome analyses as part of the TMM Project will aid in the development of a high-fidelity whole-genome Japanese reference panel, in designing custom single-nucleotide polymorphism (SNP) arrays specific to Japanese, and in estimation of the biological significance of genetic variations through linked investigations of the cohorts. Whole-genome sequencing from >3,500 unrelated Japanese and establishment of a Japanese reference genome sequence from long-read data have been done. We next aim to obtain genotype data for all TMM cohort participants (>150,000) using our custom SNP arrays. These data will help identify disease-associated genomic signatures in the Japanese population, while genomic data from TMM BirThree Cohort participants will be used to improve the reference genome panel. Follow-up of the cohort participants will allow us to test the genetic markers and, consequently, contribute to the realization of PHC.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Genética Médica/tendências , Genoma Humano/genética , Genômica , Medicina de Precisão/tendências , Estudos de Coortes , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Padrões de Referência
15.
Genet Med ; 21(4): 861-866, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30214068

RESUMO

PURPOSE: Clinical laboratories performing exome or genome sequencing (ES/GS) are familiar with the challenges associated with proper consenting for and reporting of medically actionable secondary findings based on recommendations from the American College of Medical Genetics and Genomics (ACMG). Misattributed parentage is another type of unanticipated finding a laboratory may encounter during family-based ES/GS; however, there are currently no professional recommendations related to the proper consenting for and reporting of misattributed parentage encountered during ES/GS. METHODS: We surveyed 10 clinical laboratories offering family-based ES/GS regarding their consent language, discovery, and reporting of misattributed parentage. RESULTS: Many laboratories have already developed their own practices/policies for these issues, which do not necessarily agree with those from other labs. CONCLUSION: There are several other possibilities besides true misattributed parentage that could result in similar laboratory findings, and laboratories often feel they lack sufficient information to make formal conclusions on a report regarding the true genetic relatedness of the submitted samples. However, understanding the genetic relatedness (or lack thereof) of the samples submitted for family-based ES/GS has medical relevance. Therefore, professional recommendations for the appropriate handling of suspected misattributed parentage encountered during ES/GS are needed to help standardize current clinical laboratory practices.


Assuntos
Testes Genéticos/tendências , Genética Médica/tendências , Genômica/tendências , Pais , Serviços de Laboratório Clínico , Exoma/genética , Feminino , Genoma Humano/genética , Humanos , Achados Incidentais , Consentimento Livre e Esclarecido , Masculino , Inquéritos e Questionários , Sequenciamento Completo do Exoma/tendências , Sequenciamento Completo do Genoma/tendências
16.
Genet Med ; 21(1): 81-88, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29899502

RESUMO

PURPOSE: Data sharing between clinicians, laboratories, and patients is essential for improvements in genomic medicine, but obtaining consent for individual-level data sharing is often hindered by a lack of time and resources. To address this issue, the Clinical Genome Resource (ClinGen) developed tools to facilitate consent, including a one-page consent form and online supplemental video with information on key topics, such as risks and benefits of data sharing. METHODS: To determine whether the consent form and video accurately conveyed key data sharing concepts, we surveyed 5,162 members of the general public. We measured comprehension at baseline, after reading the form and watching the video. Additionally, we assessed participants' attitudes toward genomic data sharing. RESULTS: Participants' performance on comprehension questions significantly improved over baseline after reading the form and continued to improve after watching the video. CONCLUSION: Results suggest reading the form alone provided participants with important knowledge regarding broad data sharing, and watching the video allowed for broader comprehension. These materials are now available at http://www.clinicalgenome.org/share . These resources will provide patients a straightforward way to share their genetic and health information, and improve the scientific community's access to data generated through routine healthcare.


Assuntos
Genética Médica/tendências , Genômica , Disseminação de Informação , Adulto , Feminino , Humanos , Consentimento Livre e Esclarecido , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários
17.
Genet Med ; 20(10): 1114-1121, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30093710

RESUMO

Advances in genetic and genomic technology changed health-care services rapidly in low and middle income countries (LMICs) in the Asia-Pacific region. While genetic services were initially focused on population-based disease prevention strategies, they have evolved into clinic-based and therapeutics-oriented service. Many LMICs struggled with these noncommunicable diseases and were unprepared for the needs of a clinical genetic service. The emergence of a middle class population, the lack of regulatory oversight, and weak capacity-building in medical genetics expertise and genetic counseling services led to a range of genetic services of variable quality with minimal ethical oversight. Some of the current shortcomings faced include the lack of awareness of cultural values in genetic health care, the variable stages of socioeconomic development and educational background that led to increased demand and abuse of genetics, the role of women in society and the crisis of gender selection, the lack of preventive and care services for genetic and birth defects, the issues of gene ethics in medicine, and the lack of understanding of some religious controversies. These challenges provide opportunities for both developing and developed nations to work together to reduce the inequalities and to ensure a caring, inclusive, ethical, and cost-effective genetic service in the region.


Assuntos
Aconselhamento Genético/tendências , Serviços em Genética/tendências , Genética Médica/tendências , Ásia , Assistência à Saúde , Países em Desenvolvimento , Necessidades e Demandas de Serviços de Saúde , Humanos
18.
Curr Opin Genet Dev ; 53: 98-104, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30125792

RESUMO

Hispanic/Latino (H/L) populations, although linked by culture and aspects of shared history, reflect the complexity of history and migration influencing the Americas. The original settlement by indigenous Americans, followed by postcolonial admixture from multiple continents, has yielded localized genetic patterns. In addition, numerous H/L populations appear to have signatures of pre-colonization and post-colonization bottlenecks, indicating that tens of millions of H/Ls may harbor signatures of founder effects today. Based on both population and medical genetic findings we highlight the extreme differentiation across the Americas, providing evidence for why H/Ls should not be considered a single population in modern human genetics. We highlight the need for additional sampling of understudied H/L groups, and ramifications of these findings for genomic medicine in one-tenth of the world's population.


Assuntos
Variação Genética/genética , Genética Médica/tendências , Genética Populacional , Genoma Humano/genética , Grupo com Ancestrais do Continente Africano/genética , Grupo com Ancestrais do Continente Europeu/genética , Genômica/tendências , Humanos , América Latina/epidemiologia
19.
Genet Med ; 20(10): 1105-1113, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29915380

RESUMO

PURPOSE: Chromosomal microarray (CMA) is recommended as the first-tier test in evaluation of individuals with neurodevelopmental disability and congenital anomalies. CMA may not detect balanced cytogenomic abnormalities or uniparental disomy (UPD), and deletion/duplications and regions of homozygosity may require additional testing to clarify the mechanism and inform accurate counseling. We conducted an evidence review to synthesize data regarding the benefit of additional testing after CMA to inform a genetic diagnosis. METHODS: The review was guided by key questions related to the detection of genomic events that may require additional testing. A PubMed search for original research articles, systematic reviews, and meta-analyses was evaluated from articles published between 1 January 1983 and 31 March 2017. Based on the key questions, articles were retrieved and data extracted in parallel with comparison of results and discussion to resolve discrepancies. Variables assessed included study design and outcomes. RESULTS: A narrative synthesis was created for each question to describe the occurrence of, and clinical significance of, additional diagnostic findings from subsequent testing performed after CMA. CONCLUSION: These findings may be used to assist the laboratory and clinician when making recommendations about additional testing after CMA, as it impacts clinical care, counseling, and diagnosis.


Assuntos
Anormalidades Congênitas/genética , Testes Genéticos , Deficiência Intelectual/genética , Transtornos do Neurodesenvolvimento/genética , Aberrações Cromossômicas , Cromossomos/genética , Anormalidades Congênitas/diagnóstico , Anormalidades Congênitas/fisiopatologia , Genética Médica/tendências , Genômica/tendências , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/fisiopatologia , Cariotipagem , Análise em Microsséries , Transtornos do Neurodesenvolvimento/diagnóstico , Transtornos do Neurodesenvolvimento/fisiopatologia
20.
Eur J Hum Genet ; 26(7): 946-954, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29681620

RESUMO

Advances in genomic medicine are improving diagnosis and treatment of some health conditions, and the question of whether former patients should be recontacted is therefore timely. The issue of recontacting is becoming more important with increased integration of genomics in 'mainstream' medicine. Empirical evidence is needed to advance the discussion over whether and how recontacting should be implemented. We administered a web-based survey to genetic services in European countries to collect information about existing infrastructures and practices relevant to recontacting patients. The majority of the centres stated they had recontacted patients to update them about new significant information; however, there were no standardised practices or systems in place. There was also a multiplicity of understandings of the term 'recontacting', which respondents conflated with routine follow-up programmes, or even with post-test counselling. Participants thought that recontacting systems should be implemented to provide the best service to the patients and families. Nevertheless, many barriers to implementation were mentioned. These included: lack of resources and infrastructure, concerns about potential negative psychological consequences of recontacting, unclear operational definitions of recontacting, policies that prevent healthcare professionals from recontacting, and difficulties in locating patients after their last contact. These barriers are also intensified by the highly variable development (and establishment) of the specialties of medical genetics and genetic counselling across different European countries. Future recommendations about recontacting need to consider these barriers. It is also important to reach an 'operational definition' that can be useful in different countries.


Assuntos
Dever de Recontatar , Aconselhamento Genético/tendências , Serviços em Genética/tendências , Genética Médica/tendências , Europa (Continente) , Genômica/tendências , Pessoal de Saúde , Humanos , Inquéritos e Questionários
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