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1.
Curr Opin Pediatr ; 31(6): 732-738, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31693580

RESUMO

PURPOSE OF REVIEW: Identifying pathogenic variation underlying pediatric developmental disease is critical for medical management, therapeutic development, and family planning. This review summarizes current genetic testing options along with their potential benefits and limitations. We also describe results from large-scale genomic sequencing projects in pediatric and neonatal populations with a focus on clinical utility. RECENT FINDINGS: Recent advances in DNA sequencing technology have made genomic sequencing a feasible and effective testing option in a variety of clinical settings. These cutting-edge tests offer much promise to both medical providers and patients as it has been demonstrated to detect causal genetic variation in ∼25% or more of previously unresolved cases. Efforts aimed at promoting data sharing across clinical genetics laboratories and systematic reanalysis of existing genomic sequencing data have further improved diagnostic rates and reduced the number of unsolved cases. SUMMARY: Genomic sequencing is a powerful and increasingly cost-effective alternative to current genetic tests and will continue to grow in clinical utility as more of the genome is understood and as analytical methods are improved. The evolution of genomic sequencing is changing the landscape of clinical testing and requires medical professionals who are adept at understanding and returning genomic results to patients.

2.
Curr Opin Pediatr ; 2019 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-31408017

RESUMO

PURPOSE OF REVIEW: Identifying pathogenic variation underlying pediatric developmental disease is critical for medical management, therapeutic development, and family planning. This review summarizes current genetic testing options along with their potential benefits and limitations. We also describe results from large-scale genomic sequencing projects in pediatric and neonatal populations with a focus on clinical utility. RECENT FINDINGS: Recent advances in DNA sequencing technology have made genomic sequencing a feasible and effective testing option in a variety of clinical settings. These cutting-edge tests offer much promise to both medical providers and patients as it has been demonstrated to detect causal genetic variation in ∼25% or more of previously unresolved cases. Efforts aimed at promoting data sharing across clinical genetics laboratories and systematic reanalysis of existing genomic sequencing data have further improved diagnostic rates and reduced the number of unsolved cases. SUMMARY: Genomic sequencing is a powerful and increasingly cost-effective alternative to current genetic tests and will continue to grow in clinical utility as more of the genome is understood and as analytical methods are improved. The evolution of genomic sequencing is changing the landscape of clinical testing and requires medical professionals who are adept at understanding and returning genomic results to patients.

3.
Genet Med ; 21(9): 2036-2042, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30739909

RESUMO

PURPOSE: To define the clinical characteristics of patients with variants in TCF20, we describe 27 patients, 26 of whom were identified via exome sequencing. We compare detailed clinical data with 17 previously reported patients. METHODS: Patients were ascertained through molecular testing laboratories performing exome sequencing (and other testing) with orthogonal confirmation; collaborating referring clinicians provided detailed clinical information. RESULTS: The cohort of 27 patients all had novel variants, and ranged in age from 2 to 68 years. All had developmental delay/intellectual disability. Autism spectrum disorders/autistic features were reported in 69%, attention disorders or hyperactivity in 67%, craniofacial features (no recognizable facial gestalt) in 67%, structural brain anomalies in 24%, and seizures in 12%. Additional features affecting various organ systems were described in 93%. In a majority of patients, we did not observe previously reported findings of postnatal overgrowth or craniosynostosis, in comparison with earlier reports. CONCLUSION: We provide valuable data regarding the prognosis and clinical manifestations of patients with variants in TCF20.

5.
Artigo em Inglês | MEDLINE | ID: mdl-30559313

RESUMO

Diamond-Blackfan Anemia (DBA) is a rare polygenic disorder defined by congenital hypoplastic anemia with marked decrease or absence of bone marrow erythroid precursors. Identifying the specific genetic etiology is important for counseling and clinical management. A 6-yr-old boy with a clinical diagnosis of DBA has been followed by our pediatric hematology team since birth. His clinical course includes transfusion-dependent hypoplastic anemia and progressive autoimmune cytopenias. Genetic testing failed to identify a causative mutation in any of the classical DBA-associated genes. He and his parents underwent trio whole-exome sequencing (WES) with no genetic etiology identified initially. Clinical persistence and suspicion led to testing for adenosine deaminase 2 (ADA2) activity and whole-genome sequencing (WGS) that identified compound heterozygous pathogenic mutations in the ADA2-encoding CECR1 gene, a recently appreciated etiology for congenital hypoplastic anemia. This case illustrates current challenges in genetic testing and how they can be overcome by multidisciplinary expertise in clinical medicine and genomics.


Assuntos
Adenosina Desaminase/genética , Anemia de Diamond-Blackfan/genética , Anemia Hipoplástica Congênita/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Anemia de Diamond-Blackfan/diagnóstico , Anemia Hipoplástica Congênita/diagnóstico , Medula Óssea/fisiopatologia , Criança , Testes Genéticos/métodos , Humanos , Masculino , Mutação , Pais , Proteínas Ribossômicas , Sequenciamento Completo do Exoma
6.
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.

7.
Artigo em Inglês | MEDLINE | ID: mdl-30133189

RESUMO

BACKGROUND: Clinical genome and exome sequencing (CGES) is primarily used to address specific clinical concerns by detecting risk of future disease, clarifying diagnosis, or directing treatment. Additionally, CGES makes possible the disclosure of autosomal recessive and X-linked carrier results as additional secondary findings, and research about the impact of carrier results disclosure in this context is needed. METHODS: Representatives from 11 projects in the clinical sequencing exploratory research (CSER) consortium collected data from their projects using a structured survey. The survey focused on project characteristics, which variants were offered and/or disclosed to participants as carrier results, methods for carrier results disclosure, and project-specific outcomes. We recorded quantitative responses and report descriptive statistics with the aim of describing the variability in approaches to disclosing carrier results in translational genomics research projects. RESULTS: The proportion of participants with carrier results was related to the number of genes included, ranging from 3% (three genes) to 92% (4,600 genes). Between one and seven results were disclosed to those participants who received any positive result. Most projects offered participants choices about whether to receive some or all of the carrier results. There were a range of approaches to communicate results, and many projects used separate approaches for disclosing positive and negative results. CONCLUSION: Future translational genomics research projects will need to make decisions regarding whether and how to disclose carrier results. The CSER consortium experience identifies approaches that balance potential participant interest while limiting impact on project resources.

8.
Genet Med ; 2018 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-29790872

RESUMO

PurposeClinically relevant secondary variants were identified in parents enrolled with a child with developmental delay and intellectual disability.MethodsExome/genome sequencing and analysis of 789 "unaffected" parents was performed.ResultsPathogenic/likely pathogenic variants were identified in 21 genes within 25 individuals (3.2%), with 11 (1.4%) participants harboring variation in a gene defined as clinically actionable by the American College of Medical Genetics and Genomics. These 25 individuals self-reported either relevant clinical diagnoses (5); relevant family history or symptoms (13); or no relevant family history, symptoms, or clinical diagnoses (7). A limited carrier screen was performed yielding 15 variants in 48 (6.1%) parents. Parents were also analyzed as mate pairs (n = 365) to identify cases in which both parents were carriers for the same recessive disease, yielding three such cases (0.8%), two of which had children with the relevant recessive disease. Four participants had two findings (one carrier and one noncarrier variant). In total, 71 of the 789 enrolled parents (9.0%) received secondary findings.ConclusionWe provide an overview of the rates and types of clinically relevant secondary findings, which may be useful in the design and implementation of research and clinical sequencing efforts to identify such findings.Genetics in Medicine advance online publication, 12 April 2018; doi:10.1038/gim.2018.53.

9.
Hum Genet ; 2018 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-29740699

RESUMO

Many genetic causes of developmental delay and/or intellectual disability (DD/ID) are extremely rare, and robust discovery of these requires both large-scale DNA sequencing and data sharing. Here we describe a GeneMatcher collaboration which led to a cohort of 13 affected individuals harboring protein-altering variants, 11 of which are de novo, in MED13; the only inherited variant was transmitted to an affected child from an affected mother. All patients had intellectual disability and/or developmental delays, including speech delays or disorders. Other features that were reported in two or more patients include autism spectrum disorder, attention deficit hyperactivity disorder, optic nerve abnormalities, Duane anomaly, hypotonia, mild congenital heart abnormalities, and dysmorphisms. Six affected individuals had mutations that are predicted to truncate the MED13 protein, six had missense mutations, and one had an in-frame-deletion of one amino acid. Out of the seven non-truncating mutations, six clustered in two specific locations of the MED13 protein: an N-terminal and C-terminal region. The four N-terminal clustering mutations affect two adjacent amino acids that are known to be involved in MED13 ubiquitination and degradation, p.Thr326 and p.Pro327. MED13 is a component of the CDK8-kinase module that can reversibly bind Mediator, a multi-protein complex that is required for Polymerase II transcription initiation. Mutations in several other genes encoding subunits of Mediator have been previously shown to associate with DD/ID, including MED13L, a paralog of MED13. Thus, our findings add MED13 to the group of CDK8-kinase module-associated disease genes.

10.
Genet Med ; 20(8): 855-866, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29144510

RESUMO

PURPOSE: As massively parallel sequencing is increasingly being used for clinical decision making, it has become critical to understand parameters that affect sequencing quality and to establish methods for measuring and reporting clinical sequencing standards. In this report, we propose a definition for reduced coverage regions and describe a set of standards for variant calling in clinical sequencing applications. METHODS: To enable sequencing centers to assess the regions of poor sequencing quality in their own data, we optimized and used a tool (ExCID) to identify reduced coverage loci within genes or regions of particular interest. We used this framework to examine sequencing data from 500 patients generated in 10 projects at sequencing centers in the National Human Genome Research Institute/National Cancer Institute Clinical Sequencing Exploratory Research Consortium. RESULTS: This approach identified reduced coverage regions in clinically relevant genes, including known clinically relevant loci that were uniquely missed at individual centers, in multiple centers, and in all centers. CONCLUSION: This report provides a process road map for clinical sequencing centers looking to perform similar analyses on their data.

11.
Genome Med ; 9(1): 72, 2017 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-28754123

RESUMO

BACKGROUND: Psychiatric disorders are multigenic diseases with complex etiology that contribute significantly to human morbidity and mortality. Although clinically distinct, several disorders share many symptoms, suggesting common underlying molecular changes exist that may implicate important regulators of pathogenesis and provide new therapeutic targets. METHODS: We performed RNA sequencing on tissue from the anterior cingulate cortex, dorsolateral prefrontal cortex, and nucleus accumbens from three groups of 24 patients each diagnosed with schizophrenia, bipolar disorder, or major depressive disorder, and from 24 control subjects. We identified differentially expressed genes and validated the results in an independent cohort. Anterior cingulate cortex samples were also subjected to metabolomic analysis. ChIP-seq data were used to characterize binding of the transcription factor EGR1. RESULTS: We compared molecular signatures across the three brain regions and disorders in the transcriptomes of post-mortem human brain samples. The most significant disease-related differences were in the anterior cingulate cortex of schizophrenia samples compared to controls. Transcriptional changes were assessed in an independent cohort, revealing the transcription factor EGR1 as significantly down-regulated in both cohorts and as a potential regulator of broader transcription changes observed in schizophrenia patients. Additionally, broad down-regulation of genes specific to neurons and concordant up-regulation of genes specific to astrocytes was observed in schizophrenia and bipolar disorder patients relative to controls. Metabolomic profiling identified disruption of GABA levels in schizophrenia patients. CONCLUSIONS: We provide a comprehensive post-mortem transcriptome profile of three psychiatric disorders across three brain regions. We highlight a high-confidence set of independently validated genes differentially expressed between schizophrenia and control patients in the anterior cingulate cortex and integrate transcriptional changes with untargeted metabolite profiling.


Assuntos
Transtorno Bipolar/genética , Encéfalo/metabolismo , Transtorno Depressivo Maior/genética , Esquizofrenia/genética , Transcriptoma , Autopsia , Transtorno Bipolar/metabolismo , Imunoprecipitação da Cromatina , Transtorno Depressivo Maior/metabolismo , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Feminino , Humanos , Masculino , Metabolômica , Esquizofrenia/metabolismo , Análise de Sequência de RNA
12.
Genome Med ; 9(1): 43, 2017 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-28554332

RESUMO

BACKGROUND: Developmental disabilities have diverse genetic causes that must be identified to facilitate precise diagnoses. We describe genomic data from 371 affected individuals, 309 of which were sequenced as proband-parent trios. METHODS: Whole-exome sequences (WES) were generated for 365 individuals (127 affected) and whole-genome sequences (WGS) were generated for 612 individuals (244 affected). RESULTS: Pathogenic or likely pathogenic variants were found in 100 individuals (27%), with variants of uncertain significance in an additional 42 (11.3%). We found that a family history of neurological disease, especially the presence of an affected first-degree relative, reduces the pathogenic/likely pathogenic variant identification rate, reflecting both the disease relevance and ease of interpretation of de novo variants. We also found that improvements to genetic knowledge facilitated interpretation changes in many cases. Through systematic reanalyses, we have thus far reclassified 15 variants, with 11.3% of families who initially were found to harbor a VUS and 4.7% of families with a negative result eventually found to harbor a pathogenic or likely pathogenic variant. To further such progress, the data described here are being shared through ClinVar, GeneMatcher, and dbGaP. CONCLUSIONS: Our data strongly support the value of large-scale sequencing, especially WGS within proband-parent trios, as both an effective first-choice diagnostic tool and means to advance clinical and research progress related to pediatric neurological disease.


Assuntos
Variações do Número de Cópias de DNA , Deficiências do Desenvolvimento/genética , Genômica/métodos , Deficiência Intelectual/genética , Mutação , Análise de Sequência de DNA/métodos , Adolescente , Adulto , Criança , Pré-Escolar , Deficiências do Desenvolvimento/diagnóstico , Exoma , Feminino , Humanos , Lactente , Deficiência Intelectual/diagnóstico , Masculino , Adulto Jovem
13.
Genet Med ; 19(5): 575-582, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-27811861

RESUMO

PURPOSE: While the diagnostic success of genomic sequencing expands, the complexity of this testing should not be overlooked. Numerous laboratory processes are required to support the identification, interpretation, and reporting of clinically significant variants. This study aimed to examine the workflow and reporting procedures among US laboratories to highlight shared practices and identify areas in need of standardization. METHODS: Surveys and follow-up interviews were conducted with laboratories offering exome and/or genome sequencing to support a research program or for routine clinical services. The 73-item survey elicited multiple choice and free-text responses that were later clarified with phone interviews. RESULTS: Twenty-one laboratories participated. Practices highly concordant across all groups included consent documentation, multiperson case review, and enabling patient opt-out of incidental or secondary findings analysis. Noted divergence included use of phenotypic data to inform case analysis and interpretation and reporting of case-specific quality metrics and methods. Few laboratory policies detailed procedures for data reanalysis, data sharing, or patient access to data. CONCLUSION: This study provides an overview of practices and policies of experienced exome and genome sequencing laboratories. The results enable broader consideration of which practices are becoming standard approaches, where divergence remains, and areas of development in best practice guidelines that may be helpful.Genet Med advance online publication 03 Novemeber 2016.


Assuntos
Testes Genéticos/métodos , Laboratórios/normas , Análise de Sequência de DNA/métodos , Revelação , Testes Genéticos/normas , Humanos , Achados Incidentais , Disseminação de Informação , Laboratórios/ética , Guias de Prática Clínica como Assunto , Relatório de Pesquisa , Tamanho da Amostra , Análise de Sequência de DNA/normas , Inquéritos e Questionários
14.
Genet Med ; 19(3): 337-344, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27561086

RESUMO

PURPOSE: Eliciting and understanding patient and research participant preferences regarding return of secondary test results are key aspects of genomic medicine. A valid instrument should be easily understood without extensive pretest counseling while still faithfully eliciting patients' preferences. METHODS: We conducted focus groups with 110 adults to understand patient perspectives on secondary genomic findings and the role that preferences should play. We then developed and refined a draft instrument and used it to elicit preferences from parents participating in a genomic sequencing study in children with intellectual disabilities. RESULTS: Patients preferred filtering of secondary genomic results to avoid information overload and to avoid learning what the future holds, among other reasons. Patients preferred to make autonomous choices about which categories of results to receive and to have their choices applied automatically before results are returned to them and their clinicians. The Preferences Instrument for Genomic Secondary Results (PIGSR) is designed to be completed by patients or research participants without assistance and to guide bioinformatic analysis of genomic raw data. Most participants wanted to receive all secondary results, but a significant minority indicated other preferences. CONCLUSIONS: Our novel instrument-PIGSR-should be useful in a wide variety of clinical and research settings.Genet Med 19 3, 337-344.


Assuntos
Testes Genéticos/métodos , Adulto , Idoso , Comportamento de Escolha , Compreensão , Feminino , Grupos Focais , Testes Genéticos/ética , Testes Genéticos/instrumentação , Genoma/ética , Genoma/genética , Genômica/ética , Genômica/métodos , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Achados Incidentais , Deficiência Intelectual/genética , Masculino , Pessoa de Meia-Idade , Pais/psicologia , Preferência do Paciente/psicologia , Análise de Sequência de DNA , Inquéritos e Questionários
15.
Am J Hum Genet ; 100(1): 117-127, 2017 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-28017373

RESUMO

From a GeneMatcher-enabled international collaboration, we identified ten individuals affected by intellectual disability, speech delay, ataxia, and facial dysmorphism and carrying a deleterious EBF3 variant detected by whole-exome sequencing. One 9-bp duplication and one splice-site, five missense, and two nonsense variants in EBF3 were found; the mutations occurred de novo in eight individuals, and the missense variant c.625C>T (p.Arg209Trp) was inherited by two affected siblings from their healthy mother, who is mosaic. EBF3 belongs to the early B cell factor family (also known as Olf, COE, or O/E) and is a transcription factor involved in neuronal differentiation and maturation. Structural assessment predicted that the five amino acid substitutions have damaging effects on DNA binding of EBF3. Transient expression of EBF3 mutant proteins in HEK293T cells revealed mislocalization of all but one mutant in the cytoplasm, as well as nuclear localization. By transactivation assays, all EBF3 mutants showed significantly reduced or no ability to activate transcription of the reporter gene CDKN1A, and in situ subcellular fractionation experiments demonstrated that EBF3 mutant proteins were less tightly associated with chromatin. Finally, in RNA-seq and ChIP-seq experiments, EBF3 acted as a transcriptional regulator, and mutant EBF3 had reduced genome-wide DNA binding and gene-regulatory activity. Our findings demonstrate that variants disrupting EBF3-mediated transcriptional regulation cause intellectual disability and developmental delay and are present in ∼0.1% of individuals with unexplained neurodevelopmental disorders.


Assuntos
Ataxia/genética , Face/anormalidades , Deficiência Intelectual/genética , Transtornos do Desenvolvimento da Linguagem/genética , Mutação , Transtornos do Neurodesenvolvimento/genética , Fatores de Transcrição/genética , Transcrição Genética/genética , Adolescente , Adulto , Substituição de Aminoácidos , Criança , Pré-Escolar , Cromatina/genética , Cromatina/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/genética , Deficiências do Desenvolvimento/genética , Exoma/genética , Feminino , Regulação da Expressão Gênica/genética , Genes Reporter , Células HEK293 , Humanos , Masculino , Modelos Moleculares , Mosaicismo , Transporte Proteico/genética , Síndrome , Fatores de Transcrição/química , Fatores de Transcrição/metabolismo
16.
Neurol Genet ; 2(6): e118, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27830187

RESUMO

OBJECTIVE: To assess the prevalence of somatic MTOR mutations in focal cortical dysplasia (FCD) and of germline MTOR mutations in a broad range of epilepsies. METHODS: We collected 20 blood-brain paired samples from patients with FCD and searched for somatic variants using deep-targeted gene panel sequencing. Germline mutations in MTOR were assessed in a French research cohort of 93 probands with focal epilepsies and in a diagnostic Danish cohort of 245 patients with a broad range of epilepsies. Data sharing among collaborators allowed us to ascertain additional germline variants in MTOR. RESULTS: We detected recurrent somatic variants (p.Ser2215Phe, p.Ser2215Tyr, and p.Leu1460Pro) in the MTOR gene in 37% of participants with FCD II and showed histologic evidence for activation of the mTORC1 signaling cascade in brain tissue. We further identified 5 novel de novo germline missense MTOR variants in 6 individuals with a variable phenotype from focal, and less frequently generalized, epilepsies without brain malformations, to macrocephaly, with or without moderate intellectual disability. In addition, an inherited variant was found in a mother-daughter pair with nonlesional autosomal dominant nocturnal frontal lobe epilepsy. CONCLUSIONS: Our data illustrate the increasingly important role of somatic mutations of the MTOR gene in FCD and germline mutations in the pathogenesis of focal epilepsy syndromes with and without brain malformation or macrocephaly.

19.
Am J Hum Genet ; 98(6): 1067-1076, 2016 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-27181684

RESUMO

Evaluating the pathogenicity of a variant is challenging given the plethora of types of genetic evidence that laboratories consider. Deciding how to weigh each type of evidence is difficult, and standards have been needed. In 2015, the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) published guidelines for the assessment of variants in genes associated with Mendelian diseases. Nine molecular diagnostic laboratories involved in the Clinical Sequencing Exploratory Research (CSER) consortium piloted these guidelines on 99 variants spanning all categories (pathogenic, likely pathogenic, uncertain significance, likely benign, and benign). Nine variants were distributed to all laboratories, and the remaining 90 were evaluated by three laboratories. The laboratories classified each variant by using both the laboratory's own method and the ACMG-AMP criteria. The agreement between the two methods used within laboratories was high (K-alpha = 0.91) with 79% concordance. However, there was only 34% concordance for either classification system across laboratories. After consensus discussions and detailed review of the ACMG-AMP criteria, concordance increased to 71%. Causes of initial discordance in ACMG-AMP classifications were identified, and recommendations on clarification and increased specification of the ACMG-AMP criteria were made. In summary, although an initial pilot of the ACMG-AMP guidelines did not lead to increased concordance in variant interpretation, comparing variant interpretations to identify differences and having a common framework to facilitate resolution of those differences were beneficial for improving agreement, allowing iterative movement toward increased reporting consistency for variants in genes associated with monogenic disease.


Assuntos
Pesquisa Biomédica , Testes Genéticos/normas , Variação Genética/genética , Genômica/métodos , Laboratórios/normas , Mutação/genética , Análise de Sequência de DNA/normas , Interpretação Estatística de Dados , Prática Clínica Baseada em Evidências , Exoma/genética , Genoma Humano , Guias como Assunto , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Achados Incidentais , Software , Estados Unidos
20.
Am J Hum Genet ; 98(6): 1051-1066, 2016 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-27181682

RESUMO

Despite rapid technical progress and demonstrable effectiveness for some types of diagnosis and therapy, much remains to be learned about clinical genome and exome sequencing (CGES) and its role within the practice of medicine. The Clinical Sequencing Exploratory Research (CSER) consortium includes 18 extramural research projects, one National Human Genome Research Institute (NHGRI) intramural project, and a coordinating center funded by the NHGRI and National Cancer Institute. The consortium is exploring analytic and clinical validity and utility, as well as the ethical, legal, and social implications of sequencing via multidisciplinary approaches; it has thus far recruited 5,577 participants across a spectrum of symptomatic and healthy children and adults by utilizing both germline and cancer sequencing. The CSER consortium is analyzing data and creating publically available procedures and tools related to participant preferences and consent, variant classification, disclosure and management of primary and secondary findings, health outcomes, and integration with electronic health records. Future research directions will refine measures of clinical utility of CGES in both germline and somatic testing, evaluate the use of CGES for screening in healthy individuals, explore the penetrance of pathogenic variants through extensive phenotyping, reduce discordances in public databases of genes and variants, examine social and ethnic disparities in the provision of genomics services, explore regulatory issues, and estimate the value and downstream costs of sequencing. The CSER consortium has established a shared community of research sites by using diverse approaches to pursue the evidence-based development of best practices in genomic medicine.


Assuntos
Pesquisa Biomédica , Prática Clínica Baseada em Evidências , Exoma/genética , Genoma Humano , Genômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Polimorfismo de Nucleotídeo Único/genética , Adulto , Doenças Cardiovasculares/genética , Criança , Ensaios Clínicos como Assunto , Humanos , National Human Genome Research Institute (U.S.) , Grupos Populacionais , Software , Estados Unidos
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