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1.
Arch Pathol Lab Med ; 144(10): 1193-1198, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33002154

RESUMO

CONTEXT.­: Convenience, avoidance of doctor's appointments, curiosity, and the desire to take control of one's health are driving interest toward direct-to-consumer (DTC) testing. DTC is laboratory testing that is initiated by the consumer without a physician order. The results are reported back directly to the consumer. DTC testing is an exciting addition to the traditional healthcare model for consumers who want knowledge of their health status and disease risk, ancestry, and their body's expected response to certain medications based on their genotype. OBJECTIVES.­: To discuss the perceived and potential benefits and risks involved in DTC testing. DATA SOURCES.­: Recent published literature on DTC testing. CONCLUSIONS.­: The benefits of DTC testing are enticing and are driving the DTC testing market. Consumers must weigh the perceived benefits with the potential risks, including privacy concerns, the possibility of receiving confusing health information, and/or information that could generate unexpected emotions, misdiagnosis, and over-testing.


Assuntos
Triagem e Testes Direto ao Consumidor , Confidencialidade , Testes Genéticos , Humanos , Medição de Risco
2.
Stud Health Technol Inform ; 273: 129-135, 2020 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-33087602

RESUMO

In this paper, we describe a strategy for the development of a genetic analysis comprehensive representation. The primary intention is to ensure the available utilization of genetic analysis results in clinical practice. The system is called Personnel Genetic Card (PGC), and it is developed in cooperation of CIIRC CTU in Prague and the Mediware company. Nowadays, genetic information is more and more part of medicine and life quality services (e.g. nutritional consulting). Therefore, there is necessary to bind genetic information with the clinical phenotype, such as drug metabolism or intolerance to various substances. We proposed a structured form of the record, where we utilize the LOINC® standard to identify genetic test parameters, and several terminology databases for representing specific genetic information (e.g. HGNC, NCBI RefSeq, NCBI dbNSP, HGVS). Further, there are also several knowledge databases (PharmGKB, SNPedia, ClinVar) that collect interpretation for genetic analysis results. In the results of this paper, we describe our idea in the structure and process perspective. The structural perspective includes the representation of the analysis record and its binding with the interpretations. The process perspective describes roles and activities within the PGC system use.


Assuntos
Testes Genéticos , Informações Pessoalmente Identificáveis , Bases de Dados Genéticas , Logical Observation Identifiers Names and Codes , Fenótipo
3.
Medicine (Baltimore) ; 99(40): e21965, 2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-33019389

RESUMO

BACKGROUND: The epidermal growth factor receptor (EGFR) mutation status related to the treatment approach for advanced non-small cell lung cancer (NSCLC) patients. This study aimed to evaluate the diagnostic accuracy of peripheral blood circulating tumor DNA (ctDNA) in EGFR mutated advanced NSCLC patients. METHOD: The related database was systematically searched with keywords until January 19, 2020. Studies contained the histopathological and cytological advanced NSCLC samples were included, and the diagnostic data were recorded for calculating sensitivity and specificity. I statistics were used for detecting heterogeneity across studies, and the meta-regression was performed to seek the source of heterogeneity. RESULT: A total of 32 studies with 4527 advanced NSCLC patients were included in our meta-analysis. Among them, 87% of the patients were diagnosed as stage IV. The pooled sensitivity of peripheral blood ctDNA was 0.70 (95% CI: 0.63-0.75, I = 81.76) and the pooled specificity was 0.98 (95% CI: 0.96-0.99, I = 88.33). The meta-regression showed that the prospective study design and the ARMS detection method were the main source of heterogeneity for sensitivity (P < .05), and the publication country (Asia or non-Asia) was the main source of heterogeneity for specificity (P < .01). CONCLUSION: ctDNA biopsy has high specificity and diagnostic accuracy in detection of EGFR mutation in advanced NSCLC patients. When the ctDNA gene test result is negative, we should fully consider the risk of missed diagnosis, and further tissue biopsy is still needed to undertake.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , DNA Tumoral Circulante/sangue , Neoplasias Pulmonares/genética , Biomarcadores/sangue , Carcinoma Pulmonar de Células não Pequenas/sangue , Receptores ErbB/sangue , Feminino , Testes Genéticos , Humanos , Neoplasias Pulmonares/sangue , Masculino , Pessoa de Meia-Idade , Mutação , Estudos Prospectivos , Sensibilidade e Especificidade
4.
Medicine (Baltimore) ; 99(41): e22497, 2020 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-33031286

RESUMO

RATIONALE: Paragangliomas (PGLs) are rare neuroendocrine tumors that are strongly influenced by genetics, and succinate dehydrogenase-deficient PGLs appear to constitute one of the most important categories. Interestingly, somatic PGLs only possess genomic alterations involving the SDHB and SDHD subunits, and no SDHA alterations have been described. Here, we are presenting the clinical and genetic analyses of 2 cases with the first somatic SDHA variant identified in PGLs. PATIENT CONCERNS: Here, we reported 2 family members with the diagnosis of PGL. Patient 1 is a 55-year-old woman with a functionally perigastric PGL that co-occurred with a gastric gastrointestinal stromal tumor (GIST), and patient 2 is a 43-year-old woman with a nonfunctionally pericardial PGL, who was the younger sister of the first patient. DIAGNOSES: Imaging surveys of the 2 cases depicted the presence of a perigastric and a pericardial mass, respectively. A diagnosis of paragangliomas was established by immunohistochemistry (IHC). INTERVENTIONS: Both patients underwent single-stage resection of the lesion after preoperative oral α-adrenoceptor therapy for 2 weeks. We later performed comprehensive genomic profiling on the tumor samples, including PGL and GIST from patient 1 and PGL from patient 2, and searched for novel actionable mutations, including in all succinate dehydrogenase subunits, as the IHC results were negative for SDHB. OUTCOMES: Both patients had an uneventful recovery after surgery and the sequencing showed a novel somatic variant in the SDHA gene on chromosome 5q11 (c.1945_1946delTT). Regular follow-up with biochemical testing and image studies showed no evidence of recurrence after a year for patient 1 and 6 years for patient 2. LESSONS: PGLs often lead to considerable diagnostic difficulty due to their multiple anatomical locations and variable symptoms, as presented by our cases. The comprehensive use of images and plasma/urine catecholamine measurement can aid the diagnosis of PGLs. In addition, our findings also demonstrate the usefulness and importance of genetic analysis of SDHA mutations in patients exhibiting SDHB IHC-negative PGL. Additional studies utilizing comprehensive genomic profiling are needed to identify the group of PGLs harboring this SDHA genomic alteration.


Assuntos
Complexo II de Transporte de Elétrons/genética , Tumores do Estroma Gastrointestinal/genética , Neoplasias Primárias Múltiplas/genética , Paraganglioma Extrassuprarrenal/genética , Neoplasias Gástricas/genética , Adulto , Feminino , Tumores do Estroma Gastrointestinal/diagnóstico , Tumores do Estroma Gastrointestinal/patologia , Testes Genéticos , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Mutação , Paraganglioma Extrassuprarrenal/diagnóstico , Paraganglioma Extrassuprarrenal/patologia , Irmãos , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/patologia
5.
Nat Commun ; 11(1): 4813, 2020 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-32968076

RESUMO

Artemisinins have revolutionized the treatment of Plasmodium falciparum malaria; however, resistance threatens to undermine global control efforts. To broadly explore artemisinin susceptibility in apicomplexan parasites, we employ genome-scale CRISPR screens recently developed for Toxoplasma gondii to discover sensitizing and desensitizing mutations. Using a sublethal concentration of dihydroartemisinin (DHA), we uncover the putative transporter Tmem14c whose disruption increases DHA susceptibility. Screens performed under high doses of DHA provide evidence that mitochondrial metabolism can modulate resistance. We show that disrupting a top candidate from the screens, the mitochondrial protease DegP2, lowers porphyrin levels and decreases DHA susceptibility, without significantly altering parasite fitness in culture. Deleting the homologous gene in P. falciparum, PfDegP, similarly lowers heme levels and DHA susceptibility. These results expose the vulnerability of heme metabolism to genetic perturbations that can lead to increased survival in the presence of DHA.


Assuntos
Antimaláricos/farmacologia , Artemisininas/farmacologia , Resistência a Medicamentos/genética , Testes Genéticos/métodos , Heme/genética , Heme/metabolismo , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Técnicas de Inativação de Genes , Humanos , Malária Falciparum/tratamento farmacológico , Proteínas de Membrana Transportadoras/metabolismo , Mutação , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/genética , Proteínas de Protozoários/genética , Toxoplasma/efeitos dos fármacos , Toxoplasma/genética
6.
Ther Umsch ; 77(7): 297-301, 2020 Sep.
Artigo em Alemão | MEDLINE | ID: mdl-32996427

RESUMO

Laboratory investigations in clinical diabetic practice Abstract. Laboratory analysis are useful to diagnose the proper form of diabetes mellitus, for follow-up of the metabolic control, and to identify secondary complications or associated diseases. The proof of auto-antibodies confirms Type 1 diabetes and a broad range of endocrine entities of the polyglandular autoimmune syndrome, and genetic testing classifies monogenetic diabetes like MODY or MIDDM. In secondary diabetes forms underlying disease can be detected by clinical and laboratory investigation, and thus, causal treatment of the diabetes may be possible.


Assuntos
Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/terapia , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/terapia , Testes Genéticos , Humanos
7.
Pediatrics ; 146(4)2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32938777

RESUMO

BACKGROUND AND OBJECTIVES: Genetic testing is recommended for individuals with autism spectrum disorder (ASD). Pathogenic yield varies by clinician and/or patient characteristics. Our objectives were to determine the pathogenic yield of genetic testing, the variability in rate of pathogenic results based on subject characteristics, and the percentage of pathogenic findings resulting in further medical recommendations in toddlers with a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition diagnosis of ASD. METHODS: We conducted a retrospective chart review of 500 toddlers, 18 to 36 months, diagnosed with Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition ASD (mean age: 25.8 months, 79% male). Subject demographics, medical and neuropsychological characteristics, and genetic test results were abstracted. Genetic results were divided into negative or normal, variants of unknown significance, and pathogenic. Subject characteristics were compared across results. Manual chart review determined if further recommendations were made after pathogenic results. RESULTS: Over half of subjects (59.8%, n = 299) completed genetic testing, and of those, 36 (12.0%) had pathogenic findings. There were no significant differences in Bayley Scales of Infant Development cognitive (P = .112), language (P = .898), or motor scores (P = .488) among children with negative or normal findings versus a variant of unknown significance versus pathogenic findings. Medical recommendations in response to the genetic finding were made for 72.2% of those with pathogenic results. CONCLUSIONS: Our findings reinforce the importance of genetic testing for toddlers diagnosed with ASD given the 12% yield and lack of phenotypic differences between subjects with and without pathogenic findings. The majority of pathogenic results lead to further medical recommendations.


Assuntos
Transtorno do Espectro Autista/genética , Testes Genéticos/estatística & dados numéricos , Transtorno do Espectro Autista/diagnóstico , Transtornos Dismórficos Corporais/diagnóstico , Transtornos Dismórficos Corporais/genética , Pré-Escolar , Cromossomos Humanos 13-15 , Cognição , Manual Diagnóstico e Estatístico de Transtornos Mentais , Feminino , Proteína do X Frágil de Retardo Mental/genética , Deleção de Genes , Duplicação Gênica , Testes Genéticos/métodos , Humanos , Lactente , Desenvolvimento da Linguagem , Masculino , Análise em Microsséries , Mosaicismo , Destreza Motora , Mutação , Fenótipo , Encaminhamento e Consulta , Estudos Retrospectivos
8.
PLoS One ; 15(8): e0238295, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32866190

RESUMO

African American breast cancer genetics is less understood compared to European American breast cancer susceptibility. Despite the many advantages of gene panel screening, studies investigating African American inherited breast cancer risk and comparing variant contributions between ethnicities are infrequent. Thus, 97 breast cancer-affected individuals of African and European descent from the Alabama Hereditary Cancer Cohort were screened using the research-based gene-panel, B.O.P. (Breast, Ovarian, and Prostate cancer). Upon sequencing and bioinformatic processing, rare coding variants in 14 cancer susceptibility genes were categorized according to the American College of Medical Genetics guidelines and compared between ethnicities. Overall, 107 different variants were identified, the majority of which were benign/likely benign. A pathogenic/likely pathogenic variant was detected in 8.6% and 6.5% of African American and European American cases, respectively, which was not statistically significant. However, African Americans were more likely to have at least one variant of uncertain significance (VUS; p-value 0.006); they also had significantly more VUSs in BRCA1/2 compared to European Americans (p-value 0.015). Additionally, 51.4% of African Americans and 32.3% of European Americans harbored multiple rare variants, and African Americans were more likely to have at least one VUS and one benign/likely benign variant (p-value 0.032), as well as multiple benign/likely benign variants (p-value 0.089). Moreover, of the 15 variants detected in multiple breast cancer cases, ATM c.2289T>C (p.F763L), a VUS, along with two likely benign variants, BRCA2 c.2926_2927delinsAT (p.S976I) and RAD51D c.251T>A (p.L84H), were determined to be associated with African American breast cancer risk when compared to ethnic-specific controls. Ultimately, B.O.P. screening provides essential insight towards the variant contributions in clinically relevant cancer susceptibility genes and differences between ethnicities, stressing the need for future research to elucidate inherited breast cancer risk.


Assuntos
Neoplasias da Mama/genética , Predisposição Genética para Doença/genética , Variação Genética/genética , Grupos Populacionais/genética , Detecção Precoce de Câncer/métodos , Feminino , Testes Genéticos/métodos , Humanos
9.
PLoS Med ; 17(9): e1003263, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32941469

RESUMO

BACKGROUND: Lynch syndrome (LS) predisposes to endometrial cancer (EC), colorectal cancer, and other cancers through inherited pathogenic variants affecting mismatch-repair (MMR) genes. Diagnosing LS in women with EC can reduce subsequent cancer mortality through colonoscopic surveillance and aspirin chemoprevention; it also enables cascade testing of relatives. A growing consensus supports LS screening in EC; however, the expected proportion of test positives, and optimal testing strategy is uncertain. Previous studies from insurance-based healthcare systems were limited by narrow selection criteria, failure to apply reference standard tests consistently, and poor conversion to definitive testing. The aim of this study was to establish the prevalence of LS and the diagnostic accuracy of LS testing strategies in an unselected EC population. METHODS AND FINDINGS: This was a prospective cross-sectional study carried out at a large United Kingdom gynaecological cancer centre between October 2015 and January 2017. Women diagnosed with EC or atypical hyperplasia (AH) were offered LS testing. Tumours underwent MMR immunohistochemistry (IHC), microsatellite instability (MSI), and targeted MLH1-methylation testing. Women <50 years, with strong family histories and/or indicative tumour molecular features, underwent MMR germline sequencing. Somatic MMR sequencing was performed when indicative molecular features were unexplained by LS or MLH1-hypermethylation. The main outcome measures were the prevalence of LS in an unselected EC population and the diagnostic accuracy of clinical and tumour testing strategies for risk stratifying women with EC for MMR germline sequencing. In total, 500 women participated in the study; only 2 (<1%) declined. Germline sequencing was indicated and conducted for 136 and 135 women, respectively. A total of 16/500 women (3.2%, 95% CI 1.8% to 5.1%) had LS, and 11 more (2.2%) had MMR variants of uncertain significance. Restricting testing to age <50 years, indicative family history (revised Bethesda guidelines or Amsterdam II criteria) or endometrioid histology alone would have missed 9/16 (56%), 8/13 (62%) or 9/13 (69%), and 5/16 (31%) cases of LS, respectively. In total 132/500 tumours were MMR deficient by IHC of which 83/132 (63%) had MLH1-hypermethylation, and 16/49 (33%) of the remaining patients had LS (16/132 with MMR deficiency, 12%). MMR-IHC with targeted MLH1-methylation testing was more discriminatory for LS than MSI with targeted methylation testing, with 100% versus 56.3% (16/16 versus 9/16) sensitivity (p = 0.016) and equal 97.5% (468/484) specificity; 64% MSI-H and 73% MMR deficient tumours unexplained by LS or MLH1-hypermethylation had somatic MMR mutations. The main limitation of the study was failure to conduct MMR germline sequencing for the whole study population, which means that the sensitivity and specificity of tumour triage strategies for LS detection may be overestimated, although the risk of LS in women with no clinical or tumour predictors is expected to be extremely low. CONCLUSIONS: In this study, we observed that age, family history, and histology are imprecise clinical correlates of LS-EC. IHC outperformed MSI for tumour triage and reliably identified both germline and somatic MMR mutations. The 3.2% proportion of LS-EC is similar to colorectal cancer, supporting unselected screening of EC for LS.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Detecção Precoce de Câncer/métodos , Neoplasias do Endométrio/genética , Adulto , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Estudos Transversais , Metilação de DNA/genética , Reparo de Erro de Pareamento de DNA/genética , Neoplasias do Endométrio/diagnóstico , Feminino , Testes Genéticos/métodos , Humanos , Imuno-Histoquímica , Programas de Rastreamento/métodos , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Estudos Prospectivos , Sensibilidade e Especificidade , Reino Unido
10.
Cochrane Database Syst Rev ; 9: CD005291, 2020 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-32898291

RESUMO

BACKGROUND: In in vitro fertilisation (IVF) with or without intracytoplasmic sperm injection (ICSI), selection of the most competent embryo(s) for transfer is based on morphological criteria. However, many women do not achieve a pregnancy even after 'good quality' embryo transfer. One of the presumed causes is that such morphologically normal embryos have an abnormal number of chromosomes (aneuploidies). Preimplantation genetic testing for aneuploidies (PGT-A), formerly known as preimplantation genetic screening (PGS), was therefore developed as an alternative method to select embryos for transfer in IVF. In PGT-A, the polar body or one or a few cells of the embryo are obtained by biopsy and tested. Only polar bodies and embryos that show a normal number of chromosomes are transferred. The first generation of PGT-A, using cleavage-stage biopsy and fluorescence in situ hybridisation (FISH) for the genetic analysis, was demonstrated to be ineffective in improving live birth rates. Since then, new PGT-A methodologies have been developed that perform the biopsy procedure at other stages of development and use different methods for genetic analysis. Whether or not PGT-A improves IVF outcomes and is beneficial to patients has remained controversial. OBJECTIVES: To evaluate the effectiveness and safety of PGT-A in women undergoing an IVF treatment. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility (CGF) Group Trials Register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, and two trials registers in September 2019 and checked the references of appropriate papers. SELECTION CRITERIA: All randomised controlled trials (RCTs) reporting data on clinical outcomes in participants undergoing IVF with PGT-A versus IVF without PGT-A were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies for inclusion, assessed risk of bias, and extracted study data. The primary outcome was the cumulative live birth rate (cLBR). Secondary outcomes were live birth rate (LBR) after the first embryo transfer, miscarriage rate, ongoing pregnancy rate, clinical pregnancy rate, multiple pregnancy rate, proportion of women reaching an embryo transfer, and mean number of embryos per transfer. MAIN RESULTS: We included 13 trials involving 2794 women. The quality of the evidence ranged from low to moderate. The main limitations were imprecision, inconsistency, and risk of publication bias. IVF with PGT-A versus IVF without PGT-A with the use of genome-wide analyses Polar body biopsy One trial used polar body biopsy with array comparative genomic hybridisation (aCGH). It is uncertain whether the addition of PGT-A by polar body biopsy increases the cLBR compared to IVF without PGT-A (odds ratio (OR) 1.05, 95% confidence interval (CI) 0.66 to 1.66, 1 RCT, N = 396, low-quality evidence). The evidence suggests that for the observed cLBR of 24% in the control group, the chance of live birth following the results of one IVF cycle with PGT-A is between 17% and 34%. It is uncertain whether the LBR after the first embryo transfer improves with PGT-A by polar body biopsy (OR 1.10, 95% CI 0.68 to 1.79, 1 RCT, N = 396, low-quality evidence). PGT-A with polar body biopsy may reduce miscarriage rate (OR 0.45, 95% CI 0.23 to 0.88, 1 RCT, N = 396, low-quality evidence). No data on ongoing pregnancy rate were available. The effect of PGT-A by polar body biopsy on improving clinical pregnancy rate is uncertain (OR 0.77, 95% CI 0.50 to 1.16, 1 RCT, N = 396, low-quality evidence). Blastocyst stage biopsy One trial used blastocyst stage biopsy with next-generation sequencing. It is uncertain whether IVF with the addition of PGT-A by blastocyst stage biopsy increases cLBR compared to IVF without PGT-A, since no data were available. It is uncertain if LBR after the first embryo transfer improves with PGT-A with blastocyst stage biopsy (OR 0.93, 95% CI 0.69 to 1.27, 1 RCT, N = 661, low-quality evidence). It is uncertain whether PGT-A with blastocyst stage biopsy reduces miscarriage rate (OR 0.89, 95% CI 0.52 to 1.54, 1 RCT, N = 661, low-quality evidence). No data on ongoing pregnancy rate or clinical pregnancy rate were available. IVF with PGT-A versus IVF without PGT-A with the use of FISH for the genetic analysis Eleven trials were included in this comparison. It is uncertain whether IVF with addition of PGT-A increases cLBR (OR 0.59, 95% CI 0.35 to 1.01, 1 RCT, N = 408, low-quality evidence). The evidence suggests that for the observed average cLBR of 29% in the control group, the chance of live birth following the results of one IVF cycle with PGT-A is between 12% and 29%. PGT-A performed with FISH probably reduces live births after the first transfer compared to the control group (OR 0.62, 95% CI 0.43 to 0.91, 10 RCTs, N = 1680, I² = 54%, moderate-quality evidence). The evidence suggests that for the observed average LBR per first transfer of 31% in the control group, the chance of live birth after the first embryo transfer with PGT-A is between 16% and 29%. There is probably little or no difference in miscarriage rate between PGT-A and the control group (OR 1.03, 95%, CI 0.75 to 1.41; 10 RCTs, N = 1680, I² = 16%; moderate-quality evidence). The addition of PGT-A may reduce ongoing pregnancy rate (OR 0.68, 95% CI 0.51 to 0.90, 5 RCTs, N = 1121, I² = 60%, low-quality evidence) and probably reduces clinical pregnancies (OR 0.60, 95% CI 0.45 to 0.81, 5 RCTs, N = 1131; I² = 0%, moderate-quality evidence). AUTHORS' CONCLUSIONS: There is insufficient good-quality evidence of a difference in cumulative live birth rate, live birth rate after the first embryo transfer, or miscarriage rate between IVF with and IVF without PGT-A as currently performed. No data were available on ongoing pregnancy rates. The effect of PGT-A on clinical pregnancy rate is uncertain. Women need to be aware that it is uncertain whether PGT-A with the use of genome-wide analyses is an effective addition to IVF, especially in view of the invasiveness and costs involved in PGT-A. PGT-A using FISH for the genetic analysis is probably harmful. The currently available evidence is insufficient to support PGT-A in routine clinical practice.


Assuntos
Aneuploidia , Fertilização In Vitro , Testes Genéticos/métodos , Diagnóstico Pré-Implantação/métodos , Injeções de Esperma Intracitoplásmicas , Aborto Espontâneo/epidemiologia , Viés , Biópsia , Coeficiente de Natalidade , Blastocisto/patologia , Feminino , Humanos , Nascimento Vivo , Idade Materna , Corpos Polares/patologia , Gravidez , Ensaios Clínicos Controlados Aleatórios como Assunto
11.
Clin Dermatol ; 38(4): 399-407, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32972599

RESUMO

Genodermatoses are heritable skin diseases that can cause significant morbidity and mortality. Most of them show characteristic cutaneous findings. Genodermatoses can be associated with extracutaneous system abnormalities. Diagnosing hereditary skin disorders is still a challenging task due to their rarity and diversity, due to diseases evolving over many years, and the initial manifestations not always being diagnostic; therefore, ongoing evaluation and surveillance is often required to make the accurate diagnosis. The algorithm for the diagnosis depends on a combination of thorough clinical and family history clinical examination, laboratory findings, consultation of multiple medical specialists, and molecular analysis. Diagnostic testing targeted at differentiation of similar genodermatoses may be required. Recognition is crucial for the initiation of the treatment for skin manifestations and detection of other extracutaneous abnormalities, including malignancy. Diagnostic accuracy and molecular diagnosis may help in providing a template for ongoing management, testing, and education and prognostication for families of children with genodermatoses.


Assuntos
Técnicas e Procedimentos Diagnósticos , Doenças Raras , Dermatopatias Genéticas/diagnóstico , Dermatopatias Genéticas/patologia , Pele/patologia , Algoritmos , Diagnóstico Precoce , Feminino , Testes Genéticos , Humanos , Masculino , Síndrome
12.
Clin Dermatol ; 38(4): 408-420, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32972600

RESUMO

Genodermatoses are inherited disorders presenting with cutaneous manifestations with or without the involvement of other systems. The majority of these disorders, particularly in cases that present with a cutaneous patterning, may be explained in the context of genetic mosaicism. Despite the barriers to the genetic analysis of mosaic disorders, next-generation sequencing has led to a substantial progress in understanding their pathogenesis, which has significant implications for the clinical management and genetic counseling. Advances in paired and deep sequencing technologies in particular have made the study of mosaic disorders more feasible. In this review, we provide an overview of genetic mosaicism as well as mosaic cutaneous disorders and the techniques required to study them.


Assuntos
Mosaicismo , Dermatopatias Genéticas/diagnóstico , Dermatopatias Genéticas/genética , Feminino , Aconselhamento Genético , Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Fenótipo , Dermatopatias Genéticas/etiologia , Dermatopatias Genéticas/patologia
13.
Clin Dermatol ; 38(4): 432-454, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32972602

RESUMO

The hereditary nature of some forms of cancer was recognized long ago. Over time, recognition of associated findings led to the delineation of numerous hereditary cancer syndromes. Many of these syndromes also have cutaneous manifestations, the recognition of which can lead to their early identification. Recognition of these syndromes allows vigilant surveillance and preemptive treatment, which can dramatically impact the risks of morbidity and mortality for affected patients. The rise of rapid and accurate genetic testing now allows the early identification of asymptomatic at risk family members so that monitoring can be initiated as early as possible. The dermatologist plays a critical role in early identification of these syndromes and, in many cases, their treatment. This review summarizes many known hereditary cancer syndromes with cutaneous findings, their etiology, identification, evaluation, and management. Importantly, this is an ever evolving topic and new findings and syndromes will continue to be recognized. The dermatologist must be always alert to ensure they are detected.


Assuntos
Síndromes Neoplásicas Hereditárias , Dermatopatias Genéticas , Síndrome do Nevo Basocelular , Síndrome de Birt-Hogg-Dubé , Complexo de Carney , Neoplasias Colorretais Hereditárias sem Polipose , Diagnóstico Precoce , Feminino , Síndrome de Gardner , Testes Genéticos , Síndrome do Hamartoma Múltiplo , Humanos , Masculino , Neoplasia Endócrina Múltipla , Síndromes Neoplásicas Hereditárias/diagnóstico , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/patologia , Síndromes Neoplásicas Hereditárias/terapia , Neurofibromatoses , Pele/patologia , Dermatopatias Genéticas/diagnóstico , Dermatopatias Genéticas/genética , Dermatopatias Genéticas/patologia , Dermatopatias Genéticas/terapia
14.
Clin Dermatol ; 38(4): 467-476, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32972605

RESUMO

Basal cell nevus syndrome, also known as Gorlin syndrome, is a hereditary cancer syndrome associated with multiple basal cell carcinomas, congenital defects, and nondermatologic tumors. This disease is autosomal dominant with variable expressivity and is caused by abnormalities in the sonic hedgehog signaling pathway. Management requires a multidisciplinary approach and should include the biopsychosocial needs of patients and their families. Genetic testing is necessary to confirm an unclear diagnosis, evaluate at-risk relatives, and assist with family planning.


Assuntos
Síndrome do Nevo Basocelular/genética , Síndrome do Nevo Basocelular/terapia , Terapia de Alvo Molecular , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/terapia , Adulto , Síndrome do Nevo Basocelular/diagnóstico , Síndrome do Nevo Basocelular/patologia , Feminino , Testes Genéticos , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Humanos , Comunicação Interdisciplinar , Síndromes Neoplásicas Hereditárias/diagnóstico , Síndromes Neoplásicas Hereditárias/patologia , Receptor Patched-1/genética , Receptor Patched-1/metabolismo , Receptor Patched-2/genética , Receptor Patched-2/metabolismo , Equipe de Assistência ao Paciente , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Transdução de Sinais/genética , Pele/patologia , Adulto Jovem
15.
PLoS One ; 15(9): e0238467, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32877464

RESUMO

Resolving the genetic architecture of painful neuropathy will lead to better disease management strategies. We aimed to develop a reliable method to re-sequence multiple genes in a large cohort of painful neuropathy patients at low cost. In this study, we compared sensitivity, specificity, targeting efficiency, performance and cost effectiveness of Molecular Inversion Probes-Next generation sequencing (MIPs-NGS) and TruSeq® Custom Amplicon-Next generation sequencing (TSCA-NGS). Capture probes were designed to target nine sodium channel genes (SCN3A, SCN8A-SCN11A, and SCN1B-SCN4B). One hundred sixty-six patients with diabetic and idiopathic neuropathy were tested by both methods, 70 patients were validated by Sanger sequencing. Sensitivity, specificity and performance of both techniques were comparable, and in agreement with Sanger sequencing. The average targeted regions coverage for MIPs-NGS was 97.3% versus 93.9% for TSCA-NGS. MIPs-NGS has a more versatile assay design and is more flexible than TSCA-NGS. The cost of MIPs-NGS is >5 times cheaper than TSCA-NGS when 500 or more samples are tested. In conclusion, MIPs-NGS is a reliable, flexible, and relatively inexpensive method to detect genetic variations in a large cohort of patients. In our centers, MIPs-NGS is currently implemented as a routine diagnostic tool for screening of sodium channel genes in painful neuropathy patients.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala/métodos , Sondas Moleculares/genética , Análise de Sequência de DNA/métodos , Inversão Cromossômica/genética , Sondas de DNA/genética , Testes Genéticos/métodos , Humanos , Mutação , Neuralgia/genética , Sensibilidade e Especificidade
16.
Adv Exp Med Biol ; 1252: 129-132, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32816272

RESUMO

Genetic testing should be offered to all women less than 40 years of age who are diagnosed with breast cancer, and patients with PABC are generally among them. However, there is no specific study about these cases, and whether genetic testing should be carried out during or after pregnancy is not known. Generally, testing before delivery should only be performed if positive results change management plans, such as undergoing fetal testing and choosing mastectomy instead of breast conserving surgery.


Assuntos
Neoplasias da Mama/genética , Testes Genéticos , Lactação , Complicações Neoplásicas na Gravidez/genética , Adulto , Neoplasias da Mama/diagnóstico , Feminino , Humanos , Mastectomia , Gravidez , Complicações Neoplásicas na Gravidez/diagnóstico , Diagnóstico Pré-Natal
17.
Cancer Treat Rev ; 89: 102084, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32738738

RESUMO

Accurate identification of patients with solid tumors likely to respond to immunotherapy is crucial. Tumor mutational burden (TMB) measures the number of somatic mutations in a tumor and is an emerging prognostic and predictive biomarker for anti-programmed cell death (PD) 1/anti-PD-ligand 1 therapy and other immunotherapeutic agents. Tumor mutational burden is assessed optimally by whole exome sequencing, but next generation sequencing provides TMB estimates in a more timely and cost-effective manner. Blood-based measurement of TMB in plasma offers an alternative to the need for adequate tumor tissue for molecular testing, and has demonstrated the ability to identify patients who derive benefit from immunotherapy. Tumor mutational burden has diverse prognostic impact in different solid tumor types and also has a demonstrated role in predicting improved survival in patients receiving immunotherapy. There are challenges to TMB adoption into standard clinical practice, including variations in its definition, with the mutational number defining TMB-high appearing to vary across cancer types. The magnitude of TMB also varies across different tumor types, with the highest levels reported in melanoma and other skin cancers (where ultraviolet light is the dominant mutational process), followed by non-small cell lung cancer and other squamous carcinomas. Concerns regarding inter-laboratory and inter-platform variations in analysis methods have been raised, highlighting the need for standardization. Integration of other genomic or pathological biomarkers with TMB may increase its prognostic and predictive capabilities and validation of individual or combination models in prospective trials is warranted.


Assuntos
Biomarcadores Tumorais/genética , Análise Mutacional de DNA/métodos , Neoplasias/genética , Neoplasias/terapia , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase III como Assunto , Testes Genéticos , Humanos , Neoplasias/imunologia , Neoplasias/patologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Ensaios Clínicos Controlados Aleatórios como Assunto
18.
Artigo em Alemão | MEDLINE | ID: mdl-32816063

RESUMO

BACKGROUND: With the Act on Genetic Testing (GenDG), the German legislator has issued far-reaching regulations for human genetic services, including genetic counseling. This paper presents data on the use of human genetic counseling in the years before and after the entry into force of GenDG in order to provide an informed assessment of the possible effects of the law. MATERIALS AND METHODS: Over a period of 13 years (2005 to 2017), the human genetic counseling services provided within the framework of the statutory health insurance and billable by EBM via the Kassenärztliche associations were recorded via a database query at the Central Institute of the National Association of Statutory Health Insurance Physicians (ZI-KBV) and via individual Kassenärztliche Vereinigungen Deutschlands. For the discussion of the observable development of using genetic counseling and possible future development, additional data on the referral behavior, the waiting times, processing time, and reasons for consultations were extracted from the GenBIn database. RESULTS AND DISCUSSION: Demand for genetic counseling has steadily increased at an average rate of approximately 6% per year since 2009. This increase started well before the enactment of the GenDG and may be attributed to a multiplicity of factors. Change in demand for genetic counseling is characterized by increasing self-referrals and by increasing referrals by specialists other than obstetricians/gynecologists. Waiting times between 2011 and 2016/2017 have increased. While demand has been growing, the number of key service providers, the contracted medical specialists in human genetics, has remained almost constant. It is foreseeable that capacity limits will be reached if both trends continue.


Assuntos
Aconselhamento Genético , Programas Nacionais de Saúde , Testes Genéticos , Alemanha , Humanos , Encaminhamento e Consulta
19.
Artigo em Chinês | MEDLINE | ID: mdl-32842192

RESUMO

To study the clinical features and causes of congenital Usher hearing loss in one child. Clinical examination, audiological tests, visual acuity examination were conducted in the proband and its family members, and second-generation sequencing technology for deafness gene detection was employed. The proband exhibited profound sensorineural deafness(hearing threshold>90 dB nHL). There was no visual loss after follow-up. Other family members had no history of hearing loss. The gene test indicated that the proband had a frameshift mutation for the thymine(T) deletion at the 1527 site of the Usher1C gene. The mutation was a homozygous mutation, and was from the father and the mother, respectively, which caused the truncation of the encoded protein. Normal function, Usher syndrome or non-syndromic deafness DFNB18 can occur. This is the first case in China demonstrating congenital deafness due to homozygous mutation of Usher1C gene c. 1527delT. This study enriches the gene spectrum of deafness in China.


Assuntos
Surdez/genética , Perda Auditiva Neurossensorial/genética , Síndromes de Usher , Criança , China , Testes Genéticos , Humanos , Mutação , Linhagem
20.
Med Sci (Paris) ; 36(8-9): 735-746, 2020.
Artigo em Francês | MEDLINE | ID: mdl-32821050

RESUMO

Glycosylation is an essential and complex cellular process where monosaccharides are added one by one onto an acceptor molecule, most of the time a protein or a lipid, so called glycoprotein or glycolipid. This cellular process is found in every living organism and is tightly conserved during evolution. In human, if one of the glycosylation reactions is genetically impaired, Congenital Disorders of Glycosylation (CDG) appear. CDG are a growing family of more than a hundred genetic diseases. This review offers a panorama of CDGs from 1980 to the present, their discoveries, diagnoses and treatments.


Assuntos
Defeitos Congênitos da Glicosilação , Animais , Defeitos Congênitos da Glicosilação/diagnóstico , Defeitos Congênitos da Glicosilação/epidemiologia , Defeitos Congênitos da Glicosilação/genética , Defeitos Congênitos da Glicosilação/terapia , Estudos de Associação Genética/história , Estudos de Associação Genética/tendências , Testes Genéticos/história , Testes Genéticos/métodos , Testes Genéticos/tendências , Glicosilação , História do Século XX , História do Século XXI , Humanos
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