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1.
PLoS One ; 15(7): e0236962, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32735577

RESUMO

The diffusion of next-generation sequencing technologies has revolutionized research and diagnosis in the field of rare Mendelian disorders, notably via whole-exome sequencing (WES). However, one of the main issues hampering achievement of a diagnosis via WES analyses is the extended list of variants of unknown significance (VUS), mostly composed of missense variants. Hence, improved solutions are needed to address the challenges of identifying potentially deleterious variants and ranking them in a prioritized short list. We present MISTIC (MISsense deleTeriousness predICtor), a new prediction tool based on an original combination of two complementary machine learning algorithms using a soft voting system that integrates 113 missense features, ranging from multi-ethnic minor allele frequencies and evolutionary conservation, to physiochemical and biochemical properties of amino acids. Our approach also uses training sets with a wide spectrum of variant profiles, including both high-confidence positive (deleterious) and negative (benign) variants. Compared to recent state-of-the-art prediction tools in various benchmark tests and independent evaluation scenarios, MISTIC exhibits the best and most consistent performance, notably with the highest AUC value (> 0.95). Importantly, MISTIC maintains its high performance in the specific case of discriminating deleterious variants from benign variants that are rare or population-specific. In a clinical context, MISTIC drastically reduces the list of VUS (<30%) and significantly improves the ranking of "causative" deleterious variants. Pre-computed MISTIC scores for all possible human missense variants are available at http://lbgi.fr/mistic.


Assuntos
Doenças Genéticas Inatas , Mutação de Sentido Incorreto , Software , Sequenciamento Completo do Exoma/métodos , Biologia Computacional , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Aprendizado de Máquina
2.
Medicine (Baltimore) ; 99(27): e20989, 2020 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-32629715

RESUMO

BACKGROUND: Many genetic diseases are known to have distinctive facial phenotypes, which are highly informative to provide an opportunity for automated detection. However, the diagnostic performance of artificial intelligence to identify genetic diseases with facial phenotypes requires further investigation. The objectives of this systematic review and meta-analysis are to evaluate the diagnostic accuracy of artificial intelligence to identify the genetic diseases with face phenotypes and then find the best algorithm. METHODS: The systematic review will be conducted in accordance with the "Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols" guidelines. The following electronic databases will be searched: PubMed, Web of Science, IEEE, Ovid, Cochrane Library, EMBASE and China National Knowledge Infrastructure. Two reviewers will screen and select the titles and abstracts of the studies retrieved independently during the database searches and perform full-text reviews and extract available data. The main outcome measures include diagnostic accuracy, as defined by accuracy, recall, specificity, and precision. The descriptive forest plot and summary receiver operating characteristic curves will be used to represent the performance of diagnostic tests. Subgroup analysis will be performed for different algorithms aided diagnosis tests. The quality of study characteristics and methodology will be assessed using the Quality Assessment of Diagnostic Accuracy Studies 2 tool. Data will be synthesized by RevMan 5.3 and Meta-disc 1.4 software. RESULTS: The findings of this systematic review and meta-analysis will be disseminated in a relevant peer-reviewed journal and academic presentations. CONCLUSION: To our knowledge, there have not been any systematic review or meta-analysis relating to diagnosis performance of artificial intelligence in identifying the genetic diseases with face phenotypes. The findings would provide evidence to formulate a comprehensive understanding of applications using artificial intelligence in identifying the genetic diseases with face phenotypes and add considerable value in the future of precision medicine. OSF REGISTRATION: DOI 10.17605/OSF.IO/P9KUH.


Assuntos
Face/anormalidades , Doenças Genéticas Inatas/diagnóstico , Aprendizado Profundo , Humanos , Desenvolvimento Maxilofacial/genética , Metanálise como Assunto , Fenótipo , Revisões Sistemáticas como Assunto
3.
Am J Hum Genet ; 107(1): 3-14, 2020 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-32619490

RESUMO

Secondary genomic findings are increasingly being returned to individuals as opportunistic screening results. A secondary finding offers the chance to identify and mitigate disease that may otherwise be unrecognized in an individual. As a form of screening, secondary findings must be considered differently from sequencing results in a diagnostic setting. For these reasons, clinicians should employ an evaluation and long-term management strategy that accounts for both the increased disease risk associated with a secondary finding and the lower positive predictive value of a screening result compared to an indication-based testing result. Here we describe an approach to the clinical evaluation and management of an individual who presents with a secondary finding. This approach enumerates five domains of evaluation-(1) medical history, (2) physical exam, (3) family history, (4) diagnostic phenotypic testing, and (5) variant correlation-through which a clinician can distinguish a molecular finding from a clinicomolecular diagnosis of genomic disease. With this framework, both geneticists and non-geneticist clinicians can optimize their ability to detect and mitigate genomic disease while avoiding the pitfalls of overdiagnosis. Our goal with this approach is to help clinicians translate secondary findings into meaningful recognition, treatment, and prevention of disease.


Assuntos
Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/prevenção & controle , Genômica/métodos , Humanos , Anamnese
4.
JAMA ; 323(24): 2503-2511, 2020 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-32573669

RESUMO

Importance: Widespread adoption of rapid genomic testing in pediatric critical care requires robust clinical and laboratory pathways that provide equitable and consistent service across health care systems. Objective: To prospectively evaluate the performance of a multicenter network for ultra-rapid genomic diagnosis in a public health care system. Design, Setting, and Participants: Descriptive feasibility study of critically ill pediatric patients with suspected monogenic conditions treated at 12 Australian hospitals between March 2018 and February 2019, with data collected to May 2019. A formal implementation strategy emphasizing communication and feedback, standardized processes, coordination, distributed leadership, and collective learning was used to facilitate adoption. Exposures: Ultra-rapid exome sequencing. Main Outcomes and Measures: The primary outcome was time from sample receipt to ultra-rapid exome sequencing report. The secondary outcomes were the molecular diagnostic yield, the change in clinical management after the ultra-rapid exome sequencing report, the time from hospital admission to the laboratory report, and the proportion of laboratory reports returned prior to death or hospital discharge. Results: The study population included 108 patients with a median age of 28 days (range, 0 days to 17 years); 34% were female; and 57% were from neonatal intensive care units, 33% were from pediatric intensive care units, and 9% were from other hospital wards. The mean time from sample receipt to ultra-rapid exome sequencing report was 3.3 days (95% CI, 3.2-3.5 days) and the median time was 3 days (range, 2-7 days). The mean time from hospital admission to ultra-rapid exome sequencing report was 17.5 days (95% CI, 14.6-21.1 days) and 93 reports (86%) were issued prior to death or hospital discharge. A molecular diagnosis was established in 55 patients (51%). Eleven diagnoses (20%) resulted from using the following approaches to augment standard exome sequencing analysis: mitochondrial genome sequencing analysis, exome sequencing-based copy number analysis, use of international databases to identify novel gene-disease associations, and additional phenotyping and RNA analysis. In 42 of 55 patients (76%) with a molecular diagnosis and 6 of 53 patients (11%) without a molecular diagnosis, the ultra-rapid exome sequencing result was considered as having influenced clinical management. Targeted treatments were initiated in 12 patients (11%), treatment was redirected toward palliative care in 14 patients (13%), and surveillance for specific complications was initiated in 19 patients (18%). Conclusions and Relevance: This study suggests feasibility of ultra-rapid genomic testing in critically ill pediatric patients with suspected monogenic conditions in the Australian public health care system. However, further research is needed to understand the clinical value of such testing, and the generalizability of the findings to other health care settings.


Assuntos
Estado Terminal , Doenças Genéticas Inatas/genética , Testes Genéticos/métodos , Sequenciamento Completo do Exoma/métodos , Austrália , Criança , Pré-Escolar , Estudos de Viabilidade , Feminino , Doenças Genéticas Inatas/diagnóstico , Humanos , Lactente , Recém-Nascido , Masculino , Programas Nacionais de Saúde , Estudos Prospectivos , Fatores de Tempo
5.
Am J Med Genet A ; 182(6): 1302-1308, 2020 06.
Artigo em Inglês | MEDLINE | ID: covidwho-108928

RESUMO

In the midst of the COVID-19 pandemic, it is appropriate that our focus is on patient care and preparation. However, the genetics community is well poised to fill in the educational gap created by medical students transitioning to limiting patient contact, creation of telemedicine patient care, and online learning modules. Our history of agility in learning and teaching is now only inhibited by the time constraints of current clinical demands on the genetics community. This publication is designed to offer ideas and resources for quickly transitioning our education to meet the current demands in the time of a pandemic. Not only will this allow us to continue our strong history of education, it will enhance our strong commitment to using modern educational techniques and tools to address the genetics workforce issues that have defined the recent past. We have the opportunity to aggressively educate for trainees that now have the capacity to learn, and to lead the way in showing how the genetics community rallies together no matter the challenge.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/epidemiologia , Educação a Distância/organização & administração , Educação de Pós-Graduação em Medicina/organização & administração , Genética Médica/educação , Pandemias , Pneumonia Viral/epidemiologia , Recursos Audiovisuais/provisão & distribução , Contenção de Riscos Biológicos/métodos , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/psicologia , Infecções por Coronavirus/transmissão , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/epidemiologia , Humanos , Pneumonia Viral/diagnóstico , Pneumonia Viral/psicologia , Pneumonia Viral/transmissão , Saúde Pública/métodos , Estudantes de Medicina/psicologia , Telemedicina/métodos
6.
Pediatrics ; 145(5)2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32327449

RESUMO

As the technical ability for genetic diagnosis continues to improve, an increasing number of diagnoses are made in infancy or as early as the neonatal period. Many of these diagnoses are known to be associated with developmental delay and intellectual disability, features that would not be clinically detectable at the time of diagnosis. Others may be associated with cognitive impairment, but the incidence and severity are yet to be fully described. These neonates and infants with genetic diagnoses therefore represent an emerging group of patients who are at high risk for neurodevelopmental disabilities. Although there are well-established developmental supports for high-risk infants, particularly preterm infants, after discharge from the NICU, programs specifically for infants with genetic diagnoses are rare. And although previous research has demonstrated the positive effect of early developmental interventions on outcomes among preterm infants, the impact of such supports for infants with genetic disorders who may be born term, remains to be understood. We therefore review the literature regarding existing developmental assessment and intervention approaches for children with genetic disorders, evaluating these in the context of current developmental supports postdischarge for preterm infants. Further research into the role of developmental support programs for early assessment and intervention in high-risk neonates diagnosed with rare genetic disorders is needed.


Assuntos
Deficiências do Desenvolvimento/psicologia , Deficiências do Desenvolvimento/terapia , Doenças Genéticas Inatas/psicologia , Doenças Genéticas Inatas/terapia , Deficiências do Desenvolvimento/diagnóstico , Intervenção Educacional Precoce/métodos , Doenças Genéticas Inatas/diagnóstico , Humanos , Recém-Nascido , Recém-Nascido Prematuro/fisiologia , Doenças do Prematuro/diagnóstico , Doenças do Prematuro/psicologia , Doenças do Prematuro/terapia
7.
Acta Obstet Gynecol Scand ; 99(6): 802-808, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32242916

RESUMO

INTRODUCTION: The Israeli population, encompassing 9 million citizens, is comprised of diverse communities. The Ministry of Health genetic screening program for reproductive purposes was introduced in 2013. This program is mainly aimed at severe incurable diseases with high rates of infant and childhood morbidity and/or mortality, with a carrier frequency of at least 1:60 and/or a disease frequency of 1 in 15 000 live births. In this paper, we present the results of the national genetic carrier-screening program implementation. MATERIAL AND METHODS: Data acquisition for this study was performed by retrospectively searching Ministry of Health database, which includes the reports of 18 genetic laboratories performing genetic screening tests. RESULTS: During 2015-2017, a total of 919 820 carrier-screening genetic tests were executed. The overall number rose by 14.9% over these years. For about two-thirds of the presented disorders, carrier frequency was within the expected range. A decrease of 57% was noted in the observed number of patients with spinal muscular atrophy born during 2014-2017, compared with the expected rate. Familial dysautonomia, Canavan and Tay-Sachs diseases yielded a very low prevalence. CONCLUSIONS: Our results highlight the impact of a national genetic carrier-screening program. Couples at risk of an affected fetus mostly choose to perform preconception or prenatal diagnosis and to act accordingly. Our country has several characteristics enabling us to achieve this success, including considerable rates of endogamy and consanguineous marriages, increased frequency of founder mutations, and high fertility rates. In addition, wide accessibility of the tests and good compliance of the population must be noted. Still, raising the awareness and continuing education of population and caregivers about the importance and efficiency of carrier screening remains an important issue. Finally, expanding the existing tests into a uniform, wide genetic panel seems to be the next goal.


Assuntos
Triagem de Portadores Genéticos/estatística & dados numéricos , Aborto Induzido/estatística & dados numéricos , Grupos Étnicos/genética , Feminino , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Predisposição Genética para Doença/epidemiologia , Humanos , Israel , Gravidez , Estudos Retrospectivos
8.
Artigo em Inglês | MEDLINE | ID: mdl-32323908

RESUMO

In the midst of the COVID-19 pandemic, it is appropriate that our focus is on patient care and preparation. However, the genetics community is well poised to fill in the educational gap created by medical students transitioning to limiting patient contact, creation of telemedicine patient care, and online learning modules. Our history of agility in learning and teaching is now only inhibited by the time constraints of current clinical demands on the genetics community. This publication is designed to offer ideas and resources for quickly transitioning our education to meet the current demands in the time of a pandemic. Not only will this allow us to continue our strong history of education, it will enhance our strong commitment to using modern educational techniques and tools to address the genetics workforce issues that have defined the recent past. We have the opportunity to aggressively educate for trainees that now have the capacity to learn, and to lead the way in showing how the genetics community rallies together no matter the challenge.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/epidemiologia , Educação a Distância/organização & administração , Educação de Pós-Graduação em Medicina/organização & administração , Genética Médica/educação , Pandemias , Pneumonia Viral/epidemiologia , Recursos Audiovisuais/provisão & distribução , Contenção de Riscos Biológicos/métodos , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/psicologia , Infecções por Coronavirus/transmissão , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/epidemiologia , Humanos , Pneumonia Viral/diagnóstico , Pneumonia Viral/psicologia , Pneumonia Viral/transmissão , Saúde Pública/métodos , Estudantes de Medicina/psicologia , Telemedicina/métodos
10.
Med. clín (Ed. impr.) ; 154(7): 275-278, abr. 2020. graf
Artigo em Espanhol | IBECS | ID: ibc-190912

RESUMO

INTRODUCCIÓN Y OBJETIVOS: La analbuminemia congénita (AAC) (MIM #616000) es una enfermedad autosómica recesiva (prevalencia <1/106) causada por defectos en el gen ALB que implican la ausencia o marcada disminución de la albuminemia. En este artículo, describimos un caso de AAC detectado en nuestro hospital. MATERIAL Y MÉTODOS: Mujer de 42 años con hipoproteinemia e hipoalbuminemia de causa no filiada. El estudio bioquímico se realizó siguiendo las técnicas y los controles de calidad habituales de nuestro laboratorio: albuminemia (colorimetría y nefelometría); electroforesis de proteínas (capilar y gel de agarosa) y análisis molecular del gen ALB (extracción de ADN y amplificación PCR de los 14 exones codificantes más regiones intrónicas adyacentes y secuenciación Sanger). RESULTADOS: Descartadas las causas más frecuentes de hipoalbuminemia, se confirmó la analbuminemia por electroforesis y nefelometría. El estudio molecular del gen ALB evidenció la presencia de la variante c.1289+1G>A (variante Guimarães) en homozigosis. CONCLUSIONES: Este es el primer caso confirmado mediante estudio molecular de AAC en España. La paciente presenta la variante Guimarães descrita previamente en otros 4 pacientes en el mundo


INTRODUCTION AND OBJECTIVES: Congenital analbuminaemia (CCA) (MIM #616000) is an autosomal recessive disorder (prevalence < 1/106) caused by defects in the ALB gene leading to absence or severe reduction of albuminaemia. This paper describes a case of CCA detected and diagnosed in our hospital. MATERIALS AND METHODS: A 42-year old woman showing hypoproteinaemia and hypoalbuminaemia of unknown aetiology. Biochemical study was performed according to routine quality controlled analytical procedures: Albuminaemia (colorimetric and nephelometric methods). Protein electrophoresis (capillary and agarose gel). Molecular study of the ALB gene: DNA extraction, PCR amplification of the 14 coding exons plus adjacent intron regions and Sanger sequencing. RESULTS: After discarding the most common causes of hypoalbuminaemia, the analbuminaemia was confirmed by nephelometry and protein electrophoresis. The proband was found to be homozygous for molecular defect in the ALB gene: variant c.1289+1G>A previously reported as Guimarães variant. CONCLUSIONS: This is the first case of CCA confirmed by molecular study in Spain. The proband shows the Guimarães variant previously described in 4 patients worldwide


Assuntos
Humanos , Feminino , Adulto , Doenças Genéticas Inatas/diagnóstico , Técnicas de Diagnóstico Molecular/métodos , Albumina Sérica/genética , Doenças Genéticas Inatas/genética , Eletroforese , Hipoalbuminemia/etiologia , Colorimetria/métodos , Nefelometria e Turbidimetria/métodos , Diagnóstico Diferencial
11.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(3): 334-338, 2020 Mar 10.
Artigo em Chinês | MEDLINE | ID: mdl-32128754

RESUMO

Pre-testing preparation is the basis and starting point of genetic testing. The process includes collection of clinical information, formulation of testing scheme, genetic counseling before testing, and completion of informed consent and testing authorization. To effectively identify genetic diseases in clinics can greatly improve the diagnostic rate of next generation sequencing (NGS), thereby reducing medical cost and improving clinical efficacy. The analysis of NGS results relies, to a large extent, on the understanding of genotype-phenotype correlations, therefore it is particularly important to collect and evaluate clinical phenotypes and describe them in uniform standard terms. Different types of genetic diseases or mutations may require specific testing techniques, which can yield twice the result with half the effort. Pre-testing genetic counseling can help patients and their families to understand the significance of relevant genetic testing, formulate individualized testing strategies, and lay a foundation for follow-up.


Assuntos
Doenças Genéticas Inatas/diagnóstico , Testes Genéticos/normas , Sequenciamento de Nucleotídeos em Larga Escala/normas , Consenso , Estudos de Associação Genética , Aconselhamento Genético , Humanos , Mutação
12.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(3): 339-344, 2020 Mar 10.
Artigo em Chinês | MEDLINE | ID: mdl-32128755

RESUMO

With high accuracy and precision, next generation sequencing (NGS) has provided a powerful tool for clinical testing of genetic diseases. To follow a standardized experimental procedure is the prerequisite to obtain stable, reliable, and effective NGS data for the assistance of diagnosis and/or screening of genetic diseases. At a conference of genetic testing industry held in Shanghai, May 2019, physicians engaged in the diagnosis and treatment of genetic diseases, experts engaged in clinical laboratory testing of genetic diseases and experts from third-party genetic testing companies have fully discussed the standardization of NGS procedures for the testing of genetic diseases. Experts from different backgrounds have provided opinions for the operation and implementation of NGS testing procedures including sample collection, reception, preservation, library construction, sequencing and data quality control. Based on the discussion, a consensus on the standardization of the testing procedures in NGS laboratories is developed with the aim to standardize NGS testing and accelerate implementation of NGS in clinical settings across China.


Assuntos
Doenças Genéticas Inatas/diagnóstico , Testes Genéticos/normas , Sequenciamento de Nucleotídeos em Larga Escala/normas , China , Consenso , Humanos
13.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(3): 345-351, 2020 Mar 10.
Artigo em Chinês | MEDLINE | ID: mdl-32128756

RESUMO

Bioinformatic analysis and variant classification are the key components of high-throughput sequencing-based genetic diagnostic approach. This consensus is part of the effort to develop a standardized process for next generation sequencing (NGS)-based test for germline mutations underlying Mendelian disorders in China. The flow-chart, common software, key parameters of bioinformatics pipeline for data processing, annotation, storage and variant classification are reviewed, which is aimed to help improving and maintaining a high-quality process and obtaining consistent outcomes for NGS-based molecular diagnosis.


Assuntos
Doenças Genéticas Inatas/diagnóstico , Testes Genéticos/normas , Sequenciamento de Nucleotídeos em Larga Escala/normas , China , Biologia Computacional , Consenso , Análise de Dados , Humanos , Software
14.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(3): 352-357, 2020 Mar 10.
Artigo em Chinês | MEDLINE | ID: mdl-32128757

RESUMO

Clinical genetic testing results are compiled into a standardized report by genetic specialists and provided to clinicians and patients (Should the patient be intellectually disabled or under 18, the report will be provided to his/her parents or legal guardians). The content of genetic testing report should conform to relevant guidelines, industry standards and consensus. The decisions of clinicians will be made based on the report and clinical indications. Genetic counselors should provide post-test counseling to clinicians and patients or their authorized family members. A mechanism of follow-up visit after the genetic testing should be established with informed consent. Data should be shared by clinical institutions and genome sequencing institutions. As findings upon follow-up visit can help with further evaluation of the results, genome sequencing institutions should regularly re-analyze historical and follow-up data, and the updated results should be shared with clinical institutions. All activities involving reporting, genetic counselling, follow-up visiting, and re-analyzing should follow the relevant guidelines and regulations.


Assuntos
Aconselhamento Genético , Doenças Genéticas Inatas/diagnóstico , Testes Genéticos/normas , Sequenciamento de Nucleotídeos em Larga Escala/normas , Consenso , Humanos , Consentimento Livre e Esclarecido
15.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(4): 367-372, 2020 Apr 10.
Artigo em Chinês | MEDLINE | ID: mdl-32219815

RESUMO

Follow-up is a crucial step for the screening of neonatal genetic and metabolic diseases, which can directly influence the detection, diagnosis, efficacy of treatment, as well as the quality of neonatal screening. In view of the lack of follow-up, full understanding, and inconsistent requirement between various agencies and personnel in China, there is an urgent need for standardization. The Committee for Proficiency Testing of the Neonatal Genetic Metabolic Disease Screening Center of the National Health Committee of China has organized the writing of expert consensus for follow-up of neonatal genetic and metabolic disease screening after thorough discussion, so as to guide the follow-up work and improve its quality.


Assuntos
Doenças Genéticas Inatas/diagnóstico , Doenças Metabólicas , Triagem Neonatal , China , Consenso , Seguimentos , Humanos , Recém-Nascido , Doenças Metabólicas/diagnóstico , Doenças Metabólicas/genética
16.
Acta Obstet Gynecol Scand ; 99(6): 716-721, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32103489

RESUMO

INTRODUCTION: Assisted reproduction technologies are being rapidly developed and implementation of preimplantation genetic testing (PGT) has allowed patients with genetic disorders to initiate pregnancies while minimizing or eliminating the risk of transmitting these disorders to their offspring. Testing for numeric chromosomal anomalies has been proposed as a way to increase efficacy in assisted reproduction; however, this remains disputed. Legislation is lagging behind the rapid developments in this field. MATERIAL AND METHODS: We conducted a structured online survey of legislation and accessibility to preimplantation genetic testing in the Nordic countries to compare the regulation and uptake of this technique. The survey was designed and answered by the authors. RESULTS: Key elements in the regulation of preimplantation testing for monogenic disorders and structural rearrangements are similar in the Nordic countries, although accessibility varies since only Denmark, Finland, and Sweden have national clinics offering treatment. In addition, Denmark and Finland have private clinics offering PGT. Regulation is the most stringent in Norway where a national board evaluates all couples seeking treatment. Treatment volumes vary between the Nordic countries, with Norway and Finland having lowest treatment numbers. Preimplantation genetic testing for aneuploidy in the embryo varies between the Nordic countries: Finland and Iceland allow this form of treatment, Denmark and Sweden offer it only in the form of a research protocol, and Norway does not allow it at all. Therefore the number of treatment cycles involving testing for embryo aneuploidy are lower in the Nordic countries than in other countries where this treatment option is more common. CONCLUSIONS: Science needs to inform politics regarding the rapidly evolving field of reproductive medicine and we recommend harmonization of legislation and accessibility between the Nordic countries.


Assuntos
Testes Genéticos/legislação & jurisprudência , Testes Genéticos/estatística & dados numéricos , Acesso aos Serviços de Saúde/estatística & dados numéricos , Diagnóstico Pré-Implantação/estatística & dados numéricos , Aneuploidia , Feminino , Rearranjo Gênico , Doenças Genéticas Inatas/diagnóstico , Humanos , Gravidez , Países Escandinavos e Nórdicos , Inquéritos e Questionários
17.
BMC Med Genet ; 21(1): 35, 2020 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-32066420

RESUMO

BACKGROUND: We report a large family with four successive generations, presenting with a complex phenotype of severe congenital neutropenia (SCN), partially penetrant monocytosis, and hearing loss of varying severity. METHODS: We performed whole exome sequencing to identify the causative variants. Sanger sequencing was used to perform segregation analyses on remaining family members. RESULTS: We identified and classified a pathogenic GFI1 variant and a likely pathogenic variant in MYO6 which together explain the complex phenotypes seen in this family. CONCLUSIONS: We present a case illustrating the benefits of a broad screening approach that allows identification of oligogenic determinants of complex human phenotypes which may have been missed if the screening was limited to a targeted gene panel with the assumption of a syndromic disorder. This is important for correct genetic diagnosis of families and disentangling the range and severity of phenotypes associated with high impact variants.


Assuntos
Síndrome Congênita de Insuficiência da Medula Óssea/genética , Proteínas de Ligação a DNA/genética , Perda Auditiva Neurossensorial/genética , Cadeias Pesadas de Miosina/genética , Neutropenia/congênito , Fatores de Transcrição/genética , Adulto , Idoso , Síndrome Congênita de Insuficiência da Medula Óssea/complicações , Síndrome Congênita de Insuficiência da Medula Óssea/diagnóstico , Síndrome Congênita de Insuficiência da Medula Óssea/fisiopatologia , Exoma/genética , Feminino , Doenças Genéticas Inatas/complicações , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/fisiopatologia , Perda Auditiva Neurossensorial/complicações , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Neutropenia/complicações , Neutropenia/diagnóstico , Neutropenia/genética , Neutropenia/fisiopatologia , Linhagem , Fenótipo , Sequenciamento Completo do Exoma
18.
Arch. argent. pediatr ; 118(1): 52-56, 2020-02-00. tab, ilus
Artigo em Inglês, Espanhol | LILACS, BINACIS | ID: biblio-1095588

RESUMO

El amplio espectro de aberraciones cromosómicas observable en los trastornos del neurodesarrollo no siempre puede ser caracterizado por análisis cromosómico. El objetivo del trabajo fue determinar la etiología genética de estos trastornos en pacientes con afecciones neurológicas congénitas y sospecha clínica de un síndrome genético, aplicando un algoritmo de estudio clínico-molecular. En 71 de 111 niños analizados, se hallaron aberraciones submicroscópicas asociadas a síndromes de microdeleción-microduplicación: DiGeorge (22 casos), Prader-Willi (26 casos), Angelman (2 casos), Williams-Beuren (17 casos), Smith-Magenis (1 caso), Miller-Dieker (1 caso) y síndrome cri du chat (1 caso). Adicionalmente, se detectó una inserción desbalanceada de novo de la región 17p12p11.2, en el punto 5p13.1, en un niño de tres años. La utilización del método clínico unido a técnicas moleculares, como hibridación fluorescente in situ, ha permitido, en la mayoría de los casos, el diagnóstico certero de pacientes y/o familias con trastornos del neurodesarrollo.


The wide range of chromosome aberrations seen in neurodevelopmental disorders may not always be characterized by means of a chromosome analysis. The objective of this study was to determine the genetic etiology of these disorders in patients with congenital neurological conditions and clinical suspicion of a genetic disorder using a clinical and molecular testing algorithm. Among 111 studied children, 71 showed submicroscopic chromosome aberrations associated with microdeletion/microduplication syndromes: DiGeorge (22 cases), Prader-Willi (26 cases), Angelman (2 cases), Williams-Beuren (17 cases), Smith-Magenis (1 case), Miller-Dieker (1 case), and cri du chat syndrome (1 case). Additionally, a de novo trisomy 17p12p11.2 due to an unbalanced insertion into 5p13.1 was identified in a 3-year-old child. In most cases, the use of a clinical method together with molecular techniques, such as fluorescence in situ hybridization, has allowed to make an accurate diagnosis in patients and/or families with neurodevelopmental disorders.


Assuntos
Humanos , Masculino , Feminino , Lactente , Pré-Escolar , Criança , Transtornos do Neurodesenvolvimento/diagnóstico , Doenças Genéticas Inatas/diagnóstico , Síndrome , Algoritmos , Deficiências do Desenvolvimento , Estudos Retrospectivos , Hibridização in Situ Fluorescente , Procedimentos Clínicos , Transtornos do Neurodesenvolvimento/etiologia , Aconselhamento Genético
19.
Fertil Steril ; 113(2): 408-416, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31973902

RESUMO

OBJECTIVE: To investigate the use of preimplantation genetic testing for aneuploidy (PGT-A) among patients pursuing embryo banking (EB) for medically indicated fertility preservation (FP). DESIGN: Retrospective cohort. SETTING: University-affiliated fertility center. PATIENTS: All patients who underwent in vitro fertilization with or without PGT-A for medically indicated FP between January 2014 and April 2018. INTERVENTIONS: None MAIN OUTCOME MEASURES: EB cycle characteristics, subsequent cycle pursuit/outcomes, and frozen embryo transfer (FET) outcomes. RESULTS: A total of 58 medical EB cycles were compared; 34 cycles used PGT-A. Of the EB patients with breast cancer, 67% used PGT-A; other indications were evenly divided between PGT-A (FP/PGT-A) and no PGT-A (FP). PGT-A use increased over the study period. Groups were similar in age, days of stimulation, and days from initial FP consultation to treatment initiation. Number of oocytes (14.5 [2-63] FP vs. 17.5 [1-64] FP/PGT-A), 2PN zygotes (7 [1-38] FP vs. 9 [0-36] FP/PGT-A), and blastocysts (5.5 [0-22] FP vs. 5 [0-18] FP/PGT-A) cryopreserved were similar between groups. Equal numbers cryopreserved both oocytes and embryos (5 vs. 3). Five FP/PGT-A patients underwent a second EB cycle. Among FP/PGT-A patients, an average of 6.7 ± 5 blastocysts underwent PGT-A, with 3.5 ± 3 (48.2%) euploid embryos cryopreserved for future FET compared to an average of 7.2 ± 7 untested embryos in the FP group. CONCLUSION: PGT-A in medical EB cycles increased over time and did not limit the use of other FP methods such as oocyte cryopreservation. In some cases, poor PGT-A results informed patients to pursue a second EB cycle. When counseling patients, the prognostic benefits of PGT-A must be weighed against the financial costs and potential for "terminal" fertility diagnosis.


Assuntos
Aneuploidia , Blastocisto/patologia , Preservação da Fertilidade , Fertilização In Vitro , Doenças Genéticas Inatas/diagnóstico , Testes Genéticos , Diagnóstico Pré-Implantação , Adulto , Criopreservação , Transferência Embrionária , Feminino , Preservação da Fertilidade/efeitos adversos , Fertilização In Vitro/efeitos adversos , Aconselhamento Genético , Doenças Genéticas Inatas/genética , Humanos , Valor Preditivo dos Testes , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Resultado do Tratamento
20.
Intern Med ; 59(1): 119-120, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31366802

RESUMO

Isolated adrenocorticotropic hormone deficiency (IAD) is a cause of adrenal insufficiency (AI), which shows impaired secretion of adrenocorticotropic hormone (ACTH) with the preserved secretion of other anterior pituitary gland hormones. We herein report a case of IAD complicated by chronic thyroiditis presenting with neuropsychiatric symptoms without other signs indicative of AI that showed complete improvement of the cognitive function after the administration of corticosteroids. The clinical features of our case may be confused with autoimmune encephalopathies (AEs); however, IAD should be strictly differentiated from AEs, as it requires permanent hormone replacement without addition of immunosuppressive agents.


Assuntos
Hormônio Adrenocorticotrópico/deficiência , Disfunção Cognitiva/diagnóstico , Encefalite/diagnóstico , Doenças do Sistema Endócrino/diagnóstico , Doenças Genéticas Inatas/diagnóstico , Doença de Hashimoto/diagnóstico , Hipoglicemia/diagnóstico , Hormônio Adrenocorticotrópico/metabolismo , Doenças Autoimunes/diagnóstico , Encefalopatias/diagnóstico , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/psicologia , Diagnóstico Diferencial , Eletroencefalografia , Doenças do Sistema Endócrino/complicações , Doenças do Sistema Endócrino/tratamento farmacológico , Doenças do Sistema Endócrino/psicologia , Doenças Genéticas Inatas/complicações , Doenças Genéticas Inatas/tratamento farmacológico , Doenças Genéticas Inatas/psicologia , Doença de Hashimoto/complicações , Terapia de Reposição Hormonal , Humanos , Hidrocortisona/uso terapêutico , Hipoglicemia/complicações , Hipoglicemia/tratamento farmacológico , Hipoglicemia/psicologia , Masculino , Pessoa de Meia-Idade , Tireoidite/complicações
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