Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 3.619
Filtrar
1.
Am J Hum Genet ; 108(8): 1436-1449, 2021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-34216551

RESUMO

Despite widespread clinical genetic testing, many individuals with suspected genetic conditions lack a precise diagnosis, limiting their opportunity to take advantage of state-of-the-art treatments. In some cases, testing reveals difficult-to-evaluate structural differences, candidate variants that do not fully explain the phenotype, single pathogenic variants in recessive disorders, or no variants in genes of interest. Thus, there is a need for better tools to identify a precise genetic diagnosis in individuals when conventional testing approaches have been exhausted. We performed targeted long-read sequencing (T-LRS) using adaptive sampling on the Oxford Nanopore platform on 40 individuals, 10 of whom lacked a complete molecular diagnosis. We computationally targeted up to 151 Mbp of sequence per individual and searched for pathogenic substitutions, structural variants, and methylation differences using a single data source. We detected all genomic aberrations-including single-nucleotide variants, copy number changes, repeat expansions, and methylation differences-identified by prior clinical testing. In 8/8 individuals with complex structural rearrangements, T-LRS enabled more precise resolution of the mutation, leading to changes in clinical management in one case. In ten individuals with suspected Mendelian conditions lacking a precise genetic diagnosis, T-LRS identified pathogenic or likely pathogenic variants in six and variants of uncertain significance in two others. T-LRS accurately identifies pathogenic structural variants, resolves complex rearrangements, and identifies Mendelian variants not detected by other technologies. T-LRS represents an efficient and cost-effective strategy to evaluate high-priority genes and regions or complex clinical testing results.


Assuntos
Aberrações Cromossômicas , Análise Citogenética/métodos , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Predisposição Genética para Doença , Genoma Humano , Mutação , Variações do Número de Cópias de DNA , Feminino , Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Cariotipagem , Masculino , Análise de Sequência de DNA
2.
Eur J Med Genet ; 64(9): 104288, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34246755

RESUMO

BACKGROUND: Prenatal whole-exome sequencing (WES) is becoming increasingly used when karyotype and microarray tests are not diagnostic of fetal malformations. Although the value of WES clearly emerges in terms of higher diagnostic rates, the limitations of prenatal phenotyping together with the counseling challenges for variants of uncertain significance and incidental results suggest that the routine application of prenatal WES is not yet easy. METHODS: Structurally abnormal fetuses with a mean gestational age of 24 weeks (range 13-38 weeks) were recruited from the Chong Qing Health Center for Women and Children. We performed a retrospective WES investigation in 85 fetuses, using DNA from amniotic fluid (66 samples, 77.6%), umbilical cord blood (10 samples, 11.8%), and fetal tissues (9 samples, 10.6%). Parental DNA was extracted from peripheral blood. RESULTS: Molecular diagnosis was obtained in 16 of the 85 fetuses (18.8%). According to the variant segregation mode and family history, 7 fetuses (43.75%) were affected by an autosomal dominant condition (6 variants were de novo and 1 variant was inherited from an unknowingly affected father), 7 fetuses (43.75%) had an autosomal recessive syndrome always associated with compound heterozygosity, and 2 fetuses (12.5%) had an X-linked condition (one mother was a carrier). In addition, the highest diagnostic rate was observed in fetuses with multisystem abnormalities (38.9%, 7/18). A variant of uncertain significance was detected in 16 samples (18.8%, 16/85). CONCLUSION: Our study confirms that prenatal WES is an efficient tool for studying fetal abnormalities, although further improvements are needed to establish stronger fetal genotype-phenotype correlations.


Assuntos
Feto/anormalidades , Doenças Genéticas Inatas/diagnóstico , Testes Genéticos/normas , Diagnóstico Pré-Natal/normas , Sequenciamento Completo do Exoma/normas , Feminino , Doenças Genéticas Inatas/epidemiologia , Doenças Genéticas Inatas/genética , Testes Genéticos/estatística & dados numéricos , Humanos , Gravidez , Diagnóstico Pré-Natal/estatística & dados numéricos , Sequenciamento Completo do Exoma/estatística & dados numéricos
4.
Nat Biomed Eng ; 5(7): 643-656, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34272525

RESUMO

The accurate and timely diagnosis of disease is a prerequisite for efficient therapeutic intervention and epidemiological surveillance. Diagnostics based on the detection of nucleic acids are among the most sensitive and specific, yet most such assays require costly equipment and trained personnel. Recent developments in diagnostic technologies, in particular those leveraging clustered regularly interspaced short palindromic repeats (CRISPR), aim to enable accurate testing at home, at the point of care and in the field. In this Review, we provide a rundown of the rapidly expanding toolbox for CRISPR-based diagnostics, in particular the various assays, preamplification strategies and readouts, and highlight their main applications in the sensing of a wide range of molecular targets relevant to human health.


Assuntos
Sistemas CRISPR-Cas/genética , Doenças Transmissíveis/diagnóstico , Técnicas de Amplificação de Ácido Nucleico/métodos , Ácidos Nucleicos/análise , Doenças Transmissíveis/microbiologia , Doenças Transmissíveis/virologia , Doenças Genéticas Inatas/diagnóstico , Humanos , Técnicas de Amplificação de Ácido Nucleico/economia , Ácidos Nucleicos/metabolismo , Sistemas Automatizados de Assistência Junto ao Leito , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA
6.
Nat Med ; 27(6): 1097-1104, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34083811

RESUMO

Around 5% of the population is affected by a rare genetic disease, yet most endure years of uncertainty before receiving a genetic test. A common feature of genetic diseases is the presence of multiple rare phenotypes that often span organ systems. Here, we use diagnostic billing information from longitudinal clinical data in the electronic health records (EHRs) of 2,286 patients who received a chromosomal microarray test, and 9,144 matched controls, to build a model to predict who should receive a genetic test. The model achieved high prediction accuracies in a held-out test sample (area under the receiver operating characteristic curve (AUROC), 0.97; area under the precision-recall curve (AUPRC), 0.92), in an independent hospital system (AUROC, 0.95; AUPRC, 0.62), and in an independent set of 172,265 patients in which cases were broadly defined as having an interaction with a genetics provider (AUROC, 0.9; AUPRC, 0.63). Patients carrying a putative pathogenic copy number variant were also accurately identified by the model. Compared with current approaches for genetic test determination, our model could identify more patients for testing while also increasing the proportion of those tested who have a genetic disease. We demonstrate that phenotypic patterns representative of a wide range of genetic diseases can be captured from EHRs to systematize decision-making for genetic testing, with the potential to speed up diagnosis, improve care and reduce costs.


Assuntos
Variações do Número de Cópias de DNA/genética , Doenças Genéticas Inatas/diagnóstico , Testes Genéticos , Doenças Raras/diagnóstico , Adolescente , Adulto , Criança , Pré-Escolar , Registros Eletrônicos de Saúde , Feminino , Doenças Genéticas Inatas/patologia , Humanos , Lactente , Masculino , Análise em Microsséries , Fenótipo , Doenças Raras/genética , Doenças Raras/patologia
7.
Int J Mol Sci ; 22(11)2021 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-34073611

RESUMO

Inherited retinal diseases (IRDs) represent a collection of phenotypically and genetically diverse conditions. IRDs phenotype(s) can be isolated to the eye or can involve multiple tissues. These conditions are associated with diverse forms of inheritance, and variants within the same gene often can be associated with multiple distinct phenotypes. Such aspects of the IRDs highlight the difficulty met when establishing a genetic diagnosis in patients. Here we provide an overview of cutting-edge next-generation sequencing techniques and strategies currently in use to maximise the effectivity of IRD gene screening. These techniques have helped researchers globally to find elusive causes of IRDs, including copy number variants, structural variants, new IRD genes and deep intronic variants, among others. Resolving a genetic diagnosis with thorough testing enables a more accurate diagnosis and more informed prognosis and should also provide information on inheritance patterns which may be of particular interest to patients of a child-bearing age. Given that IRDs are heritable conditions, genetic counselling may be offered to help inform family planning, carrier testing and prenatal screening. Additionally, a verified genetic diagnosis may enable access to appropriate clinical trials or approved medications that may be available for the condition.


Assuntos
Aconselhamento Genético , Doenças Genéticas Inatas , Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Diagnóstico Pré-Natal , Doenças Retinianas , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Humanos , Doenças Retinianas/diagnóstico , Doenças Retinianas/genética
8.
Int J Mol Sci ; 22(10)2021 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-34068052

RESUMO

Splicing is an important RNA processing step. Genetic variations can alter the splicing process and thereby contribute to the development of various diseases. Alterations of the splicing pattern can be examined by gene expression analyses, by computational tools for predicting the effects of genetic variants on splicing, and by splicing reporter minigene assays for studying alternative splicing events under defined conditions. The minigene assay is based on transient transfection of cells with a vector containing a genomic region of interest cloned between two constitutive exons. Cloning can be accomplished by the use of restriction enzymes or by site-specific recombination using Gateway cloning. The vectors pDESTsplice and pSpliceExpress represent two minigene systems based on Gateway cloning, which are available through the Addgene plasmid repository. In this review, we describe the features of these two splicing reporter minigene systems. Moreover, we provide an overview of studies in which determinants of alternative splicing were investigated by using pDESTsplice or pSpliceExpress. The studies were reviewed with regard to the investigated splicing regulatory events and the experimental strategy to construct and perform a splicing reporter minigene assay. We further elaborate on how analyses on the regulation of RNA splicing offer promising prospects for gaining important insights into disease mechanisms.


Assuntos
Processamento Alternativo , Clonagem Molecular , Genes Reporter , Doenças Genéticas Inatas/diagnóstico , Vetores Genéticos/genética , Genoma Humano , Mutação , Enzimas de Restrição do DNA , Doenças Genéticas Inatas/genética , Humanos
9.
Pan Afr Med J ; 38: 310, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34178228

RESUMO

Introduction: genetic diseases and congenital anomalies place a significant burden on the health of new-borns and their mothers. Despite the availability of a variety of prenatal screening tests, mothers' knowledge has been documented to determine uptake. This study aims to assess the knowledge of pregnant women about birth defects and the associated correlates with regard to willingness to do prenatal screening. Methods: a cross-sectional descriptive study was conducted among 422 antenatal mothers recruited sequentially as they attended antenatal clinics at the Lagos University Teaching Hospital. An interviewer-administered questionnaire was used to determine their knowledge of birth defects and willingness to do prenatal testing. Results: majority of the participants (92.2%) had at least secondary education. The mean total knowledge score of the respondents was 63%. Age and knowledge scores were not significantly correlated (r=-0.071, p=0.14). Being employed predicted higher knowledge scores (95% CI: 0.09, 2.09, p=0.03). Respondents who had primary school education and those who replied "I don't know" to willingness to test had significantly lower knowledge scores (95% CI: -15.01, -1.19, p=0.02 and 95% CI: -4.52, -0.68, p=0.01 respectively). Majority (79.1%) of the respondents were willing to undergo testing. Respondents' level of education was significantly associated with willingness to test (p=0.03). Conclusion: the observed knowledge gaps were considerable. There is need for improvement in education, the empowerment of women and access to quality healthcare including prenatal screening.


Assuntos
Conhecimentos, Atitudes e Prática em Saúde , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Cuidado Pré-Natal/psicologia , Diagnóstico Pré-Natal/psicologia , Adolescente , Adulto , Idoso , Anormalidades Congênitas/diagnóstico , Estudos Transversais , Feminino , Doenças Genéticas Inatas/diagnóstico , Hospitais de Ensino , Humanos , Pessoa de Meia-Idade , Nigéria , Gravidez , Gestantes/psicologia , Inquéritos e Questionários , Adulto Jovem
10.
Eur J Med Genet ; 64(7): 104245, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33991701

RESUMO

While rare diseases collectively affect ~300 million people worldwide, the prevalence of each disease concerns a relatively small number of patients. Usually, only limited data with regard to natural history are available. Multicenter initiatives are needed to aggregate data and answer clinically relevant research questions. In 2017, we launched the NAtural course and Prognosis of PFIC and Effect of biliary Diversion (NAPPED) consortium. In three years, NAPPED created a global network focused on rare genetic liver diseases in the Progressive Familial Intrahepatic Cholestasis (PFIC) spectrum. During these years, we have learned important lessons which we feel should be taken into account when initiating and leading a global consortium. First, it is essential to 'keep it simple' from the start. Research questions, case report forms (CRFs) and data acquisition should be limited and clear to stay focused and keep the workload low for new participants. Secondly, early rewards and research output are needed to keep momentum and motivation. Quick output can only follow a clean and simple design. Thirdly, the leading team should be in touch and accessible. Ideally, an involved PhD-candidate is appointed as primary contact person. Lastly, be inclusive and actively involve all participants the consortium's course. Global consortia are critical for personalized medicine in rare diseases. Also, they are essential for setting up trials to investigate generic drugs and personalized therapies. We hope to herewith stimulate others that are starting (or are planning to start) a global consortium, ultimately to help improve the care for patients with a rare disease.


Assuntos
Colestase Intra-Hepática/genética , Doenças Genéticas Inatas/genética , Guias de Prática Clínica como Assunto , Doenças Raras/genética , Colestase Intra-Hepática/diagnóstico , Colestase Intra-Hepática/terapia , Consenso , Bases de Dados Factuais , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/terapia , Humanos , Doenças Raras/diagnóstico , Doenças Raras/terapia
11.
Eur J Med Genet ; 64(7): 104247, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34000440

RESUMO

OBJECTIVES: To study the utility of clinical exome sequencing (CES) using next generation sequencing (NGS) in evaluating neonates with suspected genetic conditions. METHODS: This is an observational study conducted in a tertiary care neonatal unit. We included neonates with suspected genetic conditions, for whom CES were done either by direct sampling or from stored DNA. Data was collected from the Sri Ramachandra centre of excellence in perinatal health (SCOPE) case records of 2016-2019. Yield of CES, percentage of pathogenic, non-pathogenic and variant of uncertain significance (VUS) and associated disorders were studied. RESULTS: CES was done in 36 neonates. Variants were detected in 78% (28/36). However, significant variants with clinical correlation were present in 20 (56%) babies. Test was carried out from the stored sample in 10 (28%) babies. Mean turn-around time was 39 ± 7 days. Specialist was involved in 1 and treatment changes were done in 5 neonates. Five out of 8 VUS were clinically correlating. Inborn errors of metabolism were the commonest (60%). Two VUS were ascertained as likely pathogenic after parental segregation analysis. CONCLUSION: CES has a definite role in evaluation of suspected genetic conditions for diagnosis and prognostication. It also helps scientific society to build in additional evidence so that the "VUS" could be asserted as "likely pathogenic" . Our experience reiterates the importance of storing and archiving DNA of the affected child.


Assuntos
Doenças Genéticas Inatas/diagnóstico , Testes Genéticos/estatística & dados numéricos , Sequenciamento Completo do Exoma/estatística & dados numéricos , Diagnóstico Diferencial , Feminino , Doenças Genéticas Inatas/epidemiologia , Doenças Genéticas Inatas/genética , Testes Genéticos/normas , Humanos , Índia , Recém-Nascido , Masculino , Centros de Atenção Terciária/estatística & dados numéricos , Sequenciamento Completo do Exoma/normas
12.
Pan Afr Med J ; 38: 188, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33995794

RESUMO

Congenital hepatic fibrosis (CHF) is a rare autosomal recessive disease derived from biliary dysgenesis secondary to ductal plate malformation; it often coexists with Caroli's disease, von Meyenburg complexes, autosomal dominant polycystic kidney disease (ADPKD), and autosomal recessive polycystic kidney disease (ARPKD). Although CHF was first named and described in detail by Kerr et al. in 1961. Its pathogenesis still remains unclear. The exact incidence and prevalence are not known, and only a few hundred patients with CHF have been reported in the literature to date. However, with the development of noninvasive diagnostic techniques such as ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI), CHF may now be more frequently detected. Anatomopathological examination of liver biopsy is the gold standard in diagnosis of CHF. Patients with CHF exhibit variable clinical presentations, ranging from no symptoms to severe symptoms such as acute hepatic decompensation and even cirrhosis. The most common presentations in these patients are splenomegaly, esophageal varices, and gastrointestinal bleeding due to portal hypertension. In addition, in younger children, CHF often is accompanied by renal cysts or increased renal echogenicity. Great variability exists among the signs and symptoms of the disease from early childhood to the 5th or 6th decade of life, and in most patients the disorder is diagnosed during adolescence or young adulthood. Here, we present two cases of congenital hepatic fibrosis in 2-years-old girl and 12-year-old male who had been referred for evaluation of an abdominal distension with persistent hyper-transaminasemia and cholestasis, the diagnostic was made according to the results of medical imaging (CT or MRI), a liver biopsy, and genetic testing.


Assuntos
Doenças Genéticas Inatas/diagnóstico , Cirrose Hepática/diagnóstico , Imageamento por Ressonância Magnética , Tomografia Computadorizada por Raios X , Abdome/diagnóstico por imagem , Biópsia , Criança , Pré-Escolar , Colestase/diagnóstico , Colestase/etiologia , Feminino , Doenças Genéticas Inatas/fisiopatologia , Humanos , Cirrose Hepática/fisiopatologia , Masculino , Transaminases/sangue
13.
Genes (Basel) ; 12(4)2021 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-33805278

RESUMO

Demands for expanded carrier screening (ECS) are growing and ECS is becoming an important part of obstetrics practice and reproductive planning. The aim of this study is to evaluate the feasibility of a small-size ECS panel in clinical implementation and investigate Chinese couples' attitudes towards ECS. An ECS panel containing 11 recessive conditions was offered to Chinese pregnant women below 16 gestational weeks. Sequential testing of their partners was recommended for women with a positive carrier status. The reproductive decision and pregnancy outcome were surveyed for at-risk couples. A total of 1321 women performed ECS successfully and the overall carrier rate was 19.23%. The estimated at-risk couple rate was 0.83%. Sequential testing was performed in less than half of male partners. Eight at-risk couples were identified and four of them performed prenatal diagnosis. Our study demonstrated that a small-size ECS panel could yield comparable clinical value to a larger-size panel when the carrier rate of the individual condition is equal or greater than 1%. In addition, more than half of male partners whose wives were carriers declined any types of sequential testing possibly due to a lack of awareness and knowledge of genetic disorders. Genetic education is warranted for the better implementation of ECS.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Aberrações Cromossômicas , Triagem de Portadores Genéticos/métodos , Doenças Genéticas Inatas/diagnóstico , Implementação de Plano de Saúde/métodos , Diagnóstico Pré-Natal/métodos , Reprodução , Adulto , China/epidemiologia , Estudos de Coortes , Feminino , Doenças Genéticas Inatas/epidemiologia , Doenças Genéticas Inatas/genética , Testes Genéticos , Humanos , Masculino , Gravidez
14.
Mayo Clin Proc ; 96(6): 1407-1417, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33890576

RESUMO

OBJECTIVE: To assess the presence of clinically actionable results and other genetic findings in an otherwise healthy population of adults seen in a medical practice setting and offered "predictive" genomic testing. PATIENTS AND METHODS: In 2014, a predictive genomics clinic for generally healthy adults was launched through the Mayo Clinic Executive Health Program. Self-identified interested patients met with a genomic nurse and genetic counselor for pretest advice and education. Two genome sequencing platforms and one gene panel-based health screen were offered. Posttest genetic counseling was available for patients who elected testing. From March 1, 2014, through June 1, 2019, 1281 patients were seen and 301 (23.5%) chose testing. Uptake rates increased to 36.3% [70 of 193]) in 2019 from 11.8% [2 of 17] in 2014. Clinically actionable results and genetic findings were analyzed using descriptive statistics. RESULTS: Clinically actionable results were detected in 11.6% of patients (35 of 301), and of those, 51.7% (15 of 29) with a cancer or cardiovascular result = did not have a personal or family history concerning for a hereditary disorder. The most common actionable results were in the BCHE, BRCA2, CHEK2, LDLR, MUTYH, and MYH7 genes. A carrier of at least one recessive condition was found in 53.8% of patients (162 of 301). At least one variant associated with multifactorial disease was found in 44.5% (134 of 301) (eg, 25 patients were heterozygous for the F5 factor V Leiden variant associated with thrombophilia risk). CONCLUSION: Our predictive screening revealed that 11.6% of individuals will test positive for a clinically actionable, likely pathogenic/pathogenic variant. This finding suggests that wider knowledge and adoption of predictive genomic services could be beneficial in medical practice, although additional studies are needed.


Assuntos
Testes Genéticos , Feminino , Aconselhamento Genético/métodos , Aconselhamento Genético/estatística & dados numéricos , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/terapia , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Testes Genéticos/métodos , Testes Genéticos/estatística & dados numéricos , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
15.
Medicine (Baltimore) ; 100(12): e25277, 2021 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-33761731

RESUMO

ABSTRACT: Drug-resistant epilepsy (DRE) affects 7% to 20% of children with epilepsy. Although some risk factors for DRE have been identified, the results have not been consistent. Moreover, data regarding the risk factors for epilepsy and its seizure outcome in the first 2 years of life are limited.We analyzed data for children aged 0 to 2 years with epilepsy and neurodevelopmental disability from January, 2013, through December, 2017. These patients were followed up to compare the risk of DRE in patients with genetic defect (genetic group) with that without genetic defect (nongenetic group). Additionally, we conducted a meta-analysis to identify the pooled prevalence of genetic factors in children with DRE.A total of 96 patients were enrolled. A total of 68 patients were enrolled in the nongenetic group, whereas 28 patients were enrolled in the genetic group. The overall DRE risk in the genetic group was 6.5 times (95% confidence interval [CI], 2.15-19.6; p = 0.03) higher than that in the nongenetic group. Separately, a total of 1308 DRE patients were participated in the meta-analysis. The pooled prevalence of these patients with genetic factors was 22.8% (95% CI 17.4-29.3).The genetic defect plays a crucial role in the development of DRE in younger children with epilepsy and neurodevelopmental disability. The results can serve as a reference for further studies of epilepsy panel design and may also assist in the development of improved treatments and prevention strategies for DRE.


Assuntos
Aberrações Cromossômicas/estatística & dados numéricos , Deficiências do Desenvolvimento , Epilepsia Resistente a Medicamentos , Doenças Genéticas Inatas , Medição de Risco/métodos , China/epidemiologia , Correlação de Dados , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/epidemiologia , Epilepsia Resistente a Medicamentos/diagnóstico , Epilepsia Resistente a Medicamentos/epidemiologia , Epilepsia Resistente a Medicamentos/genética , Feminino , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/epidemiologia , Humanos , Lactente , Recém-Nascido , Masculino , Mutação , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Canal de Sódio Disparado por Voltagem NAV1.6/genética , Prevalência , Estudos Prospectivos , Fatores de Risco , Proteína 2 do Complexo Esclerose Tuberosa/genética
18.
Genes (Basel) ; 12(2)2021 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-33572515

RESUMO

BACKGROUND: Cystic fibrosis (CF) is the most common worldwide, life-shortening multisystem hereditary disease, with an autosomal recessive inheritance pattern caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The national newborn screening (NBS) program for CF has been initiated in Turkey since 2015. If the immunoreactive trypsinogen (IRT) is elevated (higher than 70 µg/L in the second control) and confirmed by sweat test or clinical findings, genetic testing is performed. The aims of this study are to emphasize the effect of NBS on the status of genetic diagnosis centers with the increasing numbers of molecular testing methods, and to determine the numbers and types of CFTR mutations in Turkey. METHODS: The next-generation sequencing (NGS) and multiplex ligation-dependent probe amplification (MLPA) results of 1595 newborns, who were referred to Cukurova University Adana Genetic Diseases Diagnosis and Treatment Center (AGENTEM) for molecular genetic testing, were evaluated with positive CF NBS program results since 2017. RESULTS: According to the results; 560 (35.1%) of the 1595 patients carried at least 1 (one) CF-related variant, while 1035 patients (64.9%) had no mutation. Compound heterozygosity for two mutations was the most common in patients, while two detected variants were homozygote in 14 patients. A total of 161 variants were detected in 561 patients with mutations. Fifteen novel variants that have not been previously reported were found. Moreover, p.L997F was identified as the most frequent pathogenic mutation that might affect the IRT measurements used for the NBS. The distribution of mutation frequencies in our study showed a difference from those previously reported; for example, the well-known p.F508del was the third most common (n = 42 alleles), rather than the first. The most striking finding is that 313 cases had a pathogenic variant together with the V470M variant, which might have a cumulative effect on CF perpetuation. CONCLUSION: This study is the first to determine the mutational spectrum of CFTR in correlation with the NBS program in the Turkish population. NBS for CF raises issues regarding screening in diverse populations, both medical and non-medical benefits, and carrier identification. Through the lens of NBS, we focused on the integrated diagnostic algorithms and their effect on the results of genetic testing.


Assuntos
Técnicas de Laboratório Clínico/normas , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/diagnóstico , Doenças Genéticas Inatas/diagnóstico , Fibrose Cística/genética , Fibrose Cística/patologia , Feminino , Doenças Genéticas Inatas/patologia , Testes Genéticos/tendências , Humanos , Recém-Nascido , Masculino , Mutação/genética , Triagem Neonatal/tendências , Turquia/epidemiologia
19.
Blood Rev ; 48: 100793, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33419567

RESUMO

Fibrinogen is a complex protein playing a major role in coagulation. Congenital afibrinogenemia, characterized by the complete absence of fibrinogen, is associated with major hemostatic defects. Even though the clinical course is unpredictable and can be completely different among patients, severe bleeding is the prominent symptom. Patients are also at increased risk of thrombosis and sometimes suffer from spontaneous spleen rupture, bone cysts and defective wound healing. Due to the relative rarity of afibrinogenemia, there are no evidence-based strategies for helping physicians in care of these patients. Fibrinogen supplementation is the keystone to prevent or treat bleeding events. In addition, fibrinogen, a pleiotropic protein with numerous physiological roles in immunity, angiogenesis and tissue repair, is involved in many diseases. Indeed, depletion of fibrinogen in animal models of infections, tumors and neurological diseases has an effect on the clinical course. The consequences for patients with afibrinogenemia still need to be investigated.


Assuntos
Afibrinogenemia/epidemiologia , Afibrinogenemia/etiologia , Doenças Genéticas Inatas/epidemiologia , Heterogeneidade Genética , Afibrinogenemia/diagnóstico , Afibrinogenemia/terapia , Animais , Gerenciamento Clínico , Suscetibilidade a Doenças , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/terapia , Hemorragia/diagnóstico , Hemorragia/epidemiologia , Hemorragia/etiologia , Hemorragia/terapia , Humanos , Vigilância em Saúde Pública , Trombose/diagnóstico , Trombose/epidemiologia , Trombose/etiologia
20.
J Assist Reprod Genet ; 38(4): 957-963, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33501564

RESUMO

PURPOSE: When undergoing expanded carrier screening (ECS), couples are often screened sequentially to reduce need for a second individual's test. It is unknown how often partners of individuals found to be carriers complete the recommended testing with a sequential approach and what factors contribute to decision-making regarding partner testing. Additionally, the economic burden placed on individuals by ECS testing and its effect on partner testing has not been evaluated. METHODS: In part 1, all individuals at a university-affiliated reproductive endocrinology and infertility practice identified to be carriers of a recessively inherited mutation using the Counsyl/Foresight ECS were included. Conditions were categorized by severity according to a previously described classification system. In part 2, all individuals who underwent ECS with a single test provider between September 1, 2013 and February 1, 2020 were contacted via email to complete a confidential and anonymized online survey. RESULTS: In part 1, a total of 2061 patients were screened. 36.9% were carriers of one or more recessively inherited disorders. Twenty-seven percent of positively screened individuals did not have their partner screened. Carriers of a moderate condition had a trend towards a reduced odds for having their partner screened compared to a profound condition (OR 0.36, 95% CI 0.12-1.05, p = 0.06). Number of conditions was not predictive of subsequent partner screening (OR 0.95, 95% CI 0.72-1.25, p = 0.72). In part 2, the cost of ECS was not covered by insurance for 54.5% (103/189) and most paid over $300 out-of-pocket for testing (47.6%). The most common reason for not completing partner testing was that the results would not alter their course when seeking conception (33.3%). 73.5% of patients knew that the largest benefit of ECS comes from knowing a partner's results as well as their own. CONCLUSIONS: Not all carriers of recessively inherited disorders choose to undergo partner screening. Patients found to be carrier of more debilitating genetic disorders may be more likely to screen their reproductive partners. For many, ECS testing is not covered by insurance, and this test may impose a significant economic burden. For some patients, the results of ECS would not change what they would do when seeking conception. Providers should evaluate whether a patient's ECS result would change their treatment course prior to testing.


Assuntos
Triagem de Portadores Genéticos , Doenças Genéticas Inatas/genética , Infertilidade/genética , Técnicas Reprodutivas/tendências , Tomada de Decisão Clínica , Efeitos Psicossociais da Doença , Características da Família , Feminino , Aconselhamento Genético/economia , Aconselhamento Genético/tendências , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/economia , Doenças Genéticas Inatas/epidemiologia , Testes Genéticos/economia , Testes Genéticos/tendências , Humanos , Infertilidade/epidemiologia , Infertilidade/patologia , Masculino , Gravidez , Diagnóstico Pré-Natal/métodos , Reprodução/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...