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1.
Cytogenet Genome Res ; 158(1): 1-9, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31129666

RESUMO

X-linked hypohidrotic ectodermal dysplasia (XLHED; OMIM 305100) is the most common form of ectodermal dysplasia, presenting with the triad of hypotrichosis, hypodontia, and hypohidrosis. This disorder is caused by mutations in EDA, which encodes ectodysplasin A, a member of the tumor necrosis factor superfamily. In this study, we describe clinical and genetic characteristics of 10 Korean XLHED patients (9 males, 1 female) from 9 families. Nine out of the 10 patients manifested the cardinal triad of symptoms. Six patients had a positive family history, while 2 patients were brothers. The most common initial presentation was hypotrichosis or hypodontia, while 1 patient presented with recurrent high fever in early infancy. Sanger sequencing of the EDA gene was performed and revealed 9 different mutations. Three had been reported previously, and 6 were novel mutations. One female patient, carrying a previously reported missense mutation, might be affected by skewed X-inactivation. This is the first observational study investigating genetically confirmed XLHED patients in Korea. To provide appropriate supportive care and genetic counseling, clinicians should consider the possibility of XLHED in the differential diagnosis of recurrent fever in infants, as well as recognize the typical triad of symptoms.


Assuntos
Displasia Ectodérmica Anidrótica Tipo 1/genética , Ectodisplasinas/genética , Mutação , Adolescente , Substituição de Aminoácidos , Criança , Pré-Escolar , Displasia Ectodérmica Anidrótica Tipo 1/etnologia , Ectodisplasinas/química , Feminino , Mutação da Fase de Leitura , Estudos de Associação Genética , Triagem de Portadores Genéticos , Humanos , Lactente , Masculino , Mutação de Sentido Incorreto , Linhagem , República da Coreia/epidemiologia
3.
Mol Genet Genomic Med ; 7(5): e618, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30838796

RESUMO

BACKGROUND: Genomic sequencing technologies have made the possibility of population screening for whole panels of genetic disorders more feasible than ever before. As one of the most common single gene disorders affecting the UK population, hemophilia is an attractive candidate to include on such screening panels. However, very little is known about views toward genetic screening amongst people with hemophilia or their family members, despite the potential for a wide range of impacts on them. METHODS: Twenty-two in-depth qualitative interviews were undertaken to explore the views of adults with hemophilia and their family members, recruited through the Haemophilia Society UK. These interviews were used to develop a survey, the Haemophilia Screening Survey (UK), which was distributed in paper and online format through the support group, receiving 327 returns between January and June 2018. RESULTS: Fifty-seven per cent of the sample supported preconception carrier screening of the population for hemophilia, and 59% supported prenatal carrier screening. Key reasons for support included a desire to reduce pregnancy terminations and increase awareness of hemophilia. Despite support for screening however, 90% of the sample disagreed with pregnancy terminations for hemophilia. CONCLUSIONS: Families and adults living with hemophilia are more supportive of screening for information and preparation purposes than to prevent boys with hemophilia from being born. A distinction was made between preventing the disease and preventing the lives of people with it, with support shown for the use of screening to achieve the former, but not at the expense of the latter.


Assuntos
Atitude , Triagem de Portadores Genéticos/ética , Aconselhamento Genético/psicologia , Hemofilia A/psicologia , Pacientes/psicologia , Adolescente , Adulto , Idoso , Família/psicologia , Feminino , Hemofilia A/genética , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários , Reino Unido
4.
Mol Genet Genomic Med ; 7(4): e00594, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30838813

RESUMO

BACKGROUND: Previous studies showed that the fibrillin-1 gene (FBN1) is responsible for Marfan sydrome (MFS) pathogenesis. This study is conducted to screen for mutations in the FBN1 gene in Chinese families with MFS. METHODS: Eight families with MFS and related disorder were recruited in this study. All available family members underwent complete physical, ophthalmic, and cardiovascular examination. Mutation screening was performed using targeted next-generation sequencing. Candidate variants were amplified by polymerase chain reaction and verified by direct Sanger sequencing. RESULTS: Four novel heterozygous mutations in FBN1, including c.2861G>T (p.R954L), c.4087G>A (p.D1363N), c.4987T>G (p.C1663G), and c.5032T>G (p.Y1678D), as well as four known mutations, c.3617G>A (p.G1206D), c.4460A>G (p.D1487G), c.4588C>T (p.R1530C), and c.718C>T (p.R240C) were identified. Affected patients from each family were found to carry one of the mutations, whereas the unaffected members and 1,086 normal controls were not. Each mutation was found to be cosegregated with MFS phenotype and related disorder in each family. Multiple sequence alignment of the human fibrillin-1 protein showed that these mutations occurred in a highly conserved region among different species. CONCLUSIONS: Eight FBN1 mutations were identified in Chinese families with MFS and related disorder. These data expands FBN1 mutation spectrum and further emphasizes the role of FBN1 in the pathogenesis of MFS.


Assuntos
Fibrilina-1/genética , Triagem de Portadores Genéticos , Síndrome de Marfan/genética , Mutação , Adolescente , Adulto , Criança , Pré-Escolar , China , Feminino , Humanos , Masculino , Síndrome de Marfan/patologia , Pessoa de Meia-Idade , Linhagem
5.
J Hum Genet ; 64(6): 551-559, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30867548

RESUMO

Genetic diagnoses are becoming a routine in the medical practice of neuromuscular diseases. Many diagnoses, however, can have an influence on relatives and family members and thus must be handled carefully by genetic counseling (GC). Here, we aimed to assess the purpose of undergoing GC to verify the utility of collaborations between clinical and genetic divisions. We investigated consecutive GC cases of neuromuscular disease and examined the role of GC. Our study included 102 cases who underwent GC in our hospital from July 2005 to March 2018: 86.3% were women and 45.1% were in their 30's. Disease explanation was the most common reason for attending GC (29.4%), followed by prenatal diagnosis (25.5%), pre-symptomatic diagnosis (17.6%), and carrier diagnosis (14.7%). Clients typically visited the hospital for GC when some kind of life event occurred, such as marriage, had a desire to bear a child, or a change in the condition of the proband. Clinicians should be conscious of such life events from the perspective of both the client and their relatives, and guide the GC at an appropriate time. Overall, the degree of recognition of genetic risk by clients differed; thus, it is important for GC to determine the status of each unique situation and respond individually.


Assuntos
Família , Aconselhamento Genético , Doenças Neuromusculares/diagnóstico , Adulto , Feminino , Triagem de Portadores Genéticos , Testes Genéticos , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Neuromusculares/genética , Doenças Neuromusculares/patologia , Linhagem , Fatores de Risco , Adulto Jovem
6.
Rev. esp. patol ; 52(1): 20-26, ene.-mar. 2019. tab, graf
Artigo em Inglês | IBECS | ID: ibc-182663

RESUMO

Purpose: To evaluate the PCA3 (Prostate Cancer 3 gene) as a tool to improve prostate cancer (PCa) screening and its capability to predict PCa aggressiveness. Patients and methods: A retrospective study with data from consecutive patients with suspected PCa seen in the urology department between November 2009 and April 2016 and who were candidates for prostate biopsy. A total of 1038 urine samples were tested in our laboratory with a kit that generated a PCA3 score (s-PCA3). A prostate biopsy was recommended only in those patients with s-PCA3≥35. Associations between variables were analyzed using the R software. Results: In patients with a positive s-PCA3 (44.5%), a subsequent biopsy was recommended. Of a total of 151 biopsies studied, 56.3% yielded a diagnosis of PCa. The probability of a positive biopsy increased as the s-PCA3 increased (p=0.041). The percentage of affected cylinders increased as the s-PCA3 increased (p=0.015). A statistically significant relationship was observed between s-PCA3 and both the Gleason score and the Grade Group (p=0.001 and 0.008, respectively). The best log-linear models and a logistic model confirmed the relationships shown previously with Fisher's exact tests. Conclusions: S-PCA3 may serve as an additional marker to reduce the indication for biopsies and avoid overdiagnosis and overtreatment of patients with suspected PCa. The prognostic significance of s-PCA3 was confirmed, as it was associated with tumor volume and Gleason score. Importantly, to our knowledge this is the first time that an association has been demonstrated between s-PCA3 and the new Grade Group


Objetivo: Evaluar el estudio de PCA3 (gen Prostate Cancer 3) en orina como test complementario para mejorar el cribado de cáncer de próstata (CaP), así como su capacidad de predecir la agresividad tumoral antes de la biopsia. Pacientes y métodos: En este estudio retrospectivo se incluyeron pacientes consecutivos con sospecha de CaP y candidatos a biopsia, que se presentaron en la consulta del urólogo entre noviembre de 2009 y abril de 2016. Se testaron en nuestro laboratorio un total de 1.038 muestras de orina con un kit que generó un PCA3 score (s-PCA3). Se recomendó la biopsia en aquellos pacientes con s-PCA3≥35. Las asociaciones entre variables se analizaron con el software R. Resultados: En los pacientes con s-PCA3 positivo (44,5%) se recomendó la realización de una biopsia. Se estudiaron un total de 151 biopsias de las que un 56,3% fueron diagnosticadas de CaP. La probabilidad de obtener una biopsia positiva aumentó a medida que lo hacia el s-PCA3 (p=0,041). El porcentaje de cilindros afectados aumentó a medida que lo hacía el s-PCA3 (p=0,015). El s-PCA3 presentó una relación estadísticamente significativa con el grado de Gleason (p=0,001) y el grado grupo (p=0,008). El mejor modelo Log-lineal, así como el modelo logístico confirmaron las relaciones observadas previamente con las pruebas exactas de Fisher. Conclusiones: El s-PCA3 es una herramienta complementaria que permite reducir la indicación de biopsias y evitar el sobrediagnóstico y sobretratamiento de pacientes con sospecha de CaP. La significación pronóstica del s-PCA3 fue confirmada al demostrarse su asociación con el volumen tumoral y el grado de Gleason. Según la información de la que disponemos, este es el primer estudio en el que se demuestra la asociación entre el s-PCA3 y el nuevo sistema de gradación del CaP


Assuntos
Humanos , Masculino , Neoplasias da Próstata/genética , Antígeno Prostático Específico/análise , Genes Neoplásicos/genética , Triagem de Portadores Genéticos/métodos , Prostatectomia/estatística & dados numéricos , Neoplasias da Próstata/patologia , Marcadores Genéticos , Estadiamento de Neoplasias/métodos , Estudos Retrospectivos , Biópsia/métodos
7.
J Clin Lab Anal ; 33(4): e22845, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30809867

RESUMO

OBJECTIVES: Thalassemia is a highly prevalent monogenic inherited disease in southern China. It is important to collect epidemiological data comprehensively for proper prevention and treatment. METHODS: In this study, blood samples collected from 15 807 residents of Chenzhou were primarily screened by hematological tests. A total of 3973 samples of suspected thalassemia carriers were further characterized by combined next-generation sequencing (NGS) and Gap-PCR. RESULTS: In total, 1704 subjects were diagnosed as thalassemia carriers with a total prevalence rate of 10.78%, including 943 α-thalassemia carriers, 708 ß-thalassemia carriers, and 53 composite α and ß-thalassemia carriers. The prevalence rates of α-thalassemia, ß-thalassemia, and composite α and ß-thalassemia were 5.97%, 4.48%, and 0.34%, respectively. Meanwhile, we characterized 19 α-thalassemia variations and 21 ß-thalassemia variations in thalassemia carriers. Approximately 2.88% of thalassemia carriers would be missed by traditional genetic analysis. In addition, four novel thalassemia mutations and one novel abnormal hemoglobin mutation were identified. CONCLUSIONS: Our data suggest a high prevalence of thalassemia and a diverse spectrum of thalassemia-associated variations in Chenzhou. Also, combined NGS and Gap-PCR is an effective thalassemia screening method. Our findings might be helpful for prevention and treatment of thalassemia in this region.


Assuntos
Talassemia alfa/epidemiologia , Talassemia alfa/genética , Talassemia beta/epidemiologia , Talassemia beta/genética , Adolescente , Adulto , Criança , Pré-Escolar , China/epidemiologia , Feminino , Triagem de Portadores Genéticos , Hemoglobinas Anormais/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Epidemiologia Molecular , Mutação , Reação em Cadeia da Polimerase/métodos , Adulto Jovem
8.
J Hum Genet ; 64(5): 387-396, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30765868

RESUMO

Carrier screening of spinal muscular atrophy (SMA) can provide reproductive options for carriers and prevent the birth defects. Here, we developed a simple screening test based on melting analysis. The test comprises a duplex PCR with two primer pairs and three probes to simultaneous amplify SMN1, SMN2, and CFTR. By analyzing the melting profiles, we were able to determine the SMN1/SMN2 ratio and SMN1 + SMN2 copy number to subsequently determine the copy number of SMN1. Samples with one copy of SMN1 were considered as "high risk for carrier," while samples with ≥2 copies of SMN1 were considered as "low risk for carrier." We evaluated the clinical performance of this test using 215 clinical samples with various genotypes that had been previously confirmed by multiplex ligation-dependent probe amplification (MLPA). The test showed high sensitivity (100%) and specificity (97.1%) as well as high positive (97.3%) and negative (100%) predictive value, and was in perfect agreement with the gold standard test, MLPA (k = 0.97). Moreover, it is rapid, inexpensive, and easy to perform and automate, with high reproducibility and capacity. Therefore, we expect this test will advance carrier screening for SMA.


Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística/genética , Triagem de Portadores Genéticos , Atrofia Muscular Espinal/genética , Proteína 1 de Sobrevivência do Neurônio Motor/genética , Sondas de DNA/genética , Feminino , Humanos , Masculino , Desnaturação de Ácido Nucleico , Reação em Cadeia da Polimerase , Sensibilidade e Especificidade , Proteína 2 de Sobrevivência do Neurônio Motor/genética
9.
Lancet ; 393(10173): 758-767, 2019 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-30712878

RESUMO

BACKGROUND: Identification of chromosomal aneuploidies and copy number variants that are associated with fetal structural anomalies has substantial value. Although whole-exome sequencing (WES) has been applied to case series of a few selected prenatal cases, its value in routine clinical settings has not been prospectively assessed in a large unselected cohort of fetuses with structural anomalies. We therefore aimed to determine the incremental diagnostic yield (ie, the added value) of WES following uninformative results of standard investigations with karyotype testing and chromosomal microarray in an unselected cohort of sequential pregnancies showing fetal structural anomalies. METHODS: In this prospective cohort study, the parents of fetuses who were found to have a structural anomaly in a prenatal ultrasound were screened for possible participation in the study. These participants were predominantly identified in or were referred to the Columbia University Carmen and John Thain Center for Prenatal Pediatrics (New York, NY, USA). Fetuses with confirmed aneuploidy or a causal pathogenic copy number variant were excluded from WES analyses. By use of WES of the fetuses and parents (parent-fetus trios), we identified genetic variants that indicated an underlying cause (diagnostic genetic variants) and genetic variants that met the criteria of bioinformatic signatures that had previously been described to be significantly enriched among diagnostic genetic variants. FINDINGS: Between April 24, 2015, and April 19, 2017, 517 sequentially identified pregnant women found to have fetuses with a structural anomaly were screened for their eligibility for inclusion in our study. 71 (14%) couples declined testing, 87 (17%) trios were missing at least one DNA sample (from either parent or the fetus), 69 (13%) trios had a clinically relevant abnormal karyotype or chromosomal microarray finding, 51 (10%) couples did not consent to WES or withdrew consent, and five (1%) samples were not of good enough quality for analysis. DNA samples from 234 (45%) eligible trios were therefore used for analysis of the primary outcome. By use of trio sequence data, we identified diagnostic genetic variants in 24 (10%) families. Mutations with bioinformatic signatures that were indicative of pathogenicity but with insufficient evidence to be considered diagnostic were also evaluated; 46 (20%) of the 234 fetuses assessed were found to have such signatures. INTERPRETATION: Our analysis of WES data in a prospective cohort of unselected fetuses with structural anomalies shows the value added by WES following the use of routine genetic tests. Our findings suggest that, in cases of fetal anomalies in which assessment with karyotype testing and chromosomal microarray fail to determine the underlying cause of a structural anomaly, WES can add clinically relevant information that could assist current management of a pregnancy. The unique challenges of WES-based prenatal diagnostics require analysis by a multidisciplinary team of perinatal practitioners and laboratory specialists. FUNDING: Institute for Genomic Medicine (Columbia University Irving Medical Center).


Assuntos
Cariótipo Anormal/embriologia , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Aneuploidia , Variações do Número de Cópias de DNA/genética , Desenvolvimento Fetal/genética , Feto/anormalidades , Sequenciamento Completo do Exoma/estatística & dados numéricos , Anormalidades Múltiplas/epidemiologia , Amniocentese , Amostra da Vilosidade Coriônica , Feminino , Triagem de Portadores Genéticos , Humanos , Masculino , Gravidez , Estudos Prospectivos , Ultrassonografia Pré-Natal , Sequenciamento Completo do Exoma/métodos
10.
J Assist Reprod Genet ; 36(4): 709-716, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30761454

RESUMO

PURPOSE: Expanded genetic carrier screening (ECS) is an important part of gynecological practice and preconception planning. We evaluated the awareness and attitudes among women regarding ECS and factors that may influence decision-making in a family planning context. METHODS: A 32-question survey in an academic university practice was given to 521 women who were either currently pregnant (n = 108), undergoing gynecologic care who were considering future fertility (n = 308), and considering or receiving fertility treatment (n = 105). Data are reported descriptively. RESULTS: Forty-seven percent (n = 246) of patients were aware of ECS. Though most reported feeling positive or neutral towards ECS, 51% (n = 263) reported no desire for testing. Fifty-eight percent (n = 303) felt it beneficial to know their carrier status, and 55% (n = 257) said it was their responsibility to undergo testing. Those considering future fertility were found to have a more positive attitude towards ECS (51.4%) than those considering or receiving fertility treatment (34%). For positive carriers of a genetic disorder, 228 (49%) of patients would proceed with having their partner screened, 58 (13%) would undergo prenatal screening only and 12 (2.6%) would continue with vitro fertilization (IVF). Related to cost for ECS, 53.5% (n = 191) would be willing to pay at least $50-100 for testing, while 29% (n = 146) would not pay anything out of pocket. CONCLUSIONS: Despite patients' beliefs that it would be beneficial and their responsibility to undergo carrier status testing, the majority reported no desire for ECS and many were unwilling to pay out of pocket. Further education is necessary to reconcile the gap between technology and patient decision-making.


Assuntos
Triagem de Portadores Genéticos/métodos , Aconselhamento Genético/métodos , Infertilidade/genética , Diagnóstico Pré-Natal/métodos , Adolescente , Adulto , Tomada de Decisões , Feminino , Fertilização In Vitro , Conhecimentos, Atitudes e Prática em Saúde , Heterozigoto , Humanos , Infertilidade/diagnóstico , Infertilidade/fisiopatologia , Masculino , Médicos , Gravidez , Estudos Prospectivos , Adulto Jovem
11.
Fam Cancer ; 18(2): 197-201, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30582135

RESUMO

Whether monoallelic MUTYH mutations increase female breast cancer risk remains controversial. This study aimed to determine if monoallelic MUTYH mutations are associated with increased breast cancer risk in women undergoing multigene panel testing (MGPT). The prevalence of monoallelic MUTYH mutations was compared between Non-Hispanic white female breast cancer cases (n = 30,456) and cancer-free controls (n = 12,289), all of whom underwent MGPT that included MUTYH. We tested breast cancer associations with MUTYH alleles using Fisher's exact test, followed by multivariate logistic regression adjusted for age at testing and MGPT type ordered. Frequencies of the two most common MUTYH founder mutations, p.G396D and p.Y179C, were compared independently between the breast cancer cases and MGPT controls, as well as the healthy UK10K control population (n = 2640). Comparing cases to MGPT controls, no association was observed between female breast cancer and any monoallelic MUTYH carrier status (OR 0.86-1.36, p = 0.21-0.96). Similarly, comparisons to UK10K controls revealed no significant increase in breast cancer risk associated with p.G396D (OR 1.20, p = 0.44) or p.Y179C (OR 1.71, p = 0.24). This study did not find a significant increase in breast cancer risk associated with monoallelic MUTYH mutations.


Assuntos
Neoplasias da Mama/genética , DNA Glicosilases/genética , Triagem de Portadores Genéticos/estatística & dados numéricos , Predisposição Genética para Doença , Adulto , Alelos , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Heterozigoto , Humanos , Pessoa de Meia-Idade , Mutação , Medição de Risco/métodos
13.
Mol Genet Metab ; 126(1): 14-22, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30563741

RESUMO

BACKGROUND: A substantial number of severely debilitating and often ultimately fatal inborn errors of metabolism (IEMs) still lack an effective disease-modifying treatment. Informing couples before a pregnancy about an increased risk of having a child with an inherited disorder is now feasible by preconception expanded carrier screening (ECS). While knowledge about carrier status enhances reproductive autonomy, it may also result in ethical dilemmas. The purpose of this study was to assess the attitudes of the general Dutch population towards preconception ECS and to investigate which factors influence these attitudes. METHODS: Data collection was carried out in collaboration with a market research agency. In total, 1188 Dutch individuals of reproductive age (18-45 years) were invited by email to complete an online ECS questionnaire in 2016. Prior to the start of the questionnaire, a written explanation of the concepts of autosomal recessive (AR) inheritance, carrier status and ECS was presented. RESULTS: The questionnaire was completed by 781 individuals (65.7%), of whom 31% indicated they would take an ECS test themselves. In addition, 55% agreed that ECS should be offered to all prospective parents. The most frequently selected argument in favor of ECS (47.2%) was that participants want to spare a child from a life with a severe hereditary disorder. The reason most often mentioned not to participate in ECS (48%) was that participants reported not having a hereditary disorder in the family. The majority preferred receiving individual test results above a couple-based disclosure method in which participants receive the carrier status results only when they are a carrier couple of the same disorder. Participants with religious beliefs were less likely to participate in ECS, whereas participants who were considering a (future) pregnancy were more likely to participate. CONCLUSION: Our study demonstrates an overall positive attitude among participants of reproductive age in the general Dutch population towards preconception ECS. A striking misconception is that many of the participants believe that ECS is of interest only for those with a positive family history of one of the hereditary disorders. This finding emphasizes the importance of providing understandable, balanced information and education to the general public regarding the concepts of inheritance when presenting the option of carrier screening. Our results provide valuable insights that can be used in the debate about the responsible implementation of preconception ECS for AR disorders, including IEMs.


Assuntos
Triagem de Portadores Genéticos , Conhecimentos, Atitudes e Prática em Saúde , Erros Inatos do Metabolismo/diagnóstico , Adolescente , Adulto , Feminino , Aconselhamento Genético , Testes Genéticos , Humanos , Masculino , Erros Inatos do Metabolismo/genética , Pessoa de Meia-Idade , Países Baixos , Pais , Cuidado Pré-Concepcional , Gravidez , Estudos Prospectivos , Religião , Inquéritos e Questionários , Adulto Jovem
14.
Forensic Sci Med Pathol ; 15(3): 481-484, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30535908

RESUMO

Postmortem genetic testing is a diagnostic tool that is becoming increasingly utilized. The benefits and limitations of genetic testing in cases of sudden, unexpected death in the young (≤ 40 years old) are reviewed from the perspective of the Office of Chief Medical Examiner of the City of New York, whose Molecular Genetics Laboratory, accredited by College of American Pathologists, has had 15 years of postmortem testing experience. Challenges to the interpretation and communication of testing results are highlighted, and opportunities for improving testing yield are discussed for age groups across the lifespan, from infancy to adulthood.


Assuntos
Morte Súbita/etiologia , Testes Genéticos , Adolescente , Adulto , Doenças Cardiovasculares/genética , Canalopatias/genética , Criança , Pré-Escolar , Médicos Legistas , Variações do Número de Cópias de DNA , Triagem de Portadores Genéticos , Aconselhamento Genético , Predisposição Genética para Doença , Variação Genética , Humanos , Lactente , Cidade de Nova Iorque , Prevenção Primária , Morte Súbita do Lactente/genética , Adulto Jovem
15.
Cancer Genet ; 228-229: 93-97, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30553478

RESUMO

Portuguese immigration to Brazil occurred in several waves and greatly contributed to the genetic composition of current Brazilian population. In this study, we evaluated the frequency of a Portuguese founder Alu insertion in BRCA2 exon 3 (c.156_157insAlu) among individuals fulfilling Hereditary Breast and Ovarian Cancer (HBOC) syndrome criteria in 1,380 unrelated families originated from three distinct Brazilian States. We identified the c.156_157insAlu BRCA2 mutation in nine (9/1,380; 0.65%) probands analised. In carrier probands, European ancestry had the highest proportion (80%), followed by the African (10%) and Amerindian and in most families with the rearrangement, haplotype analyses were compatible with the Portuguese ancestral haplotype. In conclusion, the present study reports a low albeit relevant frequency of the Portuguese BRCA2 founder mutation c.156_157insAlu in Brazilian patients at-risk for HBOC Brazilian population.


Assuntos
Genes BRCA2 , Testes Genéticos , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Grupo com Ancestrais do Continente Asiático/genética , Brasil , Estudos de Coortes , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Efeito Fundador , Triagem de Portadores Genéticos , Haplótipos , Humanos , Mutação INDEL
16.
SEMERGEN, Soc. Esp. Med. Rural Gen. (Ed. Impr.) ; 44(7): 485-491, oct. 2018. tab
Artigo em Espanhol | IBECS | ID: ibc-181248

RESUMO

La miocardiopatía hipertrófica es la cardiopatía monogénica más frecuente. Su expresión fenotípica es bastante variable. Hasta en un 60% de los casos se describen mutaciones en los genes que codifican las proteínas del sarcómero cardiaco. La secuenciación masiva del ácido desoxirribonucleico posibilita descubrir nuevos genes responsables de la enfermedad, pero tiene el inconveniente de descubrir numerosas variantes de significado incierto en estos pacientes. La estrategia ante las mismas, sobre todo cuando no se segregan con la enfermedad, es uno de los retos de la genética. Los criterios de patogenicidad pueden ayudar a catalogar esa variante. Las pruebas genéticas al caso índice permiten realizar un diagnóstico y la posibilidad de efectuarlo en cascada a los familiares de primer grado. La presencia, o no, de un genotipo positivo en los familiares determinará las pautas de seguimiento posteriores. La aparición de un genotipo positivo empeora el pronóstico, independientemente del tipo de mutación


Hypertrophic cardiomyopathy is the most common monogenic heart disease. Its phenotypic expression is quite variable. In up to 60% of the cases, mutations are described in the genes coding for cardiac sarcomer proteins. Massive sequencing of deoxyribonucleic acid makes it possible to discover new genes responsible for the disease, but it has the disadvantage of discovering numerous variants of uncertain significance in these patients. The strategy used, especially when they do not segregate with the disease, is one of the challenges of genetics. Pathogenicity criteria may help to catalogue this variant. The genetic tests on the index case a diagnosis to be made, and the possibility of cascading to first degree relatives. The presence or not of a positive genotype in the relatives will determine the subsequent follow-up guidelines. The appearance of a positive genotype is a poor prognosis regardless of the type of mutation


Assuntos
Humanos , Cardiomiopatia Hipertrófica/diagnóstico , Predisposição Genética para Doença , Triagem de Portadores Genéticos , Cardiomiopatia Hipertrófica/genética , Genótipo , Mutação , Fenótipo , Prognóstico , Análise de Sequência de DNA
17.
Bratisl Lek Listy ; 119(7): 425-428, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30160131

RESUMO

OBJECTIVES AND BACKGROUND: Familial Mediterranean Fever (FMF) is characterized by recurrent fever episodes as a result of inflammation of serous membranes. Changes in the number of different mtDNA copy number variations, detected in FMF patients, who developed amyloidosis, might be an important parameter in the understanding of the pathophysiology of the disease. METHODS: Changes in the mtDNA copy number between 50 patients with FMF, who had M694V homozygote mutation and amyloidosis, and 50 healthy controls, who had not any MEFV mutation or FMF clinical finding, were examined. The 22 MEFV mutations were analyzed by Pyromark Q24 system. Quantitative analysis was performed on RT-PCR. The level of mtDNA was calculated using the delta Ct (ΔCt) of average Ct of mtDNA and nDNA (ΔCt = Ct mtDNA-Ct nDNA) in the same well as an exponent of 2 (2ΔCt). RESULTS: A significant decrease in the amount of mtDNA was detected in FMF patients with M694V homozygous mutation carriers, who developed amyloidosis compared to the control group (p < 0.001). CONCLUSION: In this study, mitochondrial dysfunction, which has been identified through changes in the mitochondrial genome in many diseases, was identified by showing that the copy number variations of mtDNA in leukocytes also decreased for FMF disease (Tab. 3, Fig. 1, Ref. 21).


Assuntos
Variações do Número de Cópias de DNA , DNA Mitocondrial/genética , Febre Familiar do Mediterrâneo/genética , Adulto , Amiloidose/diagnóstico , Amiloidose/genética , Análise Mutacional de DNA , Febre Familiar do Mediterrâneo/diagnóstico , Feminino , Triagem de Portadores Genéticos , Homozigoto , Humanos , Leucócitos/metabolismo , Masculino , Pirina/genética , Valores de Referência
18.
Int J Mol Sci ; 19(7)2018 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-29986434

RESUMO

Early infantile epileptic encephalopathies (EIEEs) are a group of neurological disorders characterized by early-onset refractory seizures, severe electroencephalographic abnormalities, and developmental delay or intellectual disability. Recently, genetic studies have indicated that a significant portion of previously cryptogenic EIEEs are single-gene disorders. SPTAN1 is among the genes whose mutations are associated with EIEE development (OMIM# 613477). Here, a case of the c.6923_6928dup (p.Arg2308_Met2309dup) SPTAN1 mutation associated with a severe EIEE is reported. This case shows that mutations in the α20 repeat in the C-terminal of αII spectrin can be associated with EIEE. Duplication seems essential to cause EIEE. This causation is not demonstrated for amino acid deletions in the same spectrin residues. Reportedly, children with p.(Asp2303_Leu2305del) and p.(Gln2304_Gly2306del) deletions have childhood-onset epilepsy and no or marginal magnetic resonance imaging abnormalities, suggesting that not only the location but also the type of mutation plays a role in conditioning nervous system damage. Further studies are needed for a better understanding of the phenotype/genotype correlation in SPTAN1-related encephalopathies.


Assuntos
Proteínas de Transporte/genética , Proteínas dos Microfilamentos/genética , Mutação , Espasmos Infantis/genética , Encéfalo/fisiopatologia , Pré-Escolar , Eletroencefalografia , Estudos de Associação Genética , Triagem de Portadores Genéticos , Genótipo , Humanos , Imagem por Ressonância Magnética , Masculino , Fenótipo , Espasmos Infantis/sangue , Espasmos Infantis/diagnóstico por imagem
19.
An Acad Bras Cienc ; 90(2): 1685-1693, 2018 Apr-Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29898116

RESUMO

Trifolium polymorphum Poir. is an amphicarpic forage legume from southern Brazil, Uruguay, Argentina, Paraguay and Chile. Information on the genetic diversity of natural populations in natural grasslands in southern Brazil is limited. In order to increase the knowledge about this species, an analysis of the genetic diversity was carried out in 10 natural populations of T. polymorphum with the use of 20 microsatellite markers. The expected heterozygosity in T. polymorphum populations ranged from 0.40 to 0.43, with a mean of 0.42. A total of 193 alleles were detected with a mean of 9.3 alleles per locus and polymorphic information content (PIC) for these markers of 0.62 to 0.89 with a mean of 0.84.The grouping based on the Jaccard's coefficient of similarity classified populations, regardless of their regions of origin, into two groups with a mean similarity coefficient of 0.32, reflecting the high genetic variability of the populations, especially those located in the Campanha phytogeographic region. This information on diversity can be used to plan future germplasm collection strategies for conservation purposes and also for the breeding of the species.


Assuntos
DNA de Plantas , Variação Genética , Repetições de Microssatélites/genética , Trifolium/genética , Alelos , Brasil , DNA de Plantas/análise , Triagem de Portadores Genéticos , Polimorfismo Genético , Especificidade da Espécie
20.
Psychiatr Danub ; 30(2): 157-163, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29930225

RESUMO

BACKGROUND: To assess the correlation between the antipsychotics (AP) mean daily doses, hospital stay duration and CYP2D6, DRD2 polymorphisms in naturalistic study. SUBJECTS AND METHODS: CYP2D6 polymorphisms *3, *4, *5, *6, *1XN and DRD2/ANKK1 Taq1A polymorphisms were genotyped in a cohort of 226 Caucasian schizophrenic inpatients. AP daily doses, hospital stay duration and AP treatment duration were taken from medical records. To compare mean daily doses of AP among CYP2D6 PMs, EMs, UMs and DRD2/ANKK1 Taq1A carriers the actual AP doses were converted to chlorpromazine (CPZ) equivalents and DDD (defined daily dose). RESULTS: Significant correlation (p=0.004) between CYP2D6 metabolic activity and AP mean daily doses was observed only among DRD2/ANKK1 Taq1A polymorphic allele carriers: 250.53 (95%CI: 154.90-346.17), 473.82 (95%CI: 426.99-520.64) 602.77 (95%CI: 469.65-735.88) CPZ equivalents in PMs, EMs and UMs, consequently. PMs with DRD2/ANKK1 Taq1A CT genotype received significantly lower doses of AP comparing to CC genotype (p=0.02). Mean hospital stay duration of PMs+UMs was significantly higher comparing to EMs (66.4 days (95% CI: 56.9-75.8) vs 50.2 days (95%CI: 45.5-54.7); p=0.047). CONCLUSIONS: In a cohort of schizophrenia inpatients CYP2D6 metabolic activity affects mean AP daily dose only in the presence of DRD2 Taq1A polymorphic allele. CYP2D6 metabolic activity correlates independently from DRD2 Taq1A polymorphism with hospital stay duration. Subpopulation of schizophrenia inpatients with altered CYP2D6 activity (PMs and UMs) carriers of Taq1A polymorphisms needs special attention of clinicians in aligning of AP treatment.


Assuntos
Antipsicóticos/uso terapêutico , Citocromo P-450 CYP2D6/genética , Polimorfismo Genético/genética , Receptores de Dopamina D2/genética , Esquizofrenia/tratamento farmacológico , Esquizofrenia/genética , Taq Polimerase/genética , Adolescente , Adulto , Alelos , Estudos de Coortes , Relação Dose-Resposta a Droga , Feminino , Triagem de Portadores Genéticos , Genótipo , Humanos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Proteínas Serina-Treonina Quinases/genética , Psicologia do Esquizofrênico , Estatística como Assunto , Adulto Jovem
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