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1.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(1): 57-59, 2020 Jan 10.
Artigo em Chinês | MEDLINE | ID: mdl-31922598

RESUMO

OBJECTIVE: To explore the genetic basis of a child with idiopathic mental retardation. METHODS: Clinical data and peripheral blood sample of the child were collected. Genomic DNA was extracted and subjected to copy number analysis using single nucleotide polymrophism array comparative genome hybridization (SNP-aCGH) and targeted capture and next generation sequencing (NGS). RESULTS: No microdeletion/microduplication were detected by SNP-aCGH. NGS has detected homozygous c.722delA (p.Asp241fs) variant of the LISN1 gene, which is known to underlie autosomal recessive mental retardation-27 (MRT 27). Both parents are carriers of the variant, conforming to the autosomal recessive inheritance. CONCLUSION: A novel pathogenic variant of the LINS1 gene has been identified, which probably underlies the MRT 27 in the patient.


Assuntos
Deficiência Intelectual , Proteínas , Criança , Hibridização Genômica Comparativa , Sequenciamento de Nucleotídeos em Larga Escala , Homozigoto , Humanos , Deficiência Intelectual/genética , Proteínas/genética
2.
Medicine (Baltimore) ; 98(52): e18523, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31876746

RESUMO

Prostate cancer (PCa) is a frequently diagnosed malignant solid tumor in men. The etiology of PCa has been attributed to both environmental and genetic factors. In recent years, many studies have reported that miRNA gene single-nucleotide polymorphisms (SNPs) influence the susceptibility to several diseases such as cancer. To date, the mechanisms of PCa have remained unknown. The main aim of this study was to evaluate the association between PCa susceptibility and miRNA gene SNPs. A total of 156 PCa cases and 188 control subjects were included in this case-control study. The data were collected from hospitalized cases. We collected the demographic characteristic information, which included age, body mass index, tobacco smoking, alcohol consumption, and family history of cancer. Polymorphisms were analyzed by the ligase detection reaction. Unconditional logistic and stratified analyses were used to analyze the association between these SNPs and PCa susceptibility and to calculate the adjusted odds ratios (ORs) and the 95% confidence intervals (CIs). Cox regression model and the log-rank test were used to test the association between genetic variants and the overall survival. We found that miR-23a gene polymorphism rs3745453 carrying CC homozygotes had a 4.16-fold increased risk (95% CI = 1.30-13.25) than those carrying the TT/CT genotypes (P = .02), and the C allele displayed a higher prevalence of PCa than the T allele (OR = 1.68, 95% CI = 1.16-2.45, P = .01). Moreover, miR-23a showed that the homozygous carriers of the C-variant significantly increased the risk of survival rate as compared to the carriers of the TT/CT genotype (OR = 9.67, 95% CI = 2.83-33.09, P = .001). The rs3745453 polymorphism was potentially associated with PCa in the Chinese Han population and had an interactive relationship with the environmental factors.


Assuntos
Predisposição Genética para Doença/genética , MicroRNAs/genética , Polimorfismo de Nucleotídeo Único/genética , Neoplasias da Próstata/genética , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , China/epidemiologia , Homozigoto , Humanos , Masculino , Neoplasias da Próstata/epidemiologia , Fatores de Risco
3.
Clin Exp Rheumatol ; 37 Suppl 121(6): 142-146, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31856934

RESUMO

OBJECTIVES: To describe phenotypic and functional characteristics of patients with the homozygous c.973-2A>G splice site mutation in the adenosine deaminase 2 (ADA2) gene (rs139750129), resulting in deficiency of ADA2 (DADA2). METHODS: We present case synopses of six patients from three unrelated families. Clinical data were analysed and next-generation sequencing (NGS) was performed. We also tested for aberrant RNA splicing and measured ADA2 enzyme activity. RESULTS: One family had common DADA2 symptoms, whereas Behçet's disease-like manifestations were observed in the other two families. We detected the homozygous c.973-2A>G splice site mutation in ADA2 in all patients tested. ADA2 enzyme activity was significantly lower in patients than in healthy controls, but no correlation between ADA2 activity levels and disease severity was observed. Aberrant splicing was detected in a minority of mRNA transcripts, but the formation of other, undetected, aberrant splicing products could not be excluded. Patients were treated with TNF-α inhibitors to prevent recurrence of inflammatory findings including cerebral vasculitis-associated stroke. CONCLUSIONS: We describe three families with the same homozygous splice site mutation in ADA2 and observed a novel combination of manifestations resembling Behçet's disease. This further expands the range of phenotypes caused by ADA2 mutations, although no complete genotype-phenotype association could be determined. Even without active disease, the risk of stroke should be addressed in making decisions regarding treatment of DADA2 patients.


Assuntos
Adenosina Desaminase , Síndrome de Behçet/genética , Peptídeos e Proteínas de Sinalização Intercelular , Mutação/genética , Adenosina Desaminase/deficiência , Adenosina Desaminase/genética , Variação Biológica da População , Estudos de Associação Genética , Homozigoto , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/deficiência , Peptídeos e Proteínas de Sinalização Intercelular/genética
4.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(10): 957-960, 2019 Oct 10.
Artigo em Chinês | MEDLINE | ID: mdl-31598935

RESUMO

OBJECTIVE: To explore the genetic basis of a patient with early-onset Parkinson disease from a consanguineous family. METHODS: Homozygosity mapping and Sanger sequencing of cDNA were used to identify the causative mutation. RESULTS: A homozygous missense variation (c.56C>G, p.Thr19Arg) in the PARK7 gene was identified in the patient. In silico analysis suggested the c.56C>G variation to be pathogenic. CONCLUSION: Homozygous c.56C>G variation of the PARK7 gene was the disease-causing variation in this family.


Assuntos
Doença de Parkinson/genética , Proteína Desglicase DJ-1/genética , Consanguinidade , Homozigoto , Humanos , Mutação de Sentido Incorreto , Linhagem
5.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(5): 1580-1584, 2019 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-31607315

RESUMO

OBJECTIVE: To analyze the hematological characteristics of HbE homozygotes. METHODS: Complete blood cells count and hemoglobin electrophoresis were used for phenotypic analysis of 78 cases with HbE homozygotes from Yunnan province, China. The PCR-fluorescence hybridization was used to detect the common gene mutation of thalassemia. The hematological indexes, including MCV, MCH, Hb, HbA2, HbF and HbE were statistically analyzed between groups with different sex, ages and compound α thalassemia status. RESULTS: In HbE homozygotes (HbEE), 89.5% (17/19) children presented mild to moderate microcytic hypochromic anemia, and 10.5% of them presented moderate anemia. 39.6% (19/48) of women with HbEE developed mild anemia ,while 11 cases of male with HbE homozygotes were asymptomatic. The levels of MCV and MCH in HbE homozygotes increased by co-inheritance of α thalassemia mutation. CONCLUSION: The clinical phenotype of HbE homozygote shows highly heterogeneous, which is relates with age, sex and co-inheriting α-globin genotypes. In Hb EE women and children are more likely to develop mild to moderate anemia. The microcytic hypochromic anemia degree is relieved when HbEE combined with α- thalassemia.


Assuntos
Hemoglobina E/genética , Criança , China , Feminino , Genótipo , Homozigoto , Humanos , Masculino , Fenótipo , Talassemia alfa
6.
BMC Med Genet ; 20(1): 152, 2019 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-31488071

RESUMO

BACKGROUND: Consanguine families display a high degree of homozygosity which increases the risk of family members suffering from autosomal recessive disorders. Thus, homozygous mutations in monogenic obesity genes may be a more frequent cause of childhood obesity in a consanguineous population. METHODS: We identified 23 probands from 23 Pakistani families displaying autosomal recessive obesity. We have previously excluded mutations in MC4R, LEP and LEPR in all probands. Using a chip-based, target-region capture array, 31 genes involved in monogenic forms of obesity, were screened in all probands. RESULTS: We identified 31 rare non-synonymous possibly pathogenic variants (28 missense and three nonsense) within the 31 selected genes. All variants were heterozygous, thus no homozygous pathogenic variants were found. Two of the rare heterozygous nonsense variants identified (p.R75X and p.R481X) were found in BBS9 within one proband, suggesting that obesity is caused by compound heterozygosity. Sequencing of the parents supported the compound heterozygous nature of obesity as each parent was carrying one of the variants. Subsequent clinical investigation strongly indicated that the proband had Bardet-Biedl syndrome. CONCLUSIONS: Mutation screening in 31 genes among probands with severe early-onset obesity from Pakistani families did not reveal the presence of homozygous obesity causing variants. However, a compound heterozygote carrier of BBS9 mutations was identified, indicating that compound heterozygosity must not be overlooked when investigating the genetic etiology of severe childhood obesity in populations with a high degree of consanguinity.


Assuntos
Consanguinidade , Estudos de Associação Genética , Predisposição Genética para Doença/genética , Obesidade Pediátrica/genética , Síndrome de Bardet-Biedl/genética , Índice de Massa Corporal , Pré-Escolar , Códon sem Sentido , Feminino , Genótipo , Heterozigoto , Homozigoto , Humanos , Leptina/genética , Masculino , Mutação , Paquistão , Obesidade Pediátrica/fisiopatologia , Linhagem , Receptor Tipo 4 de Melanocortina/genética , Receptores para Leptina/genética
7.
Eur J Endocrinol ; 181(5): K43-K53, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31539878

RESUMO

Background: IGF1 is a key factor in fetal and postnatal growth. To date, only three homozygous IGF1 gene defects leading to complete or partial loss of IGF1 activity have been reported in three short patients born small for gestational age. We describe the fourth patient with severe short stature presenting a novel homozygous IGF1 gene mutation. Results: We report a boy born from consanguineous parents at 40 weeks of gestational age with intrauterine growth restriction and severe postnatal growth failure. Physical examination revealed proportionate short stature, microcephaly, facial dysmorphism, bilateral sensorineural deafness and mild global developmental delay. Basal growth hormone (GH) fluctuated from 0.2 to 29 ng/mL, while IGF1 levels ranged from -1.15 to 2.95 SDS. IGFBP3 was normal-high. SNP array delimited chromosomal regions of homozygosity, including 12q23.2 where IGF1 is located. IGF1 screening by HRM revealed a homozygous missense variant NM_000618.4(IGF1):c.322T>C, p.(Tyr108His). The change of the highly conserved Tyr60 in the mature IGF1 peptide was consistently predicted as pathogenic by multiple bioinformatic tools. Tyr60 has been described to be critical for IGF1 interaction with type 1 IGF receptor (IGF1R). In vitro, HEK293T cells showed a marked reduction of IGF1R phosphorylation after stimulation with serum from the patient as compared to sera from age-matched controls. Mutant IGF1 was also less efficient in inducing cell growth. Conclusion: The present report broadens the spectrum of clinical and biochemical presentation of homozygous IGF1 defects and underscores the variability these patients may present depending on the IGF/IGF1R pathway activity.


Assuntos
Transtornos do Crescimento/genética , Perda Auditiva Neurossensorial/genética , Fator de Crescimento Insulin-Like I/deficiência , Mutação de Sentido Incorreto/genética , Anormalidades Múltiplas/genética , Proliferação de Células , Biologia Computacional , Simulação por Computador , Retardo do Crescimento Fetal/genética , Células HEK293 , Homozigoto , Humanos , Lactente , Fator de Crescimento Insulin-Like I/genética , Masculino , Linhagem , Polimorfismo de Nucleotídeo Único/genética , Receptores de Somatomedina/genética , Tirosina/genética
8.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(8): 817-820, 2019 Aug 10.
Artigo em Chinês | MEDLINE | ID: mdl-31400136

RESUMO

OBJECTIVE: To explore clinical and genetic features of a pedigree affected with autosomal recessive neuromyotonia and axonal neuropathy (NMAN). METHODS: For the proband and her parents, clinical data was collected, genomic DNA was extracted from peripheral blood samples. Triplet primed-PCR was carried out to detect dynamic mutation of DMPK and ZNF9 genes, which are responsible for myotonic dystrophy, by capillary electrophoresis. High-throughput sequencing was used to screen variants of candidate genes for Mendelian disorders involving the nervous system. Candidate variants were confirmed by Sanger sequencing. The genotype of the variant was determined in the parents and 100 healthy controls. Pathogenicity of the variant was assessed by ACMG criterion. RESULTS: Mutation of DMPK and ZNF9 genes was excluded. DNA sequencing has identified a homozygous missense variant (c.335C>T, p.R119W) in the HINT1 gene. Both parents were found to carry the variant. The same variant was not found among the healthy controls. According to the ACMG criterion, the missense variant was classified as a pathogenic variant. CONCLUSION: The c.335C>T (p.R119W) of the HINT1 gene probably underlie the disease in this pedigree. Above finding provided further evidence for the connection between HINT1 and NMAN and enriched the mutation spectrum of HINT1 gene.


Assuntos
Síndrome de Isaacs/genética , Proteínas do Tecido Nervoso/genética , Feminino , Genótipo , Homozigoto , Humanos , Linhagem
9.
Pestic Biochem Physiol ; 159: 9-16, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31400789

RESUMO

An L1024F substitution in the para gene, which encodes a subunit of the voltage-gated sodium channel, has been implicated in pyrethroid resistance in a mite pest, Halotydeus destructor, which attacks rape and other grain crops. A high-resolution melt (HRM) genotyping assay was developed for testing the relative pyrethroid susceptibility of different para genotypes and for high-throughput field screening of resistant alleles. The L1024F mutation was found to be incompletely recessive in phenotypic laboratory bioassays with the pyrethroid pesticide, bifenthrin. While the resistance ratio of heterozygotes (RS) to susceptible homozygotes (SS) was <6 in 24 h bioassays, the resistant homozygotes (RR) (with a resistance ratio > 200,000) survived the recommended field rate of bifenthrin (100 mgL-1). HRM genotyping of mites from field populations across Australia indicated the presence of resistant alleles in Western Australia and South Australia, but not in Victoria and New South Wales. The assay developed will be useful for routine screening of pyrethroid resistance, and the dominance relationships established here point to useful resistance management strategies involving the maintenance of reservoirs of susceptible mites to dilute resistant homozygotes in a population.


Assuntos
Inseticidas/farmacologia , Ácaros/efeitos dos fármacos , Piretrinas/farmacologia , Animais , Genótipo , Heterozigoto , Homozigoto , Resistência a Inseticidas/genética , Programas de Rastreamento , Ácaros/genética
10.
Plant Mol Biol ; 101(4-5): 355-371, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31401729

RESUMO

KEY MESSAGE: Protoplasts can be used for genome editing using several different CRISPR systems, either separately or simultaneously, and that the resulting mutations can be recovered in regenerated non-chimaeric plants. Protoplast transfection and regeneration systems are useful platforms for CRISPR/Cas mutagenesis and genome editing. In this study, we demonstrate the use of Cpf1 (Cas12a) and nCas9-activation-induced cytidine deaminase (nCas9-Target-AID) systems to mutagenize Nicotiana tabacum protoplasts and to regenerate plants harboring the resulting mutations. We analyzed 20 progeny plants of Cas12a-mediated phytoene desaturase (PDS) mutagenized regenerants, as well as regenerants from wild-type protoplasts, and confirmed that their genotypes were inherited in a Mendelian manner. We used a Cas9 nickase (nCas9)-cytidine deaminase to conduct C to T editing of the Ethylene receptor 1 (ETR1) gene in tobacco protoplasts and obtained edited regenerates. It is difficult to obtain homozygous edits of polyploid genomes when the editing efficiency is low. A second round of mutagenesis of partially edited regenerants (a two-step transfection protocol) allowed us to derive ETR1 fully edited regenerants without the need for sexual reproduction. We applied three different Cas systems (SaCas9, Cas12a, and nCas9-Traget AID) using either a one-step or a two-step transfection platform to obtain triply mutated and/or edited tobacco regenerants. Our results indicate that these three Cas systems can function simultaneously within a single cell.


Assuntos
Edição de Genes/métodos , Tabaco/genética , Proteínas de Bactérias/genética , Sistemas CRISPR-Cas , Francisella/genética , Homozigoto , Proteínas de Plantas/genética , Tetraploidia
11.
Clin Biochem ; 73: 70-76, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31386834

RESUMO

BACKGROUND: Chromosomal region 9p21.3 is most robustly associated with coronary artery disease (CAD) in western European populations. However, heterogeneity in CAD phenotypes leads to uncertainty whether 9p21.3 is associated with stable and/or acute clinical presentations of CAD. 9p21.3 is rich in regulatory elements, but the underlying mechanisms of its actions in CAD remain unclear. We investigate the association of 9p21.3 two haplotype blocks lead variants (rs10757278 and rs518394) with first-ever non-fatal myocardial infarction (MI) in CAD patients and their association with CDKN2B mRNA expression in peripheral blood mononuclear cells 6 months after the event. METHODS: We included CAD patients with sustained first MI (n = 523) and controls (n = 583). Gene expression was assessed in 72 patients 6 months after MI and 43 healthy controls. TaqMan® technology was used for the gene expression and genotyping analysis. RESULTS: CDKN2B mRNA was significantly lower in MI patients compared with the controls (p = 0.002) and in patients carrying the rs10757278 G risk allele versus AA homozygotes (p = 0.012) 6 months after the event. While we confirmed the association of rs10757278 with CDKN2B expression in MI patients, we failed to find an association between the investigated variants and MI or disease burden. CONCLUSIONS: We suggest a dysregulation of gene expression in the 9p21.3 region six months after acute MI, which is affected by a genetic variant in patients. The rs10757278 rare allele is one factor that might lead to prolonged risk for proatherogenic complications.


Assuntos
Cromossomos Humanos Par 9/genética , Doença da Artéria Coronariana , Inibidor de Quinase Dependente de Ciclina p15/biossíntese , Regulação da Expressão Gênica , Haplótipos , Infarto do Miocárdio , Elementos de Resposta , Adulto , Idoso , Alelos , Cromossomos Humanos Par 9/metabolismo , Doença da Artéria Coronariana/enzimologia , Doença da Artéria Coronariana/genética , Inibidor de Quinase Dependente de Ciclina p15/genética , Feminino , Seguimentos , Homozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/enzimologia , Infarto do Miocárdio/genética
12.
Anim Genet ; 50(5): 501-511, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31393638

RESUMO

The population of Spanish sheep has decreased from 24 to 15 million heads in the last 75 years due to multiple social and economic factors. Such a demographic reduction might have caused an increase in homozygosity and inbreeding, thus limiting the viability of local breeds with excellent adaptations to harsh ecosystems. The main goal of our study was to investigate the homozygosity patterns of 11 Spanish ovine breeds and to elucidate the relationship of these Spanish breeds with reference populations from Europe, Africa and the Near East. By using Ovine SNP50 BeadChip data retrieved from previous publications, we have found that the majority of studied Spanish ovine breeds have close genetic relatedness with other European populations; the one exception is the Canaria de Pelo breed, which is similar to North African breeds. Our analysis has also demonstrated that, with few exceptions, the genomes of Spanish sheep harbor fewer than 50 runs of homozygosity (ROH) with a total length of less than 350 Mb. Moreover, the frequencies of very long ROH (>30 Mb) are very low, and the inbreeding coefficients (FROH ) are generally small (FROH  < 0.10), ranging from 0.008 (Rasa Aragonesa) to 0.086 (Canaria de Pelo). The low levels of homozygosity observed in the 11 Spanish sheep under analysis might be due to their extensive management and the high number of small to medium farms.


Assuntos
Homozigoto , Carneiro Doméstico/genética , Animais , Variação Genética , Genética Populacional , Polimorfismo de Nucleotídeo Único , Carneiro Doméstico/classificação , Espanha
13.
Gene ; 715: 144027, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31374327

RESUMO

OBJECTIVES: To explore the clinical and molecular characteristics of a Chinese Zhuang minority patient with leukocyte adhesion deficiency type-1 (LAD-1) and glucose-6-phosphate dehydrogenase deficiency (G6PDD). METHODS: Routine clinical and physical examinations were performed, and patient data was collected and analyzed. Protein expression levels of Itgb2 and glucose-6-phosphate dehydrogenase (G6pd) proteins were assessed by flow cytometry and the glucose-6-phosphate (G6P) substrate method, respectively. Whole exome sequencing was performed to investigate genetic variations of the patient and his parents. RESULTS: The patient had fester disease and delayed separation of the umbilical cord at birth. Staphylococcus was detected in the fluid secretion of the auditory meatus of the patient. He exhibited a recurrent cheek scab, swollen hand, and swollen gum. Hematological examination indicated dramatic elevation of leukocytes including lymphocytes, monocytes, neutrophils and eosinophils. A novel homozygous mutation was detected in the ITGB2 gene of the patient, which was determined to be a two nucleotide deletion at the site of c.1537-1538 (c.1537-1538delGT), causing a frameshift of 24 amino acids from p.513 and inducing a stop codon (p.V513Lfs*24). A base substitution mutation was identified at c.1466 (c.1466G>T) of G6PD on chromosome X of the patient, which resulted in an amino acid change from arginine to leucine at p.489 (p.R489L). The patient also showed deficient lymphocyte expression of CD18 (2.99%) and significant downregulation of the G6pd protein. CONCLUSIONS: The patient was diagnosed with G6PDD and moderate LAD-1. The combination of LAD-1 and G6PDD in this case may have been due to the high incidence of genetic disease in this minority ethnic population. Analyzing existing LAD-1 and G6PDD cases from different populations can facilitate disease diagnosis and treatment. Particularly, reporting pathogenic mutations of LAD-1 and G6PDD will be crucial for genetic testing and prenatal diagnosis in an effort to decrease the incidence of these diseases.


Assuntos
Antígenos CD18/genética , Deficiência de Glucosefosfato Desidrogenase/genética , Homozigoto , Síndrome da Aderência Leucocítica Deficitária/genética , Mutação de Sentido Incorreto , Substituição de Aminoácidos , Grupo com Ancestrais do Continente Asiático , Antígenos CD18/metabolismo , Deficiência de Glucosefosfato Desidrogenase/patologia , Humanos , Lactente , Síndrome da Aderência Leucocítica Deficitária/metabolismo , Síndrome da Aderência Leucocítica Deficitária/patologia , Leucócitos/metabolismo , Leucócitos/patologia , Masculino
14.
BMC Med Genet ; 20(1): 147, 2019 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-31464584

RESUMO

BACKGROUND: The SLC29A3 gene, encoding a nucleoside transporter protein, is found in intracellular membranes. Based on the literatures, mutations in this gene cause a wide range of clinical manifestations including H syndrome, pigmented hypertrichosis with insulin dependent diabetes, Faisalabad histiocytosis, and dysosteosclerosis. However, all these disorders with their different names and terminologies are actually the same entity termed H syndrome. CASE PRESENTATION: We report four GJB2 and GJB6 negative deaf patients from two Iranian related families who present the associated symptoms of SLC29A3-disorder. Whole Exome Sequencing (WES) using Next Generation Illumina Sequencing was used to enrich all exons of protein-coding genes as well as some other important genomic regions in one of studied patients. A novel homozygous frame-shift mutation c.307-308delTT (p.Phe103fs) in exon 3 of SLC29A3 gene was identified in a 35 years old man with profound hearing loss, camptodactyly, rheumatoid arthritis and delayed puberty without any skin changes, short stature and insulin dependent diabetes mellitus. The mutation found was also confirmed by Sanger sequencing in other studied patients and their healthy parents. In compared to proband, however the clinical manifestations of these patients were different, indicating variable expressivity of mutant SLC29A3 gene as well as possible involvement of other modifier genes. CONCLUSION: The present study uncovered a rare novel homozygous frame-shift mutation c.307-308delTT in SLC29A3 gene of four related patients with various manifestation of SLC29A3-disorder. Such studies can help to conduct genetic counseling and subsequently, prenatal diagnosis more accurately for individuals at the high risk of these types of genetic disorders.


Assuntos
Contratura/genética , Mutação da Fase de Leitura , Predisposição Genética para Doença/genética , Perda Auditiva Neurossensorial/genética , Histiocitose/genética , Homozigoto , Proteínas de Transporte de Nucleosídeos/genética , Adulto , Sequência de Bases , Conexina 30/genética , Conexinas/genética , Diabetes Mellitus Tipo 1/genética , Éxons , Feminino , Estudos de Associação Genética , Humanos , Irã (Geográfico) , Masculino , Pessoa de Meia-Idade , Linhagem
15.
BMC Med Genet ; 20(1): 143, 2019 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-31420020

RESUMO

BACKGROUND: Mutations of the autoimmune regulator gene (AIRE), located on chromosome 21q22.3, are recognized as the cause of a rare monogenic organ-specific autoimmune disorder called autoimmune polyglandular syndrome type 1 (APS-1). Three major components of this syndrome include chronic mucocutaneous candidiasis (CMC), hypoparathyroidism, and adrenocortical failure. CASE PRESENTATION: We report a 19-year-old girl, who was born in an Iranian Muslim family with a clinical diagnosis of APS-1. To identify the causative mutation, a direct sequencing of the entire AIRE gene sequence was performed by Sanger sequencing method. Three distinct variants were discovered, including c.1095 + 2 T > A, c.1197 T > C (rs1800521) and c.1578 T > C (rs1133779), in intron 9, exons 10 and 14 of the AIRE gene, respectively. CONCLUSIONS: To the best of our knowledge, this is the first report of an Iranian Muslim APS-1 patient with combination of these variations. In addition, the effect of c.1095 + 2 T > A mutation on AIRE mRNA expression was reported for the first time. This study expands the diversity of variants that could cause APS-1. More genetic studies are required to determine the exact frequency of these variants and their diagnostic significance.


Assuntos
Predisposição Genética para Doença/genética , Mutação , Poliendocrinopatias Autoimunes/genética , Fatores de Transcrição/genética , Sequência de Bases , Éxons , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Estudos de Associação Genética , Homozigoto , Humanos , Íntrons , Irã (Geográfico) , Linhagem , Poliendocrinopatias Autoimunes/terapia , Polimorfismo de Nucleotídeo Único , RNA Mensageiro/metabolismo , Fatores de Transcrição/metabolismo , Adulto Jovem
16.
BMC Med Genet ; 20(1): 145, 2019 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-31443639

RESUMO

BACKGROUND: Inherited palmoplantar keratodermas (PPKs) are clinically and genetically heterogeneous and phenotypically diverse group of genodermatoses characterized by hyperkeratosis of the palms and soles. More than 20 genes have been reported to be associated with PPKs including desmoglein 1 (DSG1) a key molecular component for epidermal adhesion and differentiation. Mal de Meleda (MDM) is a rare inherited autosomal recessive genodermatosis characterized by transgrediens PPK, associated with mutations in the secreted LY6/PLAUR domain containing 1 (SLURP1) gene. METHODS: This study describes clinical as well as genetic whole exome sequencing (WES) and di-deoxy sequencing investigations in two Pakistani families with a total of 12 individuals affected by PPK. RESULTS: WES identified a novel homozygous nonsense variant in SLURP1, and a novel heterozygous nonsense variant in DSG1, as likely causes of the conditions in each family. CONCLUSIONS: This study expands knowledge regarding the molecular basis of PPK, providing important information to aid clinical management in families with PPK from Pakistan.


Assuntos
Antígenos Ly/genética , Desmogleína 1/genética , Estudos de Associação Genética , Predisposição Genética para Doença/genética , Ceratodermia Palmar e Plantar/genética , Ativador de Plasminogênio Tipo Uroquinase/genética , Adolescente , Adulto , Criança , Códon sem Sentido , Grupos Étnicos , Feminino , Variação Genética , Genótipo , Heterozigoto , Homozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Paquistão , Linhagem , Sequenciamento Completo do Exoma , Adulto Jovem
17.
Anim Genet ; 50(5): 512-525, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31365135

RESUMO

A dataset consisting of 787 animals with high-density SNP chip genotypes (346 774 SNPs) and 939 animals with medium-density SNP chip genotypes (33 828 SNPs) from eight indigenous Swiss sheep breeds was analyzed to characterize population structure, quantify genomic inbreeding based on runs of homozygosity and identify selection signatures. In concordance with the recent known history of these breeds, the highest genetic diversity was observed in Engadine Red sheep and the lowest in Valais Blacknose sheep. Correlation between FPED and FROH was around 0.50 and thereby lower than that found in similar studies in cattle. Mean FROH estimates from medium-density data and HD data were highly correlated (0.95). Signatures of selection and candidate gene analysis revealed that the most prominent signatures of selection were found in the proximity of genes associated with body size (NCAPG, LCORL, LAP3, SPP1, PLAG1, ALOX12, TP53), litter size (SPP1), milk production (ABCG2, SPP1), coat color (KIT, ASIP, TBX3) and horn status (RXFP2). For the Valais Blacknose sheep, the private signatures in proximity of genes/QTL influencing body size, coat color and fatty acid composition were confirmed based on runs of homozygosity analysis. These private signatures underline the genetic uniqueness of the Valais Blacknose sheep breed. In conclusion, we identified differences in the genetic make-up of Swiss sheep breeds, and we present relevant candidate genes responsible for breed differentiation in locally adapted breeds.


Assuntos
Carneiro Doméstico/genética , Animais , Cruzamento , Genética Populacional , Homozigoto , Polimorfismo de Nucleotídeo Único , Carneiro Doméstico/classificação , Suíça
18.
Medicine (Baltimore) ; 98(30): e16504, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31348261

RESUMO

RATIONALE: Autosomal recessive distal renal tubular acidosis (dRTA) is a rare condition, most cases of which are caused by genetic mutations. Several loss-of-function mutations in the ATP6V0A4 gene have been recently reported. PATIENT CONCERNS: A 2-month, 24-day-old Chinese girl presenting with vomiting and diarrhea. DIAGNOSIS: dRTA was established by metabolic acidosis and hypokalemia. Mutational analysis of the ATP6V0A4 gene revealed a homozygous deletion of exons 13 and 14. The father was found to have a heterozygous loss of both exons, whereas the mother was normal. INTERVENTIONS: Patient was treated with potassium citrate. OUTCOMES: The patient has shown normal pH and potassium levels. LESSONS: This is the first case of a homozygous deletion in ATP6V0A4 reported in the literature. Although the initial auditory screening was normal in this case, this patient will nevertheless undergo long-term auditory testing.


Assuntos
Acidose Tubular Renal/genética , Acidose/tratamento farmacológico , Acidose/etiologia , Acidose Tubular Renal/complicações , Acidose Tubular Renal/diagnóstico , China , Feminino , Homozigoto , Humanos , Hipopotassemia/tratamento farmacológico , Hipopotassemia/etiologia , Lactente , Citrato de Potássio/uso terapêutico , Deleção de Sequência
19.
Gene ; 715: 143970, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31330235

RESUMO

BACKGROUND: Bicuspid aortic valve (BAV) formation is genetically determined, with reduced penetrance and variable expressivity. NOTCH1 is a proven candidate gene and its mutations have been found in familial and sporadic cases of BAV. METHODS: 66 BAV patients from the GISSI VAR study were genotyped for the NOTCH1 gene. RESULTS: We identified 63 variants, in heterozygous and homozygous states. Fifty-two are common polymorphisms present in almost all patients. Eleven variants are new and never yet reported: two are non-synonymous substitutions, Gly540Asp in exon 10 and Glu851Gln in exon 16; one is in the 3'UTR region and seven in introns, one corresponds to a T allele insertion in intron 27. We selected four statistically noteworthy and seven new variants identified in six BAV patients and correlated them with clinical and demographic variables and with imaging and histological parameters. Preliminary data show that four were BAV patients with isolated stenosis in patients over 60 aged. These variants may correlate with a later need for surgery for the presence of stenosis and not aortic valve regurgitation or ascending aortic aneurysm. CONCLUSIONS: Completing the genotyping of 62 BAV patients we found 11 new variants in the NOTCH1 gene never yet reported. These findings confirm that the identification of new, clinically remarkable biomarkers for BAV requires a deeper genetic understanding of the NOTCH1 gene variants, which could be targeted by future diagnostic and therapeutic strategies.


Assuntos
Estenose da Valva Aórtica/genética , Valva Aórtica/anormalidades , Doenças das Valvas Cardíacas , Mutação de Sentido Incorreto , Penetrância , Receptor Notch1/genética , Adulto , Alelos , Substituição de Aminoácidos , Éxons , Feminino , Heterozigoto , Homozigoto , Humanos , Íntrons , Itália , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Análise de Sequência de DNA
20.
BMC Med Genet ; 20(1): 118, 2019 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-31266487

RESUMO

BACKGROUND: Recessive mutations of coding regions and splice sites of the SLC26A4 gene cause hearing loss with enlargement of the vestibular aqueduct (EVA). Some patients also have a thyroid iodination defect that can lead to multinodular goiter as part of Pendred syndrome. A haplotype of variants upstream of SLC26A4, called CEVA, acts as a pathogenic recessive allele in trans to mutations affecting the coding regions or splice sites of SLC26A4. Our first hypothesis is that CEVA, acting as a pathogenic recessive allele, is correlated with a less severe phenotype than mutations affecting the coding regions and splice sites of SLC26A4. Our second hypothesis is that CEVA acts as a modifier of the phenotype in patients with EVA caused by mutations affecting the coding regions or splice sites of both alleles of SLC26A4 or EVA caused by other factors. METHODS: This was a prospective cohort study of 114 individuals and 202 ears with EVA. To test our first hypothesis, we compared the thyroid and auditory phenotypes of subjects with mutations affecting coding regions of both alleles of SLC26A4 with those of subjects carrying CEVA in trans to mutations affecting the coding regions. To test our second hypothesis, we compared the phenotypes associated with the presence versus absence of CEVA among subjects with no coding region mutations, as well as among subjects with mutations affecting coding regions of both alleles. RESULTS: Subjects carrying CEVA in trans to a mutation of SLC26A4 have a normal thyroid phenotype and less severe hearing loss in comparison to individuals with mutations affecting coding regions of both alleles of SLC26A4. In subjects with no mutant alleles of SLC26A4, hearing loss was more severe in subjects who carry the CEVA haplotype in comparison to non-carriers. There was no correlation of CEVA with the phenotype of subjects with mutations affecting coding regions of both alleles. CONCLUSIONS: CEVA, acting as a likely pathogenic recessive allele, is associated with a less severe phenotype than alleles with a mutation affecting the coding regions or splice sites of SLC26A4. CEVA may act as a genetic modifier in patients with EVA caused by other factors.


Assuntos
Bócio Nodular/genética , Haplótipos , Perda Auditiva Neurossensorial/genética , Mutação , Fenótipo , Transportadores de Sulfato/genética , Aqueduto Vestibular/anormalidades , Aqueduto Vestibular/patologia , Adolescente , Adulto , Alelos , Audiometria , Criança , Pré-Escolar , Cromossomos Humanos Par 7/genética , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Variação Genética , Genótipo , Audição/genética , Perda Auditiva/genética , Heterozigoto , Homozigoto , Humanos , Masculino , Estudos Prospectivos , Sítios de Splice de RNA , Glândula Tireoide , Adulto Jovem
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