Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 82
Filtrar
1.
Breast Cancer Res Treat ; 189(2): 533-539, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34196900

RESUMO

PURPOSE: Mutations in hereditary breast cancer genes play an important role in the risk for cancer. METHODS: Cancer susceptibility genes were sequenced in 664 unselected breast cancer cases from Guatemala. Variants were annotated with ClinVar and VarSome. RESULTS: A total of 73 out of 664 subjects (11%) had a pathogenic variant in a high or moderate penetrance gene. The most frequently mutated genes were BRCA1 (37/664, 5.6%) followed by BRCA2 (15/664, 2.3%), PALB2 (5/664, 0.8%), and TP53 (5/664, 0.8%). Pathogenic variants were also detected in the moderate penetrance genes ATM, BARD1, CHEK2, and MSH6. The high ratio of BRCA1/BRCA2 mutations is due to two potential founder mutations: BRCA1 c.212 + 1G > A splice mutation (15 cases) and BRCA1 c.799delT (9 cases). Cases with pathogenic mutations had a significantly earlier age at diagnosis (45 vs 51 years, P < 0.001), are more likely to have had diagnosis before menopause, and a higher percentage had a relative with any cancer (51% vs 37%, P = 0.038) or breast cancer (33% vs 15%, P < 0.001). CONCLUSIONS: Hereditary breast cancer mutations were observed among Guatemalan women, and these women are more likely to have early age at diagnosis and family history of cancer. These data suggest the use of genetic testing in breast cancer patients and those at high risk as part of a strategy to reduce breast cancer mortality in Guatemala.


Assuntos
Neoplasias da Mama , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Feminino , Genes BRCA2 , Células Germinativas , Guatemala , Humanos
2.
Int J Biol Macromol ; 185: 876-889, 2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34237364

RESUMO

The integrity of the epidermal barrier and the maintenance of barrier homeostasis depend on the dynamic balance between the proliferation and differentiation of keratinocytes. Calcium (Ca2+) plays a crucial role in maintaining a balance of these two processes as well as in the formation of an epidermal permeability barrier. In this study, we showed that topical application of oat ß-glucan (OG) could ameliorate epidermal hyperplasia and accelerate the recovery of the epidermal barrier by promoting epidermal differentiation. Mechanistic studies revealed a positive interaction between OG and the dectin-1 receptor, and this interaction could lead to an upregulated expression of the calcium-sensing receptor (CaSR) via activation of the downstream ERK and p38 pathways. This consequently increased the sensitivity of keratinocytes to extracellular Ca2+ under the condition of calcium loss following the disruption of the epidermal barrier, resulting in the maintenance of normal keratinocyte differentiation in the epidermis, and ultimately promoting the recovery of the epidermal barrier. These findings clearly demonstrated the healing effect of OG on a physically damaged epidermal barrier. Thus, OG could be considered a valuable component in the development of skin repair agents.


Assuntos
Avena/química , Queratinócitos/citologia , Lectinas Tipo C/metabolismo , Receptores de Detecção de Cálcio/metabolismo , beta-Glucanas/efeitos adversos , Animais , Cálcio/metabolismo , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Células HaCaT , Humanos , Hiperplasia , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Lectinas Tipo C/genética , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Receptores de Detecção de Cálcio/genética , Regulação para Cima , beta-Glucanas/farmacologia
3.
J Comput Biol ; 28(8): 789-803, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34161175

RESUMO

For DNA sequence analysis, we are facing challenging tasks such as the identification of structural variants, sequencing repetitive regions, and phasing of alleles. Those challenging tasks suffer from the short length of sequencing reads, where each read may cover less than 2 single nucleotide polymorphism (SNP), or less than two occurrences of a repeated region. It is believed that long reads can help to solve those challenging tasks. In this study, we have designed new algorithms for mapping long reads to reference genomes. We have also designed efficient and effective heuristic algorithms for local alignments of long reads against the corresponding segments of the reference genome. To design the new mapping algorithm, we formulate the problem as the longest common subsequence with distance constraints. The local alignment heuristic algorithm is based on the idea of recursive alignment of k-mers, where the size of k differs in each round. We have implemented all the algorithms in C++ and produce a software package named mapAlign. Experiments on real data sets showed that the newly proposed approach can generate better alignments in terms of both identity and alignment scores for both Nanopore and single molecule real time sequencing (SMRT) data sets. For human individuals of both Nanopore and SMRT data sets, the new method can successfully math/align 91.53% and 85.36% of letters from reads to identical letters on reference genomes, respectively. In comparison, the best known method can only align 88.44% and 79.08% letters of reads for Nanopore and SMRT data sets, respectively. Our method is also faster than the best known method.

4.
J Comput Biol ; 28(8): 774-788, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33973820

RESUMO

Genome structural variants (SVs) have great impacts on human phenotype and diversity, and have been linked to numerous diseases. Long-read sequencing technologies arise to make it possible to find SVs of as long as 10,000 nucleotides. Thus, long read-based SV detection has been drawing attention of many recent research projects, and many tools have been developed for long reads to detect SVs recently. In this article, we present a new method, called SVLR, to detect SVs based on long-read sequencing data. Comparing with existing methods, SVLR can detect three new kinds of SVs: block replacements, block interchanges, and translocations. Although these new SVs are structurally more complicated, SVLR achieves accuracies that are comparable with those of the classic SVs. Moreover, for the classic SVs that can be detected by state-of-the-art methods (e.g., SVIM and Sniffles), our experiments demonstrate recall improvements of up to 38% without harming the precisions (i.e., >78%). We also point out three directions to further improve SV detection in the future. Source codes: https://github.com/GWYSDU/SVLR.

5.
J Med Genet ; 2021 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-33397747

RESUMO

High-quality interpretation of BRCA1/2 variants plays a critical role in the clinical practice of precision medicine. However, a comprehensive system to evaluate the quality and accuracy of variant interpretation has yet to be established. This study investigates the performance of an interpretation system in evaluating the capacities of BRCA1/2 interpretation among distinct laboratories in China. The evaluation system is based on a reference database that contains 750 different variants in BRCA1/2 Evaluation was performed among 41 laboratories in China. We classified their performance into five levels. Only level A was considered qualified. This level allows for a 0.3% error rate for clinical decision-related misinterpretation; 26 of 41 laboratories (63%) met the qualified standard, while 7 laboratories were at levels D and E, which indicated egregious mistakes and systemic problems in variant interpretation. Due to strict quality demands, the interpretation of several variants was amended, which largely influenced the quality rate. The number of qualified laboratories would decrease from 26 to 17 if those incorrect recommended interpretations were not corrected. This evaluation system provides a potential approach for standardisation of variant interpretation and lowers the discordance of variant interpretation between different laboratories. A well-designed interpretation ability evaluation is essential to evaluate the interpretation level of laboratories before they provide service in real-world clinical settings.

6.
Environ Microbiol ; 2020 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-32939951

RESUMO

Thermococcales has a strong adaptability to extreme environments, which is of profound interest in explaining how complex life forms emerge on earth. However, their gene composition, thermal stability and evolution in hyperthermal environments are still little known. Here, we characterized the pan-genome architecture of 30 Thermococcales species to gain insight into their genetic properties, evolutionary patterns and specific metabolisms adapted to niches. We revealed an open pan-genome of Thermococcales comprising 6070 gene families that tend to increase with the availability of additional genomes. The genome contents of Thermococcales were flexible, with a series of genes experienced gene duplication, progressive divergence, or gene gain and loss events exhibiting distinct functional features. These archaea had concise types of heat shock proteins, such as HSP20, HSP60 and prefoldin, which were constrained by strong purifying selection that governed their conservative evolution. Furthermore, purifying selection forced genes involved in enzyme, motility, secretion system, defence system and chaperones to differ in functional constraints and their disparity in the rate of evolution may be related to adaptation to specific niche. These results deepened our understanding of genetic diversity and adaptation patterns of Thermococcales, and provided valuable research models for studying the metabolic traits of early life forms.

7.
Transl Vis Sci Technol ; 9(8): 11, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32855858

RESUMO

Purpose: Leber hereditary optic neuropathy (LHON) and autosomal dominant optic atrophy (ADOA) are the two commonest forms of hereditary optic neuropathy. The aim of this study was to comprehensively investigate the incidence and spectrum of mutations in patients with suspected hereditary optic neuropathy by combining mitochondrial DNA (mtDNA) genome-wide and targeted exon sequencing. Methods: A cohort of 1101 subjects were recruited to participate in the study, comprising 177 families (177 probands and their family members, a total of 537 subjects, including 254 patients) and 164 sporadic cases with suspected hereditary optic neuropathy, and 400 unrelated control subjects for genetic analysis: all subjects (including control subjects) underwent a comprehensive ophthalmologic examination and were subjected to sequencing analysis of mtDNA genome-wide and targeted exon. Overall, targeted exon sequencing was used to screen 792 genes associated with common hereditary eye diseases, and the mtDNA genome-wide were screened by next-generation sequencing. Results: We found variants detected in 168 (40.2%, 168/418) of the 418 patients screened. Among these, 132 cases (78.6%, 132/168) were detected with known LHON disease-causing mtDNA variants; 40 cases (23.8%, 40/168) were detected with nuclear DNA (ntDNA) variants, which included 36 cases (21.4%, 36/168) with detected OPA1 mutations, 4 patients (2.4%, 4/168) with detected OPA3 mutations, and 2 patients (1.2%, 2/168) with detected TMEM126A homozygous mutation. Coexistence variation (mtDNA/mtDNA [n = 16], ntDNA/ntDNA [n = 4], mtDNA/ntDNA [n = 7]) was found in 27 patients (16.4%, 27/165), including mtDNA/ntDNA coexistence variation that was detected in seven patients. Among these ntDNA mutations, 38 distinct disease-causing variants, including autosomal recessive heterozygous mutations, were detected, which included 22 novel variants and two de novo variants. Total haplogroup distribution showed that 34.5% (29/84) and 28.6% (24/84) of the affected subjects with m.11778G>A belonged to haplogroup D and M, with a high frequency of subhaplogroups D4, D5, and M7. Conclusions: The LHON-mtDNA mutations are the commonest genetic defects in this Chinese cohort, followed by the OPA1 mutations. To our knowledge, this is the first comprehensive study of LHON, ADOA, and autosomal recessive optic atrophy combined with mtDNA genome-wide and targeted exon sequencing, as well as haplogroup analysis, in a large cohort of Chinese patients with suspected hereditary optic neuropathy. Our findings provide a powerful basis for genetic counseling in patients with suspected hereditary optic neuropathy. Translational Relevance: We applied mtDNA genome-wide sequencing combined with panel-based targeted exon sequencing to explore the pathogenic variation spectrum and genetic characteristics of patients with suspected hereditary optic neuropathy, providing a comprehensive research strategy for clinical assistant diagnosis, treatment, and genetic counseling.


Assuntos
Atrofia Óptica Hereditária de Leber , Doenças do Nervo Óptico , DNA Mitocondrial/genética , Éxons/genética , Humanos , Proteínas de Membrana , Mutação , Atrofia Óptica Hereditária de Leber/diagnóstico
8.
J Fluoresc ; 30(4): 883-890, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32494936

RESUMO

Based on boron-dipyrromethene (BODIPY), taking 2-hydroxy-N-(2-hydroxyphenyl)benzamide as recognition site, a new fluorescent probe HHPBA-BODIPY aimed at sensitively detecting Cu ions was designed, synthesized and characterized.The emission spectra of HHPBA-BODIPY exhibited an intensive green fluorescence around 510 nm, with a maximum absorption near 500 nm. When Cu2+ ions are present, the fluorescence at 510 nm can be quenched with a good linearity between the copper ion concentrationand the fluorescence intensity and the detection limit is 0.35 µM. HHPBA-BODIPY is also selective toward Cu2+, while other metal ions show no interfere except Fe3+ and Cr3+ ions. In addition, HHPBA-BODIPY also proved efficient to detect Cu2+ in water samples which offers the possibility to detect trace amount of Cu2+ for environmental monitoring. Copper ions; BODIPY; fluorescent probe.

9.
Mol Genet Genomic Med ; 8(7): e1218, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32337810

RESUMO

BACKGROUND: Age-related cataracts (ARC) is the most common blinding eye disease worldwide, and its incidence tend to become younger. However, the relationship between genetic factors and mechanisms is not fully understood. The aim of the study was to further clarify the relationship between ARC and genetic mechanisms in East Asian populations and to elucidate the pathogenesis. METHODS: The study collected 191 sporadic cataracts and 208 healthy people from the eastern provinces of China, with an average age of about 60 years. All participants were subjected to a comprehensive ophthalmic clinical examination and peripheral blood samples were collected and their genomic DNA was extracted. Mutations were screened among 792 candidate genes to enhance understanding of the disease through targeted capture and high-throughput sequencing. RESULTS: We identified novel candidate susceptibility gene, which may serve as a potential susceptibility factor leading to an increase in the incidence of age-related cataracts. Three novel loci are associated with age-related cataracts significant significance: rs129882 in DBH (p = 5.27E-07, odds ratio = 3.9), rs1800280 in DMD (p = 2.85E-06, odds ratio = 1.4) and rs2871776 in ATP13A2 (p = 4.18E-05, odds ratio = 0.04). Gene-gene interaction analysis revealed that the most significant interactions between genes include the interaction between DBH and TUB (rs17847537 in TUB, rs129882 in DBH, p-value = 2.12E-14), and the interaction between DBH and DMD (rs1800280 in DMD, rs129882 in DBH, p-value = 2.12E-14). Pathway analysis shows that the most significant processes are concentrated in response to light stimulation (adjusted p-Value = 5.56E-03), response to radiation (adjusted P-Value = 5.56E-03), abiotic stimulus (adjusted p-Value = 5.56E-03). eQTL analysis shows that DBH rs129882 could regulate the expression of DBH mRNA in various tissues including retina. CONCLUSION: Our study indicates rs129882 and rs1800280 loci are associated with age-related cataracts, which enlarge the gene map of age-related cataracts.


Assuntos
Catarata/genética , Exoma , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Proteínas Adaptadoras de Transdução de Sinal/genética , Idoso , Dopamina beta-Hidroxilase/genética , Distrofina/genética , Epistasia Genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , ATPases Translocadoras de Prótons/genética
10.
J Comput Biol ; 27(9): 1422-1432, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32048865

RESUMO

The problem of computing the rooted subtree prune and regraft (rSPR) distance of two phylogenetic trees is computationally hard and so is the problem of computing the hybridization number of two phylogenetic trees (denoted by Hybridization Number Computation [HNC]). Since they are important problems in phylogenetics, they have been studied extensively in the literature. Indeed, quite a number of exact or approximation algorithms have been designed and implemented for them. In this article, we design and implement several approximation algorithms for them and one exact algorithm for HNC. Our experimental results show that the resulting exact program is much faster (namely, more than 80 times faster for the easiest dataset used in the experiments) than the previous best and its superiority in speed becomes even more significant for more difficult instances. Moreover, the resulting approximation program's output has much better results than the previous bests; indeed, the outputs are always nearly optimal and often optimal. Of particular interest is the usage of the Monte Carlo tree search (MCTS) method in the design of our approximation algorithms. Our experimental results show that with MCTS, we can often solve HNC exactly within short time.

11.
Mol Genet Genomic Med ; 8(4): e1184, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32100970

RESUMO

BACKGROUND: Panel-based targeted exome sequencing was used to analyze the genetic and clinical findings of targeted genes in a cohort of northeast Chinese with retinitis pigmentosa. METHODS: A total of 87 subjects, comprising 23 probands and their family members (total patients: 32) with confirmed retinitis pigmentosa were recruited in the study. Panel-based targeted exome sequencing was used to sequence the patients and family members, all subjects with retinitis pigmentosa underwent a complete ophthalmologic examination. RESULTS: Of the 23 probands, the clinical manifestations include night blindness, narrowing of vision, secondary cataracts, choroidal atrophy, color blindness, and high myopia, the average age of onset of night blindness is 12.9 ± 14 (range, 0-65; median, 8). Posterior subcapsular opacities is the most common forms of secondary cataracts (nine cases, 39.1%), and peripheral choroidal atrophy is the most common form of secondary choroidal atrophy (12 cases, 52.2%). Of these probands with complication peripheral choroidal atrophy, there were eight probands (66.7%, 8/12) caused by the pathogenic variation in USH2A gene. A total of 17 genes and 45 variants were detected in 23 probands. Among these genes, the commonest genes were USH2A (40%; 18/45), RP1 (15.6%; 7/45), and EYS (8.9%; 4/45), and the top three genes account for 56.5% (13/23) of diagnostic probands. Among these variants, comprising 22 (48.9%) pathogenic variants, 14 (31%) likely pathogenic variants, and nine (20%) uncertain clinical significance variants, and 22 variants was discovered first time. Most of the mutations associated with RP were missense (53.3%, 24/45), and the remaining mutation types include frameshift (35.6%, 16/45), nonsense (6.7%, 3/45), and spliceSite (4.4%, 2/45). Among the probands with mutations detected, compound heterozygous forms was detected in 13 (56.5%, 13/23) probands, and digenic inheritance (DI) forms was detected in five (21.7%, 5/23) probands. CONCLUSION: Panel-based targeted exome sequencing revealed 23 novel mutations, recognized different combinations forms of variants, and extended the mutational spectrum of retinitis pigmentosa and depicted common variants in northeast China.


Assuntos
Frequência do Gene , Fenótipo , Retinite Pigmentosa/genética , Adolescente , Adulto , Idoso de 80 Anos ou mais , Criança , China , Exoma , Proteínas da Matriz Extracelular/genética , Proteínas do Olho/genética , Feminino , Testes Genéticos , Humanos , Masculino , Proteínas Associadas aos Microtúbulos/genética , Pessoa de Meia-Idade , Retinite Pigmentosa/patologia
12.
Mol Genet Genomic Med ; 8(3): e1117, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31944634

RESUMO

BACKGROUND: Panel-based targeted exome sequencing was applied to identify the pathogenic variants and genetic characteristics of retinitis pigmentosa (RP) in two Chinese families, and to gain a deeper understanding of the relationship between clinical manifestations and genotypes. METHODS: A total of 17 subjects, comprising two probands (total patients: four subjects) and their family member, were recruited in this study. All subjects underwent comprehensive ophthalmic examinations and clinical evaluations, and the complete history and medical records were collected according to the standard procedures. All participants were screened using the multigene panel test (Target_Eye_792_V2 chip), and Sanger sequencing was used to confirm the candidate variants. RESULTS: Among these two families, a total of three novel mutations in the EYS gene were identified in patients, including a homozygous frameshift mutation c.9252_9253insT detected in two patients in one family, and the compound heterozygous splicesite mutation c.5644+2T>C and frameshift mutation c.1920_1923delTGAG detected in two patients in the another family. All patients in both families had early onset of night blindness and poor visual acuity, and with typical posterior capsule opacification. The mutation co-segregated within all recruited individuals. In addition, one patient with compound heterozygous mutations was found to have typical blue-blindness symptoms and detected a previously reported disease-causing mutation c.235G>A in OPN1SW gene, which caused blue blindness manifestations and was first discovered in patient combined with RP causative genes. CONCLUSIONS: Panel-based targeted exome sequencing was used to identify three novel variants of RP causative gene, and we also detected a known pathogenic variants of blue-blindness causative genes in two patients. Our finding will provide a powerful basis for genetic counseling and enhance our current understanding of the genetics factors for RP families.


Assuntos
Proteínas do Olho/genética , Retinite Pigmentosa/genética , Adulto , Feminino , Mutação da Fase de Leitura , Heterozigoto , Homozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Retinite Pigmentosa/patologia
13.
J Comput Biol ; 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31638413

RESUMO

Given a set [Formula: see text]. of phylogenetic trees with the same leaf-label set X, we wish to remove some leaves from the trees so that there is a tree T with leaf-label set X displaying all the resulting trees. Note that the labels of leaves removed from one input tree may be different from those of leaves removed from another input tree. One objective is to minimize the total number of leaves removed from the trees, whereas the other is to minimize the maximum number of leaves removed from an input tree. Chauve et al. refer to the problem with the first (respectively, second) objective as AST-LR (respectively, AST-LR-d), and they show that both problems are NP-hard, where NP is the class of problems solvable in non-deterministic polynomial time. They further present algorithms for the parameterized versions of both problems. In this article, we point out that their algorithm for the parameterized version of AST-LR is flawed and present a new algorithm. Since neither Chauve et al.'s algorithm for AST-LR-d nor our new algorithm for AST-LR looks practical, we further design integer-linear programming (ILP for short) models for AST-LR and AST-LR-d, and we discuss speedup issues when using popular ILP solvers (say, GUROBI or CPLEX) to solve the models. Our experimental results show that our ILP approach is quite efficient.

14.
mSystems ; 4(5)2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31641046

RESUMO

The genus Aeromonas is a common gastrointestinal pathogen associated with human and animal infections. Due to the high level of cross-species similarity, their evolutionary dynamics and genetic diversity are still fragmented. Hereby, we investigated the pan-genomes of 29 Aeromonas species, as well as Aeromonas species in microbial communities, to clarify their evolutionary dynamics and genetic diversity, with special focus on virulence factors and horizontal gene transfer events. Our study revealed an open pan-genome of Aeromonas containing 10,144 gene families. These Aeromonas species exhibited different functional constraints, with the single-copy core genes and most accessory genes experiencing purifying selection. The significant congruence between core genome and pan-genome trees revealed that core genes mainly affected evolutionary divergences of Aeromonas species. Gene gains and losses revealed a high level of genome plasticity, exhibited by hundreds of gene expansions and contractions, horizontally transferred genes, and mobile genetic elements. The selective constraints shaped virulence gene pools of these Aeromonas strains, where genes encoding hemolysin were ubiquitous. Of these strains, Aeromonas aquatica MX16A seemed to be more resistant, as it harbored most resistance genes. Finally, the virulence factors of Aeromonas in microbial communities were quite dynamic in response to environment changes. For example, the virulence diversity of Aeromonas in microbial communities could reach levels that match some of the most virulent Aeromonas species (such as A. hydrophila) in penetrated-air and modified-air packaging. Our work shed some light onto genetic diversity, evolutionary history, and functional features of Aeromonas, which could facilitate the detection and prevention of infections.IMPORTANCE Aeromonas has long been known as a gastrointestinal pathogen, yet it has many species whose evolutionary dynamics and genetic diversity had been unclear until now. We have conducted pan-genome analysis for 29 Aeromonas species and revealed a high level of genome plasticity exhibited by hundreds of gene expansions and contractions, horizontally transferred genes, and mobile genetic elements. These species also contained many virulence factors both identified from single isolated species and microbial community. This pan-genome study could elevate the level for detection and prevention of Aeromonas infections.

15.
Ren Fail ; 41(1): 842-849, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31488014

RESUMO

Purpose: Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive development of kidney cysts and enlargement and dysfunction of the kidneys. The Consortium of Radiologic Imaging Studies of the Polycystic Kidney Disease (CRISP) cohort revealed that 89.1% had either a PKD1 or PKD2 mutation. Of the CRISP patients with a genetic cause detected, mutations in PKD1 accounted for 85%, while mutations in the PKD2 accounted for the remaining 15%. Here, we report exome sequencing of 16 Saudi patients diagnosed with ADPKD and 16 ethnically matched controls. Methods: Exome sequencing was performed using combinatorial probe-anchor synthesis and improved DNA Nanoballs technology on BGISEQ-500 sequencers (BGI, China) using the BGI Exome V4 (59 Mb) Kit. Identified variants were validated with Sanger sequencing. Results: With the exception of GC-rich exon 1, we obtained excellent coverage of PKD1 (mean read depth = 88) including both duplicated and non-duplicated regions. Of nine patients with typical ADPKD presentations (bilateral symmetrical kidney involvement, positive family history, concordant imaging, and kidney function), four had protein truncating PKD1 mutations, one had a PKD1 missense mutation, and one had a PKD2 mutation. These variants have not been previously observed in the Saudi population. In seven clinically diagnosed ADPKD cases but with atypical features, no PKD1 or PKD2 mutations were identified, but rare predicted pathogenic heterozygous variants were found in cystogenic candidate genes including PKHD1, PKD1L3, EGF, CFTR, and TSC2. Conclusions: Mutations in PKD1 and PKD2 are the most common cause of ADPKD in Saudi patients with typical ADPKD. Abbreviations: ADPKD: Autosomal dominant polycystic kidney disease; CFTR: Cystic fibrosis transmembrane conductance regulator; EGF: Epidermal growth factor; MCIC: Mayo Clinic Imaging Classification; PKD: Polycystic kidney disease; TSC2: Tuberous sclerosis complex 2.


Assuntos
Rim Policístico Autossômico Dominante/genética , Adulto , Idoso , Árabes/genética , Canais de Cálcio/genética , Estudos de Casos e Controles , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Análise Mutacional de DNA , Fator de Crescimento Epidérmico/genética , Éxons/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Rim Policístico Autossômico Dominante/diagnóstico por imagem , Receptores de Superfície Celular/genética , Arábia Saudita , Canais de Cátion TRPP/genética , Tomografia Computadorizada por Raios X , Proteína 2 do Complexo Esclerose Tuberosa/genética , Sequenciamento Completo do Exoma
16.
Sensors (Basel) ; 19(18)2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31492027

RESUMO

Physiological information such as respiratory rate and heart rate in the sleep state can be used to evaluate the health condition of the sleeper. Traditional sleep monitoring systems need body contact and are intrusive, which limits their applicability. Thus, a comfortable sleep biosignals detection system with both high accuracy and low cost is important for health care. In this paper, we design a sleep biosignals detection system based on low-cost piezoelectric ceramic sensors. 18 piezoelectric ceramic sensors are deployed under the mattress to capture the pressure data. The appropriate sensor that captures respiration and heartbeat sensitively is selected by the proposed channel-selection algorithm. Then, we propose a dynamic smoothing algorithm to extract respiratory rate and heart rate using the selected data. The dynamic smoothing can separate heartbeat signals from respiratory signals with low complexity by dynamically choosing the smooth window, and it is suitable for real-time implementation in low-cost embedded systems. For comparison, wavelet analysis and ensemble empirical mode decomposition (EEMD) are performed in a personal computer (PC). Experimental results show that data collected by piezoelectric ceramic sensors can be used for respiratory-rate and heart-rate detection with high accuracy. In addition, the dynamic smoothing can achieve high accuracy close to wavelet analysis and EEMD, while it has much lower complexity.

17.
Front Genet ; 10: 773, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31543898

RESUMO

Purpose: To clarify the mutation spectrum and frequency of ABCA4 in a Chinese cohort with Stargardt disease (STGD1). Methods: A total of 153 subjects, comprising 25 families (25 probands and their family members) and 71 sporadic cases, were recruited for the analysis of ABCA4 variants. All probands with STGD1 underwent a comprehensive ophthalmologic examination. Overall, 792 genes involved in common inherited eye diseases were screened for variants by panel-based next-generation sequencing (NGS). Variants were filtered and analyzed to evaluate possible pathogenicity. Results: The total variant detection rate of at least one ABCA4 mutant allele was 84.3% (129/153): two or three disease-associated variants in 86 subjects (56.2%), one mutant allele in 43 subjects (28.1%), and no variants in 24 subjects (15.7%). Ninety-six variants were identified in the total cohort, which included 62 missense (64%), 15 splicing (16%), 11 frameshift (12%), 6 nonsense (6%), and 2 small insertion or deletion (2%) variants. Thirty-seven novel variants were found, including a de novo variant, c.4561delA. The most prevalent variant was c.101_106delCTTTAT (10.5%), followed by c.2894A > G (6.5%) and c.6563T > C (4.6%), in STGD1 patients from eastern China. Conclusion: Thirty-seven novel variants were detected using panel-based NGS, including one de novo variant, further extending the mutation spectrum of ABCA4. The common variants in a population from eastern China with STGD1 were also identified.

18.
Mol Genet Genomic Med ; 7(10): e00948, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31452356

RESUMO

BACKGROUND: Familial exudative vitreoretinopathy (FEVR) is a severe clinically and genetically heterogeneous retinal disorder characterized with failure of vascular development of the peripheral retina. The symptoms of FEVR vary widely among patients in the same family, and even between the two eyes of a given patient. The purpose of this study was to investigate the molecular mechanisms by which the start codon mutation of the TSPAN12 causes difference in clinical manifestations between individuals in the same family. METHODS: Next-generation sequencing (NGS)-based target capture sequencing was performed in proband with a diagnosis of FEVR and their normal visual acuity family members. Cosegregation analysis of the candidate causative variant was performed in additional family members by using Sanger sequencing. Complete fundus examination, fundus fluorescein angiography (FFA), and family history collection were performed in all family members. Potential candidate causative variants were verified with reference to guidelines and standards from the American College of Medical Genetics and Genomics. RESULTS: We identified a novel heterozygous missense mutation (c.1A>G, p.M1V) localized in the start codon of the TSPAN12 and was detected as a potentially disease-causing variant for the proband. Retrospective analysis of clinical data, fundus examination, and FFA showed that the mutant carrier presented peripheral retinal vascular anomalies in early stages, and visual acuity did not show significant effects. However, the proband who carried this mutation and his cousin showed typical high-stage FEVR fundus changes coupled with a sharp decline in vision. CONCLUSIONS: We report a novel start codon mutation (c.1A>G, p.M1V) in the TSPAN12 that causes clinically heterogeneous manifestations. Our results expand the mutation spectrums of TSPAN12, and will be valuable for disease diagnosis, prognosis, genetic counseling, and enriching our understanding of the role of the tetraspanin-12 protein in the pathogenesis of FEVR.


Assuntos
Vitreorretinopatias Exsudativas Familiares/diagnóstico , Tetraspaninas/genética , Criança , China , Códon de Iniciação , Olho/diagnóstico por imagem , Vitreorretinopatias Exsudativas Familiares/genética , Vitreorretinopatias Exsudativas Familiares/patologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Mutação de Sentido Incorreto , Linhagem , Fenótipo , Índice de Gravidade de Doença , Ultrassonografia
19.
Mater Sci Eng C Mater Biol Appl ; 103: 109786, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31349454

RESUMO

The purpose of our research was to verify the feasibility and effectiveness of a novel three-dimensional printed biopolymer device (3DP-BPD) for duct-to-mucosa pancreaticojejunostomy (PJ) in minipigs. Polylactic acid (PLA) was selected as the raw materials for 3DP-BPD. Three components of a 3DP-BPD were designed and manufactured: hollow stent, supporting disk, and nut. A pancreatic duct dilation model was developed in six minipigs. After 4 weeks, minipigs underwent operations with duct-to-mucosa PJ using 3DP-BPD. The operation time and postoperative complications were analyzed. The anastomotic sites were evaluated grossly 4 weeks and 24 weeks after PJ, and the histological evaluation of anastomotic sites was performed 24 weeks after PJ. The operation time of six stitches duct-to-mucosa PJ was 9.1 ±â€¯1.7 min. All minipigs survived without any adverse events like postoperative pancreatic fistula (POPF). Serum C reactive protein (CRP) and procalcitonin (PCT) levels were normal, and the anastomotic sites were connected tightly on gross observation and touch at 4 weeks and 24 weeks. Histological examinations indicated that the tissues were continuous between the pancreas and the jejunum. The use of 3DP-BPD did not increase the risk of severe local inflammation and POPF. 3DP-BPD used for duct-to-mucosa PJ is more convenient and clinically feasible for pancreatoenteric reconstruction.


Assuntos
Biopolímeros/química , Impressão Tridimensional , Stents , Animais , Proteína C-Reativa/análise , Módulo de Elasticidade , Jejuno/patologia , Pâncreas/patologia , Pâncreas/cirurgia , Fístula Pancreática/cirurgia , Pancreaticojejunostomia/efeitos adversos , Poliésteres/química , Complicações Pós-Operatórias , Suínos , Porco Miniatura , Resistência à Tração
20.
Ophthalmology ; 126(11): 1549-1556, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31054281

RESUMO

PURPOSE: To characterize the genetic landscape of patients with suspected retinitis pigmentosa (RP) in the Chinese population. DESIGN: Cohort study. PARTICIPANTS: A total of 1243 patients of Chinese origin with clinically suspected RP and their available family members (n = 2701) were recruited. METHODS: All patients and available family members were screened using multigene panel testing (including 586 eye disease-associated genes), followed by clinical variant interpretation. MAIN OUTCOME MEASURES: Diagnostic yield, the 17 most commonly implicated genes, age at onset, de novo mutations, and clinical usefulness of genetic testing. RESULTS: Overall, 72.08% of patients received a molecular diagnosis, and the 17 top genes covered 75.63% of diagnostic cases. Diagnostic yield was higher among patients in the early-onset subgroup (≤5 years old, 79.58%) than in the childhood or adolescence-onset subgroup (6-16 years old, 73.74%) and late-onset subgroup (≥17 years old, 65.99%). Moreover, different genes associated with different onset ages and subgroups with different onset ages showed a diverse mutation spectrum. Only 11 de novo mutations (3.18%) were identified. Furthermore, 16.84% of the patients who received a molecular diagnosis had refinement of the initial clinical diagnoses, and the remaining 83.16% received definite genetic subtypes of RP. CONCLUSIONS: This large cohort study provides population-based data of the genome landscape of patients with suspected RP in China. The diagnostic yield was significantly higher than that in previous studies, and the mutation spectrum is completely different with other populations. Genetic testing improves the chance to establish a precise diagnosis, identifies features not previously determined, and allows a more accurate refinement of risk to family members. Our results not only expand the existing genotypic spectrum but also serve as an efficient reference for the design of panel-based genetic diagnostic testing and genetic counseling for patients with suspected RP in China.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Proteínas do Olho/genética , Retinite Pigmentosa/genética , Adolescente , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , China/epidemiologia , Estudos de Coortes , Análise Mutacional de DNA , Feminino , Estudos de Associação Genética , Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Mutação , Retinite Pigmentosa/diagnóstico
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...