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1.
J Theor Biol ; 484: 110027, 2019 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-31568791

RESUMO

Repeated outbreaks of Hand, foot and mouth disease (HFMD) infections have been observed in recent decades and dominated by various enteroviral serotypes. In particular, enterovirus 71 (EV-A71), coxsackievirus A16 (CV-A16) and coxsackievirus A6 (CV-A6) dominated the prevalence of HFMD infections alternatively in recent years with various outbreak sizes in Baoji, a city of Shaanxi Province in Northwest China. Estimating the reproduction number for various enteroviruses serotypes in northwest China (north temperate zone) and identification of cyclicity of HFMD infections are therefore an issue of great importance for future epidemics prediction and control. The basic/effective reproduction numbers for EV-A71, CV-A16 and CV-A6 were estimated based on daily new cases in 2010, 2011 and 2018, respectively, in which the corresponding pathogen dominated the epidemic. Two different methods based on serial interval were adopted and the basic reproduction number were estimated to be in the range of (1.33, 1.46) for CV-A16, (1.20, 1.29) for EV-A71, and (1.38, 1.59) for CV-A6, respectively. The estimated daily effective reproduction numbers significantly fluctuated before June or after July but varied mildly in (0.5,2) in around June to July for three serotypes. The weekly effective reproduction number for HFMD was estimated based on weekly new cases from year 2010 to 2018, and in most years it peaked in the range of (1.6,2.0) in February to March as well as in the range of (1.0,1.2) in September to October. The wavelet analysis based on the time series of HFMD cases from 2008 to 2018 showed obvious annual and semi-annual cyclicity, while the inter-annual cycles are infeasible. In this study we found that CV-A6 shows the greatest transmission ability among these three pathogens while EV-A71 exhibits the weakest ability of transmission, and moreover, the estimated values of basic reproduction number in northwest China are lower than those in Singapore, Hongkong and Guangdong, which may be due to different climatic circumstances.

2.
Mol Genet Genomic Med ; : e973, 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31568715

RESUMO

BACKGROUND: The nuclear encoded gene RMND1 (Required for Meiotic Nuclear Division 1 homolog) has recently been linked to RMND1-related mitochondrial disease (RRMD). This autosomal recessive condition characteristically presents with an infantile-onset multisystem disease characterized by severe hypotonia, global developmental delay, failure to thrive, sensorineural hearing loss, and lactic acidosis. Renal disease, however, appears to be one of the more prominent features of RRMD, affecting patients at significantly higher numbers compared to other mitochondrial diseases. We report the clinical, histological, and molecular findings of four RRMD patients across three academic institutions with a focus on the renal manifestations. METHODS: Four patients were identified for the purpose of this study, all of whom had molecular confirmation at the time of inclusion, which included the common pathogenic variant c.713A>G (p.N238S) as well as the three rare variants: c.485delC (p.P162fs), c.533C>T (p.T178M), and c.1317 + 1G>C splice donor variant. Medical history and laboratory findings were collected from the medical records and medical providers. RESULTS: In this study, all four patients developed renal disease characterized as tubulopathy (3/4), renal tubular acidosis (2/4), interstitial nephritis (1/4), and/or end-stage renal disease (4/4) necessitating renal transplantation (2/4). Histological evaluation of renal biopsy specimens revealed generalized tubular atrophy and on electron microscopy, abundant mitochondria with pleomorphism and abnormal cristae. CONCLUSION: Our experience with RRMD demonstrates a specific pattern of renal disease manifestations and clinical course. Patients are unlikely to respond to traditional chronic kidney disease (CKD) treatments, making early diagnosis and consideration of renal transplantation paramount to the management of RRMD.

3.
Nat Prod Bioprospect ; 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31385190

RESUMO

In the original publication the corresponding author appeared incorrectly as Xin-Wen Zhang. The corrected text is given below: The corresponding author of the article is Gang Xu.

4.
Anal Bioanal Chem ; 411(25): 6645-6653, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31372699

RESUMO

Carbon dot (CD)-based fluorescent probes have been widely exploited; however, multi-component detection using CDs without tedious surface modification is always a challenging task. Here, we develop a convenient and simple CD-based "on-off-on" fluorescent probe for detection of copper(II) ion (Cu2+), ascorbic acid (AA), and acid phosphatase (ACP). Cu2+ leads to the fluorescence quenching of CDs. The limit of detection (LOD) for Cu2+ is 2.4 µM. When AA is added into the CDs + Cu2+ solution, Cu2+ is reduced by AA to Cu+, causing the fluorescence recovery of CDs. The fluorescent intensity linearly correlates with the concentration of AA in the range of 100-2800 µM with LOD of 60 µM. Besides, the probe has potential application for detection of AA in real samples such as VC tablets, orange juice, and fresh orange. The probe can also indirectly detect ACP that enzymatically hydrolyzes ascorbic acid-phosphate (AAP) to produce AA. This work expands the application of CDs in the multi-component detection and provides a facile fluorescent probe for detection of AA in real samples. Graphical abstract.

5.
Genome Med ; 11(1): 48, 2019 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-31349857

RESUMO

BACKGROUND: Although mosaic variation has been known to cause disease for decades, high-throughput sequencing technologies with the analytical sensitivity to consistently detect variants at reduced allelic fractions have only recently emerged as routine clinical diagnostic tests. To date, few systematic analyses of mosaic variants detected by diagnostic exome sequencing for diverse clinical indications have been performed. METHODS: To investigate the frequency, type, allelic fraction, and phenotypic consequences of clinically relevant somatic mosaic single nucleotide variants (SNVs) and characteristics of the corresponding genes, we retrospectively queried reported mosaic variants from a cohort of ~ 12,000 samples submitted for clinical exome sequencing (ES) at Baylor Genetics. RESULTS: We found 120 mosaic variants involving 107 genes, including 80 mosaic SNVs in proband samples and 40 in parental/grandparental samples. Average mosaic alternate allele fraction (AAF) detected in autosomes and in X-linked disease genes in females was 18.2% compared with 34.8% in X-linked disease genes in males. Of these mosaic variants, 74 variants (61.7%) were classified as pathogenic or likely pathogenic and 46 (38.3%) as variants of uncertain significance. Mosaic variants occurred in disease genes associated with autosomal dominant (AD) or AD/autosomal recessive (AR) (67/120, 55.8%), X-linked (33/120, 27.5%), AD/somatic (10/120, 8.3%), and AR (8/120, 6.7%) inheritance. Of note, 1.7% (2/120) of variants were found in genes in which only somatic events have been described. Nine genes had recurrent mosaic events in unrelated individuals which accounted for 18.3% (22/120) of all detected mosaic variants in this study. The proband group was enriched for mosaicism affecting Ras signaling pathway genes. CONCLUSIONS: In sum, an estimated 1.5% of all molecular diagnoses made in this cohort could be attributed to a mosaic variant detected in the proband, while parental mosaicism was identified in 0.3% of families analyzed. As ES design favors breadth over depth of coverage, this estimate of the prevalence of mosaic variants likely represents an underestimate of the total number of clinically relevant mosaic variants in our cohort.

6.
Talanta ; 204: 762-768, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31357363

RESUMO

Herein we reported a two-photon (TP) fluorescence "turn-on" probe MNPO, exhibiting high selectivity and sensitivity towards intracellular cysteine (Cys) with excellent lysosomal localization. The probe displayed fast response towards Cys over homocysteine (Hcy), glutathione (GSH), and other various analytes under physiological conditions. Low cytotoxicity made it successful for TP imaging of Cys in HeLa cells with an ultralow probe concentration of 250 nM, and a rapid response of only 10 min. Simultaneously, colocalization experiments in lysosome demonstrated its ability for specific in situ detection of lysosomal Cys in living cells, which shed light on its potential applications in biomedical applications. Beyond that MNPO was successfully applied for TP imaging of Cys in mice organ tissues such as heart, liver, and spleen, and the penetration depth of mice heart tissue was up to 184 µm, which disclosed the predominant TP characteristic. We believe that this study will provide some useful information toward diagnosis and treatment of pathogenesis associated with Cys or lysosomes in future.

7.
PLoS One ; 14(7): e0218726, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31344138

RESUMO

OBJECTIVES: Dexmedetomidine (DEX) is a selective α2-adrenoceptor agonist that has anti-inflammatory and cardioprotective effects in myocardial ischemia/reperfusion (I/R) injury. The present study aimed to investigate the underlying mechanism by which DEX protects against myocardial I/R. METHODS: Sprague Dawley rats were subjected to either sham operation or myocardial I/R, which was induced by ligating the left anterior descending coronary artery for 30 min followed by reperfusion for 120 min. Rats were treated with either DEX or saline prior to surgery. We measured heart infarct size, serum cardiac Troponin I (cTnI), cardiac High mobility group box-1 (HMGB1) expression, myocardial apoptosis and cytokine production of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Besides, we evaluated the heart function at 4 weeks post-reperfusion by echocardiography. Unilateral vagotomy or inhibition of the α7 nicotinic acetylcholine receptor (α7nAChR) with methyllycaconitine (MLA) was applied to investigate whether DEX-induced cardioprotection is mediated via the cholinergic anti-inflammatory pathway. Cardiac-selective overexpression of HMGB1 was administered to further confirm if HMGB1 is a key anti-inflammatory target during DEX-induced cardioprotection. RESULTS: DEX pretreatment significantly attenuated I/R-induced cardiac damage, as evidenced by decreases in short-term injury indicators including myocardial infarct size, cTnI release, myocardial apoptosis, cardiac HMGB1 expression, IL-6 and TNF-α production, as well as improvement on long-term cardiac function at 4 weeks post-reperfusion. These effects were partially reversed by either unilateral vagotomy or methyllycaconitine treatment. Besides, cardiac HMGB1-overexpression nearly abolished DEX-induced cardioprotection. CONCLUSIONS: DEX pretreatment protects against myocardial I/R by inhibiting cardiac HMGB1 production and activating the cholinergic anti-inflammatory pathway.

8.
Biomaterials ; 218: 119330, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31301577

RESUMO

The combination of photodynamic therapy (PDT) and chemotherapy (CT) offers a promising approach for the tumor eradication for overcoming multidrug resistance (MDR), which is a major obstacle to effective cancer treatment. However, for PDT, simultaneously achieving near-infrared (NIR) emission and efficient reactive oxygen species (ROS) generation with low dark toxicity is urgently needed but remains challenging. Herein, a series of novel fluorophores with strong NIR emission, hybridized local and charge transfer characteristics, good two-photon absorption, high photostability, low dark cytotoxicity and excellent ROS generation ability are developed. By encapsulating the NIR fluorophore (DEB-BDTO) as a photosensitizer along with a drug resistance inhibitor tariquidar (TQR) within a polymeric prodrug (PMP), a reduction-sensitive drug co-delivery system (DEB/TQR@PMP micelles) is constructed. The DEB/TQR@PMP micelles exhibit a prominent synergistic lethal effect of PDT and CT on SKOV-3 cells and SKOV-3/MDR cells, and can apparently enhance the inhibition of tumor growth compared with sole PDT or CT in the tumor-bearing mouse model. Both in vitro and in vivo experiments prove that the new NIR fluorophores are excellent photosensitizers and can furnish an efficient combination therapy of image-guided PDT and CT within drug delivery micelles, which is particularly useful for eradicating multidrug resistance cancer.

9.
Exp Cell Res ; 383(2): 111507, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31356816

RESUMO

Fibrosis is a common pathology in renal disease. Hypertensive nephropathy (HN) is one of the most common secondary nephropathies that often progresses to severe renal fibrosis with limited treatment options beyond hypertension control. Bromodomain-containing protein 4 (Brd4) was recently recognized as a target in signaling pathways that underlie the pathologies of inflammatory diseases and tumors. A recently developed inhibitor of Brd4, JQ1, has been shown to exert antifibrotic effects and is being clinically explored as an anti-inflammatory and antitumor drug. Here, using human kidney biopsies and Angiotensin II-induced mouse fibrotic kidney samples, we show that Brd4 was upregulated in renal tissue from HN patients and hypertensive mouse models. In mice, JQ1 alleviated Angiotensin II-induced kidney fibrosis and blocked epithelial-mesenchymal transition (EMT) by altering the expression of EMT-related proteins. Using an in vitro model of HK2 cells exposed to Angiotensin II, we also demonstrated that JQ1 suppressed the protein expression of fibrotic genes in these cells. These results further implicate Brd4 in the fibrotic response in HN and reveal that Brd4 is a potential antifibrotic target. BET inhibitors are currently being investigated in clinical trials as antitumor agents and show potent pharmacological effects. Our findings suggest that BET inhibitors may also be potential translational therapies for HN.

10.
Org Lett ; 21(14): 5670-5674, 2019 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-31268339

RESUMO

Salpratlactones A (1) and B (2), a pair of abietane cis-trans tautomers from Salvia prattii, were identified as the first naturally occurring agonists of T-type calcium channel (TTCC). Structurally, 1 and 2 were featured by unique 6/5 carbocyclic rings bearing a γ-lactone ring through an exocyclic double bond. Moreover, both compounds and their mixture at 10 µM potently and equally increased Cav3.1 TTCC peak currents, and 1 had an EC50 value of 12.48 µM.

11.
Talanta ; 202: 591-599, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31171226

RESUMO

Photodynamic therapy (PDT) was considered as an effective treatment. Whereas only PDT is not enough to achieve effective therapy on account of irradiation intensity decreases as depth increases as well as tumor hypoxia. Combination with gene therapy and photodynamic therapy have emerged as an effective strategy to improve therapeutic effectiveness. In the present study, a GSH responsive MnO2 was employed to delivery TB and DNAzyme for cancer imaging and PDT-gene combination treatment. TB, a photosensiters with aggregation-induced emission characteristic, was employed for photodynamic therapy, while DNAzyme, acting as catalysts for the degradation of EGR-1 mRNA, was exploited for gene silencing. All of the results of tumor treatment in vitro have implied that MnO2-DNAzyme-TB nanocomposite (MDT) can internalize into cells. Subsequently, MDT could decrease the expression of EGR-1 by gene silencing that enabling inhibition of cell growth. In addition, the singlet oxygen which was generated by the aggregated TB were able to further suppress cell growth. Combination therapy of photodynamic as well as gene therapy greatly enhanced antitumor efficiencies. Furthermore, in vivo tumor treatment experiments demonstrated that MDT under illumination can effectively inhibit the tumor growth of MCF-7 tumor-bearing mice by photodynamic and gene silencing combination therapy.


Assuntos
Antineoplásicos/farmacologia , DNA Catalítico/metabolismo , Terapia Genética , Compostos de Manganês/farmacologia , Óxidos/farmacologia , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , DNA Catalítico/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Proteína 1 de Resposta de Crescimento Precoce/antagonistas & inibidores , Proteína 1 de Resposta de Crescimento Precoce/genética , Feminino , Humanos , Células MCF-7 , Neoplasias Mamárias Experimentais/diagnóstico por imagem , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/metabolismo , Compostos de Manganês/síntese química , Compostos de Manganês/química , Camundongos , Camundongos Nus , Nanocompostos , Imagem Óptica , Óxidos/síntese química , Óxidos/química , Tamanho da Partícula , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química , RNA Mensageiro/antagonistas & inibidores , RNA Mensageiro/genética , Relação Estrutura-Atividade , Propriedades de Superfície
12.
J Immunother ; 2019 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-31219975

RESUMO

Chimeric antigen receptor T-cell (CAR-T) therapy demonstrates impressive efficacy in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). However, CAR-T therapy-related severe cytokine release syndrome and neurological toxicity limit its clinical application in R/R DLBCL patients with high tumor burden. Here, we conducted a phase II clinical trial testing the efficacy and toxicities of CAR-T therapy in R/R non-Hodgkin lymphoma patients (NCT03196830). Among the enrolled patients, 10 R/R DLBCL patients with high tumor burden were analyzed. Before CAR-T therapy, 4 were treated with intensive combined chemotherapy (C-CAR-cohort), and 6 were exposed to radiotherapy (R-CAR-cohort). Patients in the R-CAR-T-cohort showed a higher overall response rate (100% vs. 25%, P=0.033) and less severe cytokine release syndrome (0% vs. 100%, P=0.0048) and neurotoxicity (0% vs. 75%, P=0.033) incidences than patients in the C-CAR-T-cohort. Furthermore, one case who responded to CAR-T therapy initially and who suffered a relapse shortly was exposed to radiation and achieved complete remission, with an increase in the number of CAR-T copies detected. This study demonstrates that radiotherapy is an optimal debulking regimen to managing R/R DLBCL patients before CAR-T therapy and a promising alternative salvage therapy for patients who suffer a relapse after CAR-T therapy by fuelling CAR-T copies.

14.
Biometrics ; 2019 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-31237680

RESUMO

Stepped wedge designed trials are a type of cluster-randomized study in which the intervention is introduced to each cluster in a random order over time. This design is often used to assess the effect of a new intervention as it is rolled out across a series of clinics or communities. Based on a permutation argument, we derive a closed form expression for an estimate of the intervention effect, along with its standard error, for a stepped wedge design trial. We show that these estimates are robust to mis-specification of both the mean and covariance structure of the underlying data-generating mechanism, thereby providing a robust approach to inference for the intervention effect in stepped wedge designs. We use simulations to evaluate the type I error and power of the proposed estimate and to compare the performance of the proposed estimate to the optimal estimate when the correct model specification is known. The limitations, possible extensions, and open problems regarding the method are discussed. This article is protected by copyright. All rights reserved.

15.
Artigo em Inglês | MEDLINE | ID: mdl-31195136

RESUMO

High-dose chemotherapy and/or radiation given before an allogeneic hematopoietic cell transplantation severely damage thymic epithelial cells (TECs), resulting in poor post-transplant immune recovery. IL-22 mediates recovery of TECs via a proregenerative effect, but the precise mechanism by which this occurs is unknown. In this study, we found IL-22 improved thymus recovery after damage from irradiation in association with increased number of TECs. This effect was blocked by ruxolitinib, a JAK1/JAK2 inhibitor. IL-22 increased the number of TECs via a Stat3-dependent signaling in the mTEC1 murine thymic epithelial cell line. This, in turn, upregulated transcription of myeloid cell leukemia sequence 1 (Mcl1), resulting in increased number of TECs. Similar effects were seen in irradiated mice given IL-22. Defects in IL-22 resulted in delayed thymus recovery in irradiated mice and had an impact on levels of thymus function-related genes such as Foxn1, Aire, and Kgf. In mice, post-transplant use of IL-22 improved repair of TECs, increased the numbers of thymus T cells, increased the intrathymic levels of Aire, and increased the proportion of natural regulatory T cells, resulting in decreased severity of chronic graft-versus-host disease (GVHD). Our data highlight the critical role of the IL-22/Stat3/Mcl-1 pathway in the regeneration of TECs after damage from irradiation in mice and highlight circumstances where normalizing thymus T cell function with IL-22 decreases GVHD after allotransplants. © 2019 American Society for Blood and Marrow Transplantation.

16.
Nat Prod Bioprospect ; 2019 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-31073808

RESUMO

Six new polyphenols with different isoprenylated xanthones, isoprenylated acylphloroglucinols, and chromone architectures, hyperfaberols A-F (1-6), were isolated from the whole plants of Hypericum faberi along with seven other related known compounds. In which hyperfaberols A/B (1/2) and 12-13 were isoprenylated xanthones, hyperfaberols C-E (3-5) and 8-11 were seven isoprenylated acylphloroglucinol derivatives, while 6-7 were two chromones. Their structures were elucidated by comprehensive analysis of their spectroscopic data as well as detailed comparison with the literature data. Compounds 1 and 11 showed cytotoxities against the human esophageal cancer cell line (ECA-109) and the pancreatic tumor cell line (PANC-1) in vitro, respectively.

17.
Environ Technol ; : 1-11, 2019 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-31050606

RESUMO

This paper used cetyltrimethylammonium chloride (CTAC) pre-loaded activated carbon (AC) to research nitrate adsorption. Effects of various parameters such as AC types, AC dosage as well as initial pH were studied. The results indicated that the ACs modified by CTAC can get higher nitrate removal. Even pH is neutral and basic, an accepted removal about 2.5 mg/g can be observed. The more CTAC pre-loaded on the AC surface, the higher nitrate adsorption capacity can be obtained. pH is regarded as a key factor affecting interactions between adsorbent and adsorbate, and the results confirmed that the nitrate adsorption on modified AC decreases gradually with the growth of initial pH. Besides, the acidic pH condition is much favoured for adsorption while the results gained a nitrate adsorption about 4.28 mg/g at pH = 3 condition. Sorption mechanism of nitrate on CTAC modified AC was investigated through two kinetic modellings including pseudo-second-order and Weber and Morris intra-particle diffusion model. The results imply that the generalized kinetic models tally well with experimental data. Additionally, interference of co-existing anions is examined, and the results showed that higher co-anions concentration would bring a heavier depression of the nitrate uptake due to its competing for adsorption sites.

18.
Genome Med ; 11(1): 30, 2019 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-31101064

RESUMO

BACKGROUND: Exome sequencing (ES) has been successfully applied in clinical detection of single nucleotide variants (SNVs) and small indels. However, identification of copy number variants (CNVs) using ES data remains challenging. The purpose of this study is to understand the contribution of CNVs and copy neutral runs of homozygosity (ROH) in molecular diagnosis of patients referred for ES. METHODS: In a cohort of 11,020 consecutive ES patients, an Illumina SNP array analysis interrogating mostly coding SNPs was performed as a quality control (QC) measurement and for CNV/ROH detection. Among these patients, clinical chromosomal microarray analysis (CMA) was performed at Baylor Genetics (BG) on 3229 patients, either before, concurrently, or after ES. We retrospectively analyzed the findings from CMA and the QC array. RESULTS: The QC array can detect ~ 70% of pathogenic/likely pathogenic CNVs (PCNVs) detectable by CMA. Out of the 11,020 ES cases, the QC array identified PCNVs in 327 patients and uniparental disomy (UPD) disorder-related ROH in 10 patients. The overall PCNV/UPD detection rate was 5.9% in the 3229 ES patients who also had CMA at BG; PCNV/UPD detection rate was higher in concurrent ES and CMA than in ES with prior CMA (7.2% vs 4.6%). The PCNVs/UPD contributed to the molecular diagnoses in 17.4% (189/1089) of molecularly diagnosed ES cases with CMA and were estimated to contribute in 10.6% of all molecularly diagnosed ES cases. Dual diagnoses with both PCNVs and SNVs were detected in 38 patients. PCNVs affecting single recessive disorder genes in a compound heterozygous state with SNVs were detected in 4 patients, and homozygous deletions (mostly exonic deletions) were detected in 17 patients. A higher PCNV detection rate was observed for patients with syndromic phenotypes and/or cardiovascular abnormalities. CONCLUSIONS: Our clinical genomics study demonstrates that detection of PCNV/UPD through the QC array or CMA increases ES diagnostic rate, provides more precise molecular diagnosis for dominant as well as recessive traits, and enables more complete genetic diagnoses in patients with dual or multiple molecular diagnoses. Concurrent ES and CMA using an array with exonic coverage for disease genes enables most effective detection of both CNVs and SNVs and therefore is recommended especially in time-sensitive clinical situations.

19.
Hum Mol Genet ; 28(17): 2900-2919, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31127942

RESUMO

N-alpha-acetylation is one of the most common co-translational protein modifications in humans and is essential for normal cell function. NAA10 encodes for the enzyme NAA10, which is the catalytic subunit in the N-terminal acetyltransferase A (NatA) complex. The auxiliary and regulatory subunits of the NatA complex are NAA15 and Huntington-interacting protein (HYPK), respectively. Through a genotype-first approach with exome sequencing, we identified and phenotypically characterized 30 individuals from 30 unrelated families with 17 different de novo or inherited, dominantly acting missense variants in NAA10 or NAA15. Clinical features of affected individuals include variable levels of intellectual disability, delayed speech and motor milestones and autism spectrum disorder. Additionally, some subjects present with mild craniofacial dysmorphology, congenital cardiac anomalies and seizures. One of the individuals is an 11-year-old boy with a frameshift variant in exon 7 of NAA10, who presents most notably with microphthalmia, which confirms a prior finding with a single family with Lenz microphthalmia syndrome. Biochemical analyses of variants as part of the human NatA complex, as well as enzymatic analyses with and without the HYPK regulatory subunit, help to explain some of the phenotypic differences seen among the different variants.

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