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Objective To assess the association between the HLA-B*51 allele and Behcet Disease (BD) in Argentinean patients. Methods We enrolled 34 consecutive Argentinean patients with definitive diagnosis of BD between October 2016 and March 2017. None of the patients had the HLA-B*51 allele determined at study entry. Unrelated controls (n = 240) were randomly obtained from the national cadaveric donor database. Demographic and clinical features of the patients were recorded by attending physicians through a questionnaire. Results Mean age of cases was 42 years old. Nineteen (55.8%) were male, and the mean age at diagnosis was 35 years old; twenty (58.8%) were Mestizos, 8 (23.5%) were Caucasian, and 6 (17.6%) were Amerindians. Thirteen (38.2%) of 34 cases were HLA-B*51 allele positive; 11 were heterozygous and 2 homozygous for the allele. Thirty-four (14.2%) of 240 controls were positive for the HLA-B*51 allele. The association between BD and HLA-B*51 allele was greater than that of control group (OR = 3.75; p = 0.0012). Conclusions The HLA-B*51 allele is strongly associated with BD in Argentinean patients. Our finding is consistent with previous studies indicating that the HLA-B*51 allele is an important susceptibility gene in BD regardless the geographical region and ethnicity.

Familial nonmedullary thyroid cancer (FNMTC) constitutes 3-9% of all thyroid cancer cases. FNMTC is divided into two groups: syndromic and nonsyndromic. Nonsyndromic FNMTC is more common as compared with syndromic FNMTC. In syndromic FNMTC, patients are at risk of nonmedullary thyroid cancer (NMTC) and other tumors, and the susceptibility genes are known. In nonsyndromic FNMTC, NMTC is the major feature of the disease and occurs in isolation with an autosomal dominant pattern of inheritance and variable penetrance. New data have emerged on the genetics, clinical characteristics, and outcomes of patients with FNMTC that may have clinical relevance in the management of patients. In this review, we focus on newly characterized syndromic FNMTC entities, criteria for screening and surveillance of nonsyndromic FNMTC, and the classification of nonsyndromic FNMTC as well as the genetic background and heterogeneity of nonsyndromic FNMTC.

PurposeThe endothelial and cell-specific angiopoietin-Tie pathway plays an important regulatory role in angiogenesis. In this study, we investigated the associations of the TIE2 (tyrosine kinase, endothelial, TEK) gene with neovascular age-related macular degeneration (nAMD) and polypoidal choroidal vasculopathy (PCV), using haplotype-tagging single-nucleotide polymorphisms (SNPs) analysis.MethodsThis study involved totally 2343 subjects, including a Hong Kong Chinese cohort (214 nAMD patients, 236 PCV patients and 433 control subjects), a Shantou Chinese cohort (189 nAMD patients, 187 PCV patients and 531 control subjects) and an Osaka Japanese cohort (192 nAMD patients, 204 PCV patients and 157 control subjects). Thirty haplotype-tagging SNPs in TIE2 were genotyped in the Hong Kong cohort using TaqMan technology. Two SNPs (rs625767 and rs2273717) showing association in the Hong Kong cohort were genotyped in the Shantou and Osaka cohorts. The SNP-disease association of individual and pooled cohorts were analysed.ResultsTwo SNPs (rs625767 and rs2273717) showed suggestive association with both nAMD and PCV in the Hong Kong cohort. In the meta-analysis involving all the three cohorts, rs625767 showed significant associations with nAMD (p=0.01; OR=0.82, 95% CI 0.70 to 0.96; I2=0%), PCV (p=0.02; OR=0.83, 95% CI 0.71 to 0.97; I2=27%) and pooled nAMD and PCV (p=0.002; OR=0.82, 95% CI 0.72 to 0.93; I2=0%), with low inter-cohort heterogeneities.ConclusionThis study revealed TIE2 as a novel susceptibility gene for nAMD and PCV in Japanese and Chinese. Further studies in other populations are warranted to confirm its role.

A small but important proportion of patients with myelodysplasia (MDS) and acute leukaemia (AL) have underlying germline mutations in leukaemia susceptibility genes. The majority of these variants predispose to myeloid neoplasms with a smaller number associated with acute lymphoblastic leukaemia (ALL). The 2016 revision of the WHO classification of tumours of haematopoietic and lymphoid tissues has defined a number of myeloid neoplasms with germline predisposition (Blood, 127, 2016, 2391) alerting clinicians to the importance of this underlying diagnosis. Advances in genetic technology and access to testing will undoubtably result in increased numbers of patients and families with leukaemia predisposition syndromes being identified. Here we summarize the salient biology and genetic and clinical features of a number of these conditions including some more recently described genetic variants.

Yazhan is a restorer rice line bred by Jiangxi Tianya Seed Industry Co., LTD, and its hybrid combination has a high yield, excellent rice quality, and strong resistance. In this study, Yazhan, Huazhan, and Zhanhui 15 were used as the experimental materials. Based on agronomic traits, SSR primer screening and second-generation resequencing were conducted to study the genetic basis of Yazhan. The results showed that the plant height of Yazhan was significantly lower than Zhanhui 15, and the yield was not different from the parent lines. The genetic material on chromosome 1, 3, 4, 5, and 10 in the genome of Yazhan were mainly from Zhanhui 15, genetic materials from chromosomes 2, 6, 8, 9, 11, and 12 mainly come from Huazhan, and the chromosomes 1, 5, and 6 had the most variation. In terms of genomic similarity, Yazhan was more similar to the male parent (Huazhan). Yazhan and Huazhan carried the Wxb genotype, while Zhanhui 15 carried the Wxa genotype. The amylose contents of Yazhan and Huazhan were significantly lower than Zhanhui 15. Yazhan and Huazhan carried the Pita blast resistance gene, and Zhanhui 15 carried the Pita susceptibility gene. The results of this study provide a theoretical reference for elucidating the genetic composition of Yazhan and determining the main genetic sources of its important agronomic traits.

As an extremely prevalent disease worldwide, allergic rhinitis (AR) is a condition characterized by chronic inflammation of the nasal mucosa. To identify the finer molecular mechanisms associated with the AR susceptibility genes, differentially expressed genes (DEGs) in AR were investigated. The DEG expression and clinical data of the GSE19187 data set were used for weighted gene co-expression network analysis (WGCNA). After the modules related to AR had been screened, the genes in the module were extracted for Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, whereby the genes enriched in the KEGG pathway were regarded as the pathway-genes. The DEGs in patients with AR were subsequently screened out from GSE19187, and the sensitive genes were identified in GSE18574 in connection with the allergen challenge. Two kinds of genes were compared with the pathway-genes in order to screen the AR susceptibility genes. Receiver operating characteristic (ROC) curve was plotted to evaluate the capability of the susceptibility genes to distinguish the AR state. Based on the WGCNA in the GSE19187 data set, 10 co-expression network modules were identified. The correlation analyses revealed that the yellow module was positively correlated with the disease state of AR. A total of 89 genes were found to be involved in the enrichment of the yellow module pathway. Four genes (CST1, SH2D1B, DPP4, and SLC5A5) were upregulated in AR and sensitive to allergen challenge, whose potentials were further confirmed by ROC curve. Taken together, CST1, SH2D1B, DPP4, and SLC5A5 are susceptibility genes to AR.

Objective: To identify the susceptible single nucleotide polymorphisms (SNPs) loci in HCC patients in Guangxi Region, screen biomarkers from differential SNPs loci by using predictors, and establish risk prediction models for HCC, to provide a basis of screening high-risk individuals of HCC. Methods: Blood sample and clinical data of 50 normal participants and 50 hepatic cancer (HCC) patients in Rui Kang Hospital affiliated to Guangxi University of Traditional Chinese Medicine were collected. Normal participants and HCC patients were assigned to training set and testing set, respectively. Whole Exome Sequencing (WES) technique was employed to compare the exon sequence of the normal participants and HCC patients. Five predictors were used to screen the biomarkers and construct HCC prediction models. The prediction models were validated with both training and testing set. Results: Two-hundred seventy SNPs were identified to be significantly different from HCC, among which 100 SNPs were selected as biomarkers for prediction models. Five prediction models constructed with the 100 SNPs showed good sensitivity and specificity for HCC prediction among the training set and testing set. Conclusion: A series of SNPs were identified as susceptible genes for HCC. Some of these SNPs including CNN2, CD177, KMT2C, and HLADQB1 were consistent with the previously identified polymorphisms by targeted genes examination. The prediction models constructed with part of those SNPs could accurately predict HCC development.

Objectives People with schizophrenia (SCZ) present serious and generalised deficits in social cognition (SC), which affect negatively patients' functioning and treatment outcomes. The genetic background of SC has been investigated in disorders other than SCZ providing weak and sparse results. Thus, our aim was to explore possible genetic correlates of SC dysfunctions in SCZ patients with a genome-wide study (GWAS) approach. Methods We performed a GWAS meta-analysis of data coming from two cohorts made of 242 and 160 SCZ patients, respectively. SC was assessed with different tools in order to cover its different domains. Results We found GWAS significant association between the TMEM74 gene and the patients' ability in social inference as assessed by The Awareness of Social Inference Test; this association was confirmed by both SNP-based analysis (lead SNP rs3019332 p-value = 5.24 × 10-9) and gene-based analysis (p-value = 1.09 × 10-7). Moreover, suggestive associations of other genes with different dimensions of SC were also found. Conclusions Our study shows for the first time GWAS significant or suggestive associations of some gene variants with SC domains in people with SCZ. These findings should stimulate further studies to characterise the genetic underpinning of SC dysfunctions in SCZ.

Psoriasis is a chronically relapsing, inflammatory, autoimmune, genetically mediated, skin disorder. Most often association of psoriasis with metabolic syndrome has been seen. Components of metabolic syndrome like diabetes, hypertension and obesity are oftenly linked with psoriasis therefore it is crucial to understand this interlink and prompt diagnosis and treatment therefore plays important role to reduce the morbidity and mortality. It has been seen that psoriasis is associated with metabolic syndrome and its components, such as obesity, diabetes and hypertension. These phenotypically diverse conditions are found to share similar pathologic changes owing to similar susceptibility genes and genetic loci. Objectives: 1: Selection of clinically diagnosed cases of psoriasis vulgaris attending the Derma OPD; 2: Evaluation of the psoriasis vulgaris patients on different parameters ; 3: Comparision of the cases with age and sex matched control groups; 4: Study the link of psoriasis vulgaris with metabolic syndrome. Study Design: It is Case Control study (100 cases and 100 controls). Results: Our study shows that in comparision to non-psoriatic patients i.e 12 (12%) metabolic syndrome is present in 37 (37%) of the psoriatic patients attending the OPD during the period of Jan 2017 to Dec 2017 i.e 1 year duration.the result is statistically significant (odds ratio (OR) –3-175, Degree of freedom(df)-1,p value-0.002. c 2 -8.772]. Conclusion: Study shows that psoriasis is highly linked with metabolic syndrome and its components. Keywords: Metabolic Syndrome, TNF alpha, Psoriasis, Hyperlipidemia, Hypertension, BMI, Obesity, Interleukins.

To study effect of nanomedicine on lower extremity deep vein thrombosis (LEDVT) and its correlation with susceptibility genes (SGs), preliminary nanoparticle LSA was constructed using lauric acid and stearic acid, and CTAB-HAuCL4-TEOS (CHT) was obtained using cetyltrimethyl ammonium bromide (CTAB), chloroauric acid (HAuCL4), and tetraethoxysilane (TEOS) to prepare UK-LSA-CHT by combining with urokinase (UK). 20 rabbits were grouped into UK-LSA-CHT, LSA, UK, and D0 group. Human umbilical vein endothelial cells (HUVEC) were selected for cytotoxicity test. The plasma endothelin (ET-1), interleukin 6 (IL-6), and nuclear factor κβ (NF-κβ) of the rabbits were detected with double antibody sandwich method. Expression of platelet activating factor (PAF) was detected by immumohistochemical staining. Genotype distribution was detected with the second-generation sequencing technology (SGST). The results showed that expressions of ET-1, IL-6, and NF-κβ) in UK-LSA-CHT group were lower than those in the LSA group and the UK group after 12 hours (P < 0.05). Frequency of allele G and T, and GT and TT genotype ratio of SG NOS3 rs1799983 in UK -LSA-CHT group were less than those in LSA and UK group (P < 0.05). UK-LSA-CHT group had observably lower value in PAF positive expression than LSA and UK groups (P < 0.05). In short, UK-LSA-CHT had good biocompatibility and safety and good therapeutic effect on LEDVT. N0S3 rs1799983 alleles G and T may be the key risk factors for the occurrence and development of LEDVT.

Precision medicine is a term used to describe medical care, which is specifically tailored to an individual patient or disease with the aim of ensuring the best clinical outcome whilst reducing the risk of adverse effects. Phaeochromocytoma and paraganglioma (PPGL) are rare neuroendocrine tumours with uncertain malignant potential. Over recent years, the molecular profiling of PPGLs has increased our understanding of the mechanisms that drive tumorigenesis. A high proportion of PPGLs are hereditary, with non-hereditary tumours commonly harbouring somatic mutations in known susceptibility genes. Through detailed interrogation of genotype-phenotype, correlations PPGLs can be classified into three different subgroups or clusters. Thus, PPGLs serve as an ideal paradigm for developing, testing and implementing precision medicine concepts in the clinic. In this review, we provide an overview of PPGLs and highlight how detailed molecular characterisation of these tumours provides current and future opportunities for precision oncology.

Simple Summary Current cancer testing gene panels tend to be comprehensive. One of the genes commonly included in the testing panels is BARD1. To establish whether BARD1 mutations predispose to prostate cancer, we sequenced BARD1 in 390 hereditary prostate cancer cases, genotyped 5715 men with unselected prostate cancer and 10,252 controls for three recurrent rare BARD1 variants in Poland. We did not see an elevated prostate risk cancer given p.Q564X truncating mutation, p.R658C missense mutation and p.R659= synonymous variant. Neither variant influenced prostate cancer characteristics or survival. Our study is the first to evaluate the association between BARD1 mutations and prostate cancer susceptibility. It is not justified to inform men about increased prostate cancer risk in case of identification of a BARD1 mutation. However, a female relative of a man with a BARD1 mutation may benefit from this information and be tested, because BARD1 is a breast cancer susceptibility gene. Abstract The current cancer testing gene panels tend to be comprehensive rather than site-specific. BARD1 is one of the genes commonly included in the multi-cancer testing panels. Mutations in BARD1 confer an increase in the risk for breast cancer, but it is not studied whether or not they predispose to prostate cancer. To establish if BARD1 mutations also predispose to prostate cancer, we screened BARD1 in 390 Polish patients with hereditary prostate cancer. No truncating mutations were identified by sequencing. We also genotyped 5715 men with unselected prostate cancer, and 10,252 controls for three recurrent BARD1 variants, including p.Q564X, p.R658C and p.R659=. Neither variant conferred elevated risk of prostate cancer (ORs between 0.84 and 1.15, p-values between 0.57 and 0.93) nor did they influence prostate cancer characteristics or survival. We conclude that men with a BARD1 mutation are not at elevated prostate cancer risk. It is not justified to inform men about increased prostate cancer risk in case of identification of a BARD1 mutation. However, a female relative of a man with a BARD1 mutation may benefit from this information and be tested for the mutation, because BARD1 is a breast cancer susceptibility gene.

Sweet orange (Citrus sinensis) is the most economically important species for the citrus industry. However, it is susceptible to many diseases including citrus bacterial canker caused by Xanthomonas citri subsp. citri (Xcc) that triggers devastating effects on citrus production. Conventional breeding has not met the challenge to improve disease resistance of sweet orange due to the long juvenility and other limitations. CRISPR-mediated genome editing has shown promising potentials for genetic improvements of plants. Generation of biallelic/homozygous mutants remains difficult for sweet orange due to low transformation rate, existence of heterozygous alleles for target genes, and low biallelic editing efficacy using the CRISPR technology. Here, we report improvements in the CRISPR/Cas9 system for citrus gene editing. Based on the improvements we made previously [dicot codon optimized Cas9, tRNA for multiplexing, a modified sgRNA scaffold with high efficiency, citrus U6 (CsU6) to drive sgRNA expression], we further improved our CRISPR/Cas9 system by choosing superior promoters [Cestrum yellow leaf curling virus (CmYLCV) or Citrus sinensis ubiquitin (CsUbi) promoter] to drive Cas9 and optimizing culture temperature. This system was able to generate a biallelic mutation rate of up to 89% for Carrizo citrange and 79% for Hamlin sweet orange. Consequently, this system was used to generate canker-resistant Hamlin sweet orange by mutating the effector binding element (EBE) of canker susceptibility gene CsLOB1, which is required for causing canker symptoms by Xcc. Six biallelic Hamlin sweet orange mutant lines in the EBE were generated. The biallelic mutants are resistant to Xcc. Biallelic mutation of the EBE region abolishes the induction of CsLOB1 by Xcc. This study represents a significant improvement in sweet orange gene editing efficacy and generating disease-resistant varieties via CRISPR-mediated genome editing. This improvement in citrus genome editing makes genetic studies and manipulations of sweet orange more feasible.

Traditional rice blast resistance breeding largely depends on utilizing the typical resistance (R) genes. The lack of durable R genes prompts rice breeders to find new source of resistance. The susceptibility (S) genes could be the potentially useful targets for genetic engineering using the cutting-edging genome-editing technologies. However, how to identify S genes is challenging. Here, by combining genome-wide association study and transcriptional analysis, we identified the candidate genes in the rice genome whose expression levels were negatively associated with rice blast resistance. We initially identified five candidate genes by qRT-PCR and comparison of their sequences among the rice blast resistant and susceptible varieties. The obtained results showed that the polymorphisms in 3’ un-translated regions (3’-UTR) of two genes, Os02g39360 and Os08g29170, named RNG1 and RNG3, respectively, were tightly associated with their expression levels and rice blast susceptibility. Subsequently, the negatively association between the expression levels and blast resistance was confirmed using the 3K rice population. Meanwhile, the frequency of the resistance genotype of these two genes was significantly decreased during the first step of rice domestication from wild rice to landrace rice. In contrast, the frequency was increased during the second step of domestication from landrace rice to modern cultivars. Nucleotide diversity analysis found an obvious selective sweep in the surrounding loci of RNG3, means that RNG3 has been artificially selected. The results obtained in this study provide new targets for further gene functional analysis as well as genome editing-based rice blast resistance breeding.

International audience; Alternatives to protect crops against diseases are desperately needed to secure world food production and make agriculture more sustainable. Genetic resistance to pathogens utilized so far is mostly based on single dominant resistance genes that mediate specific recognition of invaders and that is often rapidly broken by pathogen variants. Perturbation of plant susceptibility (S) genes offers an alternative providing plants with recessive resistance that is proposed to be more durable. S genes enable the establishment of plant disease, and their inactivation provides opportunities for resistance breeding of crops. However, loss of S gene function can have pleiotropic effects. Developments in genome editing technology promise to provide powerful methods to precisely interfere with crop S gene functions and reduce tradeoffs.

This work provides a comprehensive study of the molecular events mediated by the transcription activator-like (TAL) effectors of Xanthomonas axonopodis pv. manihotis (Xam) during infection of its host plant cassava (Manihot esculenta). TAL effectors are secreted via the bacterial type III secretion system into plant cells where they localize to the nucleus, bind specific sequences of nucleotides in plant promoters, and activate the expression of downstream genes. The DNA binding activity of Xam TAL effectors is carried out by a central domain containing a variable number of 34 amino acid repeats, where the 12th and 13th amino acid residues, the repeat variable diresidues (RVDs), of each repeat dictate which nucleotide will be bound at that site. Genetic analysis of the TAL effectors of highly virulent Xam strain Xam668 showed a virulence role for TAL20Xam668, which contributes to in planta bacterial growth and watersoaking symptom development, and TAL14Xam668, which contributes to in planta bacterial growth. RNA-Sequencing (RNA-Seq) revealed a single host gene target of TAL20Xam668, MeSWEET10a, which is a member of the SWEET family of sugar transporters. Designer TAL effectors that activate MeSWEET10a complemented the Xam668∆TAL20 mutant phenotype, revealing the role of MeSWEET10a in cassava’s susceptibility to Xam. SWEETs are known X. oryzae pv. oryzae TAL effector-targeted susceptibility genes in rice and thus this result establishes the activation of SWEET sugar transporters as a common mechanism of disease promotion for diverse species of Xanthomonas. In contrast to TAL20Xam668 which has a single target gene, RNA-Seq showed that TAL14Xam668 activates over 50 genes during the infection process. A subset of the TAL14Xam668-targeted genes were tested for activation by TAL14CIO151 from Xam strain CIO151 and, although TAL14CIO151 and TAL14Xam668 differ by only a single RVD, they display differential activation of host gene targets. TAL14CIO151 complements the TAL14Xam668 mutant defect, implying that shared target genes are important for TAL14Xam668-mediated disease susceptibility. This type of complementation with closely related TAL effectors is a novel approach to narrowing down biologically relevant susceptibility genes of TAL effectors with multiple targets. The comparison of the activities of TAL14Xam668 and TAL14CIO151 provides an example of how TAL effector target activation by two strains within a single species of Xanthomonas can be dramatically affected by a small change in RVD-nucleotide affinity at a single site and reflects the parameters of RVD-nucleotide interaction determined using artificial TAL effectors in transient systems. Finally, we present proof-of-concept experiments showing TAL effector-induced resistance to Xam in cassava.

Genetic correlations and an increased incidence of psychiatric disorders in inflammatory-bowel disease (IBD) have been reported, but shared molecular mechanisms are unknown. We performed cross-tissue and multiple-gene conditioned transcriptome-wide association studies (TWAS) for 23 tissues of the gut-brain-axis (GBA) using GWAS data sets (total 246,772 patients and 638,454 controls) for Crohn’s disease (CD), ulcerative colitis (UC), primary sclerosing cholangitis (PSC), schizophrenia (SCZ), bipolar disorder (BD), major depressive disorder (MDD) and attention-deficit/hyperactivity disorder (ADHD). We identified NR5A2, SATB2, and PPP3CA (encoding a target for calcineurin inhibitors in refractory UC) as shared susceptibility genes with transcriptome-wide significance both for CD/UC and SCZ, largely explaining fine-mapped association signals at nearby GWAS susceptibility loci. Analysis of bulk and single-cell RNA-sequencing data showed that PPP3CA expression was strongest in neurons and in enteroendocrine and Paneth-like cells of the ileum, colon, and rectum, indicating a possible link to the GBA. Gene-disease associations as part of calcineurin-related signaling pathways such as NFAT activation or Wnt are the most likely shared candidate pathways for IBD and SCZ, where risk is mediated by gene expression.

Preeclampsia (PE) is a complex complication that occurs during pregnancy. Studies indicated that morbidity from PE exhibits marked variations among geographical areas. Disparities in the incidence of PE between China and the US may be due to differences in ethnicity and genetic susceptibility, maternal age, sexual culture, body mass index, diet, exercise, multiple pregnancies and educational background. These epidemiological differences may give rise to differences between the two countries in terms of diagnostic and therapeutic criteria for PE. PE may be largely attributed to susceptibility genes and lifestyles, such as diet, body mass index and cultural norms regarding sexual relationships. The epidemiologic differences of patients with PE between the two countries indicated that appropriate prevention plans for PE require to be developed according to local conditions.

Atopic dermatitis (AD) is a common and complex skin disorder, and the 5q22.1 region had been reported to be associated with AD. To confirm the susceptibility gene for AD in the 5q22.1 region by haplotype and targeted capture sequencing. The haplotypes were reconstructed with the genotyping data of four SNPs and six deletions from 3624 Chinese Hans AD patients and 5076 controls. The targeted capture sequencing spanning 5q22.1 region was performed in the selected samples. The gene level enrichment analysis was done using loss of function variants. A total of 62 haplotypes were found, and the H15 haplotype had the strongest association with AD (P = 3.92 × 10−10, OR 0.17, 95% CI 0.09–0.32). However, no co-segregation mutation sites were found in the sequencing analysis within the 16 selected samples, while the enrichment analysis indicated that TMEM232 was significantly associated with AD (P = 7.33 × 10–5, OR 0.33, 95% CI 0.19–0.58). This study confirms previous findings that the TMEM232 gene is associated with AD by haplotype analysis and targeted capture sequencing.

Background: Genetic generalized epilepsies (GGE) including childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), and GGE with tonic–clonic seizures alone (GGE-TCS), are common types of epilepsy mostly determined by a polygenic mode of inheritance. Recent studies showed that susceptibility genes for GGE are numerous, and their variants rare, challenging their identification. In this study, we aimed to assess GGE genetic etiology in a Sudanese population. Methods: We performed whole-exome sequencing (WES) on DNA of 40 patients from 20 Sudanese families with GGE searching for candidate susceptibility variants, which were prioritized by CADD software and functional features of the corresponding gene. We assessed their segregation in 138 individuals and performed genotype–phenotype correlations. Results: In a family including three sibs with GGE-TCS, we identified a rare missense variant in ADGRV1 encoding an adhesion G protein-coupled receptor V1, which was already involved in the autosomal recessive Usher type C syndrome. In addition, five other ADGRV1 rare missense variants were identified in four additional families and absent from 119 Sudanese controls. In one of these families, an ADGRV1 variant was found at a homozygous state, in a female more severely affected than her heterozygous brother, suggesting a gene dosage effect. In the five families, GGE phenotype was statistically associated with ADGRV1 variants (0R = 0.9 103). Conclusion: This study highly supports, for the first time, the involvement of ADGRV1 missense variants in familial GGE and that ADGRV1 is a susceptibility gene for CAE/JAE and GGE-TCS phenotypes.

Despite rapid progress in characterizing the role of host genetics in SARS-Cov-2 infection, there is limited understanding of genes and pathways that contribute to COVID-19. Here, we integrate a genome-wide association study of COVID-19 hospitalization (7,885 cases and 961,804 controls from COVID-19 Host Genetics Initiative) with mRNA expression, splicing, and protein levels (n = 18,502). We identify 27 genes related to inflammation and coagulation pathways whose genetically predicted expression was associated with COVID-19 hospitalization. We functionally characterize the 27 genes using phenome- and laboratory-wide association scans in Vanderbilt Biobank (n = 85,460) and identified coagulation-related clinical symptoms, immunologic, and blood-cell-related biomarkers. We replicate these findings across trans-ethnic studies and observed consistent effects in individuals of diverse ancestral backgrounds in Vanderbilt Biobank, pan-UK Biobank, and Biobank Japan. Our study highlights and reconfirms putative causal genes impacting COVID-19 severity and symptomology through the host inflammatory response., Genome-wide association studies of COVID-19 have identified genetic loci affecting disease severity, but the mechanisms remain to be fully described. Here, the authors use genetically predicted transcriptome, splicing and proteome data to identify potential genes and pathways underlying COVID- 19 severity.

Genome-wide association studies (GWAS) have identified hundreds of loci associated with Crohns disease (CD), however, as with all complex diseases, deriving pathogenic mechanisms from these non-coding GWAS discoveries has been challenging. To complement GWAS and better define actionable biological targets, we analysed sequenced data from more than 30,000 CD patients and 80,000 population controls. We observe rare coding variants in established CD susceptibility genes as well as ten genes where coding variation directly implicates the gene in disease risk for the first time.

CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior O arroz (Oryza sativa L.) consiste na principal cultura alimentar de mais da metade da população mundial. Entretanto, esta cultura tem sido severamente atingida pela brusone, uma devastadora doença de plantas causada pelo fungo Magnaporthe oryzae. Dessa forma, o desenvolvimento de cultivares de arroz com maior resistência à brusone consiste em um dos principais focos dos programas de melhoramento. No entanto, devido à complexa biologia do patógeno, cultivares de arroz geneticamente resistentes ao fungo tornam-se suscetíveis em um curto período de tempo. O nocaute (deleção) de genes de suscetibilidade no genoma do arroz representa uma notável estratégia para a obtenção de uma resistência mais ampla e duradoura contra o fungo M. oryzae. O presente estudo teve como objetivo utilizar a tecnologia de edição genômica - sistema CRISPR/Cas9, para o nocaute de genes de arroz envolvidos na susceptibilidade à infecção fúngica. A partir de resultados anteriores de transcriptômica de duas linhagens semi-isogênicas de arroz - NILs submetidas a infecção por M. oryzae, foram selecionados potenciais genes de suscetibilidade. A prospecção por candidatos à edição gênica foi complementada por uma análise proteômica shotgun comparativa do perfil de proteínas da interação entre as NILs IRBLi-F5 (suscetível) e IRBL5-M (resistente) em estágios iniciais da infecção por M. oryzae, que revelou um conjunto específico de proteínas potencialmente associadas à suscetibilidade. Após a caracterização e validação da expressão gênica por RTqPCR dos candidatos mais proeminentes, os genes-alvos OsDjA2, OsERF104 e OsPyl5, foram selecionados e submetidos a validação funcional via silenciamento gênico in planta, utilizando oligonucleotídeos antissenso (ASO), onde se observou notável redução dos sintomas foliares da doença na interação compatível. Em seguida, a variedade-modelo de arroz cv. Nipponbare foi transformada com os vetores CRISPR/Cas9 visando o nocaute, independente, de cada um dos genes-alvo. Plantas de arroz da geração T1 e homozigotas para mutação-nula (perda de função) foram testadas quanto a resistência ao fungo M. oryzae. Conforme esperado, plantas editadas mostraram considerável redução dos sintomas da doença em relação às linhagens controle. Espera-se que os resultados obtidos contribuam para a geração de cultivares de arroz resistentes à brusone, além de lançar luz sobre novos potenciais genes de susceptibilidade à M. oryzae Rice (Oryza sativa L.) is the main food crop for more than half of the world population but unfortunately, it is severely affected by blast, one of the most widespread and devastating plant diseases, caused by the fungus Magnaporthe oryzae. Hence, the development of rice cultivars with greater resistance to blast is one of the main focuses of breeding programs. However, due to the complex biology of the pathogen, rice cultivars genetically resistant to the fungus become susceptible in a short period of time. In this context, the knockout of rice susceptibility genes represents a flourishing approach to obtain rice cultivars with a broader and longer-lasting resistance to M. oryzae. The present study aimed to use the genomic editing technology - CRISPR/Cas9 system, for knocking-out genes engaged with rice susceptibility to fungal infection. From previous transcriptomics results of two semi-isogenic rice lines - NILs infected by M. oryzae, potential rice-blast susceptibility genes were selected. The prospection of candidate genes for gene editing was complemented by a comparative shotgun proteomic analysis of the protein profile of the interaction between IRBLi-F5 (susceptible) and IRBL5-M (resistant) NILs in early stages of M. oryzae infection, that revealed a specific set of proteins potentially associated with susceptibility. After the characterization and validation of gene expression by RT-qPCR of the most prominent candidates, the target genes OsDjA2, OsERF104 and OsPyl5 were selected and submitted to a functional validation via gene silencing in planta, using antisense oligonucleotides (ASO), in which a clear reduction of leaf symptoms was observed in the compatible identification. Subsequently, the model japonica rice variety Nipponbare was transformed with simplex CRISPR/Cas9 vectors aiming to the independent knockout of each target gene. The T1 progeny of rice-edited plants, homozygous for the null (loss of function)-mutation were tested for blast resistance. As expected, mutant plants showed a decrease of disease symptoms in comparison with control lines (transformant non-edited plants). The results obtained in this study can contribute for the development of rice cultivars resistant to blast disease, besides shedding light on new potential rice-blast susceptibility genes.

Verticillium dahliae is a particularly notorious vascular wilt pathogen of tomato and poses a reoccurring challenge to crop protection as limited qualitative resistance is available. Therefore, alternative approaches for crop protection are pursued. One such strategy is the impairment of disease susceptibility (S) genes, which are plant genes targeted by pathogens to promote disease development. In Arabidopsis and cotton, the Walls Are Thin 1 (WAT1) gene has shown to be a S gene for V. dahliae. In this study, we identified the tomato WAT1 homolog Solyc04g080940 (SlWAT1). Transient and stable silencing of SlWAT1, based on virus-induced gene silencing (VIGS) and RNAi, respectively, did not consistently lead to reduced V. dahliae susceptibility in tomato. However, CRISPR-Cas9 tomato mutant lines carrying targeted deletions in SlWAT1 showed significantly enhanced resistance to V. dahliae, and furthermore also to Verticillium albo-atrum and Fusarium oxysporum f. sp. lycopersici (Fol). Thus, disabling the tomato WAT1 gene resulted in broad-spectrum resistance to various vascular pathogens in tomato. Unfortunately these tomato CRISPR mutant lines suffered from severe growth defects. In order to overcome the pleiotropic effect caused by the impairment of the tomato WAT1 gene, future efforts should be devoted to identifying tomato SlWAT1 mutant alleles that do not negatively impact tomato growth and development.

Background: In this study, we aimed to investigate the association between polymorphisms in the RNF213 and MMP3 genes and Moyamoya disease (MMD) and to screen susceptibility genes for families with MMD.Methods: The mutation of RNF213 gene (rs112735431,rs148731719) and MMP3 gene rs3025058 were detected by first generation sequencing and CRISPR-Cas12a. The genetic susceptibility genes of MMD families samples were studied by whole exome sequencing (WES). Results: The application of CRISPR-Cas12a and Sanger sequencing identified rs112735431 and rs148731719 mutations in the RNF213 gene, and an insertion mutation in the MMP3 gene (rs3025058) with significant regional differences (PTTN) gene (rs771533925, rs559712998 and rs72677250) was significantly associated with point mutations. Screening of the Exome Aggregation Consortium (EXAC) database identified significant differences between these populations with respect to frequency. PROVEAN，nvariant Feature Transform (SIFT) and PolyPhen algorithms further demonstrated that rs771533925 and rs72677250 were potentially damaging in three databases, rs559712998 was considered to be tolerated in above mentioned databases. Scale Invariant Feature Transform (SIFT) and PolyPhen algorithms further demonstrated that rs771533925 and rs72677250 were potentially damaging by all three databases and that rs559712998 was considered to be tolerated in above mentioned databases. Gene Ontology (GO) analysis demonstrated that the target of TTN is involved in many important biological processes. The screening of 50 sporadic MMD samples failed to identify any mutations, thus indicating that single nucleotide polymorphism (SNP) mutation sites (rs771533925, rs559712998, and rs72677250) within the TTN gene may play an important role in the inheritance of MMD. Conclusions: In summary, our study investigated susceptibility genes for MMD from multiple perspectives and found that CRISPR-Cas12a technology can efficiently detect MMD mutation sites. Our findings provide a theoretical basis for future investigations of the molecular mechanisms that underlie MMD.

OBJECTIVE The authors’ objective was to investigate the influence of the RNF213 p.R4810K variant on the clinical presentation and outcomes of Japanese pediatric patients with moyamoya disease. METHODS A total of 129 Japanese patients with pediatric-onset moyamoya disease (onset age ≤ 15 years) who visited the authors’ department from 2012 to 2020 participated in this study. After RNF213 p.R4810K genotyping of each patient was performed, the relationship between genotype and clinical presentation or outcomes, including onset age, initial presentation, surgical outcomes, and subsequent cerebrovascular events, was evaluated. Patients without the p.R4810K variant were tested for RNF213 variants other than p.R4810K. The authors especially focused on the results of patients who presented with moyamoya disease at younger than 1 year of age (infantile onset). RESULTS Compared with the patients with heterozygous variants, patients without the p.R4810K variant were younger at onset (7.1 ± 3.7 vs 4.4 ± 0.9 years), and all 4 patients with infantile onset lacked the p.R4810K variant. A greater proportion of patients without the p.R4810K variant presented with infarction than patients with the heterozygous variant (24.0% vs 7.6%) and a decreased proportion presented with transient ischemic attack (36.0% vs 71.7%). No significant correlation was observed between p.R4810K genotype and clinical outcomes, including surgical outcomes and subsequent cerebrovascular events; however, a decreased proportion of patients without the p.R4810K variant had good surgical outcomes compared with that of patients with the heterozygous variant (76.5% vs 92.2%). Among the 25 patients without the p.R4810K variant, 8 rare variants other than p.R4810K were identified. Three of 4 patients with infantile onset had RNF213 variants other than p.R4810K, which had a more severe functional effect on this gene than p.R4810K. CONCLUSIONS Absence of the RNF213 p.R4810K variant may be a novel biomarker for identification of a severe form of pediatric moyamoya disease.

Autism spectrum disorder (ASD) comprises a group of neurodevelopmental disorders characterized by impaired social interaction and communication, and restricted, repetitive patterns of behaviors, interests, or activities. It had been demonstrated that potassium channels played a key role in regulating neuronal excitability, which was closely associated with neurological diseases including epilepsy, ataxia, myoclonus, and psychiatric disorders. In recent years, a growing body of evidence from whole-genome sequencing and whole-exome sequencing had identified several ASD susceptibility genes of potassium channels in ASD subjects. Genetically dysfunction of potassium channels may be involved in altered neuronal excitability and abnormal brain function in the pathogenesis of ASD. This review summarizes current findings on the features of ASD-risk genes (KCND2, KCNQ2, KCNQ3, KCNH5, KCNJ2, KCNJ10, and KCNMA1) and further expatiate their potential role in the pathogenicity of ASD.

Cucurbit downy mildew (DM), caused by the obligate biotroph Pseudoperonospora cubensis, is a destructive disease in cucumber. A valuable source of DM resistance is the Indian cucumber accession PI 197088, which harbours several quantitative trait loci (QTLs) contributing to quantitatively inherited DM resistance. With a combination of fine‐mapping and transcriptomics, we identified Amino Acid Permease 2A (CsAAP2A) as a candidate gene for QTL DM4.1.3. Whole‐genome and Sanger sequencing revealed the insertion of a Cucumis Mu‐like element (CUMULE) transposon in the allele of the resistant near‐isogenic line DM4.1.3. To confirm whether loss of CsAAP2A contributes to partial DM resistance, we performed targeting induced local lesions in genomes on a DM‐susceptible cucumber genotype to identify an additional csaap2a mutant, which indeed was partially DM resistant. In view of the loss of the putative function as amino acid transporter, we measured amino acids in leaves. We found that DM‐inoculated leaves of line DM4.1.3 (with the csaap2a mutation) contained significantly fewer amino acids than wild‐type cucumber. The decreased flow of amino acids towards infected leaves in csaap2a plants compared to the wild type might explain the resistant phenotype of the mutant, as this would limit the available nutrients for the pathogen and thereby its fitness. To examine whether AAP genes play a conserved role as susceptibility factors in plant–oomycete interactions, we made targeted mutations in two AAP genes from tomato and studied the effect on susceptibility to Phytophthora infestans. We conclude that not only CsAAP2A but also SlAAP5A/SlAAP5B are susceptibility genes for oomycete pathogens., Loss‐of‐function mutations in amino acid permease genes were found to contribute to resistance to Pseudoperonospora cubensis in cucumber and to Phytophthora infestans in tomato by restricting pathogen feeding.

Downy mildew, caused by the oomycete Plasmopara viticola, is one of the diseases causing the most severe economic losses to grapevine (Vitis vinifera) production. To date, the application of fungicides is the most efficient method to control the pathogen and the implementation of novel and sustainable disease control methods is a major challenge. RNA interference (RNAi) represents a novel biotechnological tool with a great potential for controlling fungal pathogens. Recently, a candidate susceptibility gene (VviLBDIf7) to downy mildew has been identified in V. vinifera. In this work, the efficacy of RNAi triggered by exogenous double-stranded RNA (dsRNA) in controlling P. viticola infections has been assessed in a highly susceptible grapevine cultivar (Pinot noir) by knocking down VviLBDIf7 gene. The effects of dsRNA treatment on this target gene were assessed by evaluating gene expression, disease severity, and development of vegetative and reproductive structures of P. viticola in the leaf tissues. Furthermore, the effects of dsRNA treatment on off-target (EF1α, GAPDH, PEPC, and PEPCK) and jasmonic acid metabolism (COI1) genes have been evaluated. Exogenous application of dsRNA led to significant reductions both in VviLBDIf7 gene expression, 5 days after the treatment, and in the disease severity when artificial inoculation was carried out 7 days after dsRNA treatments. The pathogen showed clear alterations to both vegetative (hyphae and haustoria) and reproductive structures (sporangiophores) that resulted in stunted growth and reduced sporulation. Treatment with dsRNA showed signatures of systemic activity and no deleterious off-target effects. These results demonstrated the potential of RNAi for silencing susceptibility factors in grapevine as a sustainable strategy for pathogen control, underlying the possibility to adopt this promising biotechnological tool in disease management strategies.

Single nucleotide polymorphisms (SNPs) and genes associated with susceptibility to hepatitis B virus (HBV) infection that have been identified by genome-wide association studies explain only a limited portion of the known heritability, indicating more genetic variants remain to be discovered. In this study, we adopted a new research strategy to identify more susceptibility genes and variants for HBV infection. We first performed genetic association analysis of 300 sib-pairs and 3,087 case-control samples, which revealed that 36 SNPs located in 31 genes showed nominal associations with HBV infection in both samples. Of these genes, we selected SEC24D for further molecular analysis according to the following two main lines of evidence. First, a time course analysis of the expression profiles from HBV-infected primary human hepatocytes (PHH) demonstrated that SEC24D expression increased markedly as time passed after HBV infection (P = 4.0 × 10−4). Second, SNP rs76459466 in SEC24D was adversely associated with HBV risk (ORmeta = 0.82; Pmeta = 0.002), which again indicated that SEC24D represents a novel susceptibility gene for HBV infection. Moreover, SEC24D appeared to be protective against HBV infection in vitro. Consistently, we found that SEC24D expression was significantly enhanced in non-infected liver tissues (P = 0.002). We conclude that SEC24D is a novel candidate gene linked to susceptibility to HBV infection.

Existing studies have shown that primary gout and hyperuricemia are a group of polygenetic hereditary diseases, which are the results of the combination of genetic and environmental factors. However, the study on the genetic susceptibility of gout and hyperuricemia is not yet complete and it is not yet possible to predict which populations are susceptible to gout and hyperuricemia. Genome-wide association study (GWAS), a method developed in recent years, is used to identify susceptibility genes for complex disease pathogenesis. Through screening patients and the normal control, and combined with computer technology and statistical analysis, genome-wide variation can be used to identify minor gene and its interaction with related diseases. In our study, we summarized and classified uric acid related genes discovered in recent years, so as to provide a basis for further understanding of the molecular mechanism of gout and hyperuricemia, and provide a beneficial reference for further study on the etiology of gout and hyperuricemia.

The ring-finger protein 213 ( RNF213) gene is a major susceptibility gene for moyamoya disease. The homozygote of the p.R4810K variant on RNF213 exhibits an early onset age and severe form of moyamoya disease. We report 4 unrelated pediatric moyamoya disease cases with the homozygous p.R4810K variant and the long-term surgical outcomes. Published reports on surgical outcome of moyamoya disease case with the homozygous p.R4810K variant were reviewed. Cerebral angiography revealed classic angiographic findings of moyamoya disease in 7 hemispheres of the 4 children. All patients underwent successful indirect revascularization. Abundant collateral blood flow from the external carotid arteries to the internal carotid arteries was observed in all bypass procedures by angiography. Improvements in symptoms and cerebral blood volume were observed in all patients at long-term follow-up. This report is the first case series in the literature on the surgical management of these patients. These cases highlight the effectiveness of indirect revascularization for moyamoya disease patients with the homozygous p.R4810K variant. Early diagnosis and treatment are crucial to avoid irreversible neurologic deficits in these patients.

Purpose: Gene-disease associations implicated in hereditary colorectal cancer and polyposis susceptibility were evaluated using the ClinGen Clinical Validity framework. Methods: Forty-two gene-disease pairs were assessed for strength of evidence supporting an association with hereditary colorectal cancer and/or polyposis. Genetic and experimental evidence supporting each gene-disease relationship was curated independently by two trained biocurators. Evidence was reviewed with experts and assigned a final clinical validity classification. Results: Of all gene-disease pairs evaluated, 14/42 (33.3%) were Definitive, 1/42 (2.4%) were Strong, 6/42 (14.3%) were Moderate, 18/42 (42.9%) were Limited, and 3/42 (7.1%) were either No Reported Evidence, Disputed, or Refuted. Of panels in the NIH Genetic Testing Registry, 4/26 (~15.4%) contain genes with Limited clinical evidence. Conclusion: Clinicians and laboratory diagnosticians should note that 40% have only Moderate, Limited, Disputed, or Refuted evidence. Continuing to expand the structured assessment of the clinical relevance of genes listed on hereditary cancer testing panels will help clinicians and diagnostic laboratories focus the communication of genetic testing results on clinically significant genes.