Targeted Sequencing and Integrative Analysis to Prioritise Candidate Genes in Neurodevelopmental Disorders

2021 ◽  
Author(s):  
Yi Zhang ◽  
Tao Wang ◽  
Yan Wang ◽  
Kun Xia ◽  
Jinchen Li ◽  
...  
Keyword(s):  
Candidate Genes ◽  
Neurodevelopmental Disorders ◽  
De Novo ◽  
Genetic Data ◽  
Chinese Patients ◽  
The Novel ◽  
Mutational Spectrum ◽  
Functional Variants ◽  
Public Data ◽  
Chromosomal Genes

Abstract Neurodevelopmental disorders (NDDs) are a group of diseases characterized by highly heterogeneity and frequently co-occur symptoms. The mutational spectrum in patients with NDDs is largely incomplete. Here, we sequenced 547 genes from 1,102 patients with NDDs and validated 1,271 potential functional variants, including 108 de novo variants (DNVs) in 78 autosomal genes and seven inherited hemizygous variants in six X chromosomal genes. Notably, 36 of these 78 genes are the first to be reported in Chinese patients with NDDs. By integrating our genetic data with public data, we prioritised 212 NDD candidate genes with FDR < 0.1, including 17 novel genes. The novel candidate genes interacted or were co-expressed with known candidate genes, forming a functional network involved in known pathways. We highlighted MSL2, which carried two de novo protein-truncating variants (p.L192Vfs*3 and p.S486Ifs*11) and was most frequently connected with known candidate genes. This study provides the mutational spectrum of NDDs in China and prioritises 212 NDD candidate genes for further functional validation and genetic counseling.

scholarly journals Targeted sequencing and integrative analysis to prioritize candidate genes in neurodevelopmental disorders

2021 ◽  
Author(s):  
Yi Zhang ◽  
Tao Wang ◽  
Yan Wang ◽  
Kun Xia ◽  
Jinchen Li ◽  
...  
Keyword(s):  
Candidate Genes ◽  
Neurodevelopmental Disorders ◽  
De Novo ◽  
Genetic Data ◽  
Chinese Patients ◽  
The Novel ◽  
Mutational Spectrum ◽  
Functional Variants ◽  
Public Data ◽  
Chromosomal Genes

AbstractNeurodevelopmental disorders (NDDs) are a group of diseases characterized by high heterogeneity and frequently co-occurring symptoms. The mutational spectrum in patients with NDDs is largely incomplete. Here, we sequenced 547 genes from 1102 patients with NDDs and validated 1271 potential functional variants, including 108 de novo variants (DNVs) in 78 autosomal genes and seven inherited hemizygous variants in six X chromosomal genes. Notably, 36 of these 78 genes are the first to be reported in Chinese patients with NDDs. By integrating our genetic data with public data, we prioritized 212 NDD candidate genes with FDR < 0.1, including 17 novel genes. The novel candidate genes interacted or were co-expressed with known candidate genes, forming a functional network involved in known pathways. We highlighted MSL2, which carried two de novo protein-truncating variants (p.L192Vfs*3 and p.S486Ifs*11) and was frequently connected with known candidate genes. This study provides the mutational spectrum of NDDs in China and prioritizes 212 NDD candidate genes for further functional validation and genetic counseling.

scholarly journals Cross-Disorder Analysis of De Novo Variants Increases the Power of Prioritising Candidate Genes

Life ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 233
Author(s):  
Kuokuo Li ◽  
Zhengbao Ling ◽  
Tengfei Luo ◽  
Guihu Zhao ◽  
Qiao Zhou ◽  
...  
Keyword(s):  
Cohort Studies ◽  
Candidate Genes ◽  
Genetic Heterogeneity ◽  
Neurodevelopmental Disorders ◽  
Genetic Similarity ◽  
De Novo ◽  
Integrated Analysis ◽  
Cohort Size ◽  
Functional Variants ◽  
Small Cohort

De novo variants (DNVs) are critical to the treatment of neurodevelopmental disorders (NDDs). However, effectively identifying candidate genes in small cohorts is challenging in most NDDs because of high genetic heterogeneity. We hypothesised that integrating DNVs from multiple NDDs with genetic similarity can significantly increase the possibility of prioritising the candidate gene. We catalogued 66,186 coding DNVs in 50,028 individuals with nine types of NDDs in cohorts with sizes spanning from 118 to 31,260 from Gene4Denovo database to validate this hypothesis. Interestingly, we found that integrated DNVs can effectively increase the number of prioritised candidate genes for each disorder. We identified 654 candidate genes including 481 shared candidate genes carrying putative functional variants in at least two disorders. Notably, 13.51% (65/481) of shared candidate genes were prioritised only via integrated analysis including 44.62% (29/65) genes validated in recent large cohort studies. Moreover, we estimated that more novel candidate genes will be prioritised with the increase in cohort size, in particular for some disorders with high putative functional DNVs per individual. In conclusion, integrated DNVs may increase the power of prioritising candidate genes, which is important for NDDs with small cohort size.

scholarly journals Gene4Denovo: an integrated database and analytic platform for de novo mutations in humans

2019 ◽  
Author(s):  
Guihu Zhao ◽  
Kuokuo Li ◽  
Bin Li ◽  
Zheng Wang ◽  
Zhenghuan Fang ◽  
...  
Keyword(s):  
Candidate Genes ◽  
De Novo ◽  
Unmet Need ◽  
Genetic Data ◽  
De Novo Mutations ◽  
False Discovery Rates ◽  
False Discovery ◽  
Whole Exome ◽  
Gene Level ◽  
Analyse Data

Abstract De novo mutations (DNMs) significantly contribute to sporadic diseases, particularly in neuropsychiatric disorders. Whole-exome sequencing (WES) and whole-genome sequencing (WGS) provide effective methods for detecting DNMs and prioritizing candidate genes. However, it remains a challenge for scientists, clinicians, and biologists to conveniently access and analyse data regarding DNMs and candidate genes from scattered publications. To fill the unmet need, we integrated 580 799 DNMs, including 30 060 coding DNMs detected by WES/WGS from 23 951 individuals across 24 phenotypes and prioritized a list of candidate genes with different degrees of statistical evidence, including 346 genes with false discovery rates <0.05. We then developed a database called Gene4Denovo (http://www.genemed.tech/gene4denovo/), which allowed these genetic data to be conveniently catalogued, searched, browsed, and analysed. In addition, Gene4Denovo integrated data from >60 genomic sources to provide comprehensive variant-level and gene-level annotation and information regarding the DNMs and candidate genes. Furthermore, Gene4Denovo provides end-users with limited bioinformatics skills to analyse their own genetic data, perform comprehensive annotation, and prioritize candidate genes using custom parameters. In conclusion, Gene4Denovo conveniently allows for the accelerated interpretation of DNM pathogenicity and the clinical implication of DNMs in humans.

scholarly journals The ‘Tommy Atkins’ mango genome reveals candidate genes for fruit quality

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Ian S. E. Bally ◽  
◽  
Aureliano Bombarely ◽  
Alan H. Chambers ◽  
Yuval Cohen ◽  
...  
Keyword(s):  
Candidate Genes ◽  
Fruit Quality ◽  
De Novo ◽  
Mapping Population ◽  
Mangifera Indica ◽  
Consensus Sequence ◽  
Fruit Size ◽  
Hybrid Population ◽  
High Molecular Weight Dna ◽  
Tropical Fruit

Abstract Background Mango, Mangifera indica L., an important tropical fruit crop, is grown for its sweet and aromatic fruits. Past improvement of this species has predominantly relied on chance seedlings derived from over 1000 cultivars in the Indian sub-continent with a large variation for fruit size, yield, biotic and abiotic stress resistance, and fruit quality among other traits. Historically, mango has been an orphan crop with very limited molecular information. Only recently have molecular and genomics-based analyses enabled the creation of linkage maps, transcriptomes, and diversity analysis of large collections. Additionally, the combined analysis of genomic and phenotypic information is poised to improve mango breeding efficiency. Results This study sequenced, de novo assembled, analyzed, and annotated the genome of the monoembryonic mango cultivar ‘Tommy Atkins’. The draft genome sequence was generated using NRGene de-novo Magic on high molecular weight DNA of ‘Tommy Atkins’, supplemented by 10X Genomics long read sequencing to improve the initial assembly. A hybrid population between ‘Tommy Atkins’ x ‘Kensington Pride’ was used to generate phased haplotype chromosomes and a highly resolved phased SNP map. The final ‘Tommy Atkins’ genome assembly was a consensus sequence that included 20 pseudomolecules representing the 20 chromosomes of mango and included ~ 86% of the ~ 439 Mb haploid mango genome. Skim sequencing identified ~ 3.3 M SNPs using the ‘Tommy Atkins’ x ‘Kensington Pride’ mapping population. Repeat masking identified 26,616 genes with a median length of 3348 bp. A whole genome duplication analysis revealed an ancestral 65 MYA polyploidization event shared with Anacardium occidentale. Two regions, one on LG4 and one on LG7 containing 28 candidate genes, were associated with the commercially important fruit size characteristic in the mapping population. Conclusions The availability of the complete ‘Tommy Atkins’ mango genome will aid global initiatives to study mango genetics.

scholarly journals Safety and efficacy of the treatment of in-stent restenosis and de novo complex lesions with the novel paclitaxel-coated scoring balloon (Angiosculpt X)

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
D.P Agip Fustamante ◽  
S Ortiz Cruces ◽  
S Camacho Freire ◽  
A Gutierrez Barrios ◽  
A Gomez Menchero ◽  
...  
Keyword(s):  
Real World ◽  
Cardiac Death ◽  
De Novo ◽  
Funding Source ◽  
The Novel ◽  
Safety And Efficacy ◽  
Stent Restenosis ◽  
Scoring Balloon ◽  
In Stent Restenosis ◽  
Complex Lesions

Abstract Background The AngioSculpt X (Spectranetics) is a novel paclitaxel-coated scoring balloon with encouraging preliminary data for the treatment of in-stent restenosis or de novo complex lesions. Purpose To assess the safety and efficacy of real-world patients with in-stent restenosis (ISR) or de novo complex lesions (vessels &lt;2.5 mm, calcified lesions, bifurcation lesions...) treated with the novel paclitaxel-coated scoring balloon. Methods A “real-world”, prospective registry from two centers was performed including consecutive patients presenting with ISR or de novo complex lesions and treated with AngioSculpt X. Their clinical data were prospectively registered. Major adverse cardiac events (MACE) were defined as a composite of cardiac death, stent thrombosis, nonfatal myocardial infarction, target lesion revascularization (TLR) and target vessel revascularization (TVR). Results Overall, 87 real-world patients and 93 lesions (73% male, 68±10 years, 46% smoker, 83% hypertensive, 62% diabetic, 71% hyperlipidemic, 35% LVEF &lt;60% impairment) were enrolled in the study. Clinical presentation was stable angina in 19%, unstable angina in 33%, NSTEMI in 29% and STEMI in 5%. Radial access account 84%. The median fluoroscopy time was 17 (IQ range 10,0 - 37.5) min. De novo complex lesions were treated in 35% (n=32) while ISR in 63% (n=57), (Prior BMS 19%; Sirolimus DES 9%; Everolimus DES 26%; Biolimus/Anfilimus DES 20%; Zotarolimus DES 26%) with a median time to ISR of 3.6 (IQ range 1.1 - 10.7) years. Total stent length was 28±18 mm, with an overlap spot affected in 18%, and 27% had &gt;1 treatment for ISR. The most frequent artery treated was left anterior descending (41%) followed by left circumflex (35%) and right coronary artery (17%). Quantitative coronary angiography reference diameter of lesions was 2.7±0.5 mm and length 9.0±4.8 mm, with a % stenosis of 75±20. Predilatation/postdilatation was performed in 60/24% respectively. Device diameter was 2.9±0.4 mm and length 13.6±3.9 mm, deployed at 16±3 atmospheres, with an inflation time of 33±16 seconds. The balloon/artery ratio was 0.99±0.03. Crossover was decided on 18 cases (19%) due to remaining intimal flap, but the success rate (residual stenosis &lt;30%) was 100%. Intracoronary imaging technique was performed in 12% (OCT=7, IVUS=4). At 7±6 month follow-up, there were 10 MACE (cardiac death=1, nonfatal myocardial infarction =4, TLR=4 and TVR=1). Conclusions Paclitaxel-coated scoring balloon offers a safe and valuable treatment option for ISR and de novo complex lesions. Funding Acknowledgement Type of funding source: Public hospital(s). Main funding source(s): Juan Ramόn Jiménez University Hospital

scholarly journals Illuminating the Plant Rhabdovirus Landscape through Metatranscriptomics Data

Viruses ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1304
Author(s):  
Nicolás Bejerman ◽  
Ralf G. Dietzgen ◽  
Humberto Debat
Keyword(s):  
Plant Species ◽  
High Throughput Sequencing ◽  
Plant Viruses ◽  
The Novel ◽  
Coding Regions ◽  
Public Data ◽  
Invaluable Tool ◽  
Sequencing Platforms ◽  
Viral Sequences ◽  
Plant Rhabdovirus

Rhabdoviruses infect a large number of plant species and cause significant crop diseases. They have a negative-sense, single-stranded unsegmented or bisegmented RNA genome. The number of plant-associated rhabdovirid sequences has grown in the last few years in concert with the extensive use of high-throughput sequencing platforms. Here, we report the discovery of 27 novel rhabdovirus genomes associated with 25 different host plant species and one insect, which were hidden in public databases. These viral sequences were identified through homology searches in more than 3000 plant and insect transcriptomes from the National Center for Biotechnology Information (NCBI) Sequence Read Archive (SRA) using known plant rhabdovirus sequences as the query. The identification, assembly and curation of raw SRA reads resulted in sixteen viral genome sequences with full-length coding regions and ten partial genomes. Highlights of the obtained sequences include viruses with unique and novel genome organizations among known plant rhabdoviruses. Phylogenetic analysis showed that thirteen of the novel viruses were related to cytorhabdoviruses, one to alphanucleorhabdoviruses, five to betanucleorhabdoviruses, one to dichorhaviruses and seven to varicosaviruses. These findings resulted in the most complete phylogeny of plant rhabdoviruses to date and shed new light on the phylogenetic relationships and evolutionary landscape of this group of plant viruses. Furthermore, this study provided additional evidence for the complexity and diversity of plant rhabdovirus genomes and demonstrated that analyzing SRA public data provides an invaluable tool to accelerate virus discovery, gain evolutionary insights and refine virus taxonomy.

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