Objective:Gain a better understanding of sex-specific differences in individuals with global developmental delay (GDD), with a focus on phenotypes and genotypes.Methods:Using the Deciphering Developmental Disorders (DDD) dataset, we extracted phenotypic information from 6,588 individuals with GDD and then identified statistically significant variations in phenotypes and genotypes based on sex. We compared genes with pathogenic variants between sex and then performed gene network and molecular function enrichment analysis and gene expression profiling between sex. Finally, we contrasted individuals with autism as an associated condition.Results:We identified significantly differentially expressed phenotypes in males vs. females individuals with GDD. Autism and macrocephaly were significantly more common in males whereas microcephaly and stereotypies were more common in females. Importantly, 66% of GDD genes with pathogenic variants overlapped between both sexes. In the cohort, males presented with only slightly increased X-linked genes (9% vs. 8%, respectively). Individuals from both sexes harbored a similar number of pathogenic variants overall (3) but females presented with a significantly higher load for GDD genes with high intolerance to loss of function. Sex difference in gene expression correlated with genes identified in a sex specific manner. While we identified sex-specific GDD gene mutations, their pathways overlapped. Interestingly, individuals with GDD but also co-morbid autism phenotypes, we observed distinct mutation load, pathways and phenotypic presentation.Conclusion:Our study shows for the first time that males and females with GDD present with significantly different phenotypes. Moreover, while most GDD genes overlapped, some genes were found uniquely in each sex. Surprisingly they shared similar molecular functions. Sorting genes by predicted tolerance to loss of function (pLI) led to identifying an increased mutation load in females with GDD, suggesting potentially a tolerance to GDD genes of higher pLI compared to overall GDD genes. Finally, we show that considering associated conditions (for instance autism) may influence the genomic underpinning found in individuals with GDD and highlight the importance of comprehensive phenotyping.

Motivation: Computational identification of copy number variants (CNVs) in sequencing data is a challenging task. Existing CNV-detection methods account for various sources of variation and perform different normalization strategies. However, their applicability and predictions are restricted to specific enrichment protocols. Here, we introduce a novel tool named varAmpliCNV, specifically designed for CNV-detection in amplicon-based targeted resequencing data (Haloplex (TM) enrichment protocol) in the absence of matched controls. VarAmpliCNV utilizes principal component analysis (PCA) and/or metric dimensional scaling (MDS) to control variances of amplicon associated read counts enabling effective detection of CNV signals. Results: Performance of VarAmpliCNV was compared against three existing methods (ConVaDING, ONCOCNV and DECoN) on data of 167 samples run with an aortic aneurysm gene panel (n = 30), including 9 positive control samples. Additionally, we validated the performance on a large deafness gene panel (n = 145) run on 138 samples, containing 4 positive controls. VarAmpliCNV achieved higher sensitivity (100%) and specificity (99.78%) in comparison to competing methods. In addition, unsupervised clustering of CNV segments and visualization plots of amplicons spanning these regions are included as a downstream strategy to filter out false positives. Availability and implementation: he tool is freely available through galaxy toolshed and at:https://hub.docker.com/r/cmgantwerpen/varamplicnv.Supplementary Data File S1:https://tinyurl.com/2yzswyhh;Supplementary DataFile S2:https://tinyurl.com/ycyf2fb4. Contact: maaike.alaerts @uantwerpen.be or geert.vandeweyer@uantwerpen.be Supplementary information: Supplementary dataare available atBioinformatics online.

ObjectiveIndividuals with neurodevelopmental disorders such as global developmental delay (GDD) present both genotypic and phenotypic heterogeneity. This diversity has hampered developing of targeted interventions given the relative rarity of each individual genetic etiology. Novel approaches to clinical trials where distinct, but related diseases can be treated by a common drug, known as basket trials, which have shown benefits in oncology but have yet to be used in GDD. Nonetheless, it remains unclear how individuals with GDD could be clustered. Here, we assess two different approaches: agglomerative and divisive clustering.MethodsUsing the largest cohort of individuals with GDD, which is the Deciphering Developmental Disorders (DDD), characterized using a systematic approach, we extracted genotypic and phenotypic information from 6,588 individuals with GDD. We then used a k-means clustering (divisive) and hierarchical agglomerative clustering (HAC) to identify subgroups of individuals. Next, we extracted gene network and molecular function information with regard to the clusters identified by each approach.ResultsHAC based on phenotypes identified in individuals with GDD revealed 16 clusters, each presenting with one dominant phenotype displayed by most individuals in the cluster, along with other minor phenotypes. Among the most common phenotypes reported were delayed speech, absent speech, and seizure. Interestingly, each phenotypic cluster molecularly included several (3–12) gene sub-networks of more closely related genes with diverse molecular function. k-means clustering also segregated individuals harboring those phenotypes, but the genetic pathways identified were different from the ones identified from HAC.ConclusionOur study illustrates how divisive (k-means) and agglomerative clustering can be used in order to group individuals with GDD for future basket trials. Moreover, the result of our analysis suggests that phenotypic clusters should be subdivided into molecular sub-networks for an increased likelihood of successful treatment. Finally, a combination of both agglomerative and divisive clustering may be required for developing of a comprehensive treatment.

To facilitate early deployment of whole-genome sequencing (WGS) for severely ill children, a standardized pipeline for WGS analysis with timely turnaround and primary care pediatric uptake is needed. We developed a bioinformatics pipeline for comprehensive gene-agnostic trio WGS analysis of children suspected of having an undiagnosed monogenic disease that included detection and interpretation of primary genetic mechanisms of disease, including SNVs/indels, CNVs/SVs, uniparental disomy (UPD), imprinted genes, short tandem repeat expansions, mobile element insertions, SMN1/2 copy number calling, and mitochondrial genome variants. We assessed primary care practitioner experience and competence in a large cohort of 521 families (comprising 90% WGS trios). Children were identified by primary practitioners for recruitment, and we used the UK index of multiple deprivation to confirm lack of patient socio-economic status ascertainment bias. Of the 521 children sequenced, 176 (34%) received molecular diagnoses, with rates as high as 45% for neurology clinics. Twenty-three of the diagnosed cases (13%) required bespoke methods beyond routine SNV/CNV analysis. In our multidisciplinary clinician user experience assessment, both pediatricians and clinical geneticists expressed strong support for rapid WGS early in the care pathway, but requested further training in determining patient selection, consenting, and variant interpretation. Rapid trio WGS provides an efficacious single-pass screening test for children when deployed by primary practitioners in clinical settings that carry high a priori risk for rare pediatric disease presentations.

BackgroundAlthough carpal tunnel syndrome (CTS) is the most common form of peripheral entrapment neuropathy, its pathogenesis remains largely unknown. An estimated heritability index of 0.46 and an increased familial occurrence indicate that genetic factors must play a role in the pathogenesis.Methods and resultsWe report on a family in which CTS occurred in subsequent generations at an unusually young age. Additional clinical features included brachydactyly and short Achilles tendons resulting in toe walking in childhood. Using exome sequencing, we identified a heterozygous variant (c.5009T>G; p.Phe1670Cys) in the fibrillin-2 (FBN2) gene that co‐segregated with the phenotype in the family. Functional assays showed that the missense variant impaired integrin-mediated cell adhesion and migration. Moreover, we observed an increased transforming growth factor-β signalling and fibrosis in the carpal tissues of affected individuals. A variant burden test in a large cohort of patients with CTS revealed a significantly increased frequency of rare (6.7% vs 2.5%–3.4%, p<0.001) and high-impact (6.9% vs 2.7%, p<0.001) FBN2 variants in patient alleles compared with controls.ConclusionThe identification of a novel FBN2 variant (p.Phe1670Cys) in a unique family with early onset CTS, together with the observed increased frequency of rare and high-impact FBN2 variants in patients with sporadic CTS, strongly suggest a role of FBN2 in the pathogenesis of CTS.

Background: The visual pathway is a complex multi-synaptic neuronal circuit prone to alteration in conductivity under the influence of various neuro-hormonal modulators. The female sex steroids have shown significant effect on these circuits during different phases of menstrual cycle and pregnancy. The reaction time is the elapsed time between the presentation of a stimulus and the subsequent behavioral response i.e. time required for an observer to react to a stimulus. Various studies have shown changes in reaction time during pregnancy but there are no studies that show changes in reaction time and its effect on the woman in the postpartum stage. Dearyliewald reaction time tester was used in this study to calculate the simple and choice reaction time and a total of 30 subjects were included in this study which were divided into 2 groups i.e. primiparous LSCS and multiparous LSCS and they were screened on 4th and 14th day postpartum Aim: To compare reaction time in post-partum LSCS primi parous and multi parous females on 4th and 14th day. Objectives: To assess and compare reaction time in post-partum primiparous and multi parous LSCS females on 4th and 14th day. Material and Methods: A total of 30females were selected as per the inclusion and exclusion criteria. The subjects were allocated in 2 groups of 15 females in each group. Group A consisted of postpartum primiparous females and group B consisted of postpartum multi parous females. Reaction time was assessed using Deary- Liewald Reaction time tester software. Result: The study result show that significant difference was found in the simple and choice reaction time on 4th and 14th day when a comparison is made in the same group i.e. within Group A and within Group B. Conclusion: The study concludes that there is a significant difference in the reaction time when a comparison is made in the same group. But there is no significant difference in the reaction time when an inter-group comparison is made between primiparous and multiparous females.

Bicuspid aortic valve (BAV) is the most common congenital heart defect (CHD), affecting 1–2% of the population. BAV is associated with thoracic aortic aneurysms (TAAs). Deleterious copy number variations (CNVs) were found previously in up to 10% of CHD cases. This study aimed at unravelling the contribution of deleterious deletions or duplications in 95 unrelated BAV/TAA patients. Seven unique or rare CNVs were validated, harbouring protein-coding genes with a role in the cardiovascular system. Based on the presence of overlapping CNVs in patients with cardiovascular phenotypes in the DECIPHER database, the identification of similar CNVs in whole-exome sequencing data of 67 BAV/TAA patients and suggested topological domain involvement from Hi-C data, supportive evidence was obtained for two genes (DGCR6 and TBX20) of the seven initially validated CNVs. A rare variant burden analysis using next-generation sequencing data from 637 BAV/TAA patients was performed for these two candidate genes. This revealed a suggestive genetic role for TBX20 in BAV/TAA aetiology, further reinforced by segregation of a rare TBX20 variant with the phenotype within a BAV/TAA family. To conclude, our results do not confirm a significant contribution for deleterious CNVs in BAV/TAA as only one potentially pathogenic CNV (1.05%) was identified. We cannot exclude the possibility that BAV/TAA is occasionally attributed to causal CNVs though, or that certain CNVs act as genetic risk factors by creating a sensitised background for BAV/TAA. Finally, accumulative evidence for TBX20 involvement in BAV/TAA aetiology underlines the importance of this transcription factor in cardiovascular disease.

On average a human cell type expresses around 10,000 different protein coding genes synthesizing all the different molecular forms of the protein product (proteoforms) found in a cell. In a typical shotgun bottom up proteomic approach, the proteins are enzymatically cleaved, producing several 100,000 s of different peptides that are analyzed with liquid chromatography-tandem mass spectrometry (LC-MSMS). One of the major consequences of this high sample complexity is that coelution of peptides cannot be avoided. Moreover, low abundant peptides are difficult to identify as they have a lower chance of being selected for fragmentation due to ion-suppression effects and the semi-stochastic nature of the precursor selection in data-dependent shotgun proteomic analysis where peptides are selected for fragmentation analysis one-by-one as they elute from the column. In the current study we explore a simple novel approach that has the potential to counter some of the effect of coelution of peptides and improves the number of peptide identifications in a bottom-up proteomic analysis. In this method, peptides from a HeLa cell digest were eluted from the reverse phase column using three different elution solvents (acetonitrile, methanol and acetone) in three replicate reversed phase LC-MS/MS shotgun proteomic analysis. Results were compared with three technical replicates using the same solvent, which is common practice in proteomic analysis. In total, we see an increase of up to 10% in unique protein and up to 30% in unique peptide identifications from the combined analysis using different elution solvents when compared to the combined identifications from the three replicates of the same solvent. In addition, the overlap of unique peptide identifications common in all three LC-MS analyses in our approach is only 23% compared to 50% in the replicates using the same solvent. The method presented here thus provides an easy to implement method to significantly reduce the effects of coelution and ion suppression of peptides and improve protein coverage in shotgun proteomics. Data are available via ProteomeXchange with identifier PXDO11908.

Motivation Computational gene prioritization can aid in disease gene identification. Here, we propose pBRIT (prioritization using Bayesian Ridge regression and Information Theoretic model), a novel adaptive and scalable prioritization tool, integrating Pubmed abstracts, Gene Ontology, Sequence similarities, Mammalian and Human Phenotype Ontology, Pathway, Interactions, Disease Ontology, Gene Association database and Human Genome Epidemiology database, into the prediction model. We explore and address effects of sparsity and inter‐feature dependencies within annotation sources, and the impact of bias towards specific annotations. Results pBRIT models feature dependencies and sparsity by an Information‐Theoretic (data driven) approach and applies intermediate integration based data fusion. Following the hypothesis that genes underlying similar diseases will share functional and phenotype characteristics, it incorporates Bayesian Ridge regression to learn a linear mapping between functional and phenotype annotations. Genes are prioritized on phenotypic concordance to the training genes. We evaluated pBRIT against nine existing methods, and on over 2000 HPO‐gene associations retrieved after construction of pBRIT data sources. We achieve maximum AUC scores ranging from 0.92 to 0.96 against benchmark datasets and of 0.80 against the time‐stamped HPO entries, indicating good performance with high sensitivity and specificity. Our model shows stable performance with regard to changes in the underlying annotation data, is fast and scalable for implementation in routine pipelines. Availability and implementation http://biomina.be/apps/pbrit/; https://bitbucket.org/medgenua/pbrit.

Background: Postnatal Depression (PND) is depression with onset usually 6 weeks of delivery.The prevalence of PND according to western studies is 13-19% and in India rates are 11-26.3%.Socioeconomic Status (SES) is an important determinant of health, nutritional status, mortality and morbidity of an individual.Women belonging to Upper SES have ability to access to all the up to date facilities available in the market required during pregnancy, delivery and post-delivery whereas considering women of lower SES, they lack even the basic of the adequate facilities and access to mental health services and are least likely to report symptoms of depression.This scenario calls for more studies on PND, in an attempt to better understand the disease and its associations, with a view to prevention, early diagnosis and management.Materials and Methods: An observational study was conducted for duration of 1 year in metropolitan city with a sample size of 300 women between age of 20-30 years also the inclusion criteria consisted of women who had Full term normal vaginal delivery, immediate postpartum to 6 weeks postpartum and primiparous women .Outcome Measures: Women were classified into Upper, Middle and lower SES using the Modified Kuppuswamy Scale.A Score of 26-29 -Upper Class, 11-15 middle class and <5 lower class.Women were screened for depression using the Edinburgh Postnatal Depression Scale.(EPDS).A score of e"10 on the EPDS was used as a measure of primary outcome, depression.Results: Mean scores of PND was 1.58, 10.58 and 14.80 of upper, middle and lower SES women respectively which was analysed statistically and found to be significant. Conclusion:This study concludes that there is significant difference in the level of postnatal depression when compared between upper, middle and lower socioeconomic status women.

Bicuspid aortic valve (BAV) is a common congenital heart defect (population incidence, 1-2%)1-3 that frequently presents with ascending aortic aneurysm (AscAA)4. BAV/AscAA shows autosomal dominant inheritance with incomplete penetrance and male predominance. Causative gene mutations (for example, NOTCH1, SMAD6) are known for ≤1% of nonsyndromic BAV cases with and without AscAA5-8, impeding mechanistic insight and development of therapeutic strategies. Here, we report the identification of variants in ROBO4 (which encodes a factor known to contribute to endothelial performance) that segregate with disease in two families. Targeted sequencing of ROBO4 showed enrichment for rare variants in BAV/AscAA probands compared with controls. Targeted silencing of ROBO4 or mutant ROBO4 expression in endothelial cell lines results in impaired barrier function and a synthetic repertoire suggestive of endothelial-to-mesenchymal transition. This is consistent with BAV/AscAA-associated findings in patients and in animal models deficient for ROBO4. These data identify a novel endothelial etiology for this common human disease phenotype.

[This corrects the article on p. 400 in vol. 8, PMID: 28659821.].

Intellectual disability (ID) affects approximately 1-2% of the general population and is characterized by impaired cognitive abilities. ID is both clinically as well as genetically heterogeneous, up to 2000 genes are estimated to be involved in the emergence of the disease with various clinical presentations. For many genes, only a few patients have been reported and causality of some genes has been questioned upon the discovery of apparent loss-of-function mutations in healthy controls. Description of additional patients strengthens the evidence for the involvement of a gene in the disease and can clarify the clinical phenotype associated with mutations in a particular gene. Here, we present two large four-generation families with a total of 11 males affected with ID caused by mutations in ZNF711, thereby expanding the total number of families with ID and a ZNF711 mutation to four. Patients with mutations in ZNF711 all present with mild to moderate ID and poor speech accompanied by additional features in some patients, including autistic features and mild facial dysmorphisms, suggesting that ZNF711 mutations cause non-syndromic ID.

ABSTRACT Taphrina deformans is a fungus responsible for peach leaf curl, an important plant disease. It is phylogenetically assigned to the Taphrinomycotina subphylum, which includes the fission yeast and the mammalian pathogens of the genus Pneumocystis. We describe here the genome of T. deformans in the light of its dual plant-saprophytic/plant-parasitic lifestyle. The 13.3-Mb genome contains few identifiable repeated elements (ca. 1.5%) and a relatively high GC content (49.5%). A total of 5,735 protein-coding genes were identified, among which 83% share similarities with other fungi. Adaptation to the plant host seems reflected in the genome, since the genome carries genes involved in plant cell wall degradation (e.g., cellulases and cutinases), secondary metabolism, the hallmark glyoxylate cycle, detoxification, and sterol biosynthesis, as well as genes involved in the biosynthesis of plant hormones. Genes involved in lipid metabolism may play a role in its virulence. Several locus candidates for putative MAT cassettes and sex-related genes akin to those of Schizosaccharomyces pombe were identified. A mating-type-switching mechanism similar to that found in ascomycetous yeasts could be in effect. Taken together, the findings are consistent with the alternate saprophytic and parasitic-pathogenic lifestyles of T. deformans. IMPORTANCE Peach leaf curl is an important plant disease which causes significant losses of fruit production. We report here the genome sequence of the causative agent of the disease, the fungus Taphrina deformans. The genome carries characteristic genes that are important for the plant infection process. These include (i) proteases that allow degradation of the plant tissues; (ii) secondary metabolites which are products favoring interaction of the fungus with the environment, including the host; (iii) hormones that are responsible for the symptom of severely distorted leaves on the host; and (iv) drug detoxification enzymes that confer resistance to fungicides. The availability of the genome allows the design of new drug targets as well as the elaboration of specific management strategies to fight the disease.

BACKGROUND:Gene Ontology (GO) is a popular standard in the annotation of gene products and provides information related to genes across all species. The structure of GO is dynamic and is updated on a daily basis. However, the popular existing methods use outdated versions of GO. Moreover, these tools are slow to process large datasets consisting of more than 20,000 genes.RESULTS:We have developed GOParGenPy, a platform independent software tool to generate the binary data matrix showing the GO class membership, including parental classes, of a set of GO annotated genes. GOParGenPy is at least an order of magnitude faster than popular tools for Gene Ontology analysis and it can handle larger datasets than the existing tools. It can use any available version of the GO structure and allows the user to select the source of GO annotation. GO structure selection is critical for analysis, as we show that GO classes have rapid turnover between different GO structure releases.CONCLUSIONS:GOParGenPy is an easy to use software tool which can generate sparse or full binary matrices from GO annotated gene sets. The obtained binary matrix can then be used with any analysis environment and with any analysis methods.