International Undiagnosed Diseases Programs (UDPs): components and outcomes

Over the last 15 years, Undiagnosed Diseases Programs have emerged to address the significant number of individuals with suspected but undiagnosed rare genetic diseases, integrating research and clinical care to optimize diagnostic outcomes. This narrative review summarizes the published literature surrounding Undiagnosed Diseases Programs worldwide, including thirteen studies that evaluate outcomes and two commentary papers. Commonalities in the diagnostic and research process of Undiagnosed Diseases Programs are explored through an appraisal of available literature. This exploration allowed for an assessment of the strengths and limitations of each of the six common steps, namely enrollment, comprehensive clinical phenotyping, research diagnostics, data sharing and matchmaking, results, and follow-up. Current literature highlights the potential utility of Undiagnosed Diseases Programs in research diagnostics. Since participants have often had extensive previous genetic studies, research pipelines allow for diagnostic approaches beyond exome or whole genome sequencing, through reanalysis using research-grade bioinformatics tools and multi-omics technologies. The overall diagnostic yield is presented by study, since different selection criteria at enrollment and reporting processes make comparisons challenging and not particularly informative. Nonetheless, diagnostic yield in an undiagnosed cohort reflects the potential of an Undiagnosed Diseases Program. Further comparisons and exploration of the outcomes of Undiagnosed Diseases Programs worldwide will allow for the development and improvement of the diagnostic and research process and in turn improve the value and utility of an Undiagnosed Diseases Program

Effects of vitamin E supplementation on renal non-enzymatic antioxidants in young rats submitted to exhaustive exercise stress

<p>Abstract</p> <p>Background</p> <p>Exercise stress was shown to increase oxidative stress in rats. It lacks reports of increased protection afforded by dietary antioxidant supplements against ROS production during exercise stress. We evaluated the effects of vitamin E supplementation on renal non-enzymatic antioxidants in young rats submitted to exhaustive exercise stress.</p> <p>Methods</p> <p>Wistar rats were divided into three groups: 1) control group; 2) exercise stress group and; 3) exercise stress + Vitamin E group. Rats from the group 3 were treated with gavage administration of 1 mL of Vitamin E (5 mg/kg) for seven consecutive days. Animals from groups 2 and 3 were submitted to a bout of swimming exhaustive exercise stress. Kidney samples were analyzed for Thiobarbituric Acid Reactive Substances to (TBARS) by malondialdehyde (MDA), reduced glutathione (GSH) and vitamin-E levels.</p> <p>Results</p> <p>The group treated with vitamin E and submitted to exercise stress presented the lowest levels of renal MDA (1: 0.16+0.02 mmmol/mgprot vs. 2: 0.34+0.07 mmmol/mgprot vs. 3: 0.1+0.01 mmmol/mgprot; p < 0.0001), the highest levels of renal GSH (1: 23+4 μmol/gprot vs. 2: 23+2 μmol/gprot vs. 3: 58+9 μmol/gprot; p < 0.0001) and the highest levels of renal vitamin E (1: 24+6 μM/gtissue vs. 2: 28+2 μM/gtissue vs. 3: 43+4 μM/gtissue; p < 0.001).</p> <p>Conclusion</p> <p>Vitamin E supplementation improved non-enzymatic antioxidant activity in young rats submitted to exhaustive exercise stress.</p

Different types of disease-causing non-coding variants revealed by genomic and gene expression analyses in families with X-linked intellectual disability

The pioneering discovery research of X-linked intellectual disability (XLID) genes has benefitted thousands of individuals worldwide however, approximately 30% of XLID families still remain unresolved. We postulated that non-coding variants that affect gene regulation or splicing may account for the lack of a genetic diagnosis in some cases. Detecting pathogenic, gene-regulatory variants with the same sensitivity and specificity as structural and coding variants is a major challenge for Mendelian disorders. Here, we describe three pedigrees with suggestive XLID where distinctive phenotypes associated with known genes guided the identification of three different non-coding variants. We used comprehensive structural, single nucleotide and repeat expansion analyses of genome sequencing. RNA-Seq from patient-derived cell lines, RT-PCRs, western blots and reporter gene assays were used to confirm the functional effect of three fundamentally different classes of pathogenic non-coding variants: a retrotransposon insertion, a novel intronic splice donor and a canonical splice variant of an untranslated exon. In one family, we excluded a rare coding variant in ARX, a known XLID gene, in favour of a regulatory non-coding variant in OFD1 that correlated with the clinical phenotype. Our results underscore the value of genomic research on unresolved XLID families to aid novel, pathogenic non-coding variant discovery.Michael J. Field, Raman Kumar, Anna Hackett, Sayaka Kayumi, Cheryl A. Shoubridge, Lisa J. Ewans, Atma M. Ivancevic, Tracy Dudding, Byth, Renée Carroll, Thessa Kroes, Alison E. Gardner, Patricia Sullivan, Thuong T. Ha, Charles E. Schwartz, Mark J. Cowley, Marcel E. Dinger, Elizabeth E. Palmer, Louise Christie, Marie Shaw, Tony Roscioli, Jozef Gecz, Mark A. Corbet

Disorders of sex development : insights from targeted gene sequencing of a large international patient cohort

Background: Disorders of sex development (DSD) are congenital conditions in which chromosomal, gonadal, or phenotypic sex is atypical. Clinical management of DSD is often difficult and currently only 13% of patients receive an accurate clinical genetic diagnosis. To address this we have developed a massively parallel sequencing targeted DSD gene panel which allows us to sequence all 64 known diagnostic DSD genes and candidate genes simultaneously. Results: We analyzed DNA from the largest reported international cohort of patients with DSD (278 patients with 46, XY DSD and 48 with 46, XX DSD). Our targeted gene panel compares favorably with other sequencing platforms. We found a total of 28 diagnostic genes that are implicated in DSD, highlighting the genetic spectrum of this disorder. Sequencing revealed 93 previously unreported DSD gene variants. Overall, we identified a likely genetic diagnosis in 43% of patients with 46, XY DSD. In patients with 46, XY disorders of androgen synthesis and action the genetic diagnosis rate reached 60%. Surprisingly, little difference in diagnostic rate was observed between singletons and trios. In many cases our findings are informative as to the likely cause of the DSD, which will facilitate clinical management. Conclusions: Our massively parallel sequencing targeted DSD gene panel represents an economical means of improving the genetic diagnostic capability for patients affected by DSD. Implementation of this panel in a large cohort of patients has expanded our understanding of the underlying genetic etiology of DSD. The inclusion of research candidate genes also provides an invaluable resource for future identification of novel genes

Chromosomal contacts connect loci associated with autism, BMI and head circumference phenotypes

Copy number variants (CNVs) are major contributors to genomic imbalance disorders. Phenotyping of 137 unrelated deletion and reciprocal duplication carriers of the distal 16p11.2 220 kb BP2-BP3 interval showed that these rearrangements are associated with autism spectrum disorders and mirror phenotypes of obesity/underweight and macrocephaly/microcephaly. Such phenotypes were previously associated with rearrangements of the non-overlapping proximal 16p11.2 600 kb BP4-BP5 interval. These two CNV-prone regions at 16p11.2 are reciprocally engaged in complex chromatin looping, as successfully confirmed by 4C-seq, fluorescence in situ hybridization and Hi-C, as well as coordinated expression and regulation of encompassed genes. We observed that genes differentially expressed in 16p11.2 BP4-BP5 CNV carriers are concomitantly modified in their chromatin interactions, suggesting that disruption of chromatin interplays could participate in the observed phenotypes. We also identified cis- and trans-acting chromatin contacts to other genomic regions previously associated with analogous phenotypes. For example, we uncovered that individuals with reciprocal rearrangements of the trans-contacted 2p15 locus similarly display mirror phenotypes on head circumference and weight. Our results indicate that chromosomal contacts’ maps could uncover functionally and clinically related genes.Molecular Psychiatry advance online publication, 31 May 2016; doi:10.1038/mp.2016.84

Fast computation of large scale marginal extremes with multi-dimensional covariates

Safe and reliable design and operation of fixed and floating marine structures often located in remote and hostile environments is challenging. Rigorous extreme value analysis of meteorological and oceanographic data can greatly aid the design of such structures. Extreme value analysis is typically undertaken for single spatial locations or for small neighbourhoods; moreover, non-stationary effects of covariates on extreme values are typically accommodated in an ad-hoc manner. The objective of the work summarised here is to improve design practice by estimating environmental design conditions (such as return values for extreme waves, winds and currents) for a whole ocean basin, including additional covariate effects (such as storm direction) as necessary, in a consistent manner. Whole-basin non-stationary extreme value modelling is computationally complex, requiring inter-alia the estimation of tail functions, the parameters of which vary with respect to multi-dimensional covariates characterised by us using tensor products of penalised B-splines. We outline two technical contributions which make whole-basin non-stationary analysis feasible. Firstly, we adopt generalised linear array methods to reduce the computational burden of matrix manipulations. Secondly, using high-performance computing, we develop a parallel implementation of maximum likelihood estimation for the generalised Pareto distribution. Together, these innovations allow estimation of rigorous whole-basin extreme value models in reasonable time. We evaluate the new approach in application to marginal extreme value modelling of storm peak significant wave heights in two ocean basins, accommodating spatial and directional covariate effects. © 2015 Elsevier B.V

Consistent design criteria for south China sea with a large-scale extreme value model

Existing metocean design criteria for offshore facilities in the South China Sea have been estimated using different data and procedures, some of which are at least partly ad hoc. As a result, it is probable that existing criteria are inconsistent, in the sense that assets designed to the same design codes have different realised levels of integrity. To address this concern in this paper, we apply a large-scale extreme value model adapted to parallel computing environment, applied to the recent high-resolution SEAFINE hindcast database. This not only ensures design criteria that are statistically and spatially consistent but is also faster by avoiding the need for repetitive site-specific analysis. We have to overcome several challenges before we can apply a large-scale extreme model on the SEAFINE database. These include identifying a spatially consistent set of storm peaks and validating the hindcast data with real measurements. We then estimate marginal return values for significant wave height for locations within a large spatial neighbourhood, accounting for spatial and storm directional variability of peaks over threshold. A quantile regression identifies the extreme value threshold, the rate of exceedance of which is described using a Poisson process. The size of threshold exceedances is described by a generalised Pareto model. The characteristics of the threshold, rate and size models are all non-stationary with respect to directional and spatial covariates, parameterised in terms of (multidimensional) penalised B-splines. Parameter estimation is computationally challenging, but a combination of efficient generalised linear array algorithms executed within a parallel computing environment enable maximum likelihood estimation of all models. Bootstrap resampling is used to estimate uncertainties of model parameters and return values. We thus estimate consistent marginal return values for significant wave height and their uncertainties, at all locations in the spatial neighbourhood. In addition, we quantify directional variability of return values across different return periods. We rigorously validate the proposed spatio-directional model with that of a direction-only model by deriving model diagnostics for the same site and demonstrating equivalent goodness of fits. To our knowledge this is the first of a kind of application of large-scale estimation for the South China Sea. With this approach, design criteria for large spatial domains, non-stationary with respect to the appropriate environmental covariates, can be estimated efficiently, consistently and with quantified uncertainty. © 2016, Offshore Technology Conferenc