Novel VPS13B Mutations in Three Large Pakistani Cohen Syndrome Families Suggests a Baloch Variant with Autistic-Like Features.

BackgroundCohen Syndrome (COH1) is a rare autosomal recessive disorder, principally identified by ocular, neural and muscular deficits. We identified three large consanguineous Pakistani families with intellectual disability and in some cases with autistic traits.MethodsClinical assessments were performed in order to allow comparison of clinical features with other VPS13B mutations. Homozygosity mapping followed by whole exome sequencing and Sanger sequencing strategies were used to identify disease-related mutations.ResultsWe identified two novel homozygous deletion mutations in VPS13B, firstly a 1 bp deletion, NM_017890.4:c.6879delT; p.Phe2293Leufs*24, and secondly a deletion of exons 37-40, which co-segregate with affected status. In addition to COH1-related traits, autistic features were reported in a number of family members, contrasting with the "friendly" demeanour often associated with COH1. The c.6879delT mutation is present in two families from different regions of the country, but both from the Baloch sub-ethnic group, and with a shared haplotype, indicating a founder effect among the Baloch population.ConclusionWe suspect that the c.6879delT mutation may be a common cause of COH1 and similar phenotypes among the Baloch population. Additionally, most of the individuals with the c.6879delT mutation in these two families also present with autistic like traits, and suggests that this variant may lead to a distinct autistic-like COH1 subgroup

Evolutionary Dynamics of Human Toll-Like Receptors and Their Different Contributions to Host Defense

Infectious diseases have been paramount among the threats to health and survival throughout human evolutionary history. Natural selection is therefore expected to act strongly on host defense genes, particularly on innate immunity genes whose products mediate the direct interaction between the host and the microbial environment. In insects and mammals, the Toll-like receptors (TLRs) appear to play a major role in initiating innate immune responses against microbes. In humans, however, it has been speculated that the set of TLRs could be redundant for protective immunity. We investigated how natural selection has acted upon human TLRs, as an approach to assess their level of biological redundancy. We sequenced the ten human TLRs in a panel of 158 individuals from various populations worldwide and found that the intracellular TLRs—activated by nucleic acids and particularly specialized in viral recognition—have evolved under strong purifying selection, indicating their essential non-redundant role in host survival. Conversely, the selective constraints on the TLRs expressed on the cell surface—activated by compounds other than nucleic acids—have been much more relaxed, with higher rates of damaging nonsynonymous and stop mutations tolerated, suggesting their higher redundancy. Finally, we tested whether TLRs have experienced spatially-varying selection in human populations and found that the region encompassing TLR10-TLR1-TLR6 has been the target of recent positive selection among non-Africans. Our findings indicate that the different TLRs differ in their immunological redundancy, reflecting their distinct contributions to host defense. The insights gained in this study foster new hypotheses to be tested in clinical and epidemiological genetics of infectious disease.</p

A machine learning platform to optimize the translation of personalized network models to the clinic

PURPOSE Dynamic network models predict clinical prognosis and inform therapeutic intervention by elucidating disease-driven aberrations at the systems level. However, the personalization of model predictions requires the profiling of multiple model inputs, which hampers clinical translation. PATIENTS AND METHODS We applied APOPTO-CELL, a prognostic model of apoptosis signaling, to showcase the establishment of computational platforms that require a reduced set of inputs. We designed two distinct and complementary pipelines: a probabilistic approach to exploit a consistent subpanel of inputs across the whole cohort (Ensemble) and a machine learning approach to identify a reduced protein set tailored for individual patients (Tree). Development was performed on a virtual cohort of 3,200,000 patients, with inputs estimated from clinically relevant protein profiles. Validation was carried out in an in-house stage III colorectal cancer cohort, with inputs profiled in surgical resections by reverse phase protein array (n = 120) and/or immunohistochemistry (n = 117). RESULTS Ensemble and Tree reproduced APOPTO-CELL predictions in the virtual patient cohort with 92% and 99% accuracy while decreasing the number of inputs to a consistent subset of three proteins (40% reduction) or a personalized subset of 2.7 proteins on average (46% reduction), respectively. Ensemble and Tree retained prognostic utility in the in-house colorectal cancer cohort. The association between the Ensemble accuracy and prognostic value (Spearman ρ = 0.43; P = .02) provided a rationale to optimize the input composition for specific clinical settings. Comparison between profiling by reverse phase protein array (gold standard) and immunohistochemistry (clinical routine) revealed that the latter is a suitable technology to quantify model inputs. CONCLUSION This study provides a generalizable framework to optimize the development of network-based prognostic assays and, ultimately, to facilitate their integration in the routine clinical workflow

The role of the melanoma gene MC1R in Parkinson disease and REM sleep behavior disorder

The MC1R gene, suggested to be involved in Parkinson disease (PD) and melanoma, was sequenced in PD patients (n=539) and controls (n=265) from New-York, and PD patients (n=551), rapid eye movement sleep behavior disorder (RBD) patients (n=351) and controls (n=956) of European ancestry. Sixty-eight MC1R variants were identified, including 7 common variants with frequency>0.01. None of the common variants was associated with PD or RBD in the different regression models. In a meta-analysis with fixed-effect model, the p.R160W variant was associated with an increased risk for PD (OR=1.22, 95%CI 1.02-1.47, p=0.03) but with significant heterogeneity (p=0.048). Removing one study that introduced the heterogeneity resulted in nonsignificant association (OR=1.11, 95%CI 0.92-1.35, p=0.27, heterogeneity p=0.57). Rare variants had similar frequencies in patients and controls (10.54% and 10.15%, respectively, p=0.75), and no cumulative effect of carrying more than one MC1R variant was found. The current study does not support a role for the MC1R p.R160W and other variants in susceptibility for PD or RBD

Risk to human health related to the presence of perfluorooctane sulfonic acid and perfluorooctanoic acid in food

Acknowledgements: The Panel wishes to thank the hearing experts: Tony Fletcher, Philippe Adam Grandjean and Marco Zeilmaker, and EFSA staff members: Davide Arcella for the support provided to this scientific output. The Panel acknowledges all European Competent Authorities that provided occurrence data on perfluoroalkylated substances in food, and supported the data collection for the Comprehensive European Food Consumption Database. The Panel would also like to thank the following authors and co‐authors for providing additional data in relation to their respective studies: Esben Budtz‐Jørgensen, Jerry Campbell, Jessie A Gleason, Berit Granum, Mette Sørenson, Kyle Steenland and Kristina W Whitworth.Peer reviewedPublisher PD

Analysis of common and rare VPS13C variants in late-onset Parkinson disease

Objective We aimed to study the role of coding VPS13C variants in a large cohort of patients with lateonset Parkinson disease (PD) (LOPD). Methods VPS13C and its untranslated regions were sequenced using targeted next-generation sequencing in 1,567 patients with PD and 1,667 controls from 3 cohorts. Association tests of rare potential homozygous and compound heterozygous variants and burden tests for rare heterozygous variants were performed. Common variants were analyzed using logistic regression adjusted for age and sex in each of the cohorts, followed by a meta-analysis. Results No biallelic carriers of rare VPS13C variants were found among patients, and 2 carriers of compound heterozygous variants were found in 2 controls. There was no statistically significant burden of rare (minor allele frequency [MAF] <1%) or very rare (MAF <0.1%) coding VPS13C variants in PD. A VPS13C haplotype including the p.R153H-p.I398I-p.I1132V-p.Q2376Q variants was nominally associated with a reduced risk for PD (meta-analysis of the tagging SNP p.I1132V [odds ratio = 0.48, 95% confidence interval = 0.28–0.82, p = 0.0052]). This haplotype was not in linkage disequilibrium with the known genome-wide association study top hit. Conclusions Our results do not support a role for rare heterozygous or biallelic VPS13C variants in LOPD. Additional genetic replication and functional studies are needed to examine the role of the haplotype identified here associated with reduced risk for PD

Healthcare expenditure on Indigenous and non-Indigenous Australians at high risk of cardiovascular disease

Background: In spite of bearing a heavier burden of death, disease and disability, there is mixed evidence as to whether Indigenous Australians utilise more or less healthcare services than other Australians given their elevated risk level. This study analyses the Medicare expenditure and its predictors in a cohort of Indigenous and non-Indigenous Australians at high risk of cardiovascular disease. Methods: The healthcare expenditure of participants of the Kanyini Guidelines Adherence with the Polypill (GAP) pragmatic randomised controlled trial was modelled using linear regression methods. 535 adult (48% Indigenous) participants at high risk of cardiovascular disease (CVD) were recruited through 33 primary healthcare services (including 12 Aboriginal Medical Services) across Australia. Results: There was no significant difference in the expenditure of Indigenous and non-Indigenous participants in non-remote areas following adjustment for individual characteristics. Indigenous individuals living in remote areas had lower MBS expenditure ($932 per year P< 0.001) than other individuals. MBS expenditure was found to increase with being aged over 65 years ($128, p=0.013), being female ($472, p=0.003), lower baseline reported quality of life ($102 per 0.1 decrement of utility p=0.004) and a history of diabetes ($324, p=0.001), gout ($631, p=0.022), chronic obstructive pulmonary disease ($469, p=0.019) and established CVD whether receiving guideline-recommended treatment prior to the trial ($452, p=0.005) or not ($483, p=0.04). When controlling for all other characteristics, morbidly obese patients had lower MBS expenditure than other individuals (-$887, p=0.002). Conclusion: The findings suggest that for the majority of participants, once individuals are engaged with a primary care provider, factors other than whether they are Indigenous determine the level of Medicare expenditure for each person. Trial Registration: Australian New Zealand Clinical Trials Registry ACTRN 126080005833347

A large scale hearing loss screen reveals an extensive unexplored genetic landscape for auditory dysfunction

The developmental and physiological complexity of the auditory system is likely reflected in the underlying set of genes involved in auditory function. In humans, over 150 non-syndromic loci have been identified, and there are more than 400 human genetic syndromes with a hearing loss component. Over 100 non-syndromic hearing loss genes have been identified in mouse and human, but we remain ignorant of the full extent of the genetic landscape involved in auditory dysfunction. As part of the International Mouse Phenotyping Consortium, we undertook a hearing loss screen in a cohort of 3006 mouse knockout strains. In total, we identify 67 candidate hearing loss genes. We detect known hearing loss genes, but the vast majority, 52, of the candidate genes were novel. Our analysis reveals a large and unexplored genetic landscape involved with auditory function

LSST: from Science Drivers to Reference Design and Anticipated Data Products

(Abridged) We describe here the most ambitious survey currently planned in the optical, the Large Synoptic Survey Telescope (LSST). A vast array of science will be enabled by a single wide-deep-fast sky survey, and LSST will have unique survey capability in the faint time domain. The LSST design is driven by four main science themes: probing dark energy and dark matter, taking an inventory of the Solar System, exploring the transient optical sky, and mapping the Milky Way. LSST will be a wide-field ground-based system sited at Cerro Pach\'{o}n in northern Chile. The telescope will have an 8.4 m (6.5 m effective) primary mirror, a 9.6 deg$^2$ field of view, and a 3.2 Gigapixel camera. The standard observing sequence will consist of pairs of 15-second exposures in a given field, with two such visits in each pointing in a given night. With these repeats, the LSST system is capable of imaging about 10,000 square degrees of sky in a single filter in three nights. The typical 5$\sigma$ point-source depth in a single visit in $r$ will be $\sim 24.5$ (AB). The project is in the construction phase and will begin regular survey operations by 2022. The survey area will be contained within 30,000 deg$^2$ with $\delta<+34.5^\circ$, and will be imaged multiple times in six bands, $ugrizy$, covering the wavelength range 320--1050 nm. About 90\% of the observing time will be devoted to a deep-wide-fast survey mode which will uniformly observe a 18,000 deg$^2$ region about 800 times (summed over all six bands) during the anticipated 10 years of operations, and yield a coadded map to $r\sim27.5$. The remaining 10\% of the observing time will be allocated to projects such as a Very Deep and Fast time domain survey. The goal is to make LSST data products, including a relational database of about 32 trillion observations of 40 billion objects, available to the public and scientists around the world.Comment: 57 pages, 32 color figures, version with high-resolution figures available from https://www.lsst.org/overvie

Rhinovirus Genome Variation during Chronic Upper and Lower Respiratory Tract Infections

Routine screening of lung transplant recipients and hospital patients for respiratory virus infections allowed to identify human rhinovirus (HRV) in the upper and lower respiratory tracts, including immunocompromised hosts chronically infected with the same strain over weeks or months. Phylogenetic analysis of 144 HRV-positive samples showed no apparent correlation between a given viral genotype or species and their ability to invade the lower respiratory tract or lead to protracted infection. By contrast, protracted infections were found almost exclusively in immunocompromised patients, thus suggesting that host factors rather than the virus genotype modulate disease outcome, in particular the immune response. Complete genome sequencing of five chronic cases to study rhinovirus genome adaptation showed that the calculated mutation frequency was in the range observed during acute human infections. Analysis of mutation hot spot regions between specimens collected at different times or in different body sites revealed that non-synonymous changes were mostly concentrated in the viral capsid genes VP1, VP2 and VP3, independent of the HRV type. In an immunosuppressed lung transplant recipient infected with the same HRV strain for more than two years, both classical and ultra-deep sequencing of samples collected at different time points in the upper and lower respiratory tracts showed that these virus populations were phylogenetically indistinguishable over the course of infection, except for the last month. Specific signatures were found in the last two lower respiratory tract populations, including changes in the 5′UTR polypyrimidine tract and the VP2 immunogenic site 2. These results highlight for the first time the ability of a given rhinovirus to evolve in the course of a natural infection in immunocompromised patients and complement data obtained from previous experimental inoculation studies in immunocompetent volunteers