A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing

Purpose Within the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the “ClinVar low-hanging fruit” reanalysis, reasons for the failure of previous analyses, and lessons learned. Methods Data from the first 3576 exomes (1522 probands and 2054 relatives) collected from European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies was reanalyzed by the Solve-RD consortium by evaluating for the presence of single-nucleotide variant, and small insertions and deletions already reported as (likely) pathogenic in ClinVar. Variants were filtered according to frequency, genotype, and mode of inheritance and reinterpreted. Results We identified causal variants in 59 cases (3.9%), 50 of them also raised by other approaches and 9 leading to new diagnoses, highlighting interpretation challenges: variants in genes not known to be involved in human disease at the time of the first analysis, misleading genotypes, or variants undetected by local pipelines (variants in off-target regions, low quality filters, low allelic balance, or high frequency). Conclusion The “ClinVar low-hanging fruit” analysis represents an effective, fast, and easy approach to recover causal variants from exome sequencing data, herewith contributing to the reduction of the diagnostic deadlock

Three years of monitoring using leveling and hybrid gravimetry applied to the geothermal sites of Soultz-sous-Forêts and Rittershoffen, Rhine Graben, France

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New results on the gravity monitoring (2014–2017) of Soultz-sous-Forêts and Rittershoffen geothermal sites (France)

Abstract This article presents the study of the mass redistribution associated with the geothermal energy exploitation of the Soultz-sous-Forêts and Rittershoffen plants by microgravity monitoring in the period 2014–2017. The two plants are located in the eastern part of France in the Rhine Graben. This rift is characterized by thermal anomalies. The Soultz-sous-Forêts enhanced geothermal system is a demonstration site producing 1.7 MWe thanks to three wells 5 km deep. The Rittershoffen geothermal plant is used to produce heat (24 MWth) with two wells of 2 km depth. The most recent production episodes at Soultz-sous-Forets and Rittershoffen began on 24 June 2016 and 19 May 2016, respectively. Each summer, since 2014 for the Soultz-sous-Forêts network and since 2015 for the Rittershoffen network, gravity measurements have been taken with a Scintrex CG5 gravimeter in order to calculate the gravity variation compared to a reference station and a reference time. The stability of the reference station at the Soultz-sous-Forêts plant was investigated by repeated absolute gravity measurements from the FG5#206. Gravity ties with the gravity observatory of Strasbourg were also performed to compensate for the absence of superconducting gravimeter at the in situ reference station. Precise leveling was undertaken simultaneously to each gravity survey showing that vertical ground displacement is lower than 1 cm; hence, this leads us to consider that the detected gravity changes are only due to Newtonian attraction. We do not detect any signal at the Rittershoffen network in the investigated period. After the beginning of production, we noticed a small differential signal at the Soultz-sous-Forêts network, which is spatially associated with the injection and production wells’ positions. Furthermore, the maximum gravity value appears in the same area as the induced seismicity related to the preferential paths of the geothermal fluid. However, a simple model based on a geothermal reservoir of cylindrical shape cannot explain the observations in terms of amplitude

Hybrid gravimetry monitoring of Soultz-sous-Forêts and Rittershoffen geothermal sites (Alsace, France)

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Getting the Hologenome Concept Right: an Eco-Evolutionary Framework for Hosts and Their Microbiomes

International audienceGiven the complexity of host-microbiota symbioses, scientists and philosophers are asking questions at new biological levels of hierarchical organization-what is a holobiont and hologenome? When should this vocabulary be applied? Are these concepts a null hypothesis for host-microbe systems or limited to a certain spectrum of symbiotic interactions such as host-microbial coevolution? Critical discourse is necessary in this nascent area, but productive discourse requires that skeptics and proponents use the same lexicon. For instance, critiquing the hologenome concept is not synonymous with critiquing coevolution, and arguing that an entity is not a primary unit of selection dismisses the fact that the hologenome concept has always embraced multilevel selection. Holobionts and hologenomes are incontrovertible, multipartite entities that result from ecological, evolutionary, and genetic processes at various levels. They are not restricted to one special process but constitute a wider vocabulary and framework for host biology in light of the microbiome

Comprehensive In Vivo Interrogation Reveals Phenotypic Impact of Human Enhancer Variants.

Establishing causal links between non-coding variants and human phenotypes is an increasing challenge. Here, we introduce a high-throughput mouse reporter assay for assessing the pathogenic potential of human enhancer variants in vivo and examine nearly a thousand variants in an enhancer repeatedly linked to polydactyly. We show that 71% of all rare non-coding variants previously proposed as causal lead to reporter gene expression in a pattern consistent with their pathogenic role. Variants observed to alter enhancer activity were further confirmed to cause polydactyly in knockin mice. We also used combinatorial and single-nucleotide mutagenesis to evaluate the in vivo impact of mutations affecting all positions of the enhancer and identified additional functional substitutions, including potentially pathogenic variants hitherto not observed in humans. Our results uncover the functional consequences of hundreds of mutations in a phenotype-associated enhancer and establish a widely applicable strategy for systematic in vivo evaluation of human enhancer variants