Aggregated Genomic Data as Cohort-Specific Allelic Frequencies can Boost Variants and Genes Prioritization in Non-Solved Cases of Inherited Retinal Dystrophies.

The introduction of NGS in genetic diagnosis has increased the repertoire of variants and genes involved and the amount of genomic information produced. We built an allelic-frequency (AF) database for a heterogeneous cohort of genetic diseases to explore the aggregated genomic information and boost diagnosis in inherited retinal dystrophies (IRD). We retrospectively selected 5683 index-cases with clinical exome sequencing tests available, 1766 with IRD and the rest with diverse genetic diseases. We calculated a subcohort's IRD-specific AF and compared it with suitable pseudocontrols. For non-solved IRD cases, we prioritized variants with a significant increment of frequencies, with eight variants that may help to explain the phenotype, and 10/11 of uncertain significance that were reclassified as probably pathogenic according to ACMG. Moreover, we developed a method to highlight genes with more frequent pathogenic variants in IRD cases than in pseudocontrols weighted by the increment of benign variants in the same comparison. We identified 18 genes for further studies that provided new insights in five cases. This resource can also help one to calculate the carrier frequency in IRD genes. A cohort-specific AF database assists with variants and genes prioritization and operates as an engine that provides a new hypothesis in non-solved cases, augmenting the diagnosis rate.

Individuals with heterozygous variants in the Wnt-signalling pathway gene FZD5 delineate a phenotype characterized by isolated coloboma and variable expressivity.

BACKGROUND: Anophthalmia, microphthalmia and coloboma are a genetically heterogenous spectrum of developmental eye disorders. Recently, variants in the Wnt-pathway gene Frizzled Class Receptor 5 (FZD5) have been identified in individuals with coloboma and rarely microphthalmia, sometimes with additional phenotypes and variable penetrance. MATERIALS AND METHODS: We identified variants in FZD5 in individuals with developmental eye disorders from the UK (including the DDD Study [www.ddduk.org/access.html]), France and Spain using whole genome/exome sequencing or customized NGS panels of ocular development genes. RESULTS: We report eight new families with FZD5 variants and ocular coloboma. Three individuals presented with additional syndromic features, two explicable by additional variants in other genes (SLC12A2 and DDX3X). In two families initially showing incomplete penetrance, re-examination of apparently unaffected carrier individuals revealed subtle ocular colobomatous phenotypes. Finally, we report two families with microphthalmia in addition to coloboma, representing the second and third reported cases of this phenotype in conjunction with FZD5 variants. CONCLUSIONS: Our findings indicate FZD5 variants are typically associated with isolated ocular coloboma, occasionally microphthalmia, and that extraocular phenotypes are likely to be explained by other gene alterations.

A photographic data set of reef and coral communities across Venezuela.

This dataset contains 2850 photographs of the seafloor in coral communities from Venezuela that were taken during 2017 and 2018. We used a hierarchical experimental design with four random factors representing four different spatial scales: (1) region (hundreds of kilometers), (2) localities (tens of kilometers), (2) reef sites (hundreds of meters) and (3) transects (a couple meters) across the Venezuelan coast. At each site, four 30-m transects were deployed parallel to the coastline, and 15 pictures were taken every other meter at each transect, containing an area of at least 80 × 90cm with enough resolution to identify benthic groups. This dataset covers spatial scales from a few meters to hundreds of kilometers; marine protected areas, and non-protected areas; coastal zones, continental and oceanic islands. These images have the potential to be further used for training researchers in benthic organisms identification, and training artificial intelligence classification algorithms. Also, they represent and updated baseline to perform spatial and temporal comparisons in Venezuela or further studies involving multiple spatial scales in the region.

The use of pseudo-multivariate standard error to improve the sampling design of coral monitoring programs.

The characteristics of coral reef sampling and monitoring are highly variable, with numbers of units and sampling effort varying from one study to another. Numerous works have been carried out to determine an appropriate effect size through statistical power; however, these were always from a univariate perspective. In this work, we used the pseudo multivariate dissimilarity-based standard error (MultSE) approach to assess the precision of sampling scleractinian coral assemblages in reefs of Venezuela between 2017 and 2018 when using different combinations of number of transects, quadrats and points. For this, the MultSE of 36 sites previously sampled was estimated, using four 30m-transects with 15 photo-quadrats each and 25 random points per quadrat. We obtained that the MultSE was highly variable between sites and is not correlated with the univariate standard error nor with the richness of species. Then, a subset of sites was re-annotated using 100 uniformly distributed points, which allowed the simulation of different numbers of transects per site, quadrats per transect and points per quadrat using resampling techniques. The magnitude of the MultSE stabilized by adding more transects, however, adding more quadrats or points does not improve the estimate. For this case study, the error was reduced by half when using 10 transects, 10 quadrats per transect and 25 points per quadrat. We recommend the use of MultSE in reef monitoring programs, in particular when conducting pilot surveys to optimize the estimation of the community structure.

Systematic review and meta-analysis of 50 years of coral disease research visualized through the scope of network theory.

Coral disease research encompasses five decades of undeniable progress. Since the first descriptions of anomalous signs, we have come to understand multiple processes and environmental drivers that interact with coral pathologies. In order to gain a better insight into the knowledge we already have, we explored how key topics in coral disease research have been related to each other using network analysis. We reviewed 719 papers and conference proceedings published from 1965 to 2017. From each study, four elements determined our network nodes: (1) studied disease(s); (2) host genus; (3) marine ecoregion(s) associated with the study site; and (4) research objectives. Basic properties of this network confirmed that there is a set of specific topics comprising the majority of research. The top five diseases, genera, and ecoregions studied accounted for over 48% of the research effort in all cases. The community structure analysis identified 15 clusters of topics with different degrees of overlap among them. These clusters represent the typical sets of elements that appear together for a given study. Our results show that while some coral diseases have been studied considering multiple aspects, the overall trend is for most diseases to be understood under a limited range of approaches, e.g., bacterial assemblages have been considerably studied in Yellow and Black band diseases while immune response has been better examined for the aspergillosis-Gorgonia system. Thus, our challenge in the near future is to identify and resolve potential gaps in order to achieve a more comprehensive progress on coral disease research.

Tissue mortality by Caribbean ciliate infection and white band disease in three reef-building coral species.

Caribbean ciliate infection (CCI) and white band disease (WBD) are diseases that affect a multitude of coral hosts and are associated with rapid rates of tissue losses, thus contributing to declining coral cover in Caribbean reefs. In this study we compared tissue mortality rates associated to CCI in three species of corals with different growth forms: Orbicella faveolata (massive-boulder), O. annularis (massive-columnar) and Acropora cervicornis (branching). We also compared mortality rates in colonies of A. cervicornis bearing WBD and CCI. The study was conducted at two locations in Los Roques Archipelago National Park between April 2012 and March 2013. In A. cervicornis, the rate of tissue loss was similar between WBD (0.8 ± 1 mm/day, mean ± SD) and CCI (0.7 ± 0.9 mm/day). However, mortality rate by CCI in A. cervicornis was faster than in the massive species O. faveolata (0.5 ± 0.6 mm/day) and O. annularis (0.3 ± 0.3 mm/day). Tissue regeneration was at least fifteen times slower than the mortality rates for both diseases regardless of coral species. This is the first study providing coral tissue mortality and regeneration rates associated to CCI in colonies with massive morphologies, and it highlights the risks of further cover losses of the three most important reef-building species in the Caribbean.