Biallelic sequence and structural variants in RAX2 are a novel cause for autosomal recessive inherited retinal disease.

Purpose RAX2 encodes a homeobox-containing transcription factor, in which four monoallelic pathogenic variants have been described in autosomal dominant cone-dominated retinal disease. Methods Exome sequencing in a European cohort with inherited retinal disease (IRD) (n = 2086) was combined with protein structure modeling of RAX2 missense variants, bioinformatics analysis of deletion breakpoints, haplotyping of RAX2 variant c.335dup, and clinical assessment of biallelic RAX2-positive cases and carrier family members. Results Biallelic RAX2 sequence and structural variants were found in five unrelated European index cases, displaying nonsyndromic autosomal recessive retinitis pigmentosa (ARRP) with an age of onset ranging from childhood to the mid-40s (average mid-30s). Protein structure modeling points to loss of function of the novel recessive missense variants and to a dominant-negative effect of the reported dominant RAX2 alleles. Structural variants were fine-mapped to disentangle their underlying mechanisms. Haplotyping of c.335dup in two cases suggests a common ancestry. Conclusion This study supports a role for RAX2 as a novel disease gene for recessive IRD, broadening the mutation spectrum from sequence to structural variants and revealing a founder effect. The identification of biallelic RAX2 pathogenic variants in five unrelated families shows that RAX2 loss of function may be a nonnegligible cause of IRD in unsolved ARRP cases

Définition d’une base de données des pressions sur les lagunes méditerranéennes françaises - Rapport final - Convention 2010 - Action 6

The implementation of the Water Framework Directive Suits (2000 / 60 / EC) require to assess the ecological status of fish communities within transitional water bodies, in particular in the Mediterranean lagoons. Within the framework of the project LITEAU II, the Cemagref have been entrusted by the Ministry with the construction of a "fish" index adapted to these lagoons. This construction was based on a pressure-impact approach. So, metrics selection was based on their statistical response with different pressure indexes. For that purpose, a “pressure” database was organized. The objective of this contribution is to update and to complete the Mediterranean lagoons database of pressures proposed by the Cemagref. 30 lagoons distributed in 25 bodies of water of transition were studied. The proposed approach is based on the model DPSIR (Driving Forces, Pressure, State, Impact, Responses). 72 metrics of pressure have been identified among which 45 for the pollution pressures, 15 for the hydromorphological pressures and 12 for the direct pressures on habitat and the livings. 48 metrics have been informed by a bibliographical and GIS studies, investigations with administrators and with the Water Agency allowed. Results are supplied in the attached file. Additional status data from the Lagoon Monitoring Network (RSL) and the Biointegrator Network (RINBIO) are also informed. This work can be of use as base to the study of the relations between the various elements of biological quality of the WFD and pressures.La mise en oeuvre de la Directive Cadre sur l’Eau (2000/60/EC) nécessite d’évaluer l’état des communautés piscicoles des masses d’eau de transition, notamment dans les lagunes méditerranéennes. Dans le cadre du projet LITEAU II, le Ministère a confié au Cemagref la construction d’un indicateur « poisson » adapté à ces milieux. Cette construction s’est basée sur une approche de type pression-impact. Ainsi, les métriques retenues par le Cemagref pour la construction de l’indicateur sont celles qui présentent une relation statistique avec différents indicateurs de pression. Pour cela, une base de données pression a été mise en place. L’objectif de la présente étude est de mettre à jour et compléter sur les lagunes méditerranéennes la base de données des pressions proposée par le Cemagref. 30 lagunes réparties en 25 masses d’eau de transition ont été étudiées. La démarche proposée est basée sur le modèle DPSIR (Driving Forces, Pressures, State, Impact, Responses. Elle a permis d’identifier 72 métriques de pression dont 45 pour les pressions polluantes, 15 pour les pressions hydromorphologiques et 12 pour les pressions directes sur le vivant. Une étude bibliographique, des travaux à partir de SIG, des enquêtes auprès des gestionnaires et de l’Agence de l’Eau ont permis de renseigner 48 métriques. Les résultats sont fournis dans le fichier joint. En outre, des données d’état issues du Réseau de Suivi Lagunaire et du Réseau Intégrateurs Biologiques pour l’ensemble des masses d’eau suivies par ces réseaux sont fournies. Les travaux réalisés peuvent servir de base à l’étude des relations entre les différents éléments de qualité biologique de la DCE et les pressions qui s’exercent sur ces milieux

Biallelic loss-of-function variants in RAX2, encoding a homeobox-containing Rax transcription factor, cause autosomal recessive inherited retinal disease

RAX2 encodes a member of the homeobox-containing Rax family of transcription factors, which play a pivotal role in late retinogenesis in vertebrate species by regulating the spatial expression of photoreceptor-specific genes. So far, only four monoallelic RAX2 variants have been tentatively implicated in autosomal dominant cone-dominated retinal disease. Here we report biallelic missense, frameshift and structural variants in RAX2 identified by whole exome sequencing, in five unrelated index cases of Belgian, British, Italian and Spanish origin, diagnosed with non-syndromic autosomal recessive retinitis pigmentosa (RP) with a variable age of onset. Protein structure analysis of the two novel missense variants revealed a loss of Rax2 protein folding and/or stability, in agreement with a loss-of-function effect. Modeling of the previously reported dominant RAX2 missense variant on the other hand demonstrated potential roles in homeodomain/DNA higher order complex formation with no effect on protein stability or DNA binding, thus compatible with a gain-of-function effect. Haplotype analysis in three Belgian RP cases sharing the same RAX2 frameshift variant c.335dup suggested a common ancestry. Fine-mapping and bio-informatics analysis of the two identified structural variants affecting RAX2 disentangled their underlying mechanisms. In summary, our findings support a role for RAX2 as a novel disease gene for autosomal recessive RP. This study uncovered the first structural variants affecting RAX2 and a founder allele in Belgian RP patients. The identification of biallelic pathogenic RAX2 variants in five unrelated families may suggest a role in other autosomal recessive RP cases with an unknown molecular diagnosis

Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

BackgroundWe previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15-20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in similar to 80% of cases.MethodsWe report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded.ResultsNo gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5-528.7, P=1.1x10(-4)) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR=3.70[95%CI 1.3-8.2], P=2.1x10(-4)). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR=19.65[95%CI 2.1-2635.4], P=3.4x10(-3)), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR=4.40[9%CI 2.3-8.4], P=7.7x10(-8)). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD]=43.3 [20.3] years) than the other patients (56.0 [17.3] years; P=1.68x10(-5)).ConclusionsRare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old