NGS mismapping confounds the clinical interpretation of the PRSS1 p.Ala16Val (c.47C>T) variant in chronic pancreatitis

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Discovery and functional annotation of PRSS1 promoter variants in chronic pancreatitis

Recently, our resequencing of the promoter region of PRSS1 in French Caucasian individuals led to the identification of a functional variant (c.-204C > A) that is in perfect linkage disequilibrium with the “chronic pancreatitis (CP)-protective” PRSS1 c.-408C > T variant. Here, we extended the resequencing to 626 French Caucasians (242 idiopathic CP patients and 384 controls). We discovered three additional variants (c.-184G > A, c.-173C > T, and c.-147C > T), each being found only once in either patients or controls. We analyzed these three variants, together with a known PRSS1 promoter variant (c.-30_-28delTCC) long considered to be causative for CP, by luciferase promoter reporter assay in AR42J cells treated with dexamethasone. This analysis revealed that c.-30_-28delTCC resulted in reduced rather than increased PRSS1 gene expression, suggesting that it is not a CP risk factor as originally claimed. We provide evidence that c.-147C > T probably confers protection against CP by reducing the affinity of an ATF4 transcription factor binding site

Participation sociale de jeunes adultes ayant un trouble de l’acquisition de la coordination (TAC) et exploration de leurs besoins en termes de ressources d’information

Problématique : Le trouble de l'acquisition de la coordination (TAC) affecte la réalisation de nombreuses habitudes de vie, autant chez l'enfant que chez l’adulte. Toutefois, peu d’études ont décrit les défis vécus par les jeunes adultes et aucune n’a examiné leurs besoins en termes de ressources d’information. Cette étude exploratoire vise à identifier les principaux défis liés à la participation sociale des jeunes adultes ayant un TAC ainsi que les ressources d’information pouvant les aider. Méthodologie : Des jeunes adultes, âgés entre 18 et 25 ans et ayant un TAC, ainsi que des parents de jeunes adultes correspondant à ces critères ont été recrutés. Un questionnaire inspiré de la Mesure des habitudes de vie (MHAVIE) abrégée a été élaboré en collaboration avec l'Association Québécoise pour les Enfants Dyspraxiques (AQED). Les données obtenues ont été interprétées à l'aide de médianes et d’étendues, et d’une analyse thématique. Résultat : Trois jeunes adultes et trois parents ont participé à cette étude. Le travail est ressorti dans les habitudes de vie les plus atteintes, tant chez les jeunes adultes que chez les parents. Les habitudes de vie les moins satisfaisantes étaient les déplacements selon les jeunes adultes, et le travail et l’habitation selon les parents. Concernant les ressources d'information, les conséquences possibles du TAC sur la santé mentale et les stratégies pour faciliter l'intégration aux études et au travail ont été priorisées par les jeunes adultes et les parents. Le site Internet était la modalité préférée par les jeunes adultes, tandis que les parents privilégiaient le groupe de discussion. Discussion : Malgré le petit échantillon, cette étude a permis d’explorer, pour une première fois au Québec, la participation sociale de jeunes adultes ayant un TAC et leurs besoins en termes de ressources d’information. Ces connaissances permettront de développer une ressource d’information mieux adaptée à cette étape de vie, en collaboration avec l’AQED.Abstract : Problematic: Developmental Coordination Disorder (DCD) affects the realization of many life habits, both with children and adults. However, few studies have described the challenges faced by young adults and none have examined their needs in terms of information resources. The purpose of this exploratory study is to identify the main challenges related to the social participation of young adults with a DCD as well as the information resources that can help them. Methodology: Young adults, aged between 18 and 25 with a DCD, and parents of young adults meeting these criteria were recruited. A survey inspired by the Assessment of Life Habits (LIFE-H) was developed in collaboration with the Quebec Association for Dyspraxic Children. The data obtained was interpreted using medians and scopes, and a thematic analysis. Results: Three young adults and three parents participated in this study. Work came up in the most affected life habits of both young adults and parents. The least satisfactory life habits were travel by young adults, and work and housing by parents. Concerning information resources, young adults and parents prioritize the potential consequences of DCD on mental health and strategies to facilitate integration into school and work. The website was the preferred modality for young adults, while the parents favoured the focus group. Discussion: Despite the small sample, this study explored, for the first time in Quebec, the social participation of young adults with a DCD and their needs in terms of information resources. In collaboration with the Quebec Association for Dyspraxic Children, this knowledge will allow to develop an information resource better adapted to this stage of life

Nonlinear optical properties of TeO 2 crystalline phases from first principles

We have computed second and third nonlinear optical susceptibilities of two crystalline bulk tellurium oxide polymorphs: α -TeO 2 (the most stable crystalline bulk phase) and γ -TeO 2 (the crystalline phase that ressembles the more to the glass phase). Third-order nonlinear susceptibilities of the crystalline phases are two orders of magnitude larger than α -SiO 2 cristoballite, thus extending the experimental observations on glasses to the case of crystalline compounds. While the electronic lone pairs of Te contribute to those large values, a full explanation of the anisotropy of the third-order susceptibility tensor requires a detailed analysis of the structure, in particular, the presence of helical chains, that seems to be linked to cooperative nonlocal polarizabilty effects

Digging deeper into the intronic sequences of the SPINK1 gene [Letter]

We read with great interest the recent paper by Beer and Sahin-Tóth1 addressing the ‘missing heritability’ observed in approximately 60% of German cases of chronic pancreatitis.2 These authors opined that ‘discovery studies tend to focus on exons and exon–intron boundaries and may thus miss many intronic variants’.1 This premise seems eminently reasonable, given the generally much larger size of intronic sequences as compared with the coding sequences of protein-coding genes. However, there is a trade-off here. On the one hand, larger sequence size means larger target size for mutation, and hence the greater the number of mutations that could be missed if intronic sequences were not screened. On the other hand, to be of pathological significance, an intronic mutation must either create a new functional splicing donor or acceptor site or alternatively impact a functional sequence motif responsible for regulating splicing (eg, an intronic splicing enhancer), which depends upon many additional factors other than just sequence length. As yet, it is unclear what the ratio of pathological intronic:exonic variants will turn out to be, although intronic mutations are

Identification of a functional enhancer variant within the chronic pancreatitis-associated SPINK1 c.101A>G (p.Asn34Ser)-containing haplotype

The haplotype harboring the SPINK1 c.101A>G (p.Asn34Ser) variant (also known as rs17107315:T>C) represents the most important heritable risk factor for idiopathic chronic pancreatitis identified to date. The causal variant contained within this risk haplotype has however remained stubbornly elusive. Herein, we set out to resolve this enigma by employing a hypothesis-driven approach. First, we searched for variants in strong linkage disequilibrium (LD) with rs17107315:T>C using HaploReg v4.1. Second, we identified two candidate SNPs by visual inspection of sequences spanning all 25 SNPs found to be in LD with rs17107315:T>C, guided by prior knowledge of pancreas-specific transcription factors and their cognate binding sites. Third, employing a novel cis-regulatory module (CRM)-guided approach to further filter the two candidate SNPs yielded a solitary candidate causal variant. Finally, combining data from phylogenetic conservation and chromatin accessibility, cotransfection transactivation experiments, and population genetic studies, we suggest that rs142703147:C>A, which disrupts a PTF1L-binding site within an evolutionarily conserved HNF1A−PTF1L CRM located ∼4 kb upstream of the SPINK1 promoter, contributes to the aforementioned chronic pancreatitis risk haplotype. Further studies are required not only to improve the characterization of this functional SNP but also to identify other functional components that might contribute to this high-risk haplotype

Expression of 8-oxoguanine DNA glycosylase (Ogg1) in mouse retina

International audienc

Expanding ACMG variant classification guidelines into a general framework

Background: The American College of Medical Genetics and Genomics (ACMG)-recommended five variant classification categories (pathogenic, likely pathogenic, uncertain significance, likely benign, and benign) have been widely used in medical genetics. However, these guidelines are fundamentally constrained in practice owing to their focus upon Mendelian disease genes and their dichotomous classification of variants as being either causal or not. Herein, we attempt to expand the ACMG guidelines into a general variant classification framework that takes into account not only the continuum of clinical phenotypes, but also the continuum of the variants’ genetic effects, and the different pathological roles of the implicated genes. Main body: As a disease model, we employed chronic pancreatitis (CP), which manifests clinically as a spectrum from monogenic to multifactorial. Bearing in mind that any general conceptual proposal should be based upon sound data, we focused our analysis on the four most extensively studied CP genes, PRSS1, CFTR, SPINK1 and CTRC. Based upon several cross-gene and cross-variant comparisons, we first assigned the different genes to two distinct categories in terms of disease causation: CP-causing (PRSS1 and SPINK1) and CP-predisposing (CFTR and CTRC). We then employed two new classificatory categories, “predisposing” and “likely predisposing”, to replace ACMG’s “pathogenic” and “likely pathogenic” categories in the context of CP-predisposing genes, thereby classifying all pathologically relevant variants in these genes as “predisposing”. In the case of CP-causing genes, the two new classificatory categories served to extend the five ACMG categories whilst two thresholds (allele frequency and functional) were introduced to discriminate “pathogenic” from “predisposing” variants. Conclusion: Employing CP as a disease model, we expand ACMG guidelines into a five-category classification system (predisposing, likely predisposing, uncertain significance, likely benign, and benign) and a seven-category classification system (pathogenic, likely pathogenic, predisposing, likely predisposing, uncertain significance, likely benign, and benign) in the context of disease-predisposing and disease-causing genes, respectively. Taken together, the two systems constitute a general variant classification framework that, in principle, should span the entire spectrum of variants in any disease-related gene. The maximal compliance of our five-category and seven-category classification systems with the ACMG guidelines ought to facilitate their practical application

Genome-wide association study identifies inversion in the CTRB1-CTRB2 locus to modify risk for alcoholic and non-alcoholic chronic pancreatitis

OBJECTIVE: Alcohol-related pancreatitis is associated with a disproportionately large number of hospitalisations among GI disorders. Despite its clinical importance, genetic susceptibility to alcoholic chronic pancreatitis (CP) is poorly characterised. To identify risk genes for alcoholic CP and to evaluate their relevance in non-alcoholic CP, we performed a genome-wide association study and functional characterisation of a new pancreatitis locus. DESIGN: 1959 European alcoholic CP patients and population-based controls from the KORA, LIFE and INCIPE studies (n=4708) as well as chronic alcoholics from the GESGA consortium (n=1332) were screened with Illumina technology. For replication, three European cohorts comprising 1650 patients with non-alcoholic CP and 6695 controls originating from the same countries were used. RESULTS: We replicated previously reported risk loci CLDN2-MORC4, CTRC, PRSS1-PRSS2 and SPINK1 in alcoholic CP patients. We identified CTRB1-CTRB2 (chymotrypsin B1 and B2) as a new risk locus with lead single-nucleotide polymorphism (SNP) rs8055167 (OR 1.35, 95% CI 1.23 to 1.6). We found that a 16.6 kb inversion in the CTRB1-CTRB2 locus was in linkage disequilibrium with the CP-associated SNPs and was best tagged by rs8048956. The association was replicated in three independent European non-alcoholic CP cohorts of 1650 patients and 6695 controls (OR 1.62, 95% CI 1.42 to 1.86). The inversion changes the expression ratio of the CTRB1 and CTRB2 isoforms and thereby affects protective trypsinogen degradation and ultimately pancreatitis risk. CONCLUSION: An inversion in the CTRB1-CTRB2 locus modifies risk for alcoholic and non-alcoholic CP indicating that common pathomechanisms are involved in these inflammatory disorders