Effects of eight neuropsychiatric copy number variants on human brain structure

Many copy number variants (CNVs) confer risk for the same range of neurodevelopmental symptoms and psychiatric conditions including autism and schizophrenia. Yet, to date neuroimaging studies have typically been carried out one mutation at a time, showing that CNVs have large effects on brain anatomy. Here, we aimed to characterize and quantify the distinct brain morphometry effects and latent dimensions across 8 neuropsychiatric CNVs. We analyzed T1-weighted MRI data from clinically and non-clinically ascertained CNV carriers (deletion/duplication) at the 1q21.1 (n = 39/28), 16p11.2 (n = 87/78), 22q11.2 (n = 75/30), and 15q11.2 (n = 72/76) loci as well as 1296 non-carriers (controls). Case-control contrasts of all examined genomic loci demonstrated effects on brain anatomy, with deletions and duplications showing mirror effects at the global and regional levels. Although CNVs mainly showed distinct brain patterns, principal component analysis (PCA) loaded subsets of CNVs on two latent brain dimensions, which explained 32 and 29% of the variance of the 8 Cohen’s d maps. The cingulate gyrus, insula, supplementary motor cortex, and cerebellum were identified by PCA and multi-view pattern learning as top regions contributing to latent dimension shared across subsets of CNVs. The large proportion of distinct CNV effects on brain morphology may explain the small neuroimaging effect sizes reported in polygenic psychiatric conditions. Nevertheless, latent gene brain morphology dimensions will help subgroup the rapidly expanding landscape of neuropsychiatric variants and dissect the heterogeneity of idiopathic conditions

Premier signalement de Salaria fluviatilis dans le lac Léman

International audienceIn May 2010, a fishing campaign by electricity on three distant sites along the French side of the lake Geneva provided regular catches of freshwater blennies, Salaria fluviatilis (Asso, 1801). This is the first record of the species in this lake

FIGURE 24 in A new species of Protonemura Kempny, 1898 (Plecoptera: Nemouridae) from the French and Swiss Jura Mountains

FIGURE 24. Protonemura lateralis, male, ventral view

PAH occurrence in chalk river systems from the Jura region (France). Pertinence of suspended particulate matter and sediment as matrices for river quality monitoring

International audienceThis study investigates the variations of polycyclic aromatic hydrocarbon (PAH) levels in surface water, suspended particulate matter (SPM) and sediment upstream and downstream of the discharges of two wastewater treatment plant (WWTP) effluents. Relationships between the levels of PAHs in these different matrices were also investigated. The sum of 16 US EPA PAHs ranged from 73.5 to 728.0 ng L-1 in surface water and from 85.4 to 313.1 ng L-1 in effluent. In SPM and sediment, Sigma(16)PAHs ranged from 749.6 to 2,463 mu g kg(-1) and from 690.7 mu g kg(-1) to 3,625.6 mu g kg(-1), respectively. Investigations performed upstream and downstream of both studied WWTPs showed that WWTP discharges may contribute to the overall PAH contaminations in the Loue and the Doubs rivers. Comparison between gammarid populations upstream and downstream of WWTP discharge showed that biota was impacted by the WWTP effluents. When based only on surface water samples, the assessment of freshwater quality did not provide evidence for a marked PAH contamination in either of the rivers studied. However, using SPM and sediment samples, we found PAH contents exceeding sediment quality guidelines. We conclude that sediment and SPM are relevant matrices to assess overall PAH contamination in aquatic ecosystems. Furthermore, we found a positive linear correlation between PAH contents of SPM and sediment, showing that SPM represents an integrating matrix which is able to provide meaningful data about the overall contamination over a given time span

How to assess temporal changes of point and diffuse contamination in arural karstic watershed? Relevance of suspended particulate matter (SPM) for efficientmonitoring

Waste water treatment plants (WWTP) have attracted attention in numerous studies in their impact on receiving surface waters because of the presence of varied contaminants in their effluents. This study investigated the relevance of particle-bound contaminants using suspended particulate matter (SPM) to monitor the temporal variability of the impact of a WWTP discharge in a chalk stream (Loue River) in France. We performed five sampling campaigns of SPM and sediment during a year at different seasons and analyzed polycyclic aromatic hydrocarbons (PAHs) and phosphorus in both matrix. PAH contents in SPM ranged from 675 to 3709 mu g kg(-1) dry weight (dw) and in sediment from 668 to 7712 mu g kg(-1) dw. Levels of phosphorus ranged from 364 to 1380 mg kg(-1) dw in SPM and from 315 to 523 mg kg(-1) dw in sediment. The WWTP increased significantly PAH levels in SPM to the Loue River. However, our results did not allow to evidence significant differences on particulate phosphorus concentration in SPM. Nevertheless, we evidenced significant seasonal variations of PAH and phosphorus concentrations in SPM. Besides sediment sampling, the collection of SPM allowed to monitor changes in contamination from the WWTP and highlighted impact of WWTP on PAH concentrations and changes of PAH and phosphorus concentrations over time. Contamination of SPM of the Loue River was driven by mixed inputs from point source like WWTP and from diffuse sources in the catchment like runoff from impervious and pervious surfaces. Combining monitoring of SPM and sediment proved to be an improved approach to assess contamination of local and diffuse sources in chalk streams

Postnatal clinical phenotype of five patients with Pallister–Killian Syndrome (tetrasomy 12p): Interest of array CGH for diagnosis and review of the literature

Abstract Background Pallister–Killian syndrome (PKS) is a rare sporadic disorder caused by tetrasomy of the short arm of chromosome 12. The main clinical manifestations are global developmental delay, intellectual disability, epilepsy, dysmorphic features, hypopigmented and/or hyperpigmented lesions, and multiple congenital anomalies. PKS is associated with tissue mosaicism, which is difficult to diagnose through peripheral blood sample by conventional cytogenetic methods and fluorescence in situ hybridization. Methods Here, we report five patients with PKS. We delineate their clinical phenotypes and we compare them with previously published cases. We used array Comparative Genomic Hybridization (aCGH) with DNA extracted from peripheral blood samples. The five patients have also been tested by conventional cytogenetics techniques. Results Four out of five patients showed tetrasomy 12p by aCGH. Three of the four patients have typical i(12p) and one of the four demonstrated atypical tetrasomy 12p. The percentage of mosaicism was as low as 20%. Our cohort exhibited the typical PKS phenotypes. Conclusion Our results demonstrate the efficacy of aCGH for the diagnosis of PKS from DNA extracted from lymphocytes. Thus, for patients suspected of PKS, we recommend performing aCGH on lymphocytes at an early age before  proceeding to skin biopsy. aCGH on peripheral blood samples is sensitive in detecting low level of mosaicism and it is less invasive method than skin biopsy. We reviewed also the literature concerning the previously published PKS patients diagnosed by aCGH

Complete characterisation of two new large Xq28 duplications involving F8 using whole genome sequencing in patients without haemophilia A

International audienceAbstract Introduction Depending on the location of insertion of the gained region, F8 duplications can have variable clinical impacts from benign impact to severe haemophilia A phenotype. Aim To characterize two large Xq28 duplications involving F8 incidentally detected by chromosome microarray analysis (CMA) in two patients presenting severe intellectual disability but no history of bleeding disorder. Methods Whole genome sequencing (WGS) was performed in order to characterize the two large Xq28 duplications at nucleotide level. Results In patient 1, a 60–73 kb gained region encompassing the exons 23–26 of F8 and SMIM9 was inserted at the int22h‐2 locus following a non‐homologous recombination between int22h‐1 and int22h‐2. We hypothesized that two independent events, micro‐homology‐mediated break‐induced replication (MMBIR) and break‐induced replication (BIR), could be involved in this rearrangement. In patient 2, the CMA found duplication from 101 to 116‐kb long encompassing the exons 16–26 of F8 and SMIM9 . The WGS analysis identified a more complex rearrangement with the presence of three genomic junctions. Due to the multiple micro‐homologies observed at breakpoints, a replication‐based mechanism such as fork stalling and template switching (FoSTeS) was greatly suspected. In both cases, these complex rearrangements preserved an intact copy of the F8 . Conclusion This study highlights the value of WGS to characterize the genomic junction at the nucleotide level and ultimately better describe the molecular mechanisms involved in Xq28 structural variations. It also emphasizes the importance of specifying the structure of the genomic gain in order to improve genotype‐phenotype correlation and genetic counselling

Familial transmission of chromoanagenesis leads to unpredictable unbalanced rearrangements through meiotic recombination

Abstract Chromoanagenesis is a cellular mechanism that leads to complex chromosomal rearrangements (CCR) during a single catastrophic event. It may result in loss and/or gain of genetic material and may be responsible for various phenotypes. These rearrangements are usually sporadic. However, some familial cases have been reported. Here, we studied six families in whom an asymptomatic or paucisymptomatic parent transmitted a CCR to its offspring in an unbalanced manner. The rearrangements were characterized by karyotyping, fluorescent in situ hybridization, chromosomal microarray (CMA) and/or whole genome sequencing (WGS) in the carrier parents and offspring. We then hypothesized meiosis‐pairing figures between normal and abnormal parental chromosomes that may have led to the formation of new unbalanced rearrangements through meiotic recombination. Our work indicates that chromoanagenesis might be associated with a normal phenotype and normal fertility, even in males, and that WGS may be the only way to identify these events when there is no imbalance. Subsequently, the CCR can be transmitted to the next generation in an unbalanced and unpredictable manner following meiotic recombination. Thereby, prenatal diagnosis using CMA should be proposed to these families to detect any pathogenic imbalances in the offspring

Cryptic genomic imbalances in de novo and inherited apparently balanced chromosomal rearrangements: array CGH study of 47 unrelated cases.

International audienceInvestigations of apparently balanced chromosomal rearrangements in patients with abnormal phenotype by molecular cytogenetics tools, especially by array CGH, revealed a proportion of unsuspected imbalances. It was estimated recently that 40% of apparently balanced de novo translocations with abnormal phenotype were associated with cryptic deletion. We explored 47 unrelated mental retardation patients carrying an apparently balanced chromosomal rearrangement with high-resolution oligonucleotides arrays. We included 33 de novo cases (21 translocations, 7 inversions and 5 complex chromosomal rearrangements (CCR)) and 14 inherited cases (7 translocations, 5 inversions and 2 CCR). Twenty of the 47 cases (42.6%) carried a cryptic deletion ranging from 60 kb to 15.37 Mb. It concerned 16/33 de novo rearrangements (8/21 translocations, 4/7 inversions and 4/5 CCR) and 4/14 inherited rearrangements (1/7 translocations, 2/5 inversions and 1/2 CCR). The proportion of imbalances was not statistically different between de novo and inherited cases. Our results support that about 40% apparently balanced chromosomal rearrangements with abnormal phenotype are in fact imbalanced and that these rearrangements should be systematically investigated by array CGH independently of their de novo or inherited character

Identification of mobile retrocopies during genetic testing: Consequences for routine diagnosis

International audienc