X-chromosome tiling path array detection of copy number variants in patients with chromosome X-linked mental retardation

Contiene 3 ficheros adicionales con información suplementaria.-- et al.[Background] Aproximately 5–10% of cases of mental retardation in males are due to copy number variations (CNV) on the X chromosome. Novel technologies, such as array comparative genomic hybridization (aCGH), may help to uncover cryptic rearrangements in X-linked mental retardation (XLMR) patients. We have constructed an X-chromosome tiling path array using bacterial artificial chromosomes (BACs) and validated it using samples with cytogenetically defined copy number changes. We have studied 54 patients with idiopathic mental retardation and 20 controls subjects.[Results] Known genomic aberrations were reliably detected on the array and eight novel submicroscopic imbalances, likely causative for the mental retardation (MR) phenotype, were detected. Putatively pathogenic rearrangements included three deletions and five duplications (ranging between 82 kb to one Mb), all but two affecting genes previously known to be responsible for XLMR. Additionally, we describe different CNV regions with significant different frequencies in XLMR and control subjects (44% vs. 20%).[Conclusion] This tiling path array of the human X chromosome has proven successful for the detection and characterization of known rearrangements and novel CNVs in XLMR patients.The authors thank the "Genoma España" and Genome Canada joint R+D+I projects in human health, plants and aquiculture; the former "Departament d'Universitats i Societat de la Informació" (DURSI) and the "Departament de Salut", from the Catalan Autonomous Government (2005SGR00008 - Generalitat de Catalunya); the Instituto de Salud Carlos III (PI041126, CIBER-ESP), the EU's Sixth Framework Programme [FP6-2005-LIFESCIHEALTH-7; ANEUPLOIDY No. 037627] and Fundación Areces (U-2006-FARECES-O).Peer reviewe

Clinical implication of FMR1 intermediate alleles in a Spanish population

FMR1 premutation carriers (55-200 CGGs) are at risk of developing Fragile X-associated primary ovarian insufficiency as well as Fragile X-associated tremor/ataxia syndrome. FMR1 premutation alleles are also associated with a variety of disorders, including psychiatric, developmental, and neurological problems. However, there is a major concern regarding clinical implications of smaller CGG expansions known as intermediate alleles (IA) or gray zone alleles (45-54 CGG). Although several studies have hypothesized that IA may be involved in the etiology of FMR1 premutation associated phenotypes, this association still remains unclear. The aim of this study was to provide new data on the clinical implications of IA. We reviewed a total of 17 011 individuals: 1142 with primary ovarian insufficiency, 478 with movement disorders, 14 006 with neurodevelopmental disorders and 1385 controls. Similar IA frequencies were detected in all the cases and controls (cases 1.20% vs controls 1.39%, P =.427). When comparing the allelic frequencies of IA = 50CGGs, a greater, albeit not statistically significant, number of alleles were detected in all the cohorts of patients. Therefore, IA below 50 CGGs should not be considered as risk factors for FMR1 premutation-associated phenotypes, at least in our population. However, the clinical implication of IA = 50CGGs remains to be further elucidated

Perivascular spaces are associated with tau pathophysiology and synaptic dysfunction in early Alzheimer’s continuum

Background: Perivascular spaces (PVS) have an important role in the elimination of metabolic waste from the brain. It has been hypothesized that the enlargement of PVS (ePVS) could be affected by pathophysiological mechanisms involved in Alzheimer’s disease (AD), such as abnormal levels of CSF biomarkers. However, the relationship between ePVS and these pathophysiological mechanisms remains unknown. Objective: We aimed to investigate the association between ePVS and CSF biomarkers of several pathophysiological mechanisms for AD. We hypothesized that ePVS will be associated to CSF biomarkers early in the AD continuum (i.e., amyloid positive cognitively unimpaired individuals). Besides, we explored associations between ePVS and demographic and cardiovascular risk factors. Methods: The study included 322 middle-aged cognitively unimpaired participants from the ALFA + study, many within the Alzheimer’s continuum. NeuroToolKit and Elecsys® immunoassays were used to measure CSF Aβ42, Aβ40, p-tau and t-tau, NfL, neurogranin, TREM2, YKL40, GFAP, IL6, S100, and α-synuclein. PVS in the basal ganglia (BG) and centrum semiovale (CS) were assessed based on a validated 4-point visual rating scale. Odds ratios were calculated for associations of cardiovascular and AD risk factors with ePVS using logistic and multinomial models adjusted for relevant confounders. Models were stratified by Aβ status (positivity defined as Aβ42/40 < 0.071). Results: The degree of PVS significantly increased with age in both, BG and CS regions independently of cardiovascular risk factors. Higher levels of p-tau, t-tau, and neurogranin were significantly associated with ePVS in the CS of Aβ positive individuals, after accounting for relevant confounders. No associations were detected in the BG neither in Aβ negative participants. Conclusions: Our results support that ePVS in the CS are specifically associated with tau pathophysiology, neurodegeneration, and synaptic dysfunction in asymptomatic stages of the Alzheimer’s continuum

LCA applied to perennial cropping systems: a review focused on the farm stage

International audienc

Evaluating the Sustainability of a Small-Scale Low-Input Organic Vegetable Supply System in the United Kingdom

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Molecular analysis of the APC and MUTYH genes in Galician and Catalonian FAP families: a different spectrum of mutations?

<p>Abstract</p> <p>Background</p> <p>Familial adenomatous polyposis (FAP) is an autosomal dominant-inherited colorectal cancer syndrome, caused by germline mutations in the <it>APC </it>gene. Recently, biallelic mutations in <it>MUTYH </it>have also been identified in patients with multiple colorectal adenomas and in <it>APC</it>-negative patients with FAP. The aim of this work is therefore to determine the frequency of <it>APC </it>and <it>MUTYH </it>mutations among FAP families from two Spanish populations.</p> <p>Methods</p> <p>Eighty-two unrelated patients with classical or attenuated FAP were screened for <it>APC </it>germline mutations. <it>MUTYH </it>analysis was then conducted in those <it>APC</it>-negative families and in 9 additional patients from a previous study. Direct sequencing, SSCP analysis and TaqMan genotyping were used to identify point and frameshift mutations, meanwhile large rearrangements in the <it>APC </it>gene were screened by multiplex ligation-dependent probe amplification (MLPA).</p> <p>Results</p> <p><it>APC </it>germline mutations were found in 39% of the patients and, despite the great number of genetic variants described so far in this gene, seven new mutations were identified. The two hotspots at codons 1061 and 1309 of the <it>APC </it>gene accounted for 9,4% of the <it>APC</it>-positive families, although they were underrepresented in Galician samples. The deletion at codon 1061 was not found in 19 <it>APC</it>-positive Galician patients but represented 23% of the Catalonian positive families (p = 0,058). The same trend was observed at codon 1309, even though statistical analysis showed no significance between populations. Twenty-four percent of the <it>APC</it>-negative patients carried biallelic <it>MUTYH </it>germline mutations, and showed an attenuated polyposis phenotype generally without extracolonic manifestations. New genetic variants were found, as well as the two hotspots already reported (p.Tyr165Cys and p.Gly382Asp).</p> <p>Conclusion</p> <p>The results we present indicate that in Galician patients the frequency of the hotspot at codon 1061 in <it>APC </it>differs significantly from the Catalonian and also other Caucasian populations. Similar results had already been obtained in a previous study and could be due to the genetic isolation of the Galician population. <it>MUTYH </it>analysis is also recommended for all <it>APC</it>-negative families, even if a recessive inheritance is not confirmed.</p