CNTN6 mutations are risk factors for abnormal auditory sensory perception in autism spectrum disorders

Contactin genes CNTN5 and CNTN6 code for neuronal cell adhesion molecules that promote neurite outgrowth in sensory-motor neuronal pathways. Mutations of CNTN5 and CNTN6 have previously been reported in individuals with autism spectrum disorders (ASDs), but very little is known on their prevalence and clinical impact. In this study, we identified CNTN5 and CNTN6 deleterious variants in individuals with ASD. Among the carriers, a girl with ASD and attention-deficit/hyperactivity disorder was carrying five copies of CNTN5. For CNTN6, both deletions (6/1534 ASD vs 1/8936 controls; P=0.00006) and private coding sequence variants (18/501 ASD vs 535/33480 controls; P=0.0005) were enriched in individuals with ASD. Among the rare CNTN6 variants, two deletions were transmitted by fathers diagnosed with ASD, one stop mutation CNTN6W923X was transmitted by a mother to her two sons with ASD and one variant CNTN6P770L was found de novo in a boy with ASD. Clinical investigations of the patients carrying CNTN5 or CNTN6 variants showed that they were hypersensitive to sounds (a condition called hyperacusis) and displayed changes in wave latency within the auditory pathway. These results reinforce the hypothesis of abnormal neuronal connectivity in the pathophysiology of ASD and shed new light on the genes that increase risk for abnormal sensory perception in ASD

De novo TBR1 variants cause a neurocognitive phenotype with ID and autistic traits:report of 25 new individuals and review of the literature

TBR1, a T-box transcription factor expressed in the cerebral cortex, regulates the expression of several candidate genes for autism spectrum disorders (ASD). Although TBR1 has been reported as a high-confidence risk gene for ASD and intellectual disability (ID) in functional and clinical reports since 2011, TBR1 has only recently been recorded as a human disease gene in the OMIM database. Currently, the neurodevelopmental disorders and structural brain anomalies associated with TBR1 variants are not well characterized. Through international data sharing, we collected data from 25 unreported individuals and compared them with data from the literature. We evaluated structural brain anomalies in seven individuals by analysis of MRI images, and compared these with anomalies observed in TBR1 mutant mice. The phenotype included ID in all individuals, associated to autistic traits in 76% of them. No recognizable facial phenotype could be identified. MRI analysis revealed a reduction of the anterior commissure and suggested new features including dysplastic hippocampus and subtle neocortical dysgenesis. This report supports the role of TBR1 in ID associated with autistic traits and suggests new structural brain malformations in humans. We hope this work will help geneticists to interpret TBR1 variants and diagnose ASD probands

Volatile fingerprinting differentiates diverse-aged craft beers

Supplementary data to this article can be found online at https:// doi.org/10.1016/j.lwt.2019.03.044.Beer ageing on wood is a complex and difficult to control process involving several reactions and compounds. Difficulties in understanding the underlying phenomena often lead to empirical and unpredictable processes and heterogeneous products. This work resorts to volatile fingerprinting along with multivariate analysis as tools to differentiate and highlight differences in beers derived from diverse production processes. Volatile composition of beers originating from barrel ageing processes and unaged beer were analyzed by GC-MS. The collected data was processed by principal component analysis, which allowed the evaluation of relations between samples and volatile compounds. Beers were distinguished by clusters comprising different groups of volatiles. Beer with the longest period in barrel was in the cluster with the most volatiles. Beer produced by resident barrel microbiota fermentation was characterized by presence of Brettanomyces sp. metabolites. Beer aged in barrel by a shorter time period showed characteristic content of ethyl esters and oak extractives. Beer produced in inox vat and beer fermented in barrel with pitching of S. cerevisiae appeared in the same cluster, relating with fermentative esters. Volatile fingerprinting was a viable approach to characterize and distinguish the analyzed beers, providing relevant information regarding the impact of production methodologies in volatile composition.This work had funding support of the Portuguese Foundation for Science and Technology (FCT) under the scope of the strategic funding of UID/BIO/04469/2019 unit and COMPETE 2020 (POCI-01-0145 FEDER-006684) and BioTecNorte operation (NORTE-01-0145-FEDER000004) funded by the European Regional Development Fund under the scope of Norte2020 – Programa Operacional Regional do Norte. Fermentum –EngenhariadasFermentações Lda.also participated incofunding and supplying materials for this work. Authors would like to thank Mr. Paulo Coutinho and Quinta do Portal for supplying the oak barrels used in this work.info:eu-repo/semantics/publishedVersio

Rare variants in the genetic background modulate cognitive and developmental phenotypes in individuals carrying disease-associated variants.

To assess the contribution of rare variants in the genetic background toward variability of neurodevelopmental phenotypes in individuals with rare copy-number variants (CNVs) and gene-disruptive variants. We analyzed quantitative clinical information, exome sequencing, and microarray data from 757 probands and 233 parents and siblings who carry disease-associated variants. The number of rare likely deleterious variants in functionally intolerant genes ("other hits") correlated with expression of neurodevelopmental phenotypes in probands with 16p12.1 deletion (n=23, p=0.004) and in autism probands carrying gene-disruptive variants (n=184, p=0.03) compared with their carrier family members. Probands with 16p12.1 deletion and a strong family history presented more severe clinical features (p=0.04) and higher burden of other hits compared with those with mild/no family history (p=0.001). The number of other hits also correlated with severity of cognitive impairment in probands carrying pathogenic CNVs (n=53) or de novo pathogenic variants in disease genes (n=290), and negatively correlated with head size among 80 probands with 16p11.2 deletion. These co-occurring hits involved known disease-associated genes such as SETD5, AUTS2, and NRXN1, and were enriched for cellular and developmental processes. Accurate genetic diagnosis of complex disorders will require complete evaluation of the genetic background even after a candidate disease-associated variant is identified

A new way of using positron-lifetime measurements to study lattice defects

With the aim of extending positron-lifetime measurements to high temperature and avoiding surface and source contributions, experiments have been performed with positron emitting isotopes in a state of diluted solid solution in the material investigated. Further, it has been shown that the positron-lifetime data can be used in a new way to obtain the vacancy formation energy E F1V without the many uncertainties of the trapping model. The previously observed linear correlation between EF1V and the inflection temperature Ti in the τ(1/T) curve has also been explained.Dans le but d'étendre les mesures de temps de vie des positons vers les hautes températures et d'éviter les complications dues aux annihilations dans la source et à la surface de l'échantillon, des experiences ont été réalisées à partir de sources intégrées où les isotopes émetteurs de positons sont à l'état d'impureté isolée dans le materiau étudié. Par ailleurs, on montre qu'il est possible, à partir des mesures de temps de vie, d'obtenir l'énergie de formation des lacunes EF1V, sans être tributaire des imperfections du modèle du piégeage. On explique aussi les correlations observées précédemment entre EF1V et la température Ti du point d'inflexion dans la courbe τ(1/T)

Type A competitiveness traits correlate with downregulation of c-Fos expression in patients with type 1 diabetes

Type A personality has been associated with increased survival in people with type 1 diabetes (T1D). Systemic low-grade inflammation may play a critical role, as suggested in recent reports, although the links between the inflammatory circulating transcriptome and Type A remain unknown. This prompted our exploration of the potential associations between Type A personality and c-Fos gene expression, a candidate gene closely linked to inflammatory processes, in T1D