A CTNNA3 compound heterozygous deletion implicates a role for \u3b1T-catenin in susceptibility to autism spectrum disorder.

Autism spectrum disorder (ASD) is a highly heritable, neurodevelopmental condition showing extreme genetic heterogeneity. While it is well established that rare genetic variation, both de novo and inherited, plays an important role in ASD risk, recent studies also support a rare recessive contribution. METHODS: We identified a compound heterozygous deletion intersecting the CTNNA3 gene, encoding \u3b1T-catenin, in a proband with ASD and moderate intellectual disability. The deletion breakpoints were mapped at base-pair resolution, and segregation analysis was performed. We compared the frequency of CTNNA3 exonic deletions in 2,147 ASD cases from the Autism Genome Project (AGP) study versus the frequency in 6,639 controls. Western blot analysis was performed to get a quantitative characterisation of Ctnna3 expression during early brain development in mouse. RESULTS: The CTNNA3 compound heterozygous deletion includes a coding exon, leading to a putative frameshift and premature stop codon. Segregation analysis in the family showed that the unaffected sister is heterozygote for the deletion, having only inherited the paternal deletion. While the frequency of CTNNA3 exonic deletions is not significantly different between ASD cases and controls, no homozygous or compound heterozygous exonic deletions were found in a sample of over 6,000 controls. Expression analysis of Ctnna3 in the mouse cortex and hippocampus (P0-P90) provided support for its role in the early stage of brain development. CONCLUSION: The finding of a rare compound heterozygous CTNNA3 exonic deletion segregating with ASD, the absence of CTNNA3 homozygous exonic deletions in controls and the high expression of Ctnna3 in both brain areas analysed implicate CTNNA3 in ASD susceptibility

VO2 Kinetics in Supra-Anaerobic Threshold Constant Tests Allow the Visualization and Quantification of the O2 Saving After Cytochrome C Oxidase Inhibition by Aerobic Training or Nitrate Administration

We tested whether the known cytochrome c oxidase (COX) inhibition by nitric oxide (NO) could be quantified by VO2 kinetics during constant load supra-Anaerobic Threshold (AT) exercises in healthy trained or untrained subjects following aerobic training or nitrate administration. In cycle ergometer constant load exercises supra-AT, identified in previous incremental tests, VO2 kinetics describe a double exponential curve, one rapid and one appreciably slower, allowing the area between them to be calculate in O2 l. After training, with increased NO availability, this area decreases in inverse ratio to treatment efficacy. In fact, in 11 healthy subjects after aerobic training for 6-7 weeks, area was decreased on average by 51 %. In 11 untrained subjects, following the assumption of an NO donor, 20 mg isosorbide 5 mononitrate, area was decreased on average by 53 %. In conclusion, supra-AT VO2 kinetics in constant load exercises permit the quantification of the inhibitory effect NO-dependent on COX after either physical training or nitrate assumption

5.26 Left Ventricular Hypertrophy Prevalence by Different Left Ventricular Mass Indexes

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An increased burden of rare exonic variants in NRXN1 microdeletion carriers is likely to enhance the penetrance for autism spectrum disorder.

Autism spectrum disorder (ASD) is characterized by a complex polygenic background, but with the unique feature of a subset of cases (~15%-30%) presenting a rare large-effect variant. However, clinical interpretation in these cases is often complicated by incomplete penetrance, variable expressivity and different neurodevelopmental trajectories. NRXN1 intragenic deletions represent the prototype of such ASD-associated susceptibility variants. From chromosomal microarrays analysis of 104 ASD individuals, we identified an inherited NRXN1 deletion in a trio family. We carried out whole-exome sequencing and deep sequencing of mitochondrial DNA (mtDNA) in this family, to evaluate the burden of rare variants which may contribute to the phenotypic outcome in NRXN1 deletion carriers. We identified an increased burden of exonic rare variants in the ASD child compared to the unaffected NRXN1 deletion-transmitting mother, which remains significant if we restrict the analysis to potentially deleterious rare variants only (P = 6.07 7 10-5 ). We also detected significant interaction enrichment among genes with damaging variants in the proband, suggesting that additional rare variants in interacting genes collectively contribute to cross the liability threshold for ASD. Finally, the proband's mtDNA presented five low-level heteroplasmic mtDNA variants that were absent in the mother, and two maternally inherited variants with increased heteroplasmic load. This study underlines the importance of a comprehensive assessment of the genomic background in carriers of large-effect variants, as penetrance modulation by additional interacting rare variants to might represent a widespread mechanism in neurodevelopmental disorders

Homozygous microdeletion of exon 5 in ZNF277 in a girl with specific language impairment

Peer reviewedPublisher PD

Contribution of ultrarare variants in mTOR pathway genes to sporadic focal epilepsies

Objective: We investigated the contribution to sporadic focal epilepsies (FE) of ultrarare variants in genes coding for the components of complexes regulating mechanistic Target Of Rapamycin (mTOR)complex 1 (mTORC1). Methods: We collected genetic data of 121 Italian isolated FE cases and 512 controls by Whole Exome Sequencing (WES) and single-molecule Molecular Inversion Probes (smMIPs) targeting 10 genes of the GATOR1, GATOR2, and TSC complexes. We collapsed \u201cqualifying\u201d variants (ultrarare and predicted to be deleterious or loss of function) across the examined genes and sought to identify their enrichment in cases compared to controls. Results: We found eight qualifying variants in cases and nine in controls, demonstrating enrichment in FE patients (P = 0.006; exact unconditional test, one-tailed). Pathogenic variants were identified in DEPDC5 and TSC2, both major genes for Mendelian FE syndromes. Interpretation: Our findings support the contribution of ultrarare variants in genes in the mTOR pathway complexes GATOR and TSC to the risk of sporadic FE and a shared genetic basis between rare and common epilepsies. The identification of a monogenic etiology in isolated cases, most typically encountered in clinical practice, may offer to a broader community of patients the perspective of precision therapies directed by the underlying genetic cause

i-Rheo: Measuring the materials' linear viscoelastic properties “in a step”!

A new analytical technique for determining a materials' linear viscoelastic properties from a simple step-strain measurement is reported. The technique avoids the need for idealisation of real measurements. The technique involves evaluating the Fourier transforms of raw experimental data describing both the time-dependent stress and strain functions. A comparison with conventional linear oscillatory measurements for a diverse range of complex materials is made and the technique is shown to be superior to existing linear oscillatory measurements in all cases

Individual common variants exert weak effects on the risk for autism spectrum disorders.

While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASDs), the contribution of common variation to the risk of developing ASD is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating the association of individual single nucleotide polymorphisms (SNPs), we also sought evidence that common variants, en masse, might affect the risk. Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level. The SNP that achieves the smallest P-value from secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD. This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2. In contrast, allele scores derived from the transmission of common alleles to Stage 1 cases significantly predict case status in the independent Stage 2 sample. Despite being significant, the variance explained by these allele scores was small (Vm< 1%). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele score results, it is reasonable to conclude that common variants affect the risk for ASD but their individual effects are modest