Targeted Next-Generation Sequencing Analysis of 1,000 Individuals with Intellectual Disability.

To identify genetic causes of intellectual disability (ID), we screened a cohort of 986 individuals with moderate to severe ID for variants in 565 known or candidate ID-associated genes using targeted next-generation sequencing. Likely pathogenic rare variants were found in ∼11% of the cases (113 variants in 107/986 individuals: ∼8% of the individuals had a likely pathogenic loss-of-function [LoF] variant, whereas ∼3% had a known pathogenic missense variant). Variants in SETD5, ATRX, CUL4B, MECP2, and ARID1B were the most common causes of ID. This study assessed the value of sequencing a cohort of probands to provide a molecular diagnosis of ID, without the availability of DNA from both parents for de novo sequence analysis. This modeling is clinically relevant as 28% of all UK families with dependent children are single parent households. In conclusion, to diagnose patients with ID in the absence of parental DNA, we recommend investigation of all LoF variants in known genes that cause ID and assessment of a limited list of proven pathogenic missense variants in these genes. This will provide 11% additional diagnostic yield beyond the 10%-15% yield from array CGH alone.Action Medical Research (SP4640); the Birth Defect Foundation (RG45448); the Cambridge National Institute for Health Research Biomedical Research Centre (RG64219); the NIHR Rare Diseases BioResource (RBAG163); Wellcome Trust award WT091310; The Cell lines and DNA bank of Rett Syndrome, X-linked mental retardation and other genetic diseases (member of the Telethon Network of Genetic Biobanks (project no. GTB12001); the Genetic Origins of Congenital Heart Disease Study (GO-CHD)- funded by British Heart Foundation (BHF)This is the final version of the article. It first appeared from Wiley via http://dx.doi.org/10.1002/humu.2290

Nonlinear response and damage indices in the seismic analysis of an RC frame

To evaluate how damage indices reproduce the structural physical response the seismic performance of an 8-story 5-bay RC frame designed according to Eurocodes 2 /1/ and 8 /2/ has been deeply investigated in this work in two ways. First of all, the seismic non-linear behaviour of the frame for different accelerograms is thoroughly analysed making use of a spread plasticity beam model. The structural response is determined not only in terms of extreme values, to check the distribution of ductility requirements along the structural elements, but also tracing the sequence of formation and evolution of inelastic zones, to study the mechanisms of damage activation. Secondly, an assessment is made of local and global structural damage through some existing and proposed damage indices; global damage is also evaluated, adopting a procedure here proposed based upon the spread plasticity model results, through the time history of the first mode period for an "equivalent" linear structure. While local indices reproduce well the results provided by non-linear analyses, global indices in some cases fail to recognise high damage situations

Chlorella virus ATCV-1 encodes a functional potassium channel of 82 amino acids

Chlorella virus PBCV-1 (Paramecium bursaria chlorella virus-1) encodes the smallest protein (94 amino acids, named Kcv) previously known to form a functional K+ channel in heterologous systems. In this paper, we characterize another chlorella virus encoded K+ channel protein (82 amino acids, named ATCV-1 Kcv) that forms a functional channel in Xenopus oocytes and rescues Saccharomyces cerevisiae mutants that lack endogenous K+ uptake systems. Compared with the larger PBCV-1 Kcv, ATCV-1 Kcv lacks a cytoplasmic N-terminus and has a reduced number of charged amino acids in its turret domain. Despite these deficiencies, ATCV-1 Kcv accomplishes all the major features of K+ channels: it assembles into a tetramer, is K+ selective and is inhibited by the canonical K+ channel blockers, barium and caesium. Single channel analyses reveal a stochastic gating behavior and a voltage-dependent conductance that resembles the macroscopic I/V relationship. One difference between PBCV-1 and ATCV-1 Kcv is that the latter is more permeable to K+ than Rb+. This difference is partially explained by the presence of a tyrosine residue in the selective filter of ATCV-1 Kcv, whereas PBCV-1 Kcv has a phenylalanine. Hence, ATCV-1 Kcv is the smallest protein to form a K+ channel and it will serve as a model for studying structure–function correlations inside the potassium channel pore