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

Protein Quality and the Protein to Carbohydrate Ratio within a High Fat Diet Influences Energy Balance and the Gut Microbiota In C57BL/6J Mice

peer-reviewedMacronutrient quality and composition are important determinants of energy balance and the gut microbiota. Here, we investigated how changes to protein quality (casein versus whey protein isolate; WPI) and the protein to carbohydrate (P/C) ratio within a high fat diet (HFD) impacts on these parameters. Mice were fed a low fat diet (10% kJ) or a high fat diet (HFD; 45% kJ) for 21 weeks with either casein (20% kJ, HFD) or WPI at 20%, 30% or 40% kJ. In comparison to casein, WPI at a similar energy content normalised energy intake, increased lean mass and caused a trend towards a reduction in fat mass (P = 0.08), but the protein challenge did not alter oxygen consumption or locomotor activity. WPI reduced HFD-induced plasma leptin and liver triacylglycerol, and partially attenuated the reduction in adipose FASN mRNA in HFD-fed mice. High throughput sequence-based analysis of faecal microbial populations revealed microbiota in the HFD-20% WPI group clustering closely with HFD controls, although WPI specifically increased Lactobacillaceae/Lactobacillus and decreased Clostridiaceae/Clostridium in HFD-fed mice. There was no effect of increasing the P/C ratio on energy intake, but the highest ratio reduced HFD-induced weight gain, fat mass and plasma triacylglycerol, non-esterified fatty acids, glucose and leptin levels, while it increased lean mass and oxygen consumption. Similar effects were observed on adipose mRNA expression, where the highest ratio reduced HFD-associated expression of UCP-2, TNFa and CD68 and increased the diet-associated expression of b3-AR, LPL, IR, IRS-1 and GLUT4. The P/C ratio also impacted on gut microbiota, with populations in the 30/ 40% WPI groups clustering together and away from the 20% WPI group. Taken together, our data show that increasing the P/C ratio has a dramatic effect on energy balance and the composition of gut microbiota, which is distinct from that caused by changes to protein quality.KN is supported by the Teagasc Vision Programme on Obesity, which also funded the work detailed in this manuscript. LM is supported by a Teagasc PhD Walsh Fellowship. HMR is supported by SFI PI (11/PI/1119)

Development of the Signposting Questionnaire for Autism (SQ-A): measurement comparison with the 10-item Autism Spectrum Quotient-Child and the Strengths and Difficulties Questionnaire in the UK and Latvia

BACKGROUND: Recognising the signs of autism spectrum disorder (ASD) can be a challenge for frontline professionals. The use of brief parent-completed questionnaires for recording the signs of ASD in school-aged children may be an important and efficient contributor to professional insight. However, to date, such questionnaires have not been designed to be used in coordination with current standardised Diagnostic and Statistical Manual of Mental Disorders (DSM-5) diagnostic tools. Furthermore, the measurement characteristics of such questionnaires have been unexplored across countries that differ in levels of national autism service provision and cultural interpretation of the signs of ASD. METHODS: A new 14-item questionnaire (Signposting Questionnaire for Autism (SQ-A)) was developed using published DSM-5 items from a clinical interview, the Diagnostic Interview for Social Communication Disorders (DISCO). Measurement comparison was tested with the Short Autism Spectrum Quotient-Child (AQ-10) and the Strengths and Difficulties Questionnaire (SDQ). Parents of 4-11-year-old children in the UK (N = 200) and Latvia (N = 104) completed all three questionnaires. Information on clinical diagnosis provided by parents led to classification into three groups: ASD diagnosis, other conditions and no conditions. In the UK, a subsample of teachers also provided cross-informant reliability. RESULTS: In both countries, there was evidence of acceptable to good internal consistency for the SQ-A, with significantly higher scores for the ASD group and evidence of convergent and discriminant validity. There was also good parent-teacher reliability for the three measures. Notably, the questionnaires designed specifically to measure autism (SQ-A, AQ-10) performed more similarly to one another compared to the broader SDQ, with differences found for the ASD group. The overall pattern of responding to the three questionnaires was highly similar between countries. CONCLUSIONS: These results indicate the potential of the 14-item SQ-A to guide frontline professionals in the recognition of the signs of autism in children, facilitating the provision of appropriate support