A Balanced Reciprocal Translocation t(5;7)(q14;q32) Associated With Autistic Disorder: Molecular Analysis of the Chromosome 7 Breakpoint

International audienceAutism is a neuropsychiatric disorder characterized by impairments in social interaction, restricted and stereotypic pattern of interest with onset by 3 years of age. The results of genetic linkage studied for autistic disorder (AD) have suggested a susceptibility locus for the disease on the long arm of chromosome 7. We report a girl with AD and a balanced reciprocal translocation t(5;7)(q14;q32). The mother carries the translocation but do not express the disease. Fluorescent in situ hybridization (FISH) analysis with chromosome 7-specific YAC clones showed that the breakpoint coincides with the candidate region for AD. We identified a PAC clone that spans the translocation breakpoint and the breakpoint was mapped to a 2 kb region. Mutation screening of the genes SSBP and T2R3 located just centromeric to the breakpoint was performed in a set of 29 unrelated autistic sibling pairs who shared at least one chromosome 7 haplotype. We found no sequence variations, which predict amino acid alterations. Two single nucleotide polymorphisms were identified in the T2R3 gene, and associations between allele variants and AD in our population were not found. The methylation pattern of different chromosome 7 regions in the patient's genomic DNA appears normal. Here we report the clinical presentation of the patient with AD and the characterization of the genomic organization across the breakpoint at 7q32. The precise localization of the breakpoint on 7q32 may be relevant for further linkage studies and molecular analysis of AD in this region

Validity of physician-diagnosed COPD in relation to spirometric definitions of COPD in a general population aged 50â-64 years - the SCAPIS pilot study

BACKGROUND: In epidemiological studies, items about physician-diagnosed COPD are often used. There is a lack of validation and standardization of these items. MATERIALS AND METHODS: In a general population-based study, 1,050 subjects completed a questionnaire and performed spirometry, including forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) after inhalation of 400 µg of salbutamol. COPD was defined as the ratio of FEV1/FVC <0.7 after bronchodilation. Physician-diagnosed COPD was defined as an affirmative answer to the single item: "Have you ever had COPD diagnosed by a physician?", physician-diagnosed COPD/emphysema as an affirmative answer to any of the two single items; "Have you ever had COPD diagnosed by a physician?" or "Have you ever been told by a physician that you have emphysema?", physician-diagnosed chronic bronchitis as an affirmative answer to; "Have you ever been told by a physician that you have chronic bronchitis?" and physician-diagnosed COPD, emphysema or chronic bronchitis was defined as an affirmative answer to either of the three items above. RESULTS: For the single item about physician-diagnosed COPD, the sensitivity was around 0.11 and the specificity was almost 0.99 in relation to COPD. The sensitivity of the combined items about COPD/emphysema in detecting COPD was 0.11 and the specificity was high, 0.985. When the items about physician-diagnosed COPD, emphysema or chronic bronchitis were merged as one entity, the sensitivity went up (0.13) and the specificity went down (0.95). CONCLUSION: Items about physician-diagnosed COPD have low sensitivity but a very high specificity, indicating that these items will minimize the proportion of false positives. The low sensitivity will underestimate the total burden of COPD in the general population. Items about physician-diagnosed COPD may be used in studies of risk factors for COPD, but are not recommended in prevalence studies

Automated analysis of liver fat, muscle and adipose tissue distribution from CT suitable for large-scale studies.

Computed Tomography (CT) allows detailed studies of body composition and its association with metabolic and cardiovascular disease. The purpose of this work was to develop and validate automated and manual image processing techniques for detailed and efficient analysis of body composition from CT data. The study comprised 107 subjects examined in the Swedish CArdioPulmonary BioImage Study (SCAPIS) using a 3-slice CT protocol covering liver, abdomen, and thighs. Algorithms were developed for automated assessment of liver attenuation, visceral (VAT) and subcutaneous (SAT) abdominal adipose tissue, thigh muscles, subcutaneous, subfascial (SFAT) and intermuscular adipose tissue. These were validated using manual reference measurements. SFAT was studied in selected subjects were the fascia lata could be visually identified (approx. 5%). In addition, precision of manual measurements of intra- (IPAT) and retroperitoneal adipose tissue (RPAT) and deep- and superficial SAT was evaluated using repeated measurements. Automated measurements correlated strongly to manual reference measurements. The SFAT depot showed the weakest correlation (r = 0.744). Automated VAT and SAT measurements were slightly, but significantly overestimated (≤4.6%, p ≤ 0.001). Manual segmentation of abdominal sub-depots showed high repeatability (CV ≤ 8.1%, r ≥ 0.930). We conclude that the low dose CT-scanning and automated analysis makes the setup suitable for large-scale studies

Automatic pericardium segmentation and quantification of epicardial fat from computed tomography angiography

Recent findings indicate a strong correlation between the risk of future heart disease and the volume of adipose tissue inside of the pericardium. So far, large-scale studies have been hindered by the fact that manual delineation of the pericardium is extremely time-consuming and that existing methods for automatic delineation lack accuracy. An efficient and fully automatic approach to pericardium segmentation and epicardial fat volume (EFV) estimation is presented, based on a variant of multi-atlas segmentation for spatial initialization and a random forest classifier for accurate pericardium detection. Experimental validation on a set of 30 manually delineated computer tomography angiography volumes shows a significant improvement on state-of-the-art in terms of EFV estimation [mean absolute EFV difference: 3.8 ml (4.7%), Pearson correlation: 0.99] with run times suitable for large-scale studies (52 s). Further, the results compare favorably with interobserver variability measured on 10 volumes

Obesity is associated with coronary artery stenosis independently of metabolic risk factors : The population-based SCAPIS study

BACKGROUND AND AIMS: Previous studies reported divergent results on whether metabolically healthy obesity is associated with increased coronary artery calcium and carotid plaques. We investigated this in a cross-sectional fashion in a large, well-defined, middle-aged population using coronary CT angiography (CCTA) and carotid ultrasound. METHODS: In the SCAPIS study (50-65 years, 51% female), CCTA and carotid artery ultrasound were performed in 23,674 individuals without clinical atherosclerotic disease. These subjects were divided into six groups according to BMI (normal weight, overweight, obese) and the presence of metabolic syndrome (MetS) according to the NCEP consensus criteria. RESULTS: The severity of coronary artery stenosis was increased in individuals with obesity without MetS compared to normal-weight individuals without MetS (OR 1.47, 95%CI 1.34-1.62; p < 0.0001), even after adjusting for non-HDL-cholesterol and several lifestyle factors. Such difference was not observed for the presence of carotid artery plaques (OR 0.94, 95%CI 0.87-1.02; p = 0.11). Obese or overweight individuals without any MetS criteria (except the waist criterion) showed significantly more pronounced stenosis in the coronary arteries as compared to the normal-weight individuals, while one criterion was needed to show increased plaque prevalence in the carotid arteries. High blood pressure was the most important single criterion for increased atherosclerosis in this respect. CONCLUSIONS: Individuals with obesity without MetS showed increased severity of coronary artery stenosis, but no increased occurrence of carotid artery plaques compared to normal-weight individuals without MetS, further emphasizing that obesity is not a benign condition even in the absence of MetS

Absolute lung size and the sex difference in breathlessness in the general population

Background: Breathlessness is associated with major adverse health outcomes and is twice as common in women as men in the general population. We evaluated whether this is related to their lower absolute lung volumes. Methods: Cross-sectional analysis of the population-based Swedish CardioPulmonarybioImage Study (SCAPIS) Pilot, including static spirometry and diffusing capacity (n = 1,013; 49% women). Breathlessness was measured using the modified Medical Research Council (mMRC) scale and analyzed using ordinal logistic regression adjusting for age, pack-years of smoking, body mass index, chronic airway limitation, asthma, chronic bronchitis, depression and anxiety in all models. Results: Breathlessness was twice as common in women as in men; adjusted odds ratio (OR) 2.20 (95% confidence interval, 1.32-3.66). Lower absolute lung volumes were associated with increased breathlessness prevalence in both men and women. The sex difference in breathlessness was unchanged when adjusting for lung function in %predicted, but disappeared when controlling for absolute values of total lung capacity (OR 1.12; 0.59-2.15), inspiratory capacity (OR 1.26; 0.68-2.35), forced vital capacity (OR 0.84; 0.42-1.66), forced expiratory volume in one second (OR 0.70; 0.36-1.35) or lung diffusing capacity (OR 1.07; 0.58-1.97). Conclusion: In the general population, the markedly higher prevalence of breathlessness in women is related to their smaller absolute lung volumes

Non-alcoholic fatty liver disease is a strong predictor of coronary artery calcification in metabolically healthy subjects : A cross-sectional, population-based study in middle-aged subjects.

OBJECTIVES: This study aims to estimate the relationship between non-alcoholic fatty liver disease (NAFLD) and measures of atherosclerotic cardiovascular disease (ASCVD), and to determine to what extent such relationships are modified by metabolic risk factors. METHODS: The study was conducted in the population-based Swedish CArdioPulmonary bioImage Study (SCAPIS) pilot cohort (n = 1015, age 50-64 years, 51.2% women). NAFLD was defined as computed tomography liver attenuation ≤40 Hounsfield Units, excluding other causes of liver fat. Coronary artery calcification score (CACS) was assessed using the Agatston method. Carotid plaques and intima media thickness (IMT) were measured by ultrasound. Metabolic status was based on assessments of glucose homeostasis, serum lipids, blood pressure and inflammation. A propensity score model was used to balance NAFLD and non NAFLD groups with regards to potential confounders and associations between NAFLD status and ASCVD variables in relation to metabolic status were examined by logistic and generalized linear regression models. RESULTS: NAFLD was present in 106 (10.4%) of the subjects and strongly associated with obesity-related traits. NAFLD was significantly associated with CACS after adjustment for confounders and metabolic risk factors (OR 1.77, 95% CI 1.07-2.94), but not with carotid plaques and IMT. The strongest association between NAFLD and CACS was observed in subjects with few metabolic risk factors (n = 612 [60% of all] subjects with 0-1 out of 7 predefined metabolic risk factors; OR 5.94, 95% CI 2.13-16.6). CONCLUSIONS: NAFLD was independently associated with coronary artery calcification but not with measures of carotid atherosclerosis in this cohort. The association between NAFLD and CACS was most prominent in the metabolically healthy subjects

Mutations in HECW2 are associated with intellectual disability and epilepsy

BACKGROUND: De novo mutations are a frequent cause of disorders related to brain development. We report the results of screening patients diagnosed with both epilepsy and intellectual disability (ID) using exome sequencing to identify known and new causative de novo mutations relevant to these conditions. METHODS: Exome sequencing was performed on 39 patient-parent trios to identify de novo mutations. Clinical significance of de novo mutations in genes was determined using the American College of Medical Genetics and Genomics standard guidelines for interpretation of coding variants. Variants in genes of unknown clinical significance were further analysed in the context of previous trio sequencing efforts in neurodevelopmental disorders. RESULTS: In 39 patient-parent trios we identified 29 de novo mutations in coding sequence. Analysis of de novo and inherited variants yielded a molecular diagnosis in 11 families (28.2%). In combination with previously published exome sequencing results in neurodevelopmental disorders, our analysis implicates HECW2 as a novel candidate gene in ID and epilepsy. CONCLUSIONS: Our results support the use of exome sequencing as a diagnostic approach for ID and epilepsy, and confirm previous results regarding the importance of de novo mutations in this patient group. The results also highlight the utility of network analysis and comparison to previous large-scale studies as strategies to prioritise candidate genes for further studies. This study adds knowledge to the increasingly growing list of causative and candidate genes in ID and epilepsy and highlights HECW2 as a new candidate gene for neurodevelopmental disorders