Genetics is believed to have an important role in intellectual disability (ID). Recent studies have emphasized the involvement of de novo mutations (DNMs) in ID but the extent to which they ...contribute to its pathogenesis and the identity of the corresponding genes remain largely unknown. Here, we report a screen for DNMs in subjects with moderate or severe ID. We sequenced the exomes of 41 probands and their parents, and confirmed 81 DNMs affecting the coding sequence or consensus splice sites (1.98 DNMs/proband). We observed a significant excess of de novo single nucleotide substitutions and loss-of-function mutations in these cases compared to control subjects, suggesting that at least a subset of these variations are pathogenic. A total of 12 likely pathogenic DNMs were identified in genes previously associated with ID (ARID1B, CHD2, FOXG1, GABRB3, GATAD2B, GRIN2B, MBD5, MED13L, SETBP1, TBR1, TCF4, WDR45), resulting in a diagnostic yield of ∼29%. We also identified 12 possibly pathogenic DNMs in genes (HNRNPU, WAC, RYR2, SET, EGR1, MYH10, EIF2C1, COL4A3BP, CHMP2A, PPP1CB, VPS4A, PPP2R2B) that have not previously been causally linked to ID. Interestingly, no case was explained by inherited mutations. Protein network analysis indicated that the products of many of these known and candidate genes interact with each other or with products of other ID-associated genes further supporting their involvement in ID. We conclude that DNMs represent a major cause of moderate or severe ID.
•Noise-canceling techniques for pavement vibration data.•Data smoothing methods for enhancing the vibration signals.•Vibration-based method for evaluation and prediction of the road pavement ...condition.
Road pavement surfaces need routine and regular monitoring and inspection to keep the surface layers in high-quality condition. However, the population growth and the increases in the number of vehicles and the length of road networks worldwide have required researchers to identify appropriate and accurate road pavement monitoring techniques. The vibration-based technique is one of the effective techniques used to measure the condition of pavement degradation and the level of pavement roughness. The consistency of pavement vibration data is directly proportional to the intensity of surface roughness. Intense fluctuations in vibration signals indicate possible defects at certain points of road pavement. However, vibration signals typically need a series of pre-processing techniques such as filtering, smoothing, segmentation, and labelling before being used in advanced processing and analyses. This research reports the use of noise-cancelling and data-smoothing techniques, including high pass filter, moving average method, median, Savitzky-Golay filter, and extracting peak envelope method, to enhance raw vibration signals for further processing and classification. The results show significant variations in the impact of noise-cancelling and data-smoothing techniques on raw pavement vibration signals. According to the results, the high pass filter is a more accurate noise-cancelling and data smoothing technique on road pavement vibration data compared to other data filtering and data smoothing methods.
PurposeThe advent of next-generation sequencing resulted in substantial increases in the number of variants detected, interpreted, and reported by molecular genetics diagnostic laboratories. Recent ...publications have provided standards for the interpretation of sequence variants, but there are currently no standards regarding reinterpretation of these variants. Recognizing that significant changes in variant classification may occur over time, many genetics diagnostic laboratories have independently developed practices for variant reinterpretation. The purpose of this study is to describe our laboratory approach to variant reinterpretation.MethodsWe surveyed eight genetics diagnostic laboratories in Canada and the United States.ResultsEach laboratory had differing protocols, but most felt that clinically relevant changes to variant classifications should be communicated to ordering providers. Based on results of this survey and our experience, we developed a cost-effective and resource-efficient approach to variant reinterpretation.ConclusionOngoing variant reinterpretation is required to maintain the highest standards for delivering genetics laboratory services. Our approach to variant reinterpretation offers an efficient solution that does not compromise accuracy or timely delivery of genetics laboratory services.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the selective death of motor neurons. Causative mutations in the global RNA-processing proteins TDP-43 and ...FUS among others, as well as their aggregation in ALS patients, have identified defects in RNA metabolism as an important feature in this disease. Lethal congenital contracture syndrome 1 and lethal arthrogryposis with anterior horn cell disease are autosomal recessive fetal motor neuron diseases that are caused by mutations in another global RNA-processing protein, hGle1. In this study, we carried out the first screening of GLE1 in ALS patients (173 familial and 760 sporadic) and identified 2 deleterious mutations (1 splice site and 1 nonsense mutation) and 1 missense mutation. Functional analysis of the deleterious mutants revealed them to be unable to rescue motor neuron pathology in zebrafish morphants lacking Gle1. Furthermore, in HeLa cells, both mutations caused a depletion of hGle1 at the nuclear pore where it carries out an essential role in nuclear export of mRNA. These results suggest a haploinsufficiency mechanism and point to a causative role for GLE1 mutations in ALS patients. This further supports the involvement of global defects in RNA metabolism in ALS.
Disruption of endoplasmic reticulum (ER) proteostasis is a salient feature of amyotrophic lateral sclerosis (ALS). Upregulation of ER foldases of the protein disulfide isomerase (PDI) family has been ...reported in ALS mouse models and spinal cord tissue and body fluids derived from sporadic ALS cases. Although in vitro studies suggest a neuroprotective role of PDIs in ALS, the possible contribution of genetic mutations of these ER foldases in the disease process remains unknown. Interestingly, intronic variants of the PDIA1 gene were recently reported as a risk factor for ALS. Here, we initially screened for mutations in two major PDI genes (PDIA1/P4HB and PDIA3/ERp57) in a US cohort of 96 familial and 96 sporadic ALS patients using direct DNA sequencing. Then, 463 familial and 445 sporadic ALS patients from two independent cohorts were also screened for mutations in these two genes using whole exome sequencing. A total of nine PDIA1 missense variants and seven PDIA3 missense variants were identified in 16 ALS patients. We have identified several novel and rare single nucleotide polymorphisms (SNPs) in both genes that are enriched in ALS cases compared with a large group of control subjects showing a frequency of around 1% in ALS cases. The possible biological and structural impact of these ALS-linked PDI variants is also discussed.
•Novel and rare exonic SNPs in PDIA1 and ERp57 are found in ALS cases.•Structural analysis predicts changes in the catalytic functioning of PDIA1 variants.•Changes in the ERp57 variant structure might affect the CNX/CRT cycle.
Background Little is known about the genetics of nonsyndromic intellectual disability (NSID). Recently, we reported de novo truncating mutations in the SYNGAP1 gene of 3 of 94 NSID cases, suggesting ...that its disruption represents a common cause of autosomal dominant NSID. Methods To further explore the involvement of SYNGAP1 in NSID, we sequenced its exons and intronic boundaries in 60 additional sporadic cases of NSID, including 30 patients with autism spectrum disorders (ASD) and 9 with epilepsy, and in 380 control individuals. Results We identified de novo out-of-frame deletions in two patients with NSID and mild generalized epilepsy (c.2677delC/p.Q893RfsX184 and c.321_324delGAAG/p. K108VfsX25) and a de novo splicing mutation (c.2294 + 1G>A), which results in the creation of a premature stop codon, in a patient with NSID and autism. No splicing or truncating mutations were found in control subjects. Conclusions We provide evidence that truncating mutations in SYNGAP1 are common in NSID and can be also associated with autism.
Acute coronary syndrome (ACS) secondary to a coronary embolism is an unusual occurrence, yet an important consideration given the difficult diagnosis. We report a case of a 69-year-old male with a ...medical history of paroxysmal atrial fibrillation who presented with chest pain and shortness of breath. A coronary angiogram was significant for three focal transluminal and translucent areas in the ostial, mid, and distal circumflex artery consistent with embolic disease. The patient was subsequently managed medically with anticoagulation. Despite being a relatively rare entity, thromboembolism into the coronary arteries can provoke an acute myocardial infarction, with atrial fibrillation being the most common risk factor. Treatment modalities for ACS secondary to thromboembolism include stent placement, intracoronary thrombolysis, and thrombus aspiration.
Aggregatibacter aphrophilus is a rare cause of infective endocarditis that was first described in 1940 by Khairat et al. and is now classified under the HACEK group of bacteria (Haemophilus spp., ...Aggregatibacter spp., Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae). There is limited literature describing the extracardiac complications of infective endocarditis caused by this organism. We report a case of a 53-year-old male with no significant past medical history who developed acute infective endocarditis complicated by a brain abscess caused by A. aphrophilus. The patient underwent aspiration of the abscess and treated with a long course of intravenous antimicrobials. This case represents a rare complication of infective endocarditis caused by A. aphrophilus and to the best of our knowledge, is the second reported case in the literature describing such a complication in a previously healthy patient. Although neurological sequela is associated with higher mortality and may be the presenting symptom of infective endocarditis, it may also be clinically silent – only detected upon imaging.
Spontaneous isolated superior mesenteric artery dissection (ISMAD) is an uncommon cause of abdominal pain. Clinical presentation ranges from an asymptomatic incidental finding to acute bowel ischemia ...or fatal aneurysmal super mesenteric artery (SMA) rupture. We report the case of a 58-year-old male presenting with abdominal pain. Imaging studies revealed an ISMAD without radiological evidence of bowel ischemia. The patient was successfully treated using a conservative approach including bowel rest and anticoagulation. ISMAD incidence is expected to increase with the utilization of advanced imaging modalities. Thus, an ISMAD should be suspected when other common causes of an acute abdomen have been excluded. Given the lack of evidence-based guidelines, management options include conservative treatment and anticoagulation, endovascular stenting, or open surgical repair.
Aortic dissection is the most devastating sequelae of aortopathy other than aortic rupture. However, aortic dissection can be asymptomatic in the acute phase with delayed symptomatic presentation or ...incidental diagnosis upon chest imaging. We report a case of a 63-year-old male who was diagnosed with pericardial effusion upon preoperative workup for elective cholecystectomy. Further investigations confirmed hemorrhagic pericardial effusion secondary to a chronic dissecting ascending aortic aneurysm. The patient condition was successfully managed with open surgical repair with an uneventful postoperative course. This case demonstrates an extremely rare presentation of incidental hemorrhagic pericardial effusion caused by a chronic dissecting ascending aortic aneurysm.
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