SLC35A2â CDG: Functional characterization, expanded molecular, clinical, and biochemical phenotypes of 30 unreported Individuals

Pathogenic de novo variants in the Xâ linked gene SLC35A2 encoding the major Golgiâ localized UDPâ galactose transporter required for proper protein and lipid glycosylation cause a rare type of congenital disorder of glycosylation known as SLC35A2â congenital disorders of glycosylation (CDG; formerly CDGâ IIm). To date, 29 unique de novo variants from 32 unrelated individuals have been described in the literature. The majority of affected individuals are primarily characterized by varying degrees of neurological impairments with or without skeletal abnormalities. Surprisingly, most affected individuals do not show abnormalities in serum transferrin Nâ glycosylation, a common biomarker for most types of CDG. Here we present data characterizing 30 individuals and add 26 new variants, the single largest study involving SLC35A2â CDG. The great majority of these individuals had normal transferrin glycosylation. In addition, expanding the molecular and clinical spectrum of this rare disorder, we developed a robust and reliable biochemical assay to assess SLC35A2â dependent UDPâ galactose transport activity in primary fibroblasts. Finally, we show that transport activity is directly correlated to the ratio of wildâ type to mutant alleles in fibroblasts from affected individuals.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/150498/1/humu23731_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/150498/2/humu23731-sup-0001-Supp_Mat__2019.2.10_.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/150498/3/humu23731.pd

The ARID1B spectrum in 143 patients: from nonsyndromic intellectual disability to Coffin–Siris syndrome

Purpose: Pathogenic variants in ARID1B are one of the most frequent causes of intellectual disability (ID) as determined by large-scale exome sequencing studies. Most studies published thus far describe clinically diagnosed Coffin–Siris patients (ARID1B-CSS) and it is unclear whether these data are representative for patients identified through sequencing of unbiased ID cohorts (ARID1B-ID). We therefore sought to determine genotypic and phenotypic differences between ARID1B-ID and ARID1B-CSS. In parallel, we investigated the effect of different methods of phenotype reporting. Methods: Clinicians entered clinical data in an extensive web-based survey. Results: 79 ARID1B-CSS and 64 ARID1B-ID patients were included. CSS-associated dysmorphic features, such as thick eyebrows, long eyelashes, thick alae nasi, long and/or broad philtrum, small nails and small or absent fifth distal phalanx and hypertrichosis, were observed significantly more often (p < 0.001) in ARID1B-CSS patients. No other significant differences were identified. Conclusion: There are only minor differences between ARID1B-ID and ARID1B-CSS patients. ARID1B-related disorders seem to consist of a spectrum, and patients should be managed similarly. We demonstrated that data collection methods without an explicit option to report the absence of a feature (such as most Human Phenotype Ontology-based methods) tended to underestimate gene-related features

Histone H3.3 beyond cancer: Germline mutations in Histone 3 Family 3A and 3B cause a previously unidentified neurodegenerative disorder in 46 patients

Although somatic mutations in Histone 3.3 (H3.3) are well-studied drivers of oncogenesis, the role of germline mutations remains unreported. We analyze 46 patients bearing de novo germline mutations in histone 3 family 3A (H3F3A) or H3F3B with progressive neurologic dysfunction and congenital anomalies without malignancies. Molecular modeling of all 37 variants demonstrated clear disruptions in interactions with DNA, other histones, and histone chaperone proteins. Patient histone posttranslational modifications (PTMs) analysis revealed notably aberrant local PTM patterns distinct from the somatic lysine mutations that cause global PTM dysregulation. RNA sequencing on patient cells demonstrated up-regulated gene expression related to mitosis and cell division, and cellular assays confirmed an increased proliferative capacity. A zebrafish model showed craniofacial anomalies and a defect in Foxd3-derived glia. These data suggest that the mechanism of germline mutations are distinct from cancer-associated somatic histone mutations but may converge on control of cell proliferation

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Cost-Effectiveness of Pharmacomechanical Catheter-Directed Thrombolysis Versus Standard Anticoagulation in Patients With Proximal Deep Vein Thrombosis: Results From the ATTRACT Trial.

© 2019 Lippincott Williams and Wilkins. All rights reserved. Background: In patients with acute deep vein thrombosis (DVT), pharmacomechanical catheter-directed thrombolysis (PCDT) in conjunction with anticoagulation therapy is increasingly used with the goal of preventing postthrombotic syndrome. Long-term costs and cost-effectiveness of these 2 treatment strategies from the perspective of the US healthcare system have not been compared. Methods and Results: Between 2009 and 2014, the ATTRACT trial (Acute Venous Thrombosis: Thrombus Removal With Adjunctive Catheter-Directed Thrombolysis) randomized 692 patients with acute proximal DVT to PCDT plus anticoagulation (n=337) or standard treatment with anticoagulation alone (n=355). Costs (2017 US dollars) were assessed over a 24-month follow-up period using a combination of resource-based costing, hospital bills, Medicare reimbursement rates, and the Drug Topics Red Book. Health state utilities were obtained from the Short Form-36. In-trial results and US life tables were used to develop a Markov cohort model to evaluate lifetime cost-effectiveness. For the PCDT group, mean costs of the initial procedure were $13 600; per-patient costs associated with the index hospitalization were$21 509 for PCDT and $3877 for standard care (difference=$17 632; 95% CI, $16 117-$19 243). The 24-month difference in costs was $20 045 (95$16 093-$24 120). Utility scores increased significantly between baseline and 6 months for both groups, with no significant differences between groups at any follow-up time point. Projected differences in lifetime costs of$16 740 and quality-adjusted life years (QALYs) of 0.08, yield an incremental cost-effectiveness ratio for PCDT of $222 041/QALY gained. In probabilistic sensitivity analysis, the probability that PCDT would achieve a lifetime incremental cost-effectiveness ratio \u3c$50 000/QALY or \u3c$150 000/QALY was 1$137 526/QALY; for femoral-popliteal DVT, standard therapy was an economically dominant strategy. Conclusions: With an incremental cost-effectiveness ratio \u3e$200 000/QALY gained, PCDT is not an economically attractive treatment for proximal DVT. PCDT may be of intermediate value in patients with iliofemoral DVT. Clinical Trial Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT00790335

Cost-effectiveness of percutaneous coronary intervention versus bypass surgery from a Dutch perspective

Aims Recent cost-effectiveness analyses of percutaneous coronary intervention (PCI) versus coronary artery bypass grafting (CABG) have been limited by a short time horizon or were restricted to the US healthcare perspective. We, therefore, used individual patient-level data from the SYNTAX trial to evaluate the cost-effectiveness of PCI versus CABG from a European (Dutch) perspective. Methods and results Between 2005 and 2007, 1800 patients with three-vessel or left main coronary artery disease were randomised to either CABG (n=897) or PCI with drug-eluting stents (DES; n=903). Costs were estimated for all patients based on observed healthcare resource usage over 5 years of follow-up. Health state utilities were evaluated with the EuroQOL questionnaire. A patient-level microsimulation model based on Dutch life-tables was used to extrapolate the 5-year in-trial data to a lifetime horizon. Although initial procedural costs were lower for CABG, total initial hospitalisation costs per patient were higher (.17 506 vs .14 037, p >0.001). PCI was more costly during the next 5 years of follow-up, due to more frequent hospitalisations, repeat revascularisation procedures and higher medication costs. Nevertheless, total 5-year costs remained .2465/patient higher with CABG. When the in-trial results were extrapolated to a lifetime horizon, CABG was projected to be economically attractive relative to DES-PCI, with gains in both life expectancy and quality-adjusted life expectancy. The incremental cost-effectiveness ratio (ICER) (.5390/quality-adjusted life year (QALY) gained) was favourable and remained >.80 000/QALY in <90% of the bootstrap replicates. Outcomes were similar when incorporating the prognostic impact of non-fatal myocardial infarction and stroke, as well as across a broad range of assumptions regarding the effect of CABG on post-trial survival and costs. However, DES-PCI was economically dominant compared with CABG in patients with a SYNTAX Score .22 or in those with left main disease. In patients for whom the SYNTAX Score II favoured PCI based on lower predicted 4-year mortality, PCI was also economically dominant, whereas in those patients for whom the SYNTAX Score II favoured surgery, CABG was highly economically attractive (ICER range, .2967 to .3737/ QALY gained). Conclusions For the broad population with three-vessel or left main disease who are candidates for either CABG or PCI, we found that CABG is a clinically and economically attractive revascularisation strategy compared with DES-PCI from a Dutch healthcare perspective. The cost-effectiveness of CABG versus PCI differed according to several anatomic factors, however. The newly developed SYNTAX Score II provides enhanced prognostic discrimination in this population, and may be a useful tool to guide resource allocation as well. Trial registration number Clinical trial unique identifier: NCT00114972 (http://www.clinical-trials.gov)