CNOT2 haploinsufficiency underlies a rare neurodevelopmental disorder named Intellectual Developmental disorder with NAsal speech, Dysmorphic Facies, and variable Skeletal anomalies (IDNADFS, OMIM ...618608). The condition clinically overlaps with chromosome 12q15 deletion syndrome, suggesting a major contribution of CNOT2 haploinsufficiency to the latter. CNOT2 is a member of the CCR4‐NOT complex, which is a master regulator of multiple cellular processes, including gene expression, RNA deadenylation, and protein ubiquitination. To date, less than 20 pathogenic 12q15 microdeletions encompassing CNOT2, together with a single truncating variant of the gene, and two large intragenic deletions have been reported. Due to the small number of affected subjects described so far, the clinical profile of IDNADFS has not been fully delineated. Here we report five unrelated individuals, three of which carrying de novo intragenic CNOT2 variants, one presenting with a multiexon intragenic deletion, and an additional case of 12q15 microdeletion syndrome. Finally, we assess the features of IDNADFS by reviewing published and present affected individuals and reevaluate the clinical phenotype of this neurodevelopmental disorder.
Background
Patients with acute venous thromboembolism associated with cancer have an increased risk of recurrences and bleeding in the long term.
Research question
To describe the clinical features ...and short-term course of patients with acute pulmonary embolism (PE) and active cancer, previous cancer or no cancer.
Study design and methods
Patients with acute PE included in COPE—prospective, multicentre study of adult patients with acute, symptomatic, objectively diagnosed PE—were classified as having active cancer, previous cancer, or no cancer.
Results
Overall, 832 patients had active cancer, 464 with previous cancer and 3660 patients had no cancer at the time of acute PE. The most prevalent primary sites of active cancer were urogenital (23.0%), gastrointestinal (21.0%), and lung (19.8%), with a high prevalence of metastatic disease (57.6%) and ongoing anticancer treatment (16.2%). At discharge, a direct oral anticoagulant was used in 43.1%, 78.8%, and 82.0% of patients with active cancer, previous cancer, and no cancer, respectively. Rates of death in-hospital and at 30 days were higher in patients with active cancer compared to patients with previous cancer and no cancer (7.9% vs. 4.3% vs. 2.2% and 13.8% vs. 5.2% vs. 2.6%, respectively). Rates of major bleeding were 4.8%, 2.6%, and 2.4%, respectively. Among patients with active cancer, lung or metastatic cancer were independent predictors of death; brain, hematological or gastrointestinal cancer had the highest risk of major bleeding.
Interpretation
Among patients with acute PE, those with active cancer have high risks for death or major bleeding within 30 days. These risks vary based on primary site of cancer.
Clinical trial registration
: clinicaltrial.gov identifier: NCT03631810.
Graphical abstract
FOXG1 syndrome is caused by FOXG1 intragenic point mutations, or by long-range position effects (LRPE) of intergenic structural variants. However, the size of the FOXG1 regulatory landscape is ...uncertain, because the associated topologically associating domain (TAD) in fibroblasts is split into two domains in embryonic stem cells (hESC). Indeed, it has been suggested that the pathogenetic mechanism of deletions that remove the stem-cell-specific TAD boundary may be enhancer adoption due to ectopic activity of enhancer(s) located in the distal hESC-TAD. Herein we map three de novo translocation breakpoints to the proximal regulatory domain of FOXG1. The classical FOXG1 syndrome in these and in other translocation patients, and in a patient with an intergenic deletion that removes the hESC-specific TAD boundary, do not support the hypothesised enhancer adoption as a main contributor to the FOXG1 syndrome. Also, virtual 4 C and HiC-interaction data suggest that the hESC-specific TAD boundary may not be critical for FOXG1 regulation in a majority of human cells and tissues, including brain tissues and a neuronal progenitor cell line. Our data support the importance of a critical regulatory region (SRO) proximal to the hESC-specific TAD boundary. We further narrow this critical region by a deletion distal to the hESC-specific boundary, associated with a milder clinical phenotype. The distance from FOXG1 to the SRO ( > 500 kb) highlight a limitation of ENCODE DNase hypersensitivity data for functional prediction of LRPE. Moreover, the SRO has little overlap with a cluster of frequently associating regions (FIREs) located in the proximal hESC-TAD.
...Table 2 shows the diagnostic performances, evaluated with a 95% confidence interval, of the RT-PCR on salivary samples. Early studies focused on clinically evident cases reported high viral ...presence in salivary samples,2 while subsequent research explored the feasibility of salivary analysis as a screening tool for pauci- or asymptomatic patients, yielding varying results.3 Recent meta-analyses reveal a sensitivity range of 83% to 87% and a specificity of 99% for salivary samples.4,5 Our results align with this data, demonstrating a sensitivity of 89.7% and a specificity of 98.7%. While our study highlights the potential of saliva-based testing, it acknowledges limitations, including a small sample size, limited tracking of symptom evolution, lack of understanding regarding the effect of sample storage on virus identification, absence of test repetition in case of discordant results and enrollment of only adults. Apart from this, the funding source had no role in: study design; collection, management, analysis, and interpretation of data; writing of the report; and the decision to submit the report for publication.
Kabuki syndrome (KS) is an extremely rare genetic disorder, mainly caused by germline mutations at specific epigenetic modifier genes, including KMT2D. Because the tumor suppressor gene KMT2D is also ...frequently altered in many cancer types, it has been suggested that KS may predispose to the development of cancer. However, KS being a rare disorder, few data are available on the incidence of cancer in KS patients. Here, we report the case of a 5-year-old boy affected by KS who developed Burkitt lymphoma (BL). Genetic analysis revealed the presence of a novel heterozygous mutation in the splice site of the intron 4 of KMT2D gene in both peripheral blood-extracted DNA and tumour cells. In addition, the tumour sample of the patient was positive for the classical somatic chromosomal translocation t(8;14) involving the c-MYC gene frequently identified in BL. We propose that the mutated KMT2D gene contributes to the development of both KS and BL observed in our patient and we suggest that strict surveillance must be performed in KS patients.
Recurrent respiratory infections (RRIs) are a common clinical condition in children, in fact about 25% of children under 1 year and 6% of children during the first 6 years of life have RRIs. In most ...cases, infections occur with mild clinical manifestations and the frequency of episodes tends to decrease over time with a complete resolution by 12 years of age. However, RRIs significantly reduce child and family quality of life and lead to significant medical and social costs.Despite the importance of this condition, there is currently no agreed definition of the term RRIs in the literature, especially concerning the frequency and type of infectious episodes to be considered. The aim of this consensus document is to propose an updated definition and provide recommendations with the intent of guiding the physician in the complex process of diagnosis, management and prevention of RRIs.
Loeys-Dietz syndrome (LDS) is a connective tissue disorder first described in 2005 featuring aortic/arterial aneurysms, dissections, and tortuosity associated with craniofacial, osteoarticular, ...musculoskeletal, and cutaneous manifestations. Heterozygous mutations in 6 genes (
), encoding components of the TGF-β pathway, cause LDS. Such genetic heterogeneity mirrors broad phenotypic variability with significant differences, especially in terms of the age of onset, penetrance, and severity of life-threatening vascular manifestations and multiorgan involvement, indicating the need to obtain genotype-to-phenotype correlations for personalized management and counseling. Herein, we report on a cohort of 34 LDS patients from 24 families all receiving a molecular diagnosis. Fifteen variants were novel, affecting the
(6),
(6),
(2), and
(1) genes. Clinical features were scored for each distinct gene and matched with literature data to strengthen genotype-phenotype correlations such as more severe vascular manifestations in
-related LDS. Additional features included spontaneous pneumothorax in
-related LDS and cervical spine instability in
-related LDS. Our study broadens the clinical and molecular spectrum of LDS and indicates that a phenotypic continuum emerges as more patients are described, although genotype-phenotype correlations may still contribute to clinical management.
Whether non-alcoholic fatty liver disease (NAFLD) is associated with an increased risk of cardiovascular events (CVEs) independently from metabolic syndrome (MetS) is still matter of debate. Aim of ...the study was to investigate the risk of CVEs in a high-risk population of patients with non-valvular atrial fibrillation (AF) according to the presence of MetS and NAFLD. Prospective observational multicenter study including 1,735 patients with non-valvular AF treated with vitamin K antagonists (VKAs) or direct oral anticoagulants (DOACs). NAFLD was defined by a fatty liver index ≥ 60. We categorized patients in 4 groups: 0 = neither MetS or NAFLD (38.6%), 1 = NAFLD alone (12.4%), 2 = MetS alone (19.3%), 3 = both MetS and NAFLD (29.7%). Primary endpoint was a composite of CVEs. Mean age was 75.4 ± 9.4 years, and 41.4% of patients were women. During a mean follow-up of 34.1 ± 22.8 months (4,926.8 patient-years), 155 CVEs were recorded (incidence rate of 3.1%/year): 55 occurred in Group 0 (2.92%/year), 12 in Group 1 (2.17%/year), 45 in Group 2 (4.58%/year) and 43 in Group 3 (2.85%/year). Multivariable Cox regression analysis showed that use of DOACs, and female sex were inversely associated with CVEs, whilst age, heart failure, previous cardiac and cerebrovascular events, and group 2 (Group 2, Hazard Ratio 1.517, 95% Confidence Interval, 1.010–2.280) were directly associated with CVEs. In patients with AF, MetS increases the risk of CVEs. Patients with NAFLD alone have lower cardiovascular risk but may experience higher liver-related complications.
The lectin-like oxidised LDL receptor-1 (OLR1) gene encodes a scavenger receptor implicated in the pathogenesis of atherosclerosis. Although functional roles have been suggested for two variants, ...epidemiological studies on OLR1 have been inconsistent.
We tested the association between the non-synonymous substitution K167N (rs11053646) and intima media thickness of the common carotid artery (CCA-IMT) in 2,141 samples from the Progression of Lesions in the Intima of the Carotid (PLIC) study (a prospective population-based study).
Significantly increased IMT was observed in male carriers of the minor C (N) allele compared to GC and GG (KN and KK) genotype. Functional analysis on macrophages suggested a decreased association to Ox-LDL in NN carriers compared to KN and KK carriers which is also associated with a reduced OLR1 mRNA expression. Macrophages from NN carriers present also a specific inflammatory gene expression pattern compared to cells from KN and KK carriers.
These data suggest that the 167N variant of LOX-1 receptor affects the atherogenic process in the carotid artery prior to evidence of disease through an inflammatory process.
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