Mapping the infectious burden in VEXAS syndrome: a systematic review and rationale for prevention.

Infections are increasingly recognised as a major cause of morbidity and mortality in patients with vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome. We conducted a systematic review to characterise the infectious burden of VEXAS syndrome and propose preventive strategies. We included 57 studies (813 patients) showing that infections in patients with VEXAS syndrome were frequent, severe in 40-60% of cases, and fatal in 6-15% of cases.

One Shock, Not One Cure: Electroporation Reveals Disease-Specific Constraints in Hepatocyte Gene Editing Therapy.

We previously demonstrated lipid nanoparticle-mediated CRISPR-Cas9 gene editing to disrupt the gene encoding cytochrome P450 oxidoreductase (Cypor), combined with transient administration of acetaminophen (APAP), to repopulate the liver with healthy hepatocytes and rescue a phenylketonuria mouse model. This study aimed to investigate electroporation-mediated delivery of -targeting CRISPR-Cas9 ribonucleoproteins into wild-type hepatocytes, combined with liver engraftment under APAP treatment, as an in vivo selection approach in a mouse model of homozygous familial hypercholesterolemia (). Electroporation provides higher delivery efficiency compared to lipid nanoparticles.

Repeat-associated ataxias in a German patient cohort analysed by targeted parallel long-read sequencing.

Hereditary adult-onset ataxias are a heterogeneous group of phenotypically overlapping conditions, often caused by pathogenic expansions of short tandem repeats. Currently, 18 repeat disorders with a core phenotype of adult-onset ataxia are known. Diagnosis typically relies on sequential PCR-based methods, which are labour-intensive and lack precision.

Mendelian randomisation analysis to discover plasma metabolites mediating the effect of obesity on cancer risk.

Background: Obesity is a risk factor for several cancers, but the mechanistic basis is poorly understood. We sought to identify circulating metabolites mediating the effect of obesity on the risk of eight common cancers.

Methods: Using European ancestry data, we applied two-sample Mendelian randomisation (2S-MR) to screen 856 plasma metabolites for associations with body mass index (BMI) and waist-hip ratio (WHR).

Familial cerebral cavernous malformations caused by a novel germline structural variant in the KRIT1 gene.

The detection of complex structural variants in patients with familial cerebral cavernous malformations (FCCM) remains challenging. Short-read whole genome sequencing was performed for a patient with strong clinical evidence of FCCM but negative results from previous genetic tests. The analysis revealed a large insertion of an intronic KRIT1 fragment into a coding exon of KRIT1.

The hidden dancers in water: the symbiotic mystery of and free-living amoebae.

, a Gram-negative bacillus, is the primary etiological agent of Legionnaires' disease, a severe respiratory infection. The symbiotic relationship between and free-living amoebae (FLAs), particularly spp., represents a critical intersection of microbial ecology and human pathogenesis.

Clinical features and natural history of pelvic organ prolapse in South Kivu (Eastern DRC): a cross-sectional study.

Introduction: pelvic organ prolapse, a common condition, is a real public health problem in developing countries. Its anamnestic and clinical features may present particularities in these environments. The objective of this study was to assess when women present for treatment and the reasons for delay in seeking care.

Blood-based DNA methylation profiles in major depressive disorder, bipolar disorder, and schizophrenia spectrum disorders.

Alterations in DNA methylation (DNAm) profiles have been implicated in affective and psychotic disorders. However, no comprehensive understanding of peripheral DNAm profiles associated with diagnostic groups, course of illness, and other clinical variables has emerged yet. In particular, studies exploring commonalities and differences across diagnoses are lacking.

Mutual reinforcement of lymphotoxin-driven myositis and impaired autophagy in murine muscle.

Inclusion body myositis (IBM) is a progressive muscle disorder characterized by inflammation and degeneration with altered proteostasis. To better understand the interrelationship between these two features, we aimed at establishing a novel preclinical mouse model. First, we used quantitative PCR to determine expression of pro-inflammatory chemo- and cytokines including lymphotoxin (LT)-signaling pathway components in human skeletal muscle tissue diagnosed with myositis.

GW-9662, a peroxisome proliferator-activated receptor γ (PPARγ) inhibitor, impairs early embryonic development in zebrafish.

Peroxisome proliferator-activated receptor γ (PPARγ) functions as a nuclear transcription factor with primary roles in lipid and glucose metabolism and adipocyte differentiation. Despite intensive research in metabolic contexts, its role during early vertebrate development remains underexplored. Our study focused on understanding PPARγ's developmental role by using a PPARγ antagonist, GW-9662 (GW), in zebrafish embryos.

Hypermobile Ehlers-Danlos Syndrome: Cerebrovascular, Autonomic and Neuropathic Features.

Background: Hypermobile Ehlers-Danlos syndrome (hEDS) affects multiple systems, but comprehensive evaluations of a larger sample of hEDS patients are lacking. The objective of this study was to describe cerebrovascular, autonomic, and neuropathic features of hEDS.

Methods: This retrospective case-control study was conducted at Brigham and Women's Faulkner Hospital between 2016-2023.

Paired plus-minus sequencing is an ultra-high throughput and accurate method for dual strand sequencing of DNA molecules.

Distinguishing real biological variation in the form of single-nucleotide variants (SNVs) from errors is a major challenge for genome sequencing technologies. This is particularly true in settings where SNVs are at low frequency such as cancer detection through liquid biopsy, or human somatic mosaicism. State-of-the-art molecular denoising approaches for DNA sequencing rely on duplex sequencing, where both strands of a single DNA molecule are sequenced to discern true variants from errors arising from single stranded DNA damage.

Evaluating the relationship between caregiver depression, social support, and children's internalizing and externalizing symptoms in families affected by 22q11.2 deletion syndrome.

Background: 22q11.2 Deletion Syndrome (22q11DS) is the most common microdeletion syndrome. It exhibits broad phenotypic variability, often including conditions like autism spectrum disorder and intellectual disability.

Non-isolated tetralogy of fallot (TOF+): exome sequencing efficacy and phenotypic expansions.

Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart defect (CHD). TOF may present in isolation or in conjunction with one or more non-cardiac congenital anomalies or neurodevelopmental disorders (TOF+). Uncertainty regarding the efficacy of various genetic testing strategies, and an incomplete understanding of the genetic causes of TOF+, may lead to hesitancy in recommending genetic testing, particularly, clinical exome sequencing (cES).

When does accounting for gene-environment interactions improve complex trait prediction? A case study with lifespan.

Gene-environment interactions (G×E) have been shown to explain a non-negligible proportion of variance for a plethora of complex traits in different species, including livestock, plants, and humans. While several studies have shown that including G×E can improve prediction accuracy in agricultural species, no increase in accuracy has been observed in human studies. In this work, we sought to investigate the reasons for the contradictory results between agricultural species and humans.

American College of Rheumatology Guidance Statement for Diagnosis and Management of VEXAS Developed by the International VEXAS Working Group Expert Panel.

Objective: Vacuoles E1 enzyme X-linked autoinflammatory somatic syndrome (VEXAS) is a recently identified rare genetic disorder associated with somatic mutations in the UBA1 gene. VEXAS presents with a combination of inflammatory and hematologic manifestations, leading to increased morbidity and mortality.

Methods: Given the variability in disease presentation and the limited number of studies to date, no clinical documents currently exist to provide guidance to health care providers about the management of VEXAS.

A schema for sporadic and heritable disease pathogenesis integrating spatiotemporal distribution with the character of genetic variants.

Studies on HIF-2α variants have shed light on genotype-phenotype correlations in Pacak-Zhuang syndrome. Here, we propose the combination of the timing of variant acquisition and molecular pathogenicity into a schema to understand phenotypic severity, with implications for other diseases.

Pangenome discovery of missing autism variants.

Autism spectrum disorders (ASDs) are genetically and phenotypically heterogeneous and the majority of cases still remain genetically unresolved. To better understand large-effect pathogenic variation, we generated long-read sequencing data to construct phased and near-complete genome assemblies (average contig N50=43 Mbp, QV=56) for 189 individuals from 51 families with unsolved cases of autism. We applied read- and assembly-based strategies to facilitate comprehensive characterization of mutations (DNMs), structural variants (SVs), and DNA methylation profiles.

Urinary renal epithelial cells for NPHP1 phenotyping and personalized therapeutic response.

Nephronophthisis (NPHP) is a recessive tubulointerstitial nephropathy and a leading genetic cause of kidney failure in children and young adults. The most common genetic cause is a homozygous deletion of NPHP1, which encodes nephrocystin-1, a protein essential for primary cilium structure and cell junctions. Using personalised medicine and deep phenotyping, we investigated a family with three siblings carrying a homozygous NPHP1 deletion.

IBD-linked Genetic Variance in Intestinal Transplantation: A Multicenter Cohort Analysis.

Background: In solid organ transplantation, the intestine remains the most challenging. Previous studies have linked NOD2 genetic variation to intestinal transplantation (ITx) outcomes. Since then, a larger set of inflammatory bowel disease-associated genetic variants (IBDGVs) has been identified.

"Phenotypic and genotypic insights, counseling strategies, and follow-up in 24 individuals with filamin a deficiency: findings from a retrospective cohort study".

Background: Filamin A (FLNA) is an actin-binding protein involved in cytoskeleton organization and cell migration. Loss-of-function (LOF) variants give rise to a wide variety of symptoms with periventricular nodular heterotopia (PVNH) and epilepsy as the most common features. FLNA deficiency manifests as a multisystemic disorder with abnormalities of connective tissue and involvement of the cardiovascular, pulmonary, gastrointestinal and hematological system.