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Background: Human studies of genetic risk factors for neural tube defects, severe birth defects associated with long‐term health consequences in surviving children, have predominantly been restricted to a subset of candidate genes in specific biological pathways including folate metabolism. Methods: In this study, we investigated the association of genetic variants spanning the genome with risk of spina bifida (i.e., myelomeningocele and meningocele) in a subset of families enrolled from December 2016 through December 2022 in a case–control study in Bangladesh, a population often underrepresented in genetic studies. Saliva DNA samples were analyzed using the Illumina Global Screening Array. We performed genetic association analyses to compare allele frequencies between 112 case and 121 control children, 272 mothers, and 128 trios. Results: In the transmission disequilibrium test analyses with trios only, we identified three novel exonic spina bifida risk loci, including rs140199800 (SULT1C2, p = 1.9 × 10−7), rs45580033 (ASB2, p = 4.2 × 10−10), and rs75426652 (LHPP, p = 7.2 × 10−14), after adjusting for multiple hypothesis testing. Association analyses comparing cases and controls, as well as models that included their mothers, did not identify genome‐wide significant variants. Conclusions: This study identified three novel single nucleotide polymorphisms involved in biological pathways not previously associated with neural tube defects. The study warrants replication in larger groups to validate findings and to inform targeted prevention strategies. [ABSTRACT FROM AUTHOR]

Short trinucleotide expansions at the FMR1 locus are associated with the late-onset condition fragile X-associated tremor/ataxia syndrome (FXTAS), which shows very different clinical and pathological features from fragile X syndrome (associated with longer expansions), with no clear molecular explanation for these marked differences. One prevailing theory posits that the shorter, premutation expansion uniquely causes extreme neurotoxic increases in FMR1 mRNA (i.e., four to eightfold increases), but evidence to support this hypothesis is largely derived from analysis of peripheral blood. We applied single-nucleus RNA sequencing to postmortem frontal cortex and cerebellum from 7 individuals with premutation and matched controls (n = 6) to assess cell type-specific molecular neuropathology. We found only modest upregulation (~1.3-fold) of FMR1 in some glial populations associated with premutation expansions. In premutation cases, we also identified decreased astrocyte proportions in the cortex. Differential expression and gene ontology analysis demonstrated altered neuroregulatory roles of glia. Using network analyses, we identified cell type-specific and region-specific patterns of FMR1 protein target gene dysregulation unique to premutation cases, with notable network dysregulation in the cortical oligodendrocyte lineage. We used pseudotime trajectory analysis to determine how oligodendrocyte development was altered and identified differences in early gene expression in oligodendrocyte trajectories in premutation cases specifically, implicating early cortical glial developmental perturbations. These findings challenge dogma regarding extremely elevated FMR1 increases in FXTAS and implicate glial dysregulation as a critical facet of premutation pathophysiology, representing potential unique therapeutic targets directly derived from the human condition. [ABSTRACT FROM AUTHOR]

Background: Children and adolescents with early-onset psychosis (EOP) have more rare genetic variants than individuals with adult-onset forms of the illness, implying that fewer EOP participants are needed for genetic discovery. The Schizophrenia Exome Sequencing Meta-analysis (SCHEMA) study predicted that 10 genes with ultra-rare variation were linked to adult-onset schizophrenia. We hypothesized that rare variants predicted "High" and "Moderate" by the Variant Effect Predictor Algorithm (abbreviated as VEPHMI) in these 10 genes would be enriched in our EOP cohort. Methods: We compared rare VEPHMI variants in individuals with EOP (N = 34) with race- and sex-matched controls (N = 34) using the sequence kernel association test (SKAT). Results: GRIN2A variants were significantly increased in the EOP cohort (p = 0.004), with seven individuals (20% of the EOP cohort) carrying a rare VEPHMI variant. The EOP cohort was then compared to three additional control cohorts. GRIN2A variants were significantly increased in the EOP cohort for two of the additional control sets (p = 0.02 and p = 0.02), and trending towards significance for the third (p = 0.06). Conclusion: Despite a small sample size, GRIN2A VEPHMI variant burden was increased in a cohort of individuals with EOP in comparison to controls. GRIN2A variants have been associated with a range of neuropsychiatric disorders including adult-onset psychotic spectrum disorder and childhood-onset schizophrenia. This study supports the role of GRIN2A in EOP and emphasizes its role in neuropsychiatric disorders. [ABSTRACT FROM AUTHOR]

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic pain disorder causing symptoms of urinary frequency, urgency, and bladder discomfort or pain. Although this condition affects a large population, little is known about its etiology. Genetic analyses of whole exome sequencing are performed on 109 individuals with IC/BPS. One family has a previously reported SIX5 variant (ENST00000317578.6:c.472G>A, p.Ala158Thr), consistent with Branchiootorenal syndrome 2 (BOR2). A likely pathogenic heterozygous variant in ATP2A2 (ENST00000539276.2:c.235G>A, p.Glu79Lys) is identified in two unrelated probands, indicating possible Darier‐White disease. Two private heterozygous variants are identified in ATP2C1 (ENST00000393221.4:c.2358A>T, p.Glu786Asp (VUS/Likely Pathogenic) and ENST00000393221.4:c.989C>G, p.Thr330Ser (likely pathogenic)), indicative of Hailey‐Hailey Disease. Sequence kernel association test analysis finds an increased burden of rare ATP2C1 variants in the IC/BPS cases versus a control cohort (p = 0.03, OR = 6.76), though does not survive Bonferroni correction. The data suggest that some individuals with IC/BPS may have unrecognized Mendelian syndromes. Comprehensive phenotyping and genotyping aid in understanding the range of diagnoses in the population‐based IC/BPS cohort. Conversely, ATP2C1, ATP2A2, and SIX5 may be candidate genes for IC/BPS. Further evaluation with larger numbers is needed. Genetically screening individuals with IC/BPS may help diagnose and treat this painful disorder due to its heterogeneous nature. [ABSTRACT FROM AUTHOR]

SET is a multifunctional histone-binding oncoprotein that regulates transcription by an unclear mechanism. Here we show that SET enhances estrogen-dependent transcription. SET knockdown abrogates transcription of estrogen-responsive genes and their enhancer RNAs. In response to 17ß-estradiol (E2), SET binds to the estrogen receptor a (ERa) and is recruited to ERa-bound enhancers and promoters at estrogen response elements (EREs). SET functions as a histone H2 chaperone that dynamically associates with H2A.Z via its acidic C-terminal domain and promotes H2A.Z incorporation, ERa, MLL1, and KDM3A loading and modulates histone methylation at EREs. SET depletion diminishes recruitment of condensin complexes to EREs and impairs E2-dependent enhancer-promoter looping. Thus, SET boosts E2-induced gene expression by establishing an active chromatin structure at ERa-bound enhancers and promoters, which is essential for transcriptional activation. [ABSTRACT FROM AUTHOR]

Background and Aims Over 80 monogenic causes of very early onset inflammatory bowel disease [VEOIBD] have been identified. Prior reports of the natural history of VEOIBD have not considered monogenic disease status. The objective of this study is to describe clinical phenotypes and outcomes in a large single-centre cohort of patients with VEOIBD and universal access to whole exome sequencing [WES]. Methods Patients receiving IBD care at a single centre were prospectively enrolled in a longitudinal data repository starting in 2012. WES was offered with enrollment. Enrolled patients were filtered by age of diagnosis <6 years to comprise a VEOIBD cohort. Monogenic disease was identified by filtering proband variants for rare, loss-of-function, or missense variants in known VEOIBD genes inherited according to standard Mendelian inheritance patterns. Results This analysis included 216 VEOIBD patients, followed for a median of 5.8 years. Seventeen patients [7.9%] had monogenic disease. Patients with monogenic IBD were younger at diagnosis and were more likely to have Crohn's disease phenotype with higher rates of stricturing and penetrating disease and extraintestinal manifestations. Patients with monogenic disease were also more likely to experience outcomes of intensive care unit [ICU] hospitalisation, gastrostomy tube, total parenteral nutrition use, stunting at 3-year follow-up, haematopoietic stem cell transplant, and death. A total of 41 patients [19.0%] had infantile-onset disease. After controlling for monogenic disease, patients with infantile-onset IBD did not have increased risk for most severity outcomes. Conclusions Monogenic disease is an important driver of disease severity in VEOIBD. WES is a valuable tool in prognostication and management of VEOIBD. [ABSTRACT FROM AUTHOR]

Studies of ETS-mediated prostate oncogenesis have been hampered by a lack of suitable experimental systems. Here we describe a new conditional mouse model that shows robust, homogenous ERG expression throughout [...]