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Parkinson's disease (PD) involves heterogeneous neurodegenerative processes across brain cell types. The cell-type-specific effects of genetic risk remain unclear. We aimed to identify cell-type-specific causal genes for PD and to link genetic risk to molecular mechanisms and therapeutic opportunities. We performed the first cell-stratified Mendelian randomization integrating single-cell expression quantitative trait loci data from eight brain cell types with large PD genome-wide association studies datasets, followed by validation, neuropathological correlation, and postmortem expression analyses. Thirteen significant causal associations for four genes (ARL17A, ARL17B, KANSL1, LRRC37A) were identified across seven cell types, with consistent replication. ARL17A increased risk, whereas ARL17B, KANSL1, and LRRC37A were protective. Gene expression correlated with disease severity and showed cell-type-specific dysregulation. Drug-gene interaction screen highlighted US Food and Drug Administration-approved agents including raloxifene and dorzolamide as potential therapeutic modulators. This study contributed to cell-type-specific genetic mechanisms in PD, linking risk variants to molecular alterations and nominating therapeutic targets. © 2026 International Parkinson and Movement Disorder Society. Show less

Fusion genes are pivotal drivers of tumorigenesis, often generating oncogenic chimeric RNAs and fusion circular RNAs. However, the mechanisms by which these transcripts synergistically contribute to cancer progression remain poorly understood. Here, we identified a lung cancer-specific chimeric RNA KANSL1-ARL17A (chKANSARL) and its circular variant fusion circular RNA KANSL1-ARL17 A (F-circKA), both derived from the fusion gene KANSARL. Functional assays revealed that overexpression of either chKANSARL or F-circKA significantly enhanced lung cancer cell proliferation, migration, and invasion, while their knockdown suppressed these malignant phenotypes. In vivo experiments demonstrated that chKANSARL overexpression accelerated tumor growth in immunodeficient mice. Notably, coexpression experiments uncovered a synergistic regulatory interaction between F-circKA and chKANSARL, amplifying oncogenic effects. Mechanistically, miRNA sequencing and dual-luciferase assays revealed that F-circKA acts as a molecular sponge for miR-6860, thereby derepressing chKANSARL expression. Rescue experiments further validated this regulatory axis, wherein miR-6860 inhibition reversed the tumor-suppressive effects of F-circKA knockdown. Collectively, our study identifies and characterizes a novel F-circKA/miR-6860/chKANSARL regulatory axis, revealing how dual transcriptional outputs from the KANSARL fusion gene can synergistically drive lung cancer progression. These findings highlight a previously unrecognized layer of cooperative regulation between linear and circular fusion RNAs in oncogenesis and provide a new framework for understanding fusion gene-mediated tumorigenesis. Show less

Koolen-de Vries Syndrome (KdVS) is a neurodevelopmental disorder (NDD) caused by KANSL1 haploinsufficiency with no treatment options. To investigate neuronal network activity in KdVS, human induced pluripotent stem cell (hiPSC)-derived neurons from KdVS patients and controls were cultured on microelectrode arrays (MEAs). KdVS networks exhibited reduced burst rates and increased variability in burst rhythmicity. To bridge molecular and functional aspects of the syndrome, we applied MEA-seq, integrating electrophysiological recordings with high-throughput transcriptome profiling. This analysis revealed a negative correlation between the NDD-associated gene CLCN4 and network burst rate. Knockdown of CLCN4 in KdVS neurons restored network bursting toward control levels, highlighting how transcriptome profiling can identify mediators linking genetic defects to relevant physiological phenotypes. We also identified significant correlations between mitochondrial gene expression and network activity and consequently confirmed impaired mitochondrial function in KdVS hiPSC-derived neurons. Using the KdVS transcriptomic signature for computational screening against the LINCS drug perturbation database, we predicted compounds capable of reversing dysregulated gene expression. Ten candidates were prioritized for experimental validation, focusing on mitochondrial function. Among these, the antioxidant phloretin improved multiple aspects of the KdVS-related network activity phenotype, reduced reactive oxygen species, and rescued synaptic density across patient lines, revealing its potential as a therapeutic candidate. Together, these findings demonstrate that integrative MEA-seq profiling can connect molecular and electrophysiological alterations in KdVS, providing a robust framework for identifying novel drugs and druggable pathways for KdVS and potentially other neurodevelopmental disorders. Show less

Resilience following combat exposure is an important factor in understanding posttraumatic stress disorder (PTSD), associated risk, and potentially resilience more generally. Identifying underlying genetic factors requires large samples; most biobanks lack extensive resilience assessments, although data regarding trauma and psychiatric symptoms are frequently present that allow computation of a resilience measure. We leveraged the Million Veteran Program (MVP) cohort to calculate discrepancy-based psychiatric resilience (DBPR) scores by regressing PTSD symptoms (PCL-17) onto combat exposure (Deployment Risk and Resilience Inventory-Combat Experiences Scale). We conducted a genome-wide association study (GWAS) of DBPR among European-ancestry (EUR) (n=94,360) and African-ancestry (AFR) participants (n=10,339). We performed conditional analyses with disorders frequently comorbid with PTSD (major depressive disorder, generalized anxiety), examined genetic correlations (r SNP-based heritability was 0.079 (SE=0.007) and three independent genome-wide significant loci were associated with DBPR in EUR; no significant loci were identified in AFR. Trans-ancestry meta-analysis revealed three significant SNPs mapping to RN7SKPP19*rs4650199, MAD1L1*rs12669370, and KANSL1:KANSL1-AS1*rs62060955. In EUR, eight genes were identified in TWAS. One gene (C7orf50) reached a posterior probability >0.90 in TWAS fine mapping. Significant correlations were observed between DBPR and other variables including neuroticism (-0.61), participation in religious groups (0.29) and engaging in sports (0.39, SE = 0.05). The r These findings extend the literature regarding DBPR as a resilience measure and help inform our understanding of the underlying biological mechanisms. Show less

Periventricular nodular heterotopia (PVNH) is a common malformation of cortical development. We describe a distinctive imaging phenotype characterized by bilateral small heterotopic nodules of grey matter in the frontal periventricular regions, with an overview of the clinical, imaging, and genetic features. Investigators reviewed available brain MRI studies, clinical records and genetic findings of 32 individuals with bilateral frontal PVNH, ascertained from multiple centres between 1996 and 2021. The imaging phenotype consists of multiple, small, bilateral nodules of PVNH maximal along the frontal horns of the lateral ventricles. Frontal PVNH was associated with heterogeneous, often subtle, additional brain malformations in 72 % (23/32) individuals. The clinical phenotype was variable and included mild focal epilepsy in 7/32 and mild-moderate cognitive impairment or developmental delay in 13/32. Microarray was normal in 13/16 and exome or genome sequencing normal in 8/13 where testing was performed. A genetic diagnosis was achieved in seven patients; pathogenic chromosome deletions of 7q11.23 and 7p22.1, pathogenic intragenic variants in KANSL1, STXBP1 and MAP1B (mother-daughter pair), and a combined 13q12.12 deletion (containing SACS) and an intragenic SACS variant. Bilateral frontal PVNH has a variable clinical phenotype, but generally milder sequelae than other forms of bilateral PVNH. A genetic diagnosis was made by chromosome microarray alone in 13 % or by exome or genome sequencing in 38 % where access to testing was available, with no recurrent genetic cause being found. Our PVNH cohort data suggest that PVNH could be classified in three main groups: FLNA-associated "classic" bilateral frontocentral PVNH, posterior/infrasylvian PVNH and this third pattern of bilateral frontal PVNH, accounting for ∼10 % of all cases of PVNH. Show less

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a prevalent inflammatory disorder characterized by nasal obstruction and polyp formation. Despite its prevalence, the complex pathogenesis of CRSwNP remains not fully understood, hindering the development of effective treatments. This study aims to delineate the immunological landscape of CRSwNP by integrating single-cell RNA sequencing (scRNA-seq) and Mendelian randomization (MR) approaches. We conducted a systematic MR analysis using summary statistics from genome-wide association studies (GWAS) and expression quantitative trait loci (eQTL) data. The identified genes were further scrutinized through scRNA-seq analysis of CRSwNP tissues to assess cell-specific expression patterns. Pathway enrichment and protein-protein interaction (PPI) network analyses were performed to explore the biological mechanisms underlying CRSwNP. The MR analysis identified several genes, including HLA-DRB1, HLA-DQA1, and HLA-DQB1, as significantly associated with CRSwNP. The scRNA-seq analysis validated these findings, revealing cell-specific enrichment in basal cells. Notably, these genes were found to be involved in immune cell recruitment and the reshaping of the immune microenvironment. Furthermore, the study highlighted the role of genes like TCF7L1, KANSL1-AS1, and POLR2J3, which showed contrasting expression patterns and potential regulatory roles in CRSwNP. This integrative study provides novel insights into the molecular and cellular underpinnings of CRSwNP. The identified genes and their role in immunopathogenesis offer potential therapeutic targets and highlight the importance of cell-specific gene expression in disease mechanisms. The combination of MR with scRNA-seq represents a powerful approach to elucidate complex traits and may pave the way for precision medicine in CRSwNP management. Show less

To investigate the genetic causality between Human blood cell (HBC) traits and sporadic lymphangioleiomyomatosis (sLAM) by mediation joint multi-omics and eQTL Mendelian randomization analysis. Quality control processes were followed to select eligible instrumental variables strongly associated with 35 kinds of HBC traits. Independent cohort of European ancestry with sLAM and lung function genome-wide association study (GWAS) summary statistics were used separately. We utilized a two-step MR approach to explore potential mediators and evaluate the proportion of effect mediated in the associations linking HBC trait candidates to sLAM. Finally MR analysis integrating single cell expression quantitative trait loci (sc-eQTL) from 14 immune cell types with GWAS of sLAM was conducted. Increased level of basophil count was positively associated with higher risk of sLAM (BASO#; OR = 3.878, 95%CI:1.137–13.221, For the first time, this study leverages mediation analysis and multi-omics MR integrated with sc-eQTL data to elucidate the roles of HBC traits, immune cells, inflammatory proteins, VEGF-related proteins and immune cell-specific genes in the pathogenesis of sLAM among the European populations. The online version contains supplementary material available at 10.1186/s13023-026-04224-6. Show less

Congenital heart defects represent a major global health burden, affecting nearly one million newborns annually. Identifying the underlying genetic causes is essential for improved diagnosis, patient management, and genetic counseling. We conducted a cytogenetic study integrating conventional karyotyping, fluorescence in situ hybridization (FISH), and chromosomal microarray analysis (CMA 44 K) in 20 Tunisian patients presenting syndromic CHDs and referred to our Genetics Department. CMA identified pathogenic copy number variations in four patients. These included an inherited 11 Mb deletion at 9p24.2 together with a 10 Mb duplication of 20pter; a de novo 1.2 Mb deletion at 15q26.2 with an 11 Mb duplication at 2q36.3; a de novo 113 kb deletion at 17q21.32; and a de novo 48 Mb duplication at 8q22. Several CNVs overlapped known deletion/duplication syndromes, some with previously infrequent cardiac involvement. Genotype-phenotype correlations enabled prioritization of CHD relevant genes including DOCK8, HTR2B, KANSL1, ZFPM2, and TRPS1, whose dosage sensitivity and interactions with cardiac developmental pathways may contribute to the observed phenotypes. This study reinforces the clinical utility of CMA in detecting cryptic chromosomal abnormalities in syndromic CHD. The identified CNVs and gene candidates offer new insights into CHD genetic architecture and support CMA as a first-tier diagnostic tool. These findings highlight the contribution of rare, pathogenic CNVs in syndromic cases and suggest their integration into refined diagnostic and counseling strategies. Further functional studies are necessary to elucidate the roles of these candidates in cardiogenesis. Show less

Sertoli cells are well known as crucial orchestrators in guaranteeing normal spermatogenesis and male fertility. Circular RNA (circRNA) has increasingly been identified within spermatogenesis-related cells, attributed with key regulatory roles. However, the functions and mechanisms of circRNAs in spermatogenesis remain largely unexplored, particularly in domestic animals. The present study was conducted to explore the regulatory and functional roles of circKANSL1, a nucleus enriched circRNA, in proliferation and apoptosis of immature porcine Sertoli cells. The circKANSL1 was confirmed as a novel, stable, nucleus-enriched circRNA in immature porcine Sertoli cells using reverse transcription PCR, Sanger sequencing assays, and fluorescence in situ hybridization assays. Overexpression of circKANSL1 facilitated cell cycle progression, enhanced cell proliferation, and inhibited cell apoptosis in immature porcine Sertoli cells. Transcriptome analysis revealed 248 differentially expressed genes that were induced by circKANSL1 overexpression, and the parental gene KANSL1 of circKANSL1 was detected as a top one up-regulated gene. Mechanistically, circKANSL1 recruited the Vimentin protein to enhance its parental gene KANSL1 expression. Furthermore, siRNA-induced KANSL1 gene knockdown exhibited an opposite effect to that of circKANSL1 overexpression. Collectively, our findings provided a novel functional mechanism of circRNA in participating spermatogenesis through deciding the fate of Sertoli cells. Show less

Tau neurofibrillary tangles are a hallmark of several neurodegenerative diseases called tauopathies, including frontotemporal dementia and Alzheimer's Disease. Ongoing clinical trials for tauopathies seek to reduce Tau in the brain through immunotherapy, antisense oligonucleotides, and siRNA. Show less

The prevalence of Type 2 diabetes mellitus (T2DM) is rapidly increasing in India, yet molecular markers that reflect early disease susceptibility remain limited. Epigenetic modifications such as DNA methylation may reflect early metabolic vulnerability preceding overt dysglycemia. In this study, we examined genome-wide DNA methylation patterns in a pilot subset nested within a prospective Indian cohort using Nanopore sequencing and assessed their associations with previously identified metabolite predictors from the same cohort. Genome-wide DNA methylation profiling was performed on buffy-coat DNA from 12 participants who were normoglycemic at baseline and later classified into normoglycemia, prediabetes, or T2DM based on their glycemic status at 6-year follow-up. At baseline, gene-level aggregation of CpG methylation revealed directionally consistent hypermethylation of seven genes (ABCG1, ADARB2, BCL2, DLC1, EGFLAM, SYK, ZNF516) in individuals who later developed T2DM, while those progressing to prediabetes exhibited six hypermethylated (ABCG1, FLT3, LCP1, MBP, NCOA2, TCF7L2) and five hypomethylated genes (ZFHX3, PAX6, PTPRN2, ERC1, HIPK1). ABCG1 showed consistent hypermethylation across both groups. Longitudinal within-individual comparisons identified additional gene-associated methylation changes, including ANK1, IQSEC1, and RUNX1, and shared alterations in CACNA1C, KANSL1, PTPRN2, and TTC34, while six genes showed stage-dependent directional shifts in methylation (ASB3, EFR3A, PCSK5, KLHL14, PDE4C, UNC5C). Correlation analyses at baseline suggested associations between ABCG1 and EGFLAM methylation, fasting glucose, phosphatidylethanolamine [PE (20:3₁₈:0)] and insulin sensitivity indices. This pilot longitudinal study suggests that gene-associated DNA methylation changes in blood may be detectable prior to the onset of dysglycemia. These findings are exploratory and hypothesis-generating, highlighting candidate genes and epigenetic-metabolic associations for targeted validation in larger, independent cohorts using alternative analytical approaches. Show less

Neurodevelopmental disorders (NDDs) exhibit complex genotype-phenotype associations that frequently result in inconclusive variant interpretations, contributing to suboptimal diagnostic yields (~ 40%). Koolen-de Vries syndrome (KdVS), an autosomal dominant NDD caused by KANSL1 haploinsufficiency, exemplifies this diagnostic challenge with its multisystem manifestations and lack of systematic genotype-phenotype associations. To address this gap, we constructed a comprehensive KdVS genotype-phenotype repository by systematically integrating all molecularly confirmed cases from global literature. Comprehensive phenotypic analysis revealed that core KdVS features include developmental delay/intellectual disability, characteristic craniofacial dysmorphism, hypotonia, and multisystem abnormalities. Phenotypic association analysis identified 249 significant correlations, demonstrating that KdVS clinical manifestations are highly interconnected rather than representing isolated features, such as the association between strabismus and hydrocephalus (OR = 14.26). Application of this repository to screen a Chinese rare disease cohort identified 53 KANSL1 variants. Among these, one de novo nonsense variant (NM₀₀₁₁₉₃₄₆₆.2: c.902T > G, p.Leu301Ter) was classified as pathogenic in a Chinese boy with classic KdVS features. The remaining 52 variants were categorized as variants of uncertain significance (VUS), approximately half of which were absent from gnomAD databases. Each VUS was comprehensively annotated with detailed clinical profiles to facilitate phenotype-driven reinterpretation. In conclusion, this study establishes KdVS as a highly interconnected multisystem disorder and demonstrates that deep phenotypic association analysis enhanced genetic diagnosis. This disease-specific repository approach provides a scalable framework for improving molecular diagnostics across rare NDDs. Show less

Congenital anomalies of the kidney and urinary tract (CAKUT) represent a major health burden in humans. Phenotypes range from renal hypoplasia or renal agenesis, cystic renal dysplasia, duplicated or horseshoe kidneys to obstruction of the ureteropelvic junction, megaureters, duplicated ureters, urethral valves or bladder malformations. Over the past decade, next-generation sequencing has identified numerous causative genes; however, the genetic basis of most cases remains unexplained. It is assumed that environmental factors have a significant impact on the phenotype, but, overall, the pathogenesis has remained poorly understood. Interestingly however, CAKUT is a common phenotypic feature in two human syndromes, Kabuki and Koolen-de Vries syndrome, caused by dysfunction of genes encoding for KMT2D and KANSL1, both members of protein complexes playing an important role in histone modifications. In this chapter, we discuss current knowledge regarding epigenetic modulation in renal development and a putatively under-recognized role of epigenetics in CAKUT. Show less

Sjögren's Syndrome (SS) and Type 1 Diabetes (T1D) are autoimmune disorders that can co-occur in patients, leading to complex clinical presentations. Despite observational evidence of their co-occurrence, the underlying genetic mechanisms remain poorly understood. To investigate the shared genetic factors and pathways between SS and T1D, we conducted a comprehensive analysis using multiomic approaches. Conditional and conjunctional false discovery rate analyses were performed to identify genetic polygenicity and overlap between the two diseases. Functional annotation and pathway analysis identified SNPs with regulatory potential. Furthermore, Mendelian Randomization (MR) analyses were employed to investigate causal associations between gene expression and disease risk. Single-cell differential gene expression analysis was also employed to validate the associations of risk genes with T1D and SS. Our analysis identified 36 shared loci, revealing common genetic enrichment between SS and T1D. Functional annotation and pathway analysis revealed 52 credible genes involved in cysteine-related processes, apoptotic signalling and immune responses. MR analyses revealed that AC007283.5 was positively linked with both SS and T1D, while PLEKHM1 and CRHR1-T1 were negatively associated. Additionally, CERS2 was positively associated with SS, DEF6 was positively associated with T1D, and KANSL1-AS1 was negatively associated with T1D, indicating the presence of complex regulatory mechanisms. Moreover, Single-cell differential gene expression analysis confirmed the dysregulation of risk genes in SS and T1D. This study identified shared genetic factors and pathways underlying SS and T1D, highlighting cysteine-related processes and apoptotic signalling. The findings underscore the complex interplay of autoimmunity and the need for targeted treatments addressing their common mechanisms. Show less

The molecular pathogenesis of lung adenocarcinoma (LUAD) involves genomic mutations, autophagy dysregulation, and signaling pathway disruptions. Autophagy, a key cellular process, is tightly linked to cancer development; genes like ATG5 and ATG10 influence lung cancer progression, and epigenetic regulators modulate autophagy-related carcinogenesis. However, the role of epigenetic-autophagy genes in LUAD's tumor microenvironment is under-researched. We used the "limma"" package to identify differential epigenetic-related genes associated with altered autophagy regulation (A-ERGs) in LUAD. Single-cell RNA sequencing was further employed to evaluate the heterogeneity of immune cells. Machine learning algorithms were utilized to construct and identify diagnostic markers for LUAD, which were then validated by receiver operating characteristic (ROC) curve analysis. Cell experiments, real-time PCR, and Western blot were conducted to verify the expression of KDM6B and KANSL1 and their effects on T-cell differentiation. Based on single-cell and transcriptome analyses, we screened 19 A-ERGs that were significantly differentially expressed in lung cancer tissues. These genes were primarily enriched in exhausted T cells. Subsequently, through machine learning, KDM6B and KANSL1 were identified to have excellent diagnostic performance. Single-cell level and transcriptome correlation analyses revealed that the expression of these two genes was associated with exhausted T cells. Results from In this study, we utilized bulk and single-cell transcriptomic data to uncover the potential molecular mechanisms of A-ERGs in lung cancer. We explored the characteristic distribution of these genes in the tumor immune microenvironment and identified two A-ERGs, KDM6B and KANSL1, as potential diagnostic biomarkers for lung adenocarcinoma (LUAD). Our findings offer novel strategies for targeted therapeutic interventions in LUAD. Show less

Although the human cerebellum is known to be neuropathologically impaired in Alzheimer's disease (AD) and AD-related dementias (ADRD), the cell type-specific transcriptional and epigenomic changes that contribute to this pathology are not well understood. Here, we report single-nucleus multiome (snRNA-seq and snATAC-seq) analysis of 103,861 nuclei isolated from both cerebellum and frontal cortex of AD/ADRD patients and normal controls. Using peak-to-gene linkage analysis, we identified 431,834 significant linkages between gene expression and cell subtype-specific chromatin accessibility regions enriched for candidate cis-regulatory elements (cCREs). These cCREs were associated with AD/ADRD-specific transcriptomic changes and disease-related gene regulatory networks, especially for RAR Related Orphan Receptor A (RORA) and E74 Like ETS Transcription Factor 1 (ELF1) in cerebellar Purkinje cells and granule cells, respectively. Trajectory analysis of granule cell populations further identified disease-relevant transcription factors, such as RORA, and their regulatory targets. Finally, we pinpointed two likely causal genes, Seizure Related 6 Homolog Like 2 (SEZ6L2) in Purkinje cells and KAT8 Regulatory NSL Complex Subunit 1 (KANSL1) in granule cells, through integrative analysis of cCREs derived from snATAC-seq, genome-wide AD/ADRD loci, and three-dimensional (3D) genome data. Via CRISPRi experiments, we found that perturbation of rs4788201 and rs62056801 significantly inhibited the expression of their target genes, SEZ6L2 and KANSL1, in human iPSC-derived neurons. This cell subtype-specific regulatory landscape in the human cerebellum identified here offers novel genomic and epigenomic insights into the neuropathology and pathobiology of AD/ADRD and other neurological disorders if broadly applied. Show less

Complex diseases arise from the interplay of genetic and environmental factors. We present a case where complex diseases seem to coexist. A 12-month-old girl was referred for short stature and hypotonia. Initial evaluation revealed central hypothyroidism, growth hormone deficiency and a small pituitary gland with ectopic neurohypophysis. Replacement therapy improved growth, but developmental delay and strabismus ensued. At age 10, she experienced a first seizure treated with levetiracetam. At age 12, she presented diabetic ketoacidosis and functional insulin therapy was started; positive autoantibodies confirmed autoimmune etiology. Initial genetic testing performed by microarray analysis retrieved normal results, but exome sequencing revealed a heterozygous pathogenic variant in KANSL1 gene, allowing for the diagnosis of Koolen-de Vries syndrome. In this patient, Koolen-de Vries syndrome presented initially as hypopituitarism and only later epilepsy. Afterwards, type 1 diabetes mellitus ensued, highlighting the complexity of intertwined conditions. Show less

Although studies have suggested a potential link between the nervous system and prostate cancer, the underlying regulatory mechanisms remain unclear. Therefore, it is crucial to identify the genes involved in regulating prostate cancer within the nervous system. We utilized eQTL data from eight neural cell types as exposure factors and GWAS data for prostate cancer as outcome events. Mendelian randomization (MR) analyses were performed to identify causative genes associated with prostate, bladder, and renal cancers in Astrocytes, Endothelial cells, Excitatory neurons, Inhibitory neurons, Microglia, Oligodendrocytes, OPCs/COPs, and Pericytes. Bladder and renal cancers were used as controls. Sensitivity analyses (heterogeneity, pleiotropy, and leave-one-out tests) were conducted to ensure reliability. In astrocytes, seven positive genes were identified as being causally related to prostate cancer: KANSL1, AC005670.2, ARL17B, LRRC37A2, LRRC37A, MAPT, and LINC02210. In. Endothelial cells, Inhibitory neuron and Microglia, three genes (LRRC37A2, ARL17B, and KANSL1) were identified as risk genes that are associated with prostate cancer. Four protective genes were identified in excitatory neurons, including LRRC37A2, ARL17B, KANSL1 and LINC02210. In oligodendrocytes, eight genes were identified, with LRRC37A2, ARL17B, and KANSL1 acting as protective factors, while OR2L13, OR2L3, OR2L5, OR2L2, and OR2M4 were identified as risk factors. Additionally, sensitivity analyses showed no heterogeneity or horizontal pleiotropy in the MR results, confirming their reliability and stability. In addition, no positive genes were found in bladder cancer and renal cancer. Our study highlights the role of the nervous system, particularly astrocytes, in regulating prostate cancer. We identified three genes, with LRRC37A2, ARL17B, and KANSL1 emerging as key protective factors. These findings provide potential targets for prostate cancer diagnosis and treatment. The online version contains supplementary material available at 10.1007/s12672-025-03711-9. Show less

The 17q21.31 locus in humans harbors several complex structural haplotypes including a ~970kb inversion. Different inversion haplotypes have been associated with susceptibility to microdeletions causing Koolen-de Vries syndrome and variation in fecundity and recombination rates. Here, using 210 haplotype-resolved human genome assemblies and pangenome graph-based approaches we characterize 11 distinct structural haplotypes, several of which have not been previously described. Extending our analyses to a set of haplotype-resolved great-ape genomes, we characterize the structure of an independent inversion in chimpanzees which extends an additional 650kb, encompasses 5 additional genes, and is ~2 million years younger than the human inversion. We further determine that gorillas exhibit an independent duplication of the Show less

Progressive supranuclear palsy (PSP) is mainly a sporadic disease. It has a multifactorial etiology and an interaction between environmental and genetic factors causes disease. While elucidation of environmental risks for PSP is still in its infancy, much has been learned about the genetic etiological component of PSP during the past few years. This article reviews genes that convey risk for PSP. All genes have been identified in association studies. Only those genes with the standard threshold for genome-wide significance of P < 5E-8 are covered. These genes include MAPT, KANSL1, PLEKHM1, STX6, MOBP, EIF2AK3, SLC01 A2, DUSP10, APOE, RUNX2, TRIM11, NFASC/CNTN2 and LRRK2. The physiologic function of these genes is described and their potential role in the etiology of PSP is discussed. Show less

Congenital heart disease (CHD) is the most common type of birth defects in humans. Genetic factors have been identified as an important contributor to the etiology of CHD. However, the underlying genetic causes in most individuals remain unclear. Here, 101 individuals with CHD and their unaffected parents were included in this study. Chromosomal microarray analysis (CMA) as a first-tier clinical diagnostic tool was applied for all affected individuals, followed by trio-based whole exome sequencing (WES) of 76 probands and proband-only WES of 3 probands. We detected aneuploidies in 2 individuals (trisomy 21 and monosomy X), 21 pathogenic and likely pathogenic copy number variants (CNVs) in 19 individuals, and pathogenic and likely pathogenic SNVs/InDels in 8 individuals. The combined genetic diagnostic yield was 28.7%, including 20.8% with chromosomal abnormalities and 7.9% with sequence-level variants. Eighteen CNVs in 17 individuals were associated with 13 recurrent chromosomal microdeletion/microduplication syndromes, the most common being 22q11.2 deletion syndrome. Pathogenic/likely pathogenic sequence-level variants were identified in 8 genes, including GATA6, FLNA, KANSL1, TRAF7, KAT6A, PKD1L1, RIT1, and SMAD6. Trio sequencing facilitated the identification of pathogenic variation (55.6% were de novo missense variants). In individuals with extracardiac features, the overall detection rate was significantly higher (61.5%) than in individuals with isolated CHD (17.3%) (P = 4.6 × 10 Show less

Developmental and epileptic encephalopathies (DEEs) comprise a diverse range of disorders that can arise from both genetic and non-genetic causes. Genetic DEEs are linked to pathogenic variants in various genes with different molecular functions. The wide clinical and genetic variability found in DEEs poses a considerable challenge for accurate diagnosis even with the use of comprehensive diagnostic approaches such as whole genome sequencing (WGS). In this study, we describe a girl with a clinical presentation of DEE. Using WGS, we identified several candidate variants in the HNRNPU, NIPBL, and KANSL1 genes with partial overlap with the patient's clinical presentation. Subsequent analysis revealed that only the variant in the HNRNPU gene arose de novo, while the others were inherited from unaffected parents. The variant in HNRNPU was determined to be causative. However, the previously reported pathogenic loss-of-function (LoF) variant in KANSL1, inherited from a healthy mother, complicated the interpretation of the results. A thorough investigation using RNA analysis showed that the variant in the KANSL1 gene is located in a duplicated locus, which does not produce a functional protein, explaining the lack of the variant's contribution to the development of the pathological phenotype. This case illustrates the importance of integrating WGS with additional analyses to accurately diagnose and understand the molecular basis of the lack of influence of the LoF variant in KANSL1 on the patient's phenotype. Show less

Koolen-de Vries syndrome (KdVS) is a rare multisystem genetic disorder due to deletions in the KANSL1 gene. The most common type of seizure documented in these patients is focal impaired consciousness seizure (FICS). These seizures present with difficult-to-distinguish characteristics, including autonomic symptoms, brief loss of consciousness, and post-ictal confusion. The ambiguity of this presentation can make it difficult to detect clinically. This case presents an eight-year-old male child with KdVS who presented to the clinic with complaints of increased outbursts, spatial disorientation, issues with mood and self-regulation, and episodes of "spacing out" as noted by his teacher. The initial diagnosis was dysautonomia and was conservatively managed. However, due to worsening neurocognitive outcomes, neurological referral and work-up were initiated to further elucidate the etiology of his symptoms. The patient's electroencephalography (EEG) findings showed frequent focal sharp waves consistent with FICS. He was then treated accordingly with diazepam and amantadine, which led to a significant improvement in neurological status. This case highlights the importance of the use of EEG in KdVS patients, as well as the implications of implementing guidelines recommending the low threshold required for use of EEG and full neurological work-up for patients with any alarm symptoms possibly indicative of FICS or other epileptiform activity. Show less

Primary open-angle glaucoma is the most common form of glaucoma worldwide and one of the leading causes of irreversible blindness. Current therapies focus on intraocular pressure control despite substantial evidence on the importance of additional pathogenic mechanisms involved in neuronal repair and regeneration. Some of these mechanisms may be shared with and across other neurodegenerative disorders, such as Alzheimer's disease. Joint analyses that address this pathogenic overlap can be leveraged to identify suspected neurodegenerative and neuroprotective pathways. In this study, we derived gene-level summary statistics from available genome-wide association studies for primary open-angle glaucoma and Alzheimer's Disease and employed a multivariate analysis to identify genes with an effect on both neurodegenerative diseases. We assessed the influence of the prioritized genes using Mendelian randomization to obtain the effect of retina- and brain cortex-specific gene expression on primary open-angle glaucoma risk. We identified ten genes with evidence of a pleiotropic effect on primary open-angle glaucoma and Alzheimer's disease: TMCO1, ANXA11, ARHGAP27, PLEKHM1, CRHR1, KANSL1, LRRC37A, ARL17A, LRRC37A2, and CBY1. Additionally, gene expression in either the retina or brain cortex of TMCO1, ANXA11, ARHGAP27, PLEKHM1, KANSL1, LRRC37A, ARL17A, LRRC37A2, and CBY1 influenced POAG risk. These genes have known roles in neurodegeneration-associated pathways. Our analysis uncovered evidence of pleiotropy and gene expression as a mechanism impacting disease risk. Further investigation into these genes may yield valuable insights into their involvement in neurodegenerative pathways potentially informing new approaches for early detection, classification, and treatment strategies. Show less

Parkinson's disease (PD) is a complex neurodegenerative disease that involves many interlinking pathways and genetic elements that remain to be fully understood and characterised. Non-coding genetic elements have long been overlooked, however recent advancements in the field have highlighted their importance with an area of interest being transposable elements. SINE-VNTR-Alu (SVA) elements are the youngest and smallest subset of retrotransposons that are only found within hominid species. SVAs have been shown to have strong regulatory impacts within our genome and can affect progression of neurodegenerative disease such as PD. Previous studies identified an SVA, polymorphic for its presence/absence, that was associated with changes in gene expression at the Show less

Pre-pregnancy obesity (ppOB) is linked to pregnancy complications and abnormal fetal growth through placental mechanisms, and long non-coding RNAs (lncRNAs) may play an epigenetic role in these processes. We investigated overall and sex-specific associations of pre-pregnancy body mass index (ppBMI), ppOB, and birthweight with placental lncRNA transcripts in two birth cohorts. Study participants were mother-child dyads recruited to the CANDLE (Memphis, TN)( Show less