Inborn errors of immunity (IEI) impairing brain-intrinsic immune defenses can underlie herpes simplex virus encephalitis. By whole-exome sequencing of cohorts of herpesvirus-associated recurrent lymphocytic meningitis and acute retinal necrosis, we identified two patients heterozygous for variants in interferon (IFN) regulatory factor 7 (IRF7). The expression of the Q185X (patient 1, P1) and A86Rfs23X (P2) IRF7 variants in HEK293T cells resulted in truncated IRF7 proteins that lacked IFN-transactivating ability. Peripheral blood mononuclear cells from P1 exhibited reduced type I IFN responses to HSV-2 infection. Genetic knock-in of the IRF7 Q185X variant in THP-1 cells and stem cell-derived plasmacytoid dendritic cells (pDC) confirmed the disrupted IFN expression, resulting in impaired paracrine antiviral protection of meningeal fibroblasts. Strikingly, genetically heterozygous index patient pDC, but not those of healthy carrier family members, showed expression of only the pathogenic IRF7 Q185X allele, resulting in a homozygous transcriptotype. Collectively, this study identifies genetically heterozygous but transcriptionally homozygous IRF7 deficiency as an IEI underlying herpesvirus central nervous system infection.

Comparing the performance of exome and genome sequencing for rare disease diagnostics: A randomized implementation effectiveness trial.

Introduction: Charcot-Marie-Tooth disease (CMT) is one of the most common inherited Neuromuscular Disorders (NMDs), classified under peripheral neuropathies and characterised by progressive motor and sensory dysfunction. Although Wholeexome Sequencing (WES), gene panels, and conventional methods have improved detection rates, they often miss deep intronic, regulatory, and Structural Variants (SVs). Wholegenome Sequencing (WGS), with its comprehensive coverage of coding and non coding regions, enables the identification of variants that are often overlooked by other approaches. Aim: To assess the diagnostic utility of WGS in CMT cases that remain unresolved by WES, analysing both coding and non coding variants. Materials and Methods: The present cross-sectional diagnostic study was conducted between July 2023 and January 2025 at the Neuberg Center for Genomic Medicine (NCGM), Ahmedabad, Gujarat, India. WGS was performed on 31 clinically suspected CMT patients, including two who had previously tested negative by WES. Both coding and non coding variants including missense, nonsense, frameshift, in-frame, intronic, and 5’ Untranslated Region (UTR) mutations were analysed. Variants were classified according to American College of Medical Genetics and Genomics (ACMG) guidelines, incorporating Combined Annotation Dependent Depletion (CADD) scores and Minor Allele Frequency (MAF) thresholds. They were interpreted based on pathogenicity, inheritance patterns, and genotypephenotype correlations. Selected non coding variants in the Gap Junction Beta-1 (GJB1; c.-16-511G>C) and Lamin A/C (LMNA; c.-142C>A) genes were validated by Sanger sequencing. Results: Sequencing data from 31 participants were processed using a standardised bioinformatics pipeline. Variants were classified according to ACMG guidelines, and their frequencies were calculated. WES and WGS results were compared to determine the additional diagnostic yield. WGS identified clinically significant non coding variants in GJB1 (intronic) and LMNA (5’ UTR) in two cases, yielding a 6.5% increase over WES. Overall, 31 variants were detected: 11 (35.5%) classified as pathogenic, 2 (6.5%) as likely pathogenic, and 18 (58.0%) as Variants of Uncertain Significance (VUS), reflecting the genetic heterogeneity of CMT. Conclusion: The WGS enhances diagnostic accuracy in CMT by detecting clinically relevant non coding variants often missed by WES. This is the first report from India confirming a GJB1 intronic variant and a Lamin A/C (LMNA) 5´ UTR variant using WGS in CMT patients. These findings support the integration of WGS into routine diagnostic workflows and highlight the value of comprehensive variant analysis for early and precise genetic diagnosis.

Sample tracking in whole exome sequencing.

An infant initially suspected to have glutaric aciduria was later diagnosed with Cantu syndrome and found to be a carrier of Congenital Disorder of Glycosylation Type 1j. This case involved a five-month-old male infant with Atrial Septal Defect (ASD) and Patent Ductus Arteriosus (PDA) who was under treatment and admitted with a history of recurrent respiratory tract infections, developmental delay, and dysmorphic facies. A metabolic workup was performed. Computed Tomography (CT) brain showed features suggestive of glutaric aciduria; however, MRI brain revealed tortuosity of the cerebral vessels, which was inconsistent with that diagnosis. Hence, Whole Exome Sequencing (WES) was performed. The WES revealed a pathogenic variant in the ABCC9 gene, which is pathognomonic of Cantu syndrome. It also showed a pathogenic variant in the DPAGT1 gene, diagnostic of Congenital Disorder of Glycosylation Type 1j. This is the first reported case in which both mutations were identified in the same patient. WES was subsequently performed for the parents, and the infant’s father was found to have heterozygous pathogenic variants in both genes identified in the proband. This study emphasises the importance of genetic sequencing in establishing an early and accurate diagnosis, thereby enabling disease-specific novel treatment approaches and long-term follow-up.

Ocular Manifestations of ROSAH Syndrome Caused by Different Mutations of the ALPK1 Gene.

Cribriform Tumor of the Skin: Identification of 6q and 9q Loss as a Recurrent Cytogenomic Alteration.

PIGA variants are associated with focal epilepsy with favorable outcome and the sub-molecular effect.

Alagille syndrome (ALGS) is a rare autosomal dominant disorder with several clinical manifestations including facial, hepatic, cardiovascular, skeletal, and renal complications. ALGS is a result of pathogenic variants in either JAG1 or NOTCH2 genes, which lead to the disruption of the Notch signaling pathway. Here, we present the case of a 17-year-old female patient, clinically and genetically diagnosed with ALGS1. The 17-year-old patient, with an ALGS-free family history, was clinically diagnosed with ALGS due to liver dysfunction, cholestasis, kidney cysts, distinct craniofacial features, and skeletal malformations. Following genetic counseling and parental informed consent, genomic DNA was extracted from a sample of peripheral blood. Subsequently, whole-exome sequencing analysis was conducted, and clinically significant findings were additionally confirmed through Sanger DNA sequencing. The genetic analysis revealed the presence of a likely pathogenic donor splice variant (c.2372+1G>C) in heterozygosity with the normal allele in the JAG1 gene at intronic position 1 of 493 (affecting splicing, MAF<0.01), which was validated by Sanger sequencing. Bioinformatic analysis indicated that the detected donor splice variant may disrupt spliceosome recognition of the canonical splice site and lead to exon skipping. Based on the clinical picture, personal/family history and genetic analyses, the patient was diagnosed with autosomal dominant ALGS type 1, caused by a de novo pathogenic mutation in the JAG1 gene. It is the first time this variant has been described in the relevant literature.

Job's not done: BCG-itis as the first manifestation of hyper-IgE syndrome. A case report and review of the literature.

We present a case series describing the management and genetic findings in five neonates with meconium ileus, presenting within 48 h of birth. Whole-exome sequencing identified cystic fibrosis transmembrane conductance regulator mutations in three neonates, confirming cystic fibrosis, with one heterozygous variant of unknown significance. Two ultimately required surgical intervention after failed conservative management. One died of septic shock.

Identification of a novel de novo NONO variants causing X-linked syndromic intellectual developmental disorder-34 in a fetus.

Genotypic and phenotypic characterization of critical pediatric cardiomyopathy: A 20-patient cohort study.

Whole exome sequencing analysis of suicidal thoughts and behaviors in a veteran cohort implicates inflammatory pathways and genes previously associated with psychiatric and neurodegenerative diseases.

Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent hereditary kidney disorder. Between 85% and 90% of cases result from variations in the PKD1 and PKD2 genes. Over 30 genes have been associated with ADPKD, contributing to its heterogeneity. This study aimed to investigate novel variations in the PKD1, PKD2, and ADPKD-related genes through whole-exome sequencing (WES) and combine the genotype and phenotype data of the patients. WES was performed on peripheral blood samples from 44 ADPKD patients, and variations were evaluated and classified based on ACMG criteria. A heterozygous pathogenic/likely pathogenic (P/LP) PKD1 variant was identified in 33 patients (75%). Seven patients had a heterozygous P/LP PKD2 variant (15.9%). No heterozygous P/LP PKD1 or PKD2 variant was found in 4 patients (9.1%), and one of them (2.3%) had a heterozygous pathogenic PKHD1 variant. Thirteen novel PKD1 variations were identified, with nine associated with fast estimated glomerular filtration rate (eGFR) decline. Potentially pathogenic Variants of Uncertain Significance in ALG9, CEP290, NPHP4, WDR19, and TTC21B were identified in three patients lacking PKD1/PKD2 variants. Survival analysis indicated that patients with PKD1 or PKD2 or without any PKD1/PKD2 mutations experienced a similar age of onset for end-stage kidney disease. The annual decline in eGFR was significantly higher in patients with a PKD1 mutation than in those with a PKD2 mutation, along with a higher Mayo Class. Genetic studies evaluating novel variants in the PKD1, PKD2, and ADPKD-related genes alongside patients’ clinical data are essential for a deeper understanding of ADPKD diagnosis, prognosis, and pathology.

Purpose To evaluate the prognostic role of pan-immune-inflammation value (PIV) in patients with oesophageal squamous cell carcinoma (ESCC) receiving chemoradiotherapy (CRT) combined with anti-programmed cell death 1 (PD-1) immunotherapy, and to explore the underlying mechanisms and dosimetric parameters that affect PIV zenith. Methods In this pooled analysis, 86 patients from two phase II trials who received toripalimab plus CRT were analysed. PIV was calculated as follows: (neutrophil count × platelet count × monocyte count)/lymphocyte count. The optimal cut-off value was determined using the receiver operating characteristic curve. Survival analysis was conducted using the Kaplan–Meier method and Cox regression models. Univariate and multivariable logistic regression analyses identified predictors of high PIV zenith. Pretreatment tumour samples from 46 patients were subjected to RNA and whole-exome sequencing (WES). Gene set enrichment analysis was performed on RNA sequencing (RNA-seq) data, and somatic mutations were assessed using WES to further explore molecular correlates. Results Significant changes in immuno-inflammatory biomarkers were observed during CRT, which gradually normalized post-radiotherapy. After a median follow-up of 35.5 months, patients with high PIV zenith during CRT exhibited significantly poorer progression-free survival (p = 0.007) and overall survival (p = 0.015). In multivariable analysis, high PIV zenith remained a significant prognostic indicator for survival. Mean lung dose (MLD) was identified as an independent predictor of high PIV zenith. Patients with high PIV zenith had decreased interferon α response, interferon γ response, transforming growth factor-β signalling and more frequent mutations in the Hippo pathway genes, resulting in pathway downregulation. Conclusions High PIV zenith during CRT strongly predicts poorer survival outcomes in patients with ESCC treated with combined immunotherapy and CRT. These peaks are associated with higher MLD, reduced interferon α response, interferon γ response and increased prevalence of Hippo pathway mutations.

Background Bladder cancer (BLCA) is a prevalent malignancy with substantial consequences for patient health. This study aimed to elucidate the underlying mechanisms of BLCA through integrated multi-omics analysis. Methods Tumor and adjacent tissues from BLCA patients underwent transcriptomic, whole-exome sequencing, metabolomic, and intratumoral microbiome analyses. These data were integrated with public datasets to identify key genes, metabolites, and microorganisms. Molecular subtypes were defined by key gene expression and compared for pathways, immune profiles, mutations, immunotherapy response, and drug sensitivity. Prognostic relevance was validated in external cohorts. Single-cell sequencing was applied to reveal cellular localization of key genes. Results Three key genes (AHNAK, CSPG4, NCAM1), 90 metabolites, and two microbes (Sphingomonas koreensis, Rhodospirillaceae) were identified. Key genes negatively correlated with metabolites but not with microbes. BLCA samples were classified into two molecular clusters with distinct ECM organization, metabolic features, immune checkpoint expression, and therapeutic sensitivity. NCAM1 correlated positively with γδ T cells and negatively with M0 macrophages. Single-cell analysis revealed nine major cell types, with fibroblasts displaying the highest expression of key genes, particularly elevated AHNAK in specific fibroblast subtypes. Drug prediction and docking identified candidate compounds targeting these genes with stable binding potential. Conclusion This comprehensive multi-omics analysis links key genes, metabolites, and microbes to BLCA pathogenesis. Fibroblasts emerge as central regulators, while identified gene–metabolite interactions and microbial associations provide novel insights into tumor heterogeneity. These findings highlight potential biomarkers and therapeutic targets to support precision treatment in BLCA.

Background PAX2 is a key developmental gene, and its mutations are primarily associated with kidney and ocular anomalies, predominantly affecting children. This study aims to analyze the clinical manifestations and genetic characteristics of children with PAX2 mutations and to assess the functional impact of novel variants. Methods Clinical data were retrospectively reviewed in 10 children diagnosed with PAX2 mutations through whole-exome sequencing from a pediatric hereditary disease cohort database. AlphaFold 3 (AF3) was used for protein structural modeling. Novel variants were functionally assessed via HK-2 cell proliferation assays. Results The median age at initial presentation was 4.2 years (IQR 0–6.5). All 10 patients presented with proteinuria or microscopic hematuria. Nine had kidney dysplasia, and five progressed to stage 5 chronic kidney disease. Five patients had PAX2-related ocular abnormalities. Hepatic dysfunction and spermatic cord hydrocele were reported as potential novel phenotypes. A total of nine distinct PAX2 mutations were identified, including five novel variants. AF3 modeling revealed significant conformational disruptions in the novel variants, with root mean square deviation (RMSD) values ranging from 1.1 to 43.6 Å. Functional assays demonstrated that four novel variants significantly impaired the proliferative capacity of HK-2 cells. Conclusions This study characterizes five novel PAX2 variants with confirmed structural (RMSD 1.1–43.6 Å) and functional (HK-2 proliferation impairment) impacts, expanding both the mutational and phenotypic spectra in Chinese children. The findings highlight the association between PAX2 mutations and early-onset kidney disease with potential extrarenal involvement. Early genetic diagnosis and timely kidney-protective interventions are essential to improve outcomes.

ABSTRACT Background: Network control theory can quantify controllability to evaluate how altered transitions between brain states contribute to cognitive, emotional, and behavioural challenges. Childhood abuse, influenced by genetics, is associated with disrupted network function, though the exact control processes are not yet understood. Objective: This study aims to investigate the association between brain network controllability and childhood abuse experiences, and to elucidate its potential mediating role in the relationship among polygenic risk scores (PRS) for childhood abuse, childhood abuse experiences, and adult health outcomes. Methods: This study measured the controllability of functional brain networks, including both average and modal controllability, in a cohort of 214 young adults with varied histories of childhood abuse. Participants also completed psychological assessments, whole-exome sequencing, and the calculation of PRS for childhood abuse. This study investigate the association between brain network controllability and childhood abuse. Furthermore, a mediation model was performed to explore the potential mediating role of brain network controllability in the relationship between genetic risk, childhood abuse experiences, and adult health outcomes. Results: The controllability of the dorsal attention and sensorimotor networks, as well as the controllability of key ROIs within the sensorimotor, default mode, dorsal attention, visual, and control networks, demonstrated significant correlations with abuse scores. Despite no direct correlation between PRS and self-reported childhood abuse, indirect effects through the controllability of visual and control network regions were identified. The controllability of the left postcentral gyrus in the dorsal attention network mediated the relationship between childhood abuse and adult anxiety. Conclusions: This study reveals that brain network controllability is a pivotal factor, not only bridging PRS and childhood abuse but also serving as a potential mediator between childhood trauma and adult anxiety, offering a new perspective on the neurobiology of childhood abuse-related psychopathology.

Genetic mutations are closely linked to various renal diseases, revealing important molecular mechanisms that contribute to kidney dysfunction. Here, we reported a 35-year-old Chinese female diagnosed of glomerulotubular nephropathy with multiple extra-renal manifestations including ptosis, corneal dystrophy, macular degeneration, right foot syndactyly. Whole-exome sequencing identified a homozygous frameshift variant in FAT1 (NM_005245: c.7444_7445delGT, p.Val2482AsnfsTer16). Further analysis revealed that this mutation caused translation repression of FAT1. RNA sequencing showed dysregulation of cell adhesion and Rap1 signaling pathways, while immunofluorescence staining demonstrated disrupted β-catenin junctions and cytoskeletal abnormalities in patient-derived primary urinary epithelial cells. Pull-down assays indicated that the reduction in activated Rap1 levels was correlated with the observed cellular defects. These findings provide compelling evidence that this loss-of-function homozygous FAT1 variant is causally associated with nephropathy and congenital anomalies, likely through degradation of transcribed mRNA and impaired protein expression. The results emphasize the critical role of FAT1 in renal development and provide new insights into the molecular mechanisms underlying these conditions.