A Novel NR3C1 Frameshift Variant Associated With Familial Glucocorticoid Resistance Syndrome: An Integrated Analysis of Steroid Profiling and Structural Modeling.

Novel truncating SF1 gene variant in a family with mild neurodevelopmental disorder: expanding the phenotype of SF1-related spliceosomopathy spectrum

The SF1 gene encodes the splicing factor 1, a part of the splicing machinery. Recently, loss-of-function (LoF) variants in the SF1 gene have been suggested as a molecular cause of a neurodevelopmental spliceosomopathy. We report a unique familial case of a novel truncating variant in a single Czech family presenting with mild neurodevelopmental disorders (NDD) and variable congenital abnormalities. The c.1764_1776del variant in the last exon of the SF1 gene (NM_004630.4) was identified through exome sequencing in three affected family members. Functional analyses at the transcriptional level confirmed that this alteration does not trigger nonsense-mediated decay (NMD), and aberrant transcripts with premature termination codons are preserved. This study expands the spectrum of pathogenic variants involved in the development of new SF1 -related spliceosomopathy and its diverse phenotypic effects. Our data emphasise the clinical benefits of comprehensive exome sequencing for uncovering new gene-disease connections.

Expanding the genetic landscape of SLC4A1-linked hereditary spherocytosis: discovery of a novel TM9 variant using high-resolution genomic profiling analysis

Introduction Hereditary spherocytosis (HS) is the most common inherited red cell membranopathy caused by defects in erythrocyte membrane and cytoskeletal proteins, including ankyrin, spectrin, band 3, and protein 4.2. Among these, mutations in SLC4A1, which encodes the erythrocyte anion exchanger band 3 (AE1), account for approximately 20–30% of HS cases and it is associated with distal renal tubular acidosis (dRTA), reflecting phenotypic and functional heterogeneity. Methods In this study, seven unrelated Indian patients with clinically suspected HS were investigated using detailed hematological, biochemical, and clinical evaluations along with eosin-5′-maleimide (EMA) binding assays. Molecular analysis was performed using targeted next-generation sequencing (t-NGS) covering 81 genes associated with red cell disorders, and the identified SLC4A1 variants were validated by Sanger sequencing. The structural and functional consequences of the variants were assessed through in silico tools including DynaMut, PolyPhen-2, and SIFT. Results Seven SLC4A1 variants were identified, including six previously reported variants and one novel variant, p.Phe702Ser, detected in heterozygous or compound heterozygous states. These variants were distributed across both cytoplasmic and transmembrane domains of the band 3 protein. Most patients presented with mild to moderate HS characterized by anemia, jaundice, splenomegaly, reticulocytosis, and reduced EMA fluorescence. One patient harboring compound heterozygous variants (p.Arg490His and p.Ala858Asp) exhibited HS associated with dRTA, highlighting the functional diversity of SLC4A1 mutations. The novel p.Phe702Ser variant, located in the transmembrane domain TM9, was predicted to destabilize AE1 structure and potentially impair anion transport. Discussion Marked intrafamilial phenotypic variability was observed despite identical genotypes. These findings expand the mutational spectrum of SLC4A1-related HS in Indian patients.

A Novel Dominantly Segregating PSMB10 Splice-Site Variant in Familial Autoinflammatory Disease with Immunoproteasome and Interferon-Related Dysregulation

Background: Systemic autoinflammatory phenotypes can clinically overlap with Familial Mediterranean Fever and other monogenic autoinflammatory diseases, yet some cases remain unclassified in the absence of pathogenic variants in MEFV or other related genes. In this study, we aimed to investigate the genetic and molecular basis of an unclassified autoinflammatory phenotype in a two-generation family comprising four affected members and one unaffected member. Methods: We performed whole-exome sequencing in all family members and prioritized variants according to rarity, predicted functional impact, segregation pattern, and biological relevance to inflammatory pathways. Downstream molecular analyses were performed using PBMCs from affected individuals and the unaffected family member. Results: Whole-exome sequencing identified a novel splice-site variant in PSMB10 (NM_002801; c.56+1G>A) affecting the canonical splice donor site. The variant segregated with the autoinflammatory phenotype and was associated with reduced full-length PSMB10 transcript levels in patient-derived PBMCs, supporting a predicted loss-of-function effect. Although pathogenic variants in PSMB10 have previously been implicated in proteasome-associated autoinflammatory syndrome (PRAAS), the clinical presentation in this family differed from the classical PRAAS phenotype. Molecular analyses showed altered immunoproteasome-related gene expression and a severity-associated interferon-related response. Severely affected individuals showed increased expression of interferon-related genes, including ISG15, IFI35, and SIGLEC1, whereas mildly affected individuals showed lower or reduced expression patterns. Notably, the extent of these molecular alterations differed among family members and broadly reflected the observed clinical heterogeneity. Conclusions: We report a novel PSMB10 splice-site variant as a strong potential contributor to an unclassified autoinflammatory disease, with a predicted disruption of canonical splicing and loss of protein function. Our findings expand the clinical spectrum of immunoproteasome-associated disorders and suggest that immunoproteasome-related dysregulation and variable interferon responses may contribute to disease severity. The intrafamilial variability observed in this family suggests that additional genetic or immunogenetic factors may modify disease expression, even in autoinflammatory disorders that appear to follow a monogenic inheritance pattern.

Clinical and functional characterization of 27 Chinese patients with 46, XY disorders of sex development caused by novel NR5A1 variants.

Beyond in silico prediction: multi-omics to identify a pathogenic deep intronic HNRNPK variant in Au-Kline syndrome.

Three FBN1 pathogenic variants in Chinese patients with Marfan syndrome: Two novel variants including a splicing-altering deletion with functional verification.

In this study, pathogenic FBN1 variants were identified in three patients, thereby confirming the clinical diagnosis of MFS and contributing two novel variants to the FBN1 variant repository, and provide a comparative assessment of genotype-phenotype correlations.