Globally, chronic kidney disease (CKD) affects over 800 million individuals and is characterized by significant genetic complexity. More than 600 genes are associated with hereditary kidney disease, which may manifest as isolated kidney issues or as part of a syndrome that also includes extrarenal manifestations. The aim of this study was to identify genetic variants in a group of ten patients who presented with clinical signs suggestive of genetic syndromes associated with CKD, or who were asymptomatic but had a positive family history of CKD. Extensive genetic testing (targeted gene panels and whole-exome sequencing-WES) identified a mutation in the PKD1 gene in 3 out of 10 cases. In one patient, a known mutation in the PKD2 gene was identified. Another four patients were diagnosed with Alport syndrome: three of these presented with de novo missense mutations in the COL4A5 gene, and one patient had a mutation in the COL4A3 gene. One patient was diagnosed with MODY5, caused by a known mutation in the HNF1B gene, and one patient was diagnosed with Bartter syndrome type 1, resulting from a known mutation in the SLC12A1 gene. We present genotype-phenotype correlations, highlighting the particularities of each patient within their family context. Our findings emphasize the importance of genotype-phenotype correlations in refining diagnosis, personalizing therapeutic management, and providing essential genetic counseling for at-risk relatives.

In this edition of Gene's "Editor's Corner", we highlight the growing importance of deep intronic variants, which are increasingly recognised as pathogenic contributors to hereditary disorders that remain unsolved after whole-exome sequencing (WES). Recent studies using whole genome sequencing (WGS), which, in contrast to WES, captures most noncoding regions, have shown that splice variants outside intron-exon junctions account for approximately 7 % to 15 % of all molecular diagnoses and are typically missed by exome sequencing. The recently published Gene article by Wang et al., 2025 (Gene 962, 2025, 149574), on a novel deep intronic SLC12A1 variant in Bartter syndrome type 1 neatly illustrates this problem. The variant was missed by exome-based approaches but identified by WGS and shown to alter splicing using a minigene assay. The study not only resolved the molecular diagnosis but also expanded the spectrum of SLC12A1 disease-causing variants. The described workflow, WGS to find candidate deep intronic changes followed by functional splicing assays to prove its effect, has become a standard paradigm for uncovering disease-causing deep intronic variants.

Uniparental disomy (UPD) constitutes an unconventional mode of inheritance that disrupts the typical biparental genetic contribution and may result in phenotypic abnormalities. This report centers on a patient diagnosed with Bartter syndrome Type 1, attributed to a homozygous pathogenic variant in SLC12A1 unmasked by mosaic paternal UPD of chromosome 15. We hypothesize that this pattern (or constellation) emerged from a trisomy rescue event, resulting in two distinct cell lines. Concurrently, the unmasking of a pathogenic paternal SLC12A1 variant by trisomy rescue resulted in the manifestation of Bartter syndrome Type 1. The maternally derived ring chromosome 15 and its impact on nondisjunction and UPD elucidate a unique etiology of Bartter syndrome. Furthermore, the presence of a pathogenic paternal SLC12A1 variant underscores the pivotal role of trisomic rescue and paternal UPD in unveiling a recessive variant.

Bartter syndrome type 1 (BS1) is a rare autosomal recessive disorder characterized by renal salt wasting, hypokalemia, metabolic alkalosis, and hyperreninemic hyperaldosteronism. Variants in the SLC12A1 gene, which encodes the Na-K-2Cl cotransporter NKCC2, are responsible for this condition. To investigate the genetic underpinnings of BS1 in an index case with clinical features indicative of the disease, we performed whole-exome sequencing (WES), followed by whole-genome sequencing (WGS) to identify potential causative variants. Functional characterization of a novel deep intronic variant was achieved through minigene analysis to assess its impact on pre-mRNA splicing. WES identified a heterozygous missense variant (c.1391G > T, p.Gly464Val) in the SLC12A1 gene. Subsequent WGS uncovered a second, previously unreported deep intronic variant (c.629-527 T > C). Minigene assays revealed that the c.629-527 T > C variant altered splicing patterns, resulting in two mRNA isoforms: one with aberrant retention of intron 4 causing a frameshift mutation leading to premature termination codon (p.Leu214IlefsTer31), and another indistinguishable from wild-type splicing. This compound heterozygosity provided molecular confirmation of BS1 diagnosis. Our study characterizes a novel intronic variant impacting SLC12A1 gene splicing in BS1, expanding the mutational spectrum of this gene. The findings underscore the utility of integrating genomic sequencing with functional assays for precise diagnosis and personalized medical management.

Mutations in NKCC2 generate antenatal Bartter syndrome type 1 (type 1 BS), a life-threatening salt-losing nephropathy characterized by arterial hypotension, as well as electrolyte abnormalities. In contrast to the genetic inactivation of NKCC2, inappropriate increased NKCC2 activity has been associated with salt-sensitive hypertension. Given the importance of NKCC2 in salt-sensitive hypertension and the pathophysiology of prenatal BS, studying the molecular regulation of this Na-K-2Cl cotransporter has attracted great interest. Therefore, several studies have addressed various aspects of NKCC2 regulation, such as phosphorylation and post-Golgi trafficking. However, the regulation of this cotransporter at the pre-Golgi level remained unknown for years. Similar to several transmembrane proteins, export from the ER appears to be the rate-limiting step in the cotransporter's maturation and trafficking to the plasma membrane. The most compelling evidence comes from patients with type 5 BS, the most severe form of prenatal BS, in whom NKCC2 is not detectable in the apical membrane of thick ascending limb (TAL) cells due to ER retention and ER-associated degradation (ERAD) mechanisms. In addition, type 1 BS is one of the diseases linked to ERAD pathways. In recent years, several molecular determinants of NKCC2 export from the ER and protein quality control have been identified. The aim of this review is therefore to summarize recent data regarding the protein quality control of NKCC2 and to discuss their potential implications in BS and blood pressure regulation.