Search Results (1,409)

Bartter syndrome (BS) represents a group of rare, autosomal recessive renal tubular disorders characterized by hypokalemic hypochloremic metabolic alkalosis, secondary hyperaldosteronism, and normal to low blood pressure. The underlying pathophysiology is primarily driven by defects in critical ion transport proteins or channels localized within the thick ascending limb of the loop of Henle, leading to impaired salt reabsorption. Recent advances in molecular genetics have refined the classification of Bartter syndrome. Current evidence supports SLC12A1, KCNJ1, CLCNKB, BSND, and MAGED2 as the core disease genes within the contemporary BS spectrum, with MAGED2 causing a distinct X-linked transient antenatal form. In contrast, gain-of-function CASR variants, historically labeled “type V Bartter syndrome”, are now more appropriately described as CaSR-associated Bartter-like phenotypes within the broader spectrum of disorders of calcium homeostasis. Despite significant progress, two primary research limitations remain. First, fully elucidating genotype–phenotype correlations and overcoming diagnostic complexities continues to be highly challenging due to substantial phenotypic overlap and genetic heterogeneity. Compounding these diagnostic hurdles is the equally critical challenge of understanding mutation-driven pathogenic mechanisms to develop viable clinical interventions. This review systematically summarizes the current molecular genetic landscape of BS to address these gaps. We highlight the relationships between specific genetic variants and clinical manifestations, delve into molecular pathophysiology including protein misfolding and trafficking defects, and explore emerging therapeutic approaches such as molecular chaperones. By integrating genetic and clinical data, this work aims to provide a comprehensive framework to facilitate precise diagnosis and individualized treatment strategies, ultimately advancing precision medicine in the management of Bartter syndrome. Full article

Congenital factor V (FV) deficiency is a rare autosomal recessive bleeding disorder caused by pathogenic variants in F5 gene and characterized by heterogeneous clinical manifestations. The aim of this study was to define the mutational spectrum of F5 in Russian patients with congenital FV deficiency. We analyzed 16 unrelated patients with different disease severity and 9 relatives from five families. All functionally relevant regions of F5 were examined by Sanger sequencing. Multiplex ligation-dependent probe amplification (MLPA) was used to detect large deletions and duplications. Whole-genome sequencing and functional cDNA analysis were performed in selected cases. This study represents the first description of the F5 mutational spectrum in a Russian cohort. We identified 12 novel variants and demonstrated the functional effect of two previously unreported variants located outside canonical splice-site dinucleotides, leading to aberrant splicing. Notably, the proportion of variants undetectable by routine diagnostic approaches was higher than that reported in other populations. No clear genotype–phenotype correlation was observed. Despite the limited sample size, our findings expand current knowledge of the molecular basis of congenital FV deficiency and may improve genetic diagnostics in Russia. Full article

Background/Objectives: X-linked Alport syndrome (XLAS) arises from pathogenic variants in COL4A5. Truncating variants are generally classified as severe, but whether clinically meaningful heterogeneity exists within this group remains unclear. This study aimed to establish a novel Col4a5 knock-in mouse model based on a clinical variant and to determine whether truncating mutation position influences disease severity. Methods: A de novo COL4A5 frameshift variant, c.2440delG, was identified in a patient with severe early-onset XLAS. A Col4a5-G814fs knock-in mouse was generated by CRISPR/Cas9 on the C57BL/6J inbred mouse strain background and compared with the established Col4a5-G5X nonsense model using survival analysis, serial functional measurements, kidney histopathology, transmission electron microscopy, and RNA sequencing. Results: The Col4a5-G814fs knock-in mouse was successfully generated and showed loss of glomerular α5(IV) collagen chain expression. Compared with G5X mice, G814fs mice exhibited shorter survival (median 141 vs. 161.5 days, p = 0.0004), earlier onset of proteinuria, and more severe kidney functional decline. By 16 weeks, G814fs mice also showed more severe glomerular basement membrane abnormalities and more extensive glomerulosclerosis. RNA sequencing revealed a shared inflammatory gene signature in both models, together with selective upregulation of genes related to the PPAR signaling pathway and fatty acid metabolism in G814fs kidneys. Conclusions: This study reports a novel de novo COL4A5 frameshift variant and establishes the first Col4a5-G814fs knock-in mouse model. Direct comparison with the G5X model shows that distinct truncating COL4A5 mutations can be associated with substantially different disease severity, providing a useful platform for future mechanistic and therapeutic studies in XLAS. Full article

Background: Glutaric acidemia type 1 (GA1) is an autosomal recessive neurometabolic disorder caused by pathogenic variants in glutaryl-CoA dehydrogenase (GCDH), with variable clinical severity despite early biochemical detectability. Population-specific mutational spectra and genotype–phenotype correlations remain insufficiently defined in infantile-onset disease. Therefore, this study aimed to define the GCDH variant spectrum in GA1 patients with mild hepatopathy and assess genotype–phenotype correlations. Methods: We performed integrated clinical, biochemical, and molecular characterization of 15 unrelated patients with infantile-onset GA1. Whole-exome sequencing (WES) was performed for all participants, and the resulting data were compared with the reference sequence of the GCDH gene. Results: All patients presented within the first 6 months of life with macrocephaly, seizures, dystonia, and feeding difficulties. Neurological impairment and mild hepatopathy were variably observed, and one patient developed an acute encephalopathic crisis. Six homozygous GCDH variants were identified, predominantly missense. A common variant, c.541G>C (p.Glu181Gln), accounted for 73.3% of cases and defined a consistent phenotype of early macrocephaly and movement disorder with frequent mild hepatic involvement, suggesting regional enrichment and raising the possibility of a founder effect that warrants confirmation in future haplotype studies. A truncating variant, c.382C>T (p.Arg128Ter), was associated with severe early encephalopathy. Exon 6 represented a mutational hotspot. Biochemically, all patients showed elevated urinary glutaric and 3-hydroxyglutaric acids, increased glutarylcarnitine, and low-to-normal free carnitine, with higher metabolite levels in clinically more severe cases. All variants were pathogenic or likely pathogenic and extremely rare in population databases. Conclusions: This cohort reveals a striking predominance of the GCDH c.541G>C variant and establishes a clear biochemical signature with genotype-associated clinical patterns in infantile-onset GA1. These findings support a population-specific mutational spectrum, refine genotype–phenotype correlations, and underscore the importance of early molecular diagnosis to guide targeted neurological and hepatic monitoring as well as regional screening strategies. Full article

Nephrocalcinosis, defined as the deposition of calcium salts within the renal parenchyma, represents a radiologic and pathologic endpoint shared by a broad spectrum of metabolic and monogenic disorders. Advances in genomic medicine have identified more than 30 genes involved in tubular transport, mineral and acid–base homeostasis, oxalate metabolism, mitochondrial function, ciliary signaling, and nephron development, reframing nephrocalcinosis as a heterogeneous manifestation of discrete molecular defects rather than a single disease entity. Despite this diversity, these conditions converge on common physicochemical pathways of tubular supersaturation, crystal nucleation, growth, and intrarenal retention. These processes are amplified by the intrinsic vulnerability of the renal medulla—characterized by hyperosmolality, hypoxia, and slow tubular flow—and by epithelial injury, loss of crystallization inhibitors, and impaired ciliary signaling. Distinct genotype–phenotype signatures, including age at onset, biochemical profiles, and extrarenal manifestations, provide important diagnostic clues and help differentiate major monogenic entities. The increasing availability of targeted gene panels, whole-exome sequencing, and whole-genome sequencing has substantially improved diagnostic yield, particularly in pediatric populations. Molecular diagnosis now directly informs therapeutic decision-making and long-term management, enabling a shift toward precision nephrology. This narrative review integrates genetic, mechanistic, and clinical perspectives to illustrate how molecular diagnosis reshapes the evaluation, prognosis, and treatment of nephrocalcinosis. Full article

This case highlights a novel genotype–phenotype correlation in the field of endocrinology. Specific endocrine and imaging assessment, in addition to next-generation sequencing (NGS), was performed on the Illumina MiSeq platform, using a TruSight One Sequencing Panel kit for genomic analysis of coding regions of 4813 genes. A 54-year-old female was confirmed with a papillary thyroid carcinoma after total thyroidectomy and underwent radioiodine ablative therapy. Three years later, a left femoral enchondroma of almost 3 cm was identified at computed tomography (CT) scan and magnetic resonance imaging (MRI). She experienced hypertension (in addition to obesity, dyslipidaemia and impaired glucose tolerance) and was later confirmed with ACTH-independent cortisol excess [lack of cortisol suppression at 1 mg dexamethasone testing of 13.9 (normal < 1.8 µg/dL)], noting bilateral adrenal tumors, of 4.7 cm (right), respectively, and of 1.6 cm (left) at CT. Right laparoscopic adrenalectomy was performed with post-operative adrenal insufficiency, requiring glucocorticoid replacement and stopping the anti-hypertensive medication. Pathology report confirmed an adrenocortical adenoma (a Ki67 proliferation index of 2%). Noting the unusual association of the mentioned conditions, NGS was performed in the peripheral blood and identified a heterozygote missense variant of the APC gene (c.5759G>A, p.Arg1920Gln), a heterozygote missense variant of the MSH6 gene (c.2092C>G, p.Gln698Glu), and an incidental additional finding: a heterozygote stop gain pathogenic variant of the CACNA1S gene (c.2707C>T, p.Arg903*). The first two are currently classified as variants of uncertain significance. Whether the co-presence of a triple mutation may change the clinical picture and the life-long outcomes across reciprocal influence is still an open matter. Further research will point out the clinical implications of this genotype–phenotype association, which, to our best knowledge, has not been previously reported. Full article

The accurate delineation of mega-environments (MEs) and the rigorous evaluation of test locations are critical for optimizing regional variety trial schemes, particularly when addressing unbalanced datasets from multi-year, multi-location wheat (Triticum aestivum L.) trials. This study aimed at refining the regional wheat trial framework in the Huanghuai Winter Wheat Region (HWWR) of China using an integrated BLUP-GGE biplot approach, which combines best linear unbiased prediction (BLUP) values with genotype main effect plus genotype-by-environment interaction (GGE) biplot analysis to account for temporal variability and experimental error. We systematically evaluated the BLUP-GGE biplot approach, focusing on its goodness of fit and its ability to resolve inter-location relationships. We further assessed test location representativeness, discriminating ability, and overall desirability via the BLUP-GGE biplot, and contrasted ME delineation outcomes between the traditional “which-won-where” polygon method and the test location clustering-based approach. The BLUP-GGE biplot explained 72.9% of total phenotypic variation, with all location vectors displaying positive correlations (maximum angle = 88.8°), confirming the ecological homogeneity of the target region and yielding robust evaluation results. Based on the ideal tester view, Puyang was identified as the most desirable location, followed by Zhumadian, Shangqiu, and Huixian, while Lianyungang and Suqian exhibited relatively poor comprehensive performance. MEs delineated by the “which-won-where” method showed strong inter-ME correlations and insufficient differentiation, whereas the location clustering-based method markedly enhanced inter-ME discrimination (maximum vector angle > 60°), stably partitioning the HWWR into three distinct MEs with clear cultivar–ME interaction patterns: ME1 (Lianyungang, Suqian, Fuyang, Suzhou, Guoyang, Huixian, Huai’an, Xinmaqiao, Huayin, and Yangling), ME2 (Luoyang, Xinxiang, Zhumadian, Shangqiu, Puyang, and Luohe), and ME3 (Baoji, Xuzhou, Yuanyang, Sheyang, and Xingyang). This study confirms the superiority of the BLUP-GGE biplot for analyzing unbalanced multi-year multi-environment trial data and validates a robust clustering strategy for ME delineation. The findings provide a scientific basis for optimizing wheat regional trial systems and facilitating precise cultivar deployment in the HWWR, and offer a reference for analogous studies on other crops or ecological regions. Full article

Background/Objectives: Infantile cardiomyopathy is a rare but often life-threatening condition in which monogenic causes are particularly relevant, especially when cardiac disease is preceded by hypotonia or multisystem involvement. Among sarcomeric genes, MYL2, encoding the ventricular regulatory myosin light chain, plays a critical role in myocardial contractility. However, biallelic MYL2-associated disease remains exceptionally rare, and its clinical spectrum is not fully defined. This study aims to describe a novel case and further delineate the phenotype of recessive MYL2-related cardiomyopathy. Methods: We report a male infant with congenital hypotonia and delayed motor development who underwent extensive metabolic, neuromuscular, and neuroimaging evaluation. Trio-based whole-exome sequencing was performed to identify a potential genetic etiology, followed by variant interpretation using standard bioinformatic and ACMG/AMP criteria. Results: The patient developed acute decompensated heart failure at approximately 10 months of age, with severe left ventricular systolic dysfunction and multiorgan failure, and died at 12 months despite maximal intensive care support. Whole-exome sequencing identified a homozygous MYL2 c.413T>A (p.Met138Lys) missense variant. The variant is absent or extremely rare in population databases, affects a highly conserved residue, is predicted to be deleterious by multiple in silico tools, and is compatible with autosomal recessive inheritance, with both parents confirmed as heterozygous carriers. In the context of a phenotype consistent with recessive MYL2-associated disease, these findings support a likely pathogenic interpretation. Conclusions: This case expands the allelic and phenotypic spectrum of recessive MYL2-associated cardiomyopathy and highlights the value of early genomic testing in infants with unexplained hypotonia and rapidly progressive cardiac dysfunction. Molecular diagnosis may aid in prognosis, clinical decision-making, and genetic counseling. Full article

Drought stress poses a significant challenge to food security in sub-Saharan Africa, particularly for smallholder farmers in dryland systems. Bambara groundnut (Vigna subterranea (L.) Verdc.), an underutilised legume with inherent drought tolerance, remains underexplored in terms of its root system traits. This greenhouse study investigated the early root and shoot responses of six Bambara groundnut genotypes under well-watered (100% field capacity) and water-stressed (50% field capacity) conditions using rhizotron-based phenotyping. Significant genotypic differences (p < 0.01) were observed in root traits such as root system depth (RSD: 11.0–19.9 cm), root system width (RSW: 6.96–12.2 cm), and root dry mass (RDM: 0.42–1.27 g). The ARC genotype exhibited a strong drought-avoidance strategy, increasing RSD from 12.2 to 19.9 cm and RDM from 0.42 to 1.16 g under stress. The Tiga Nicuru DIP-C-F7471 genotype showed adaptive plasticity, maintaining deeper roots (11.0–14.5 cm), high convex hull area (CHA), and root–shoot ratio (RSR) values, despite a reduction in RDM, suggesting a resource-conserving strategy. Principal Component Analysis (PCA) captured 93.6% of the total variability among genotypes. Root traits, particularly total root length (TRL), convex hull area (CHA), root system width (RSW), and root dry mass (RDM), were the main contributors to genotype differentiation. Strong positive correlations (r = 0.88–0.97) between root and shoot traits suggest that genotypes with more developed root systems also supported greater shoot growth, highlighting the coordinated response of above- and below-ground traits under drought stress. These findings provide valuable targets for breeding and highlight the value of rhizotron-based screening for root trait selection. Future field validation and full-season studies are recommended to confirm their relevance for improving yield stability in dryland agriculture. Full article

Background/Objectives: Amelogenesis imperfecta (AI) is a heterogeneous group of rare hereditary conditions mainly affecting the quantity and/or quality of tooth enamel. Its phenotypic expression is diverse, as is the mutational spectrum of the AI-causing genes and mutations. Integrins are cell-surface receptors that mediate adhesion between cells and between cells and the extracellular matrix. Among these, mutations in integrin αvβ6 have been shown to cause AI; however, phenotypic variation exists between the knockout mouse model and human cases, as well as among different human AI families. Methods: We recruited AI families and performed mutational analysis using whole exome sequencing. Results: We identified compound heterozygous ITGB6 mutations in two families. In Family 1, a paternally transmitted nonsense mutation (NM_000888.5: c.1060C>T, p.(Gln354*)) and a maternally transmitted missense mutation (NM_000888.5: c.2312A>G, p.(Asn771Ser)) were identified; in Family 2, a paternal missense mutation (NM_000888.5: c.1693T>C, p.(Cys565Arg)) and a maternal frameshift mutation (NM_000888.5: c.2091delC, p.(Asn698Metfs*13)) were identified, each causing AI in the respective proband. Both probands exhibited generalized hypoplastic and hypomineralized AI, but no other extraoral symptoms. Conclusions: This report will not only expand the known mutational spectrum of the ITGB6 gene but also provide evidence for the genotype–phenotype correlations, thereby improving our understanding of the functional role of ITGB6 during amelogenesis. Full article

Endocrine disorders are increasingly recognized as major contributors to secondary cardiomyopathies, leading to profound alterations in cardiac structure and function. This comprehensive review synthesizes current evidence on the genetic basis of cardiomyopathies associated with endocrine conditions, including primary aldosteronism, Cushing’s syndrome, pheochromocytoma/paraganglioma, acromegaly, thyroid disorders, hyperparathyroidism, and diabetic cardiomyopathy. We examine the contribution of somatic and germline mutations, genetic polymorphisms, shared molecular pathways transforming growth factor-β (TGF-β)/SMAD (TGF-β/SMAD signaling, the renin–angiotensin–aldosterone system, oxidative stress, and calcium handling), sarcomeric gene modifiers, ion channel variants, and epigenetic mechanisms to disease pathogenesis. We propose a conceptual framework distinguishing three major categories of genetic involvement: (i) variants causing the primary endocrinopathy; (ii) genetic modifiers of myocardial susceptibility under conditions of hormonal excess; and (iii) direct pleiotropic effects, whereby single gene variants independently cause both endocrine and cardiac phenotypes. In addition, we discuss genotype–phenotype correlations, ethnic and population differences in genetic susceptibility, the emerging role of polygenic risk scores, and precision medicine approaches. Overall, this review provides an integrated perspective on the complex genetic architecture of endocrine-related cardiomyopathies and outlines practical considerations for genetic testing aimed at improving patient management and clinical outcomes. Full article

Spider mites (Oligonychus trichardti) are emerging as a major constraint to Urochloa forage productivity in East Africa; however, knowledge of genotypic variation and tolerance remains limited. Herein, 55 Urochloa genotypes were evaluated under field-infested and non-infested conditions across two seasons using an alpha-lattice design. Agronomic and physiological traits, including plant height (PH), tiller number (TN), the Normalized Difference Vegetation Index (NDVI), total dry weight (TDW), and mite damage indices (visual severity index (VSI) and stress tolerance index (STI)) were assessed. Infestation reduced biomass by 22.4% on average, with reductions of up to 45% in susceptible genotypes. Significant genotypic variation was detected for PH, TN, TDW, and VSI. Heritability estimates under mite infestation were moderate to high for all traits except TDW, suggesting that direct selection of these traits could be effective in breeding programs aimed at improving mite resistance. VSI showed a strong negative correlation with NDVI (r = −0.63), supporting its value as a phenotyping indicator of spider mite response. Additive main effects and multiplicative interaction (AMMI) analysis revealed significant genotype × environment interactions for TDW. The AMMI biplot identified Xaraes, ILRI_13369, and ILRI_14787 as high-yielding and stable genotypes, while the AMMI Stability Value (ASV) and the Weighted Average of Absolute Scores from the Best Linear Unbiased Prediction (WAASB) identified CIAT_16122, CIAT_664, ILRI_14801, ILRI_14787, and ILRI_13266 as the most stable and broadly adapted across environments. STI further highlighted ILRI_13751 (2.71) and ILRI_13531 (2.58) as highly tolerant under stress. Overall, the study reveals substantial exploitable genetic diversity and identifies stable, high-yielding, and mite-tolerant genotypes suitable for breeding to improve Urochloa productivity in East Africa. Full article

Acinetobacter baumannii has emerged as one of the most challenging opportunistic pathogens in modern healthcare due to its remarkable ability to acquire and disseminate antimicrobial resistance determinants. Carbapenem-resistant A. baumannii (CRAB) is now recognized by the World Health Organization as a critical priority pathogen, highlighting the urgent need for improved diagnostic, surveillance, and therapeutic strategies. This review synthesizes current evidence on the relationship between phenotypic antimicrobial susceptibility patterns and underlying genetic determinants of resistance in A. baumannii. A structured literature search was conducted across major biomedical databases (PubMed/MEDLINE, Scopus, Web of Science, and the Cochrane Library), supplemented by citation tracking and relevant institutional sources, focusing on studies published between 2016 and 2026. The analysis integrates findings from studies examining phenotypic antimicrobial susceptibility testing (AST) with molecular and genomic investigations of resistance mechanisms, including carbapenemases, aminoglycoside-modifying enzymes, efflux pumps, and resistance-associated genomic islands. Particular attention is given to the complex and sometimes discordant relationship between genotype and phenotype, where the presence of resistance genes does not always translate directly into phenotypic resistance due to regulatory mechanisms, gene expression variability, and genomic context. The review further discusses methodological differences in AST standards and genomic prediction approaches that may contribute to variability across studies. Collectively, the evidence supports a multidimensional interpretation of antimicrobial resistance in A. baumannii, emphasizing the necessity of integrating phenotypic and genotypic data for accurate diagnostics, surveillance, and clinical decision-making. This integrated perspective may contribute to improved understanding of resistance evolution and support the development of more effective strategies for managing multidrug-resistant A. baumannii infections. Full article

Background: Aging is accompanied by a progressive decline in skeletal muscle regeneration, largely due to impaired myogenic differentiation. The proprotein convertase FURIN is a key protease responsible for activating several signaling molecules, including precursors of NOTCH receptors, which regulate cell fate and differentiation. In this study, we investigated whether age-associated downregulation of FURIN contributes to impaired NOTCH2/3 signaling and myogenic function. Methods: An initial bioinformatics analysis of public scRNA-seq data from Genotype-Tissue Expression (GTEx) project indicated age-related expression of genes in the NOTCH signaling pathway. In vitro verification used early- and late-passage C2C12 myoblasts as a model of muscle cell aging to compare the expression of these genes. Late-passage C2C12 cells were transiently transfected with FURIN plasmid to assess restoration of differentiation potential, quantified by the fusion index, myogenic marker expression, and morphology. Results: Expression of FURIN, NOTCH2 and NOTCH3 was negatively correlated with age, whereas GZMB increased with age in GTEx dataset. Late-passage myoblasts exhibited impaired myotube formation, reflecting age-associated loss of myogenic capacity. Restoration of FURIN expression in aged myoblasts was associated with reduced GZMB levels, increased expression of embryonic myosin heavy chain IGF1, and partial recovery of myogenic differentiation and myotube formation. Conclusions: These findings suggest that age-associated loss of FURIN contributes to impaired NOTCH2/3 pathways and myogenic dysfunction. Overexpression of FURIN partially rescues the myogenic phenotype and increases expression of early myogenic markers in aged cells, identifying FURIN as a potential regulator of muscle regenerative capacity during aging. We suggest FURIN as a promising candidate target for further investigation into the mechanisms driving aging or age-related decline. Full article

Tubular aggregate myopathy (TAM) is a rare inherited muscle disorder characterized by the abnormal accumulation of tubular aggregates (TAs) within skeletal muscle fibers. These aggregates, composed of compacted sarcoplasmic reticulum (SR) tubules, are strongly linked to disturbances in calcium (Ca²⁺) homeostasis. Clinically, TAM manifests with slowly progressive proximal muscle weakness, exercise intolerance, cramps, and myalgia, frequently beginning in childhood and often present with elevated serum creatine kinase levels. These symptoms can also be associated with some additional disorders, such as thrombocytopathy, miosis, hypocalcemia, hyposplenism, and ichthyosis, thereby resulting in a clinical picture that overlaps with symptoms of Stormorken (STRMK) syndrome. Considerable heterogeneity exists in age of onset, severity, and extra-muscular involvement, suggesting that TAM and STRMK represent a continuum rather than distinct entities. Histopathological hallmarks include TAs staining positive for SR proteins and displaying a honeycomb-like ultrastructure, consistent with aberrant SR remodeling. Mutations in genes encoding key regulators of store-operated calcium entry (SOCE), including STIM1 and ORAI1 have been identified as major contributors to TAM and its broader clinical spectrum, which encompasses STRMK syndrome, whereas mutations in CASQ1 and RYR1, have been described in only a minority of patients. Despite advances in delineating the genetic and molecular basis of TAM, key questions remain regarding the mechanisms that drive TAs formation and translate Ca²⁺ dysregulation into muscle dysfunction and multisystem disease. Understanding the molecular mechanisms underlying TAM and STRMK syndrome is crucial for developing targeted therapies. Moreover, further research is needed to elucidate additional pathways involved in disease progression and to refine genotype–phenotype correlations. This review summarizes current knowledge on the genetics, pathophysiology, clinical features, and diagnostic hallmarks of TAM, with particular emphasis on the role of Ca²⁺ homeostasis. Full article