搜索结果：Mutation research

The specific objective of this study was to investigate mutations of Hepatitis B virus (HBV) reverse transcriptase (RT) region in Chinese HBV-infected patients at different stages and their association with the progression of liver disease. HBV RT regions in serum samples were amplified and sequenced from 384 patients with chronic HBV infection, including 100 asymptomatic carriers (ASC), 101 chronic hepatitis B, 96 liver cirrhosis, and 87 hepatocellular carcinoma (HCC). Further analysis of genotyping and AA substitution within RT was performed by the online HBV genotyping tool and MEGA7.0 software. A logistic regression model was used to explore the relationship between RT mutations and advanced liver disease (ALD). The mutation rate gradually increased from ASC to HCC (P for trend&#x2009;<&#x2009;0.05). Logistic regression analysis showed that one RT site mutation, rtS106A/C, was significantly associated with the ALD. Multivariate regression analysis confirmed that two RT mutations, rtH55R/Q/K and rtS137T/Q/E, were independent risk factors for HBV-related HCC. The current study reveals that mutations within the RT region might be associated with the progression of HBV-related liver diseases and might serve as predictive biomarkers for patients with HBV infection at high risk of developing HCC.

UK Biobank has released whole genome sequence data for 500,000 participants, including allele counts for hundreds of millions of variants and these were considered in the context of the pentanucleotide background on which they occurred. Variants with an allele count of 25 were found to closely mirror previously reported de novo mutations (DNMs) in terms of the frequencies of variant types. Therefore these variants, referred to as AC25 variants, were used to investigate factors relevant to mutation frequency. The counts of AC25 variant types in a trinucleotide context could be well approximated by combining seven mutational signatures previously obtained from studies of cancer cells. Frequencies of variants were strongly influenced by context. C>T variants occurred more often in the CpG context but other features of the trinucleotide context also had marked effects. Although the trinucleotide context was a very strong predictor of the variant frequencies for the full pentanucleotide context, there were examples where the more distant nucleotides did have marked effects. Here, the configuration of bases two upstream or downstream could have a more than two-fold effect on variant frequencies, presumed to reflect mutation rates. For some variants frequencies varied between non-transcribed and transcribed regions and variants with higher frequencies in transcripts of protein coding genes also demonstrated strand asymmetry, being more frequent on the coding than template strand. Genes with high frequencies of these variants showed enrichment for basic cellular processes, meaning that they could have arisen as a result of transcriptional events during embryogenesis prior to entering the germline. Investigating the molecular mechanisms whereby contexts moderate mutation rates could lead to a better understanding of variant pathogenicity and how DNA fidelity is conserved in normal tissue. This research has been conducted using the UK Biobank Resource.

Convergent evolution in protein antigens is common across pathogens, including SARS-CoV-2; the most likely reason is the need to evade the selective pressure exerted by previous infection- or vaccine-elicited immunity. There is a pressing need for automated analysis of convergent mutations. We developed ConvMut, a tool to identify patterns of recurrent mutations in SARS-CoV-2 evolution; we exploited the granular phylogeny-based lineage hierarchy developed by PANGO, allowing us to observe deltas, i.e., groups of mutations that are acquired with respect to the immediately upstream tree nodes. Deltas comprise amino acid substitutions, insertions, and deletions. ConvMut can perform individual protein analysis to identify the most common single mutations acquired independently in a given subtree. Lineages are then gathered into clusters according to user-selected sets of shared mutations. An interactive graph orders the evolutionary steps of clusters, details the acquired amino acid change for each sublineage, and allows us to trace the evolutionary path until a selected lineage. ConvMut also supports frequency analysis for a given nucleotide or amino acid changes at a given residue across a selected phylogenetic subtree. ConvMut facilitates the exploration of convergent evolutionary trends in SARS-CoV-2, providing insights that could support the development of broadly effective anti-Spike monoclonal antibodies and Spike-based vaccines.

Hypophosphatasia (HPP) is the rare inborn-error-of-metabolism that features impaired mineralization of the skeleton and teeth due to a deactivating mutation or mutations of the gene ALPL which encodes the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). We report 17-year follow-up of twin sisters and a brother referred in middle-age for painful proximal femoral "stress fractures" and then diagnosed with HPP. They reported generalized muscle and bone pain, metatarsal fractures, arthropathy and, since childhood, tooth loss. Their concordant findings were explained by compound heterozygosity in ALPL for a rare maternal missense mutation (c.1403C&#x202f;>&#x202f;T, p.Ala468Val) in exon 12, together with a novel presumably paternal change (c.863-14G&#x202f;>&#x202f;A) predicting a cryptic mRNA splice site in intron 8. Fractures continued during follow-up until one sister received a three-and-one-half-year course of hydroxyapatite-targeted TNSALP supplementation therapy (asfotase alfa) during which substantial improvement occurred in her clinical, biochemical, and functional parameters as well as quality of life. Following subsequent unplanned treatment cessation she suffered significant clinical deterioration, including new fractures and loss of mobility. Her bone histopathology documented osteomalacia. Treatment resumption restored its benefits. Among ten asymptomatic family members evaluated in this four-generation kindred, eight were carriers heterozygous for either ALPL mutation. Those harboring the maternal missense defect manifested mild hypophosphatasemia, suggesting a dominant-negative mutation effect. This experience underscores the importance of in-depth phenotyping and then clinical follow-up to characterize ALPL variant combinations, and for maintaining effective asfotase alfa treatment.

Various animal and cellular Alzheimer's disease (AD) models harboring familial AD (fAD) mutations have been developed and widely used for AD research. In this study, we established an AD cerebral organoid (CO) model using a novel Val669Leu (APPSeoul) mutation in the APP gene. We generated a human embryonic stem cell (hESC) line overexpressing APPSeoul, referred to as the fAD-S hESC line. Using this line, we produced COs and confirmed robust AD-associated pathologies, including amyloid-&#x3b2; (A&#x3b2;) accumulation and tau phosphorylation. In addition, increased expression of &#x3b2;-secretase was observed in this model. Based on these findings, we investigated the effects of BACE1 inhibitor IV, a &#x3b2;-secretase inhibitor, in the CO model. Treatment with BACE1 inhibitor IV significantly reduced A&#x3b2; levels and tau phosphorylation. Furthermore, we differentiated the fAD-S hESC line into cortical neurons (fAD-S neurons) to establish a 2D cellular AD model. Consistent with the CO results, fAD-S neurons exhibited elevated levels of A&#x3b2; and phosphorylated tau, which were also significantly attenuated by BACE1 inhibitor IV treatment. Collectively, these results demonstrate the successful establishment of hESC-derived 2D and 3D AD models based on the APPSeoul fAD mutation.

Thrombomodulin (TM) is essential in maintaining vascular homeostasis. Its anticoagulant function is mainly mediated through the formation of thrombomodulin-thrombin complex, which could accelerate the conversion of protein C (PC) to activated protein C (APC). We identified 3 patients who carried the mutation c.1288G&#x2009;>&#x2009;A, p.G430S in THBD and suffered from recurrent thrombosis. The objective of this study is to elucidate the molecular basis of thrombosis underlying the TM Gly430Ser mutation. We expressed the wild-type and Gly430Ser mutant TM in both full-length and soluble fragment forms in mammalian cells. The cofactor capacity of TM was evaluated by measuring the thrombin-dependent generation of APC and activated TAFI in a time- and concentration-dependent manner. The binding affinity between TM and thrombin was determined by surface plasmon resonance (SPR). Furthermore, the overall impact of TM was evaluated through thrombin generation test (TGT) and APTT prolongation test. The cofactor function of TM-G430S in promoting thrombin-mediated activation of PC and TAFI was substantially compromised. SPR analysis revealed that the binding affinity of TM-G430S for thrombin was significantly impaired, with only about 10% of WT level, as reflected by the increased affinity constant. Consistent with this defect, TGT revealed that TM-G430S exhibited increased peak height and ETP at all concentrations tested and confirmed its impaired capacity to suppress thrombin generation. The ability of TM-G430S to prolong APTT was impaired as well. The Gly430Ser mutation in TM compromises the thrombin dependent activation of PC and TAFI through impaired thrombin binding, underlying the hypercoagulable state and the increased risk of thrombosis observed in patients carrying this mutation.

Coronaviruses encode a variety of non-structural proteins (NSPs) that collectively mediate viral genome replication, transcription and remodeling of the host cellular microenvironment. As a highly conserved transmembrane protein, non-structural protein 6 (NSP6) predominantly localizes to the endoplasmic reticulum. Through interactions with other viral proteins and host factors, NSP6 participates in multiple pivotal processes, including the formation and stabilization of double-membrane vesicles (DMVs), reprogramming of lipid metabolism, blockade of autophagic flux, and evasion of innate immunity. Recent advances in structural biology and research on virus-host interactions have further elucidated the essential roles of NSP6 throughout the viral life cycle. Mutations in NSP6 are closely associated with viral adaptability, transmissibility and pathogenicity. Herein, we comprehensively review the latest advances on the molecular structure, biological functions and mutation hotspots of coronavirus NSP6, as well as its implications for antiviral research. This review aims to provide a theoretical basis for further dissecting the pathogenic mechanisms of coronaviruses and developing broad-spectrum antiviral drugs.

Emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) Mycobacterium tuberculosis (M. tuberculosis) poses a major public health threat, especially in high burden countries. Current diagnostic modalities are slow, expensive, or inaccessible in low-resource setting. We designed, fabricated, and validated an in-house DNA biochip capable of detecting resistance-associated mutations in key M. tuberculosis genes linked to resistance against first- (rifampicin and isoniazid) and second-line (fluoroquinolones and second-line injectables) antituberculosis drugs. The biochip allowed the detection of 20 drug resistance-determining mutations in the rpoB, katG, inhA, gyrA, rrs, and eis genes in the M. tuberculosis genome. Biochip consists of 33 probes spotted in duplicate including probe for M. tuberculosis detection. The biochip assay is based on the amplification of 7 fragments of the genome using two sets of multiplex PCRs. The biochip assay was optimized, and enhanced chemiluminescence was used for signal detection on biochip. Performance evaluation of the biochip was done using 175 clinical isolates. Culture-based drug susceptibility test (DST) was used as the gold standard to compare biochip results, and sequencing was used to resolve the discordance. Out of 59 culture sensitive isolates, 53 were sensitive to all drugs by biochip, while 6 isolates showed different mutations. The biochip showed high concordance with culture DST. The diagnostic sensitivity of the biochip assay for all the drugs ranged from 75% to 100%. The specificities of the biochip for all the 7 drugs were over 97%. The developed biochip demonstrated analytical sensitivity of 103 genome copies per assay and showed high reproducibility, with intra-assay coefficient of variation (CV)&#x2009;<&#x2009;10% and interassay CV <&#x2009;19% across all probes on the biochip. The biochip enables simultaneous analysis of multiple resistance-associated mutation in a single assay providing a powerful tool for early detection, personalized therapy, and effective containment of both MDR and XDR-TB. The biochip is useful for clinical microbiology studies and surveillance programs.

In the progression from inflammatory bowel disease to associated cancer, the clonal mutational landscape shifts from selection of mutations in inflammatory genes to selection for cancer-driver mutations. How prevalence and expansion of either type of mutant clones could be impacted by the cellular environments in which they arise and how this affects the neoplastic outcome of colitis remains unknown. Here we combine in vivo lineage tracing, in silico modeling, mutational profiling and spatial transcriptomics in a mouse model of colitis-associated tumorigenesis to capture clone fates associated with chronic inflammation. We identify epithelial- and immune-enriched neighborhoods and propose a model in which establishment of a reparative tissue environment facilitates tumor initiation by promoting the selection and expansion of pro-oncogenic clones, reducing the span of inflammation-resistant neighborhoods containing nononcogenic clones.

This review aims to provide an overview of the molecular pathogenesis thyroid carcinomas, emphasizing genetic alterations that are therapeutically actionable. The main pathways in thyroid carcinogenesis are the MAPK and PI3K pathways. Point mutations and gene rearrangements affecting the pathway effectors and receptor tyrosine kinases are well-known drivers of thyroid cancer. Research over the past few decades has successfully introduced highly effective treatments for unresectable thyroid cancer, evolving from multi-kinase inhibitors to structurally selective agents, with constantly improving toxicity profiles and coverage of resistance mechanisms. The pros and cons of major laboratory techniques for therapeutic target identification are discussed.

Mutation-induced drug resistance challenges both pandemic surveillance and drug discovery. While experimental assays are resource-intensive, current computational predictions remain limited by the scarcity of 3D mutant protein structures. We present DeepMutDTA, a structure-independent model pre-trained on 1.5 million data points to predict drug-target affinity and uncover underlying interaction mechanisms. However, like other sequence-based approaches, it often falls short in predicting mutant affinities due to the overwhelming sequence similarity between wild-type (WT) and mutant (MT) targets. To bridge this gap, we introduce SimSiam-MuTF, a novel fine-tuning framework to enhance the detection of resistance variants by explicitly aligning latent embedding distances with the corresponding shifts in binding affinity between WT and MT targets. Compared to representative baselines, our model exhibits remarkable robustness across varied sequence identities and unseen data splits, yielding average performance gains of 2.47% (PCC) and 5.10% (SCC) in regression tasks, alongside 4.00% (AUC) and 4.17% (AUPR) in classification tasks. Applications to SARS-CoV-2, HIV-1, and cancer-related targets highlight its generalization potential and utility in informing therapeutic strategies against drug resistance. Collectively, this robust computational pipeline and fine-tuning framework deepen our understanding of mutation-induced resistance and may serve as a powerful platform to accelerate drug discovery against mutant&#xa0;targets.

This study aims to delineate the prenatal ultrasound characteristics of four cases of Rubinstein-Taybi syndrome type 2 (RSTS2) and explore potential associations with this condition as detected through prenatal ultrasound. Whole exome sequencing (WES) and Sanger sequencing were conducted on four fetuses diagnosed with RSTS2. Prenatal ultrasound data were systematically collected and analyzed. All four fetuses were found to have previously unreported EP300 variants, which were absent from ClinVar and the Human Gene Mutation Database (HGMD). The prenatal ultrasound findings were diverse; in the second trimester, two fetuses exhibited growth parameters below minus two standard deviations (M-2SD). One fetus showed an abnormal foot posture and thickened plantar skin, another was found to have exencephaly in the first trimester, and one case presented with fetal rhabdomyoma. This study prenatal ultrasound phenotypes associated with EP300 variants may add to the phenotypic profile of RSTS2 and could serve as a reference for prenatal diagnosis and counseling.

Chronic granulomatous disease (CGD) is a rare inherited primary immunodeficiency characterized by recurrent infections and aberrant inflammation due to defects in the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. We report a case of recurrent pneumonia and significantly elevated IgE levels in an adolescent. Metagenomic next-generation (mNGS) sequencing contributed to the identification of Burkholderia multivorans in bronchoalveolar lavage fluid and the initiation of appropriate treatment. Whole exome sequencing (WES) revealed two point mutations in the CYBA gene. The patient was cured by hematopoietic stem cell transplantation. Application of mNGS contributed to the early identification of B. multivorans and the initiation of appropriate treatment. Timely screening by WES contributed to the diagnosis of the patient.

IntroductionFetal lung adenocarcinoma is a rare malignant lung tumor, constituting about 0.1% to 0.5% of primary lung tumors. It is categorized into two types based on histopathological and clinical differences: low-grade and high-grade types. The primary distinction is the formation of morula bodies and &#x3b2;-catenin, P53 expression. High-grade fetal lung adenocarcinoma is more common in middle-aged to elderly men with heavy smoking history; it is highly malignant and often diagnosed with regional lymph node or distant metastasis. Recent literature mainly consists of case reports, focusing on advanced-stage high-grade type, with few reports concerning early-stage high-grade type.Case ReportThis article reviews the treatment journey of a rare early-stage high-grade fetal lung adenocarcinoma patient. The patient was a non-smoking elderly woman with no respiratory symptoms. A chest CT scan showed a nodule in the lower left lung, with normal tumor markers. Single-port thoracoscopic left lower lung wedge resection was performed, and intraoperative frozen pathology indicated invasive lung adenocarcinoma, leading to lobectomy and mediastinal lymphadenectomy. Postoperative pathology identified high-grade fetal lung adenocarcinoma, with pathological stage pT1bN0 IA2. We present the first report of early-stage high-grade fetal lung adenocarcinoma with KRAS mutation. At 17-month follow-up the patient remains disease-free without adjuvant therapy.ConclusionsDiagnosing fetal lung adenocarcinoma, an independent subtype of lung adenocarcinoma, relies on pathological evaluation, and the standard treatment is surgical resection. Since this disease is rare, early-stage high-grade fetal lung adenocarcinoma is even rarer, requiring more research to find the best treatment strategies.

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Induced mutagenesis creates novel allelic variants to improve crop yield, climate resilience, and nutritional profile. However, utilizing these mutants effectively in breeding programs requires identification of the exact genetic lesions responsible for target traits. This review covers structural DNA mapping techniques, which are divided into two primary categories, whole-genome resequencing (WGS) frameworks (like MutMap, MutMap&#x2009;+&#x2009;, and QTL-seq) and cost-effective reduced-representation sequencing approaches (such as GBS, RAD-seq, ddRAD-seq, and SLAF-seq). Whole-genome methods use bulked segregant analysis of extreme plant phenotypes to isolate single-nucleotide polymorphisms, while reducing representation libraries (RRL) make high-density genotyping affordable for complex, polyploid crops. Moving past structural DNA changes, the manuscript explores how RNA transcriptomic profiling reveals modified gene networks and alternative splicing in mutants. It explores multi-omics tools, like expression quantitative trait loci (eQTL) mapping, which help filter out non-expressing gene fragments. Once candidate genes are identified, subsequent validation is imperative to confirm their functional roles in the target phenotype. Accordingly, this review encompasses several methods of pre-validation like target exome capture, kompetitive allele-specific PCR (KASP) markers, transient gene silencing to screen targets for marker-assisted breeding or amplicon-based TILLING. Finally, it discusses using targeted gene editing tools, specifically TALENs, CRISPR/Cas9, and base editing systems to validate candidate gene action and sufficiency in elite crop backgrounds. Overall, this manuscript reviews recent phenotypic, genomic, and transcriptomic advances, emphasizing their role in efficient mutant characterization for utilization in crop improvement programs.

De novo variants in the ubiquitin-proteasome pathway are linked to autism spectrum disorder (ASD), yet their functional impact on neurodevelopment remains poorly understood. We investigated USP15, a deubiquitinating enzyme with rare damaging variants identified in individuals with ASD, using isogenic human iPSC-derived brain organoids and single-cell transcriptomics. USP15-mutant organoids showed genotype-dependent, progenitor-centered alterations during corticogenesis. Heterozygous organoids modeling haploinsufficiency displayed a shift toward later pseudotime states together with altered maturation and synaptic organization of deep-layer neurons. In contrast, homozygous organoids showed broader phenotypes, including mitotic suppression, aberrant HOX gene expression, and stress-response activation. Regulon analysis showed reduced activity of progenitor-associated regulons, including SOX2, NR2F1, and NR2F2, in heterozygous organoids, whereas homozygous organoids exhibited broader changes in transcriptional regulatory networks. Furthermore, USP15 mutant-associated gene expression patterns were significantly enriched for established ASD risk genes. Comparison with the mouse brain perturbation atlas showed that the transcriptional signature of the USP15 mutant showed notable overlap with those of Fezf2 and Foxp1 mutants, key regulators of deep-layer projection neuron identity. These findings characterize genotype-dependent neurodevelopmental phenotypes associated with reduced USP15 dosage and provide a human neural framework for investigating ASD-relevant developmental mechanisms in the context of a rare ubiquitin-pathway variant.

The interpretation of genetic variants' association (or not) with phenotypic resistance to newly introduced and repurposed antituberculosis drugs remains challenging, as many mutations detected by whole-genome sequencing (WGS) are classified as of uncertain significance (group 3) or not associated with resistance-interim (group 4) by the World Health Organization (WHO) mutation catalog v2. We evaluated the phenotypic impact of such variants on minimum inhibitory concentrations (MICs) for bedaquiline (BDQ), clofazimine (CFZ), delamanid (DLM), and pretomanid (PA) in Mycobacterium tuberculosis complex isolates from the multi-country DIAMA cohort in sub-Saharan Africa (SSA), which recruited RR/RS-TB patients na&#xef;ve to these drugs. Among 1,475 isolates with available WGS data, 163 variants met eligibility criteria; due to viable strain unavailability, 89 isolates carrying 29 unique BDQ/CFZ-related and 60 unique DLM/PA-related variants were tested for MIC determination using broth microdilution. Additional structural modeling was performed to explore potential effects of amino-acid substitutions on protein stability. Among BDQ/CFZ-related variants, MICs above the critical concentrations (CCs) were consistently associated with mmpR5 variants, whereas variants in atpE, pepQ, and Rv1979c were not. DLM/PA variants (ddn, fbiA-D, and fgd1) were frequently detected as non-fixed populations, yet rarely yielding MIC values above the CC. Predicted structural destabilization showed no consistent association with MIC values or variant fixation status. Under the conditions tested, phenotypic resistance was not detected for most group 3 and 4 variants detected by WGS. Our data provide evidence from SSA to support improved interpretation of resistance-associated mutations for new and repurposed antituberculosis drugs.IMPORTANCEWhole-genome sequencing increasingly detects Mycobacterium tuberculosis complex mutations classified by the World Health Organization (WHO) mutation catalog v2 as group 3 variants of uncertain significance or group 4 variants not associated with resistance-interim, limiting reliable prediction of resistance to new and repurposed antituberculosis drugs. By generating minimum inhibitory concentration (MIC) data for such variants identified in a multi-country sub-Saharan African cohort, this study provides phenotypic evidence to support future refinement and expansion of the WHO mutation catalog v2. Notably, mmpR5 variants associated with elevated bedaquiline/clofazimine MICs were identified in eight isolates, suggesting that some patients in this cohort may have harbored pre-existing resistance-associated variants yet remained potentially eligible for bedaquiline-containing regimens. These findings contribute to improving the interpretation of genomic resistance data and strengthening surveillance of resistance to bedaquiline, clofazimine, delamanid, and pretomanid.

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome is a&#xa0;rare, autosomal dominant tumor predisposition syndrome. It is characterized by the early onset of cutaneous and uterine leiomyomas as well as aggressive renal cell carcinomas (RCC). This review focuses on the characterization of HLRCC syndrome, its clinical manifestations, and histopathological and molecular diagnostics to optimize the identification of affected patients and families. The review was conducted based on the current WHO classifications of female genital tumours, urinary and male genital tumours, and genetic tumor syndromes, as well as the current German S3 guideline for renal cell carcinoma, supplemented by a&#xa0;selective literature review focusing on the key clinical and morphological features. The syndrome is caused by germline mutations in the fumarate hydratase (FH) gene. FH-deficient tumours are highly characteristic but not entirely specific for HLRCC. While uterine leiomyomas occur in up to 80% of affected women and often require early surgical treatment, at least 15% of patients develop aggressive renal cell carcinoma. The diagnosis is based on characteristic morphology, immunohistochemistry (including FH deficiency), and detection of the germline mutation. Given the potentially aggressive renal manifestation, early pathological identification of FH-deficient tumours plays a&#xa0;central role, as it enables the initiation of genetic testing and structured screening for affected patients and families. HINTERGRUND: Das heredit&#xe4;re Leiomyomatose-und-Nierenzellkarzinom&#xa0;(HLRCC)-Syndrom ist ein seltenes, autosomal-dominant vererbtes Tumorpr&#xe4;dispositionssyndrom. Es ist durch das fr&#xfc;hzeitige Auftreten von kutanen und uterinen Leiomyomen sowie aggressiven Nierenzellkarzinomen (RCC) gekennzeichnet. Diese &#xdc;bersicht widmet sich der Charakterisierung des HLRCC-Syndroms, seiner klinischen Manifestationen und der histopathologischen sowie molekularen Diagnostik, um die Identifizierung betroffener Patienten und Familien zu optimieren. Es erfolgte eine Aufarbeitung basierend auf der aktuellen WHO-Klassifikationen f&#xfc;r weibliche Genitaltumoren, Harntumoren und m&#xe4;nnliche Genitaltumoren sowie genetische Tumorsyndrome und der aktuellen deutschen S3-Leitlinie f&#xfc;r Nierenzellkarzinome, erg&#xe4;nzt durch eine selektive Literaturrecherche zu den Kernaussagen klinischer und morphologischer Merkmale. Das Syndrom wird durch Keimbahnmutationen im Fumarat-Hydratase-Gen (FH) verursacht. FH-defiziente Tumoren sind ein stark charakteristisches, jedoch nicht vollst&#xe4;ndig spezifisches Merkmal des HLRCC-Syndroms. W&#xe4;hrend uterine Leiomyome bei bis zu 80&#x202f;% der betroffenen Frauen auftreten und oft eine fr&#xfc;hzeitige operative Therapie erfordern, entwickeln mind.&#xa0;15&#x202f;% der Patienten aggressive Nierenzellkarzinome. Die Diagnose st&#xfc;tzt sich auf charakteristische Morphologie, Immunhistochemie (u.&#x202f;a. FH-Defizienz) und den Nachweis der Keimbahnmutation. Angesichts der potenziell aggressiven renalen Manifestation spielt die fr&#xfc;hzeitige pathologische Identifikation FH-defizienter Tumoren eine zentrale Rolle, da sie die Einleitung einer genetischen Abkl&#xe4;rung und eines strukturierten Screenings f&#xfc;r betroffene Patienten und Familien erm&#xf6;glicht.