Missense Mutation In Gene Research Articles

Abstract A002: Computational identification for missense mutations of bladder cancer candidate genes using TCGA datasets

Abstract Bladder cancer is the fourth most common cancer in men. According to the American Cancer Society, there were roughly over 80,000 cases in the United States in 2023, and nine out of ten people with this cancer are over the age of 55. The Cancer Genome Atlas (TCGA) project has made it possible for researchers to study mutations and other types of genetic signatures for multiple cancers including Bladder Urothelial Carcinoma (BLCA). A missense mutation is where a single nucleotide change in the DNA sequence results in the substitution of one amino acid for another in the protein. This could lead to a protein with an altered function. The impact of a missense mutation could be benign or harmful. In our previous study, 54 significant clusters for 15 cancer types were identified in The Cancer Genome Atlas (TCGA) network. In this study, we further investigated genes in two significant clusters reported for BLCA. We initially aim to identify genes that have missense mutations that have functional impact. To achieve this goal, we plugged the two clusters of genes (199) into the cBioPortal website and identified eight genes that had missense mutations or met three criteria (Firstly, numbers of mutations in sample must be greater than or equal to 5; secondly, functional impact must meet the following both: SIFT impact is deleterious and Polyphen-2 impact is possibly damaging or probably damaging): AKT3, PARP1, PRKN, APC, GNA11, KMT2A, NEGR1, and FYN. Further analysis showed what specific amino acid had been substituted at what specific position on the sequence. For example, for gene AKT3, at position 286, amino acid K had been substituted into amino acid N. Similarly, for gene PARP1, at position 913, amino acid G had been substituted into amino acid A. We then identified every amino acid missense substitution for all eight genes. By examining the mutation pattern, we hope to identify key genes as biomarkers so that therapeutic efficacy can be optimized. Citation Format: Kai He, Lucas Wang, Yongsheng Bai. Computational identification for missense mutations of bladder cancer candidate genes using TCGA datasets. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Optimizing Therapeutic Efficacy and Tolerability through Cancer Chemistry; 2024 Dec 9-11; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(12_Suppl):Abstract nr A002

Aggressive Sebaceous Gland Hyperplasia in a Young Girl With MSH2 Gene Mutation: A Rare Presentation.

Sebaceous gland hyperplasia is a benign cutaneous entity commonly seen in older men. Occasionally, it can develop in young patients on immunosuppression with cyclosporine or in adolescent boys in the peripubertal age group. It is extremely rare in young children with no reports of eyelid involvement. It is believed to have no systemic associations, unlike sebaceous adenoma, which is associated with Muir-Torre syndrome. Herein, we present a rare case of a young girl with recurrent and aggressive eyelid sebaceous hyperplasia who was treated by a wide local excision of the lesion. The histopathology showed intact nuclear expression of mismatch repair proteins MLH 1, MSH 2, MSH 6, and PMS 2, and the genetic testing revealed a missense mutation in the MSH2 gene.

Identification of a Missense Mutation in the FLNC Gene from a Chinese Family with Restrictive Cardiomyopathy [Letter

Identification of a Missense Mutation in the FLNC Gene from a Chinese Family with Restrictive Cardiomyopathy [Letter

Prolonged clinical response is possible with regorafenib in refractory osteosarcoma: A case report

<b>Background:</b> Treatment options for metastatic unresectable osteosarcoma are limited, and there is no standard approach after the failure of first-line chemotherapy. Conventional chemotherapy in the second and subsequent lines typically yield a median progression-free survival (PFS) of less than 4 months, with objective response rates ranging from 3 to 29%. The activity of anti-vascular endothelial growth factor receptor multi-tyrosine kinase inhibitors (TKIs) in bone sarcomas has been demonstrated. We present a case of metastatic osteosarcoma exhibiting a durable response to regorafenib treatment.<br /> <b>Case: </b>We discuss a 30-year-old male with metastatic osteosarcoma who had extensive bone and lung metastases and was ineligible for metastasectomy. The patient had received all active chemotherapy regimens in the early and metastatic stages except ifosfamide. Next generation sequencing analysis of resected tumor tissue revealed a possibly pathogenic missense mutation (P.G472E) in NOTCH1 gene. Due to the presence of heart failure with a reduced ejection fraction, chemotherapy was not considered, and regorafenib was initiated. After four cycles of regorafenib, a partial metabolic response was achieved. The patient was followed up without progression under regorafenib for 15 months, without requiring dose reduction. Unfortunately, the treatment had to be interrupted for an extended period due to challenges with recurrent tumor infection and the necessity for repeated surgeries. Following successful wound site control, we restarted full-dose regorafenib and achieved a metabolic partial response again.<br /> <b>Conclusion: </b>To our knowledge, this case represents the longest achieved PFS with regorafenib in metastatic osteosarcoma. TKIs can provide a durable clinical response in metastatic osteosarcoma patients. Clinical and molecular biomarkers are required to determine which patients are most likely to benefit from these treatments.

The Transcriptional Program of Staphylococcus aureus Phage K Is Affected by a Host rpoC Mutation That Confers Phage K Resistance.

To better understand host-phage interactions and the genetic bases of phage resistance in a model system relevant to potential phage therapy, we isolated several spontaneous mutants of the USA300 S. aureus clinical isolate NRS384 that were resistant to phage K. Six of these had a single missense mutation in the host rpoC gene, which encodes the RNA polymerase β' subunit. To examine the hypothesis that mutations in the host RNA polymerase affect the transcription of phage genes, we performed RNA-seq analysis on total RNA samples collected from NRS384 wild-type (WT) and rpoCG17D mutant cultures infected with phage K, at different timepoints after infection. Infection of the WT host led to a steady increase of phage transcription relative to the host. Our analysis allowed us to define 53 transcriptional units and to categorize genes based on their temporal expression patterns. Predicted promoter sequences defined by conserved -35, -10, and, in some cases, extended -10 elements, were found upstream of early and middle genes. However, in many cases, sequences upstream of late genes did not contain clear, complete, canonical promoter sequences, suggesting that factors in addition to host RNA polymerase are required for their expression. Infection of the rpoCG17D mutant host led to a transcriptional pattern that was similar to that of the WT at early timepoints. However, beginning at 20 min after infection, transcription of late genes (such as phage structural genes and host lysis genes) was severely reduced. Our data indicate that the rpoCG17D mutation prevents the expression of phage late genes, resulting in a failed infection cycle for phage K. In addition to illuminating the global transcriptional landscape of phage K throughout the infection cycle, this study will inform our investigations into the basis of phage K's control of its transcriptional program as well as mechanisms of phage resistance.

Segregation of Trans Mutations in the CDH23 Gene in an Emirati Family with Sensorineural Hearing Loss.

Hearing loss (HL) is a significant global health concern, affecting approximately 1 in every 1000 newborns, with over half of these cases attributed to genetic factors. This study focuses on identifying the genetic basis of autosomal recessive non-syndromic hearing loss (ARNSHL) in a consanguineous Emirati family. Clinical exome sequencing (CES) was performed on affected members of the family, followed by Sanger sequencing to validate the findings. Specific primers were used for PCR amplification of target CDH23 exons. Mutations were analyzed using various computational tools to assess their pathogenicity. We identified two heterozygous mutations in the CDH23 gene: a novel nonsense variant (c.264G>A, p.Trp88Ter) and a missense variant (c.5168G>A, p.Arg1723His). Both mutations were found in trans configuration, suggesting a compound heterozygous state contributing to the phenotype. In silico analysis predicted a significant impact on protein function, potentially leading to the observed ARNSHL. This study emphasizes the complexity of genetic factors in hearing loss, particularly in highly consanguineous populations. The identification of both nonsense and missense mutations in the CDH23 gene enhances understanding of its role in hearing loss and provides essential insights for genetic counseling and future therapeutic strategies.

De novo SCN1A missense variant in a patient with Parkinson's disease.

Variants in a gene encoding sodium voltage-gated channel alpha subunit 1 (SCN1A) are known to cause a broad clinical spectrum of epilepsy and associated features, including Dravet syndrome (MIM 607208), non-Dravet developmental and epileptic encephalopathy (MIM 619317), familial febrile seizures (MIM 604403), familial hemiplegic migraine (MIM 609634), and generalized epilepsy with febrile seizures (MIM 604403). In this study, we examined a patient with Parkinson's disease (PD) without any clinical manifestations of epilepsy and associated features. Genomic nucleic acid was extracted, and a complete coding sequence of the human genome (whole-exome sequencing) was sequenced. Moreover, Sanger sequencing of variants of interest was performed to validate the exome-discovered variants. We identified a heterozygous pathogenic missense mutation (c.1498C>T; p.Arg500Trp) in the SCN1A gene in the patient using the whole-exome sequencing approach. The onset of PD features in our patient occurred at the age of 30 years. Biochemical investigations were carried out to rule out any secondary cause of the disease, including Wilson's disease or another metabolic disorder. MRI of the brain and spinal images were unremarkable. Moreover, a dramatic response to carbidopa-levodopa treatment was also observed in the patient. Our results suggest that the pathogenic variant in SCN1A may lead to PD features without epilepsy.

Identification of a Missense Mutation in the FLNC Gene from a Chinese Family with Restrictive Cardiomyopathy.

Restrictive cardiomyopathy (RCM) is a heterogenous cardiomyopathy with various causes, and genetic variants take an important part of the pathogenesis. Whole-exome sequencing (WES) is effective to discover genes that cause genetic diseases. By using WES, we attempted to identify the genetic cause of an RCM family and clarify the clinical diagnosis of the patient and then provide a personalized treatment plan. Blood samples were obtained from the proband and his healthy parents. WES and Sanger sequencing were performed to identify the possible pathogenic gene. Co-segregation analysis was conducted for candidate variants, and the allele frequency was checked in databases including Ensembl, Exome Aggregation Consortium (ExAC) and Human Gene Mutation Database (HGMD). Furthermore, the potential effect of variant was predicted using various-free software such as SIFT, Polyphen-2 and Mutation Taster and the conservation was tested using multiple sequence alignments by ClustalX. The proband was a 20 years old boy with severe heart failure symptoms including dyspnea, massive ascites, edema of both lower limbs and chestcongestion. Echocardiography showed significant biatrial enlargement, normal left ventricular wall thickness and preserved systolic function of both ventricles. A missense mutation in FLNC (c.6451G>A, p.G2151S), encoded filamin-C was detected in proband by WES and Sanger sequencing, while it was not be found in his parents, we supposed that the FLNC mutation (c.6451G>A, p.G2151S) may be a de-novo mutation. Through multiple functional predictions, we found that it is a deleterious mutation and the mutation in filamin-C could alter its structure and normal function, contributing to RCM. Here, an FLNC missense mutation (c.6451G>A, p.G2151S) known to be pathogenic in hypertrophic cardiomyopathy, was found to be associated with RCM, indicating the genetic overlap among cardiomyopathies. This study provides insights into Phenotype-Genotype Correlations of RCM in patients with FLNC mutations.

Generation of a Vibrio-based platform for efficient conversion of raffinose through Adaptive Laboratory Evolution on a solid medium

Raffinose, a trisaccharide abundantly found in soybeans, is a potential alternative carbon source for biorefineries. Nevertheless, residual intermediate di- or monosaccharides and low catabolic efficiency limit raffinose use through conventional microbial hosts. This study presents a Vibrio-based platform to convert raffinose efficiently. Vibrio sp. dhg was selected as the starting strain for the Adaptive Laboratory Evolution (ALE) strategy to leverage its significantly higher metabolic efficiency. We conducted ALE on a solid minimal medium supplemented with raffinose to prevent the enrichment of undesired phenotypes due to the shared effect of extracellular raffinose hydrolysis among multiple strains. As a result, we generated the VRA10 strain that efficiently utilizes raffinose without leaving behind degraded di- or monosaccharides, achieving a notable growth rate (0.40 h−1) and raffinose consumption rate (1.2 g/gdcw/h). Whole genome sequencing and reverse engineering identified that a missense mutation in the melB gene (encoding a melibiose/raffinose:sodium symporter) and the deletion of the two galR genes (encoding transcriptional repressors for galactose catabolism) facilitated rapid raffinose utilization. The further engineered strain produced 6.2 g/L of citramalate from 20 g/L of raffinose. This study will pave the way for the efficient utilization of diverse raffinose-rich byproducts and the expansion of alternative carbon streams in biorefinery applications.

Desmin-related myopathy manifested by various types of arrhythmias: a case report and literature review.

Desmin is a type III intermediate filament protein specifically expressed in muscle cells, which is encoded by the DES gene. Defects in the desmin protein and cytoskeletal instability may interfere with cardiac muscle conduction signals, a fundamental mechanism for arrhythmias in patients with desmin-related myopathy. This current case report presents a female patient in her early 20s who presented with early-onset complete atrioventricular block and complete left bundle branch block over the previous decade. More recently, she had developed ventricular tachycardia, ventricular fibrillation, atrial fibrillation and other arrhythmias. Echocardiography revealed non-compaction of the ventricular myocardium and pulmonary hypertension. Whole-exome sequencing analysis identified a heterozygous missense mutation in the DES gene: c.1216C>T (p.Arg406Trp). She was eventually diagnosed with arrhythmias due to desmin-related myopathy. A literature review of international databases was undertaken to summarise the clinical characteristics of the cardiac involvement associated with this DES gene mutation.

Homozygous missense variations of APC12 cause meiotic metaphase I arrest in oocytes and female infertility

Oocyte maturation arrest is a leading cause of female infertility. However, the genetic variables remain largely unknown. In oocytes, the activation of anaphase-promoting complex/cyclosome (APC/C) is a critical step in the transition from meiosis I to meiosis II. However, the causal relationship between variants in APC/C components and female infertility hasn't been completely investigated. This study aims to find a novel gene and its pathogenic mutation as a cause for metaphase I arrest in oocytes, thus introducing a new APC/C component for screening causes of female infertility. Whole-exome sequencing was performed on 30 infertile women with recurrent oocyte maturation arrest without known gene variants. A homozygous missense mutation in the APC12 gene (p.R8H) was identified as a candidate for oocyte metaphase I arrest in a consanguineous family member. The experiment was conducted in vitro with HEK293T cells and mouse oocytes. Methods such as oocyte microinjection, western blotting, co-immunoprecipitation, and immunofluorescence were used. A knockdown mouse model was generated to verify the function of Apc12 in causing oocyte metaphase I arrest. About 100 wild-type C57BL/6J mice and 50 gene-edited mice were used in this study. APC12 p.R8H was identified in an infertile woman with oocyte metaphase I arrest. Microinjection of Apc12 mutant cRNA in mouse oocytes caused a considerably higher rate of metaphase I stage arrest (65.21±5.64% vs. 30.86±1.74%, p<0.01) with decreased APC12 protein expression and Securin accumulation compared to the control group, while oocytes injected with Apc12 cRNA showed comparable metaphase I arrest rate (31.51±3.05%). This fit the phenotype we identified in our case and suggested that Apc12 p.R8H was a loss-of-function mutation leading to oocyte metaphase I arrest. The in-vitro experiments in HEK293T cells suggested that the APC12 p.R8H mutation disrupted the interaction between APC12 and APC6, as well as impaired APC/C activity by disrupting Securin ubiquitination. Knocking down APC12 with siRNA in mouse oocytes led to metaphase I arrest (41.65±6.10% vs. 24.20±2.19%, p<0.01). Oocytes from Apc12+/- mice exhibited metaphase I arrest compared with oocytes from wild-type mice (72.29±0.51% vs. 23.33±5.82%, p<0.01), which could be rescued by injecting Apc12 cRNA (53.44±1.20%). We identified a pathogenic mutation in APC12 in a female patient and confirmed its relevance as a causative factor for metaphase I arrest in oocytes, implying its importance as an APC/C component in the pathophysiology of oocyte maturation arrest, which caused female infertility.

Extracellular vesicles characterization in patients with hypertrophic cardiomyopathy

Abstract Background Hypertrophic cardiomyopathy (HCM) is a genetic disorder, diagnosed according to the presence of phenotypical traits of the myocardium. A specific biomarker which can associate with the severity of HCM is lacking. Extracellular Vesicles (EVs), nanoparticles released by cells into biological fluids, hold promise as accessible diagnostic tools, as their abundance and molecular composition can reflect the severity of cardiac diseases (Rizzuto 2024). We aim at characterising plasma-derived EVs isolated from 28 HCM patients and 18 healthy volunteers (CTR). Methods The whole cohort underwent transthoracic echocardiography, whereas magnetic resonance and exome sequencing was performed on HCM patients. EVs were isolated via ultracentrifugation from plasma of both groups. Quantitative and qualitative assessments of EVs were performed by nanoparticle tracking analysis, transmission electron microscopy, Western blot, targeted (Olink) and untargeted (nLC-MS/MS) proteomics and FACS analysis. Plasma-derived EV subpopulations were characterised according to their cellular origin. Data are expressed as median and interquartile range (25th, 75th). Results Most patients were male (68% HCM and 66% CTR) with a median age of 58 (49-69) years (HCM) and 47 (44-52) (CTR). Among HCM patients, missense mutations in the MYH7 gene were the most identified. The median maximum wall thickness (WTMax) in HCM was 16 mm (15-19) vs 8 mm (7-9) in CTR. The isolated EVs expressed tetraspanins (CD9, CD63 and CD81), Alix and β-integrin and showed an intact phospholipid bilayer of 100 nm in size. EV concentration was reduced in HCM vs CTRL, respectively 2.8*109 EV/ml/cell count (2*109-4*109) and 4.6*10⁹ EV/ml/cell count (3*109-6*109). Among 15 plasma-derived EV subpopulations studied, those released from platelets (CD41a) and activated platelets (CD62P and CD40L) were increased in HCM patients vs CTR by 1.7 fold. Negative associations were found between E/e’, parameter of diastolic function, and cardiomyocyte-derived EVs (r= -0.2658), and between left ventricle ejection fraction and platelet-derived EVs (r=-0.2189); a positive correlation was found between WTMax and EVs derived from activated endothelial cells (r=0.2330). The proteomic analysis of EVs shows an enrichment in proteins related to platelets adhesion and inflammation in HCM patients. Conclusions HCM patients present a peculiar phenotypic pattern of EVs that may associate with diagnostic clinical features of HCM.

Insilico Identification of Association between Nicotine Dependence and Pathogenic Missense Mutations of Catechol-O-Methyltransferase Gene

Introduction: Oral cancers are known to be strongly associated with the usage of tobacco, which is majorly composed of nicotine. Genetic studies evidenced the nicotine addiction as hereditary. AIM: The aim of the present study is to analyse any genetically functional missense mutations in Catechol-O-methyl-transferase (COMT) gene and derive an association with nicotine dependence that might influence tobacco habit initiation, addiction, and cessation. Methodology: The study involved an insilico analysis about the association between COMT gene and nicotine dependence. This was done with the help of different databases available in website. Initially, database called Ensembl (https://asia.ensembl.org) was used to pool the genetic data on missense mutations of the human COMT gene. The collected data was then fed into computational tools such as SIFT, PolyPhen, PROVEAN, I-Mutant, MutPred to discover the pathogenic mutations if exists. Results: Among 78 missense mutations collected, 74 were identified as damaging variants in which 8 variants were found to cause increased protein stability and 66 were found to cause decreased protein stability. Among those 66 missense variants causing decreased protein stability, 25 variants were identified as highly pathogenic while 19 variants were identified as pathogenic. Conclusion: The in-silico analysis discovered the existence of highly pathogenic mutations in COMT gene which might have a strong association with nicotine dependence that can influence the tobacco habit initiation, addiction, and cessation.

Establishment of a human induced pluripotent stem cell (iPSC) line (JUCTCi018-A) from a patient with Charcot-Marie-Tooth disease type 2EE (CMT2EE) due to a homozygous c.122G > A p.(Arg41Gln) mutation in the MPV17 gene

(Charcot-Marie-Tooth disease (CMT) is a genetic disorder affecting peripheral nerves. The human induced pluripotent stem cell (iPSC) line JUCTCi018-A was created using dermal fibroblasts from a Charcot-Marie-Tooth disease type 2EE (CMT2EE) patient with a homozygous missense mutation in the MPV17 gene (c. 122G > A, p.Arg41Gln). These fibroblasts were reprogrammed using Sendai viruses that encoded OCT4, SOX2, KLF4, and c-MYC reprogramming factors. The iPSCs demonstrated normal morphology and karyotype, expressed pluripotency markers, and the ability to differentiate into the three germ layers. This iPSC line is valuable for investigating the mechanisms underlying CMT2EE.

Generation of human induced pluripotent stem cell lines derived from two glucose transporter 1 deficiency syndrome patients

Glucose transporter 1 deficiency syndrome (GLUT1DS), caused by impaired glucose transport at the blood–brain barriers, leads to various central nervous system dysfunctions. A comprehensive understanding of the underlying disease pathogenesis is still lacking. In this study, we have generated GLUT1DS-specific human induced pluripotent stem cells (hiPSCs) derived from two patients. These established GLUT1DS-specific hiPSC lines showed self-renewal and pluripotency and carried heterozygous frameshift or missense mutations in the responsible SLC2A1 gene. These novel cell resources provide new avenues for understanding disease mechanisms and developing new therapies for GLUT1DS.

A new-disease-causing dominant-negative variant in CARD11 gene in a Chinese case with recurrent fever

Immunodeficiency 11B with atopic dermatitis (IMD11B, OMIM:617638) is rare primary immunodeficiency disease caused by germline dominant negative (DN) mutations in the CARD11 gene. Affected patients present with immune dysfunction, recurrent infections and atopic dermatitis. In this study, we sought to identify and characterize the genetic variant in one patient with periodic fever, recurrent infections, and eczema. Trio whole-exome sequencing (WES) was employed in this patient and her parents, and Sanger sequencing validated the potential pathogenic variant. In vitro functional study was performed to evaluate the pathogenicity of genetic variant identified. A very rare missense mutation (c.2324C > T, p.S775L) in CARD11 gene (NM_032415) was identified by WES in the patient but not her parents. Luciferase reporter assays and co-immunoprecipitation demonstrated mutation exerts a dominant-interfering effect on wild-type CARD11, inhibiting the activity of NF-κB. RNA sequencing analysis also confirmed that mutant CARD11 inhibited down-stream transcriptional activity of NF-κB. A review of literature doesn’t found significant genotype–phenotype correlation. We identified a vary rare DN CARD11 mutation, expanding the genetic and phenotypic spectrum of CARD11.

Genome of Russian Snow-White Chicken Reveals Genetic Features Associated with Adaptations to Cold and Diseases.

Russian Snow White (RSW) chickens are characterized by high egg production, extreme resistance to low temperatures, disease resistance, and by the snow-white color of the day-old chicks. Studying the genome of this unique chicken breed will reveal its evolutionary history and help to understand the molecular genetic mechanisms underlying the unique characteristics of this breed, which will open new breeding opportunities and support future studies. We have sequenced and made a de novo assembly of the whole RSW genome using deep sequencing (250×) by the short reads. The genome consists of 40 chromosomes with a total length of 1.1 billion nucleotide pairs. Phylogenetic analysis placed the RSW near the White Leghorn, Fayoumi, and Houdan breeds. Comparison with other chicken breeds revealed a wide pool of mutations unique to the RSW. The functional annotation of these mutations showed the adaptation of genes associated with the development of the nervous system, thermoreceptors, purine receptors, and the TGF-beta pathway, probably caused by selection for low temperatures. We also found adaptation of the immune system genes, likely driven by selection for resistance to viral diseases. Integration with previous genome-wide association studies (GWAS) suggested several causal single nucleotide polymorphisms (SNPs). Specifically, we identified an RSW-specific missense mutation in the RALYL gene, presumably causing the snow-white color of the day-old chicks, and an RSW-specific missense mutation in the TLL1 gene, presumably affecting the egg weight.

Extreme hypernatremia after a laparoscopic hysterectomy and bilateral salpingo-oophorectomy: a case report and literature review.

Congenital nephrogenic diabetes insipidus (NDI) primarily arises from an X-linked recessive inheritance caused by mutations in the AVPR2 gene, which is responsible for approximately 90% of cases. This condition has an incidence rate of 4-8 per million male live births, with females being much less frequently affected. Symptoms typically manifest shortly after birth, predominantly in males. The key clinical features of NDI include excessive urination (polyuria), compensatory excessive thirst (polydipsia), cognitive impairment, consistently low urine specific gravity, dehydration, and imbalances in electrolyte levels. This case study highlights an unusual occurrence of NDI in a 50-year-old Chinese woman attributed to a mutation in the AVPR2 gene. For more than a year, she had been suffering from excessive urination and severe thirst. The patient, who had undergone surgery for cervical cancer, developed polyuria and hypernatremia postoperatively. Initial laboratory analyses revealed normal blood sodium and chloride levels but reduced urine osmolality and specific gravity. Imaging assessments revealed no irregularities. To validate the diagnosis of NDI, she participated in a water deprivation and vasopressin test. Subsequent genetic tests revealed a thymine (T) to adenine (A) mutation, leading to a missense mutation in the AVPR2 gene. As part of her treatment, she was placed on a low-sodium diet and prescribed oral hydrochlorothiazide and indomethacin for 1 month, resulting in a marked improvement in her symptoms. To the best of our knowledge, this is the first documented case of NDI diagnosed postoperatively in an older female patient with AVPR2 heterozygosity. This case highlights an unusual instance of an X-linked recessive clinical presentation of NDI in an elderly female patient. This study also underscores the importance of conducting water deprivation, vasopressin tests, and genetic testing in establishing the underlying cause for individuals diagnosed with NDI.

Spontaneous Puberty in a Male with Heterozygous PROK2 Gene Mutation Presenting with Micropenis and Synkinesis

Male idiopathic hypogonadotropic hypogonadism is characterized by absent or partial sexual maturation. The Prok2/ProkR2 genes are among the genes implicated in this condition. Objective: Reporting a case harbouring a missense mutation in the PROK2 gene, presenting, at 7 1/2 years with micropenis and synkinesis. History and Examination: Born at full term, with no pre/post-natal complications. On presentation his penile stretched length was 3.8 cm, (-2.5 SDS). Both testes were descended, with a testicular volume of 2ml. Results: On follow up, the testicular volume of 4ml bilaterally, was detected at 11 1/2 years, after 3 testosterone monthly injections. The penile length increased to 5.2 cm. Puberty continued to progress spontaneously. Genetic Analysis revealed a heterozygous missense mutation in PROK2 gene, exon 4, chromosome 3. Conclusion: Heterozygous mutations in the PROK2 gene can present with reproductive and non-reproductive manifestations. They may progress spontaneously into puberty, in the absence of micro/cryptorchidism.

Pitfalls in Urine Cytology: A Case of Fumarate Hydratase-Deficient Renal Cell Carcinoma Initially Diagnosed as High-Grade Urothelial Carcinoma.

Fumarate hydratase (FH)-deficient renal cell carcinoma (RCC) is a rare, aggressive, hereditary subtype of renal cancer that requires careful diagnostic considerations. We report a case of a 33-year-old Asian woman who presented with a 20-day history of hematuria. Imaging studies revealed a solid tumor in the lower pole of the right kidney with lymph node metastases. Urinary cytology revealed benign squamous cells, inflammatory cells, and atypical epithelial cells, suggestive of high-grade urothelial carcinoma. Following a right nephrectomy, the tumor displayed papillary structures composed of cells exhibiting atypical, elongated nuclei with eosinophilic nucleoli and peripheral halos. Immunohistochemical staining demonstrated negative FH expression. Genetic analysis identified a somatic missense mutation in the FH gene, confirming the diagnosis of FH-deficient RCC. This case highlights the importance of integrating cytological, histological, and genetic analyses for accurate diagnosis of FH-deficient RCC.