Whole Exome Sequencing in Children With Type 1 Diabetes Before Age 6 Years Reveals Insights Into Disease Heterogeneity.

Aims: This study is aimed at comparing whole exome sequencing (WES) data with the clinical presentation in children with type 1 diabetes onset ≤ 5 years of age (EOT1D). Methods: WES was performed in 99 unrelated children with EOT1D with subsequent analysis to identify potentially deleterious rare variants in MODY genes. High-resolution HLA class II haplotyping, SNP genotyping, and T1D-genetic risk score (T1D-GRS) were also evaluated. Results: Eight of the ninety-nine EOT1D participants carried a potentially deleterious rare variant in a MODY gene. Rare variants affected five genes: GCK (n = 1), HNF1B (n = 2), HNF4A (n = 1), PDX1 (n = 2), and RFX6 (n = 2). At diagnosis, these children had a mean age of 3.0 years, a mean HbA1c of 10.5%, a detectable C-peptide in 5/8, and a positive islet autoantibody in 6/7. Children with MODY variants tend to exhibit a lower number of pancreatic autoantibodies and a lower fasting C-peptide compared to EOT1D without MODY rare variants. They also carried at least one high-risk DR3-DQ2 or DR4-DQ8 haplotype and exhibited a T1D-GRS similar to the other individuals in the EOT1D cohort, but higher than healthy controls. Conclusions: WES found potentially deleterious rare variants in MODY genes in 8.1% of EOT1D, occurring in the context of a T1D genetic background. Such genetic variants may contribute to disease precipitation by a ß-cell dysfunction mechanism. This supports the concept of different endotypes of T1D, and WES at T1D onset may be a prerequisite for the implementation of precision therapies in children with autoimmune diabetes.

HNF1B Transcription Factor: Key Regulator in Renal Physiology and Pathogenesis.

The HNF1B gene, located on chromosome 17q12, encodes a transcription factor essential for the development of several organs. It regulates the expression of multiple genes in renal, pancreatic, hepatic, neurological, and genitourinary tissues during prenatal and postnatal development, influencing processes such as nephrogenesis, cellular polarity, tight junction formation, cilia development, ion transport in the renal tubule, and renal metabolism. Mutations that alter the function of Hnf1b deregulate those processes, leading to various pathologies characterized by both renal and extrarenal manifestations. The main renal diseases that develop are polycystic kidney disease, hypoplastic or dysplastic kidneys, structural abnormalities, Congenital Anomalies of the Kidney and Urinary Tract (CAKUT), and electrolyte imbalances such as hyperuricemia and hypomagnesemia. Extrarenal manifestations include Maturity-Onset Diabetes of the Young (MODY), hypertransaminasemia, genital and urinary tract malformations, Autism Spectrum Disorder (ASD), and other neurodevelopmental disorders. Patients with HNF1B alterations typically carry either punctual mutations or a monoallelic microdeletion in the 17q12 region. Future research on the molecular mechanisms and genotype-phenotype correlations in HNF1B-related conditions will enhance our understanding, leading to improved clinical management, genetic counseling, monitoring, and patient care.

A case series of maturity-onset diabetes of the young highlighting atypical presentations and the implications of genetic diagnosis.

Maturity-onset diabetes of the young (MODY) is a clinically heterogeneous group of monogenic diabetes characterized by onset at a young age and an autosomal dominant mode of inheritance. Notably, MODY accounts for 2%-5% of all diabetes cases, and its distinction from types 1 (T1DM) and 2 (T2DM) diabetes mellitus is often challenging. We report herein the cases of two girls and a boy who presented initially with diabetic ketoacidosis. In view of the strong family history of diabetes in all three of them, the diagnosis of MODY was considered and confirmed by molecular testing. The patient in Case 1 (a 10-year-old girl) had a variation in the HNF1A gene (MODY 3). The patient in Case 2 (a 13-year-old girl) had a variation in the HNF1B gene (MODY 5) and was also clinically diagnosed with HNF1B MODY due to short stature, abnormal renal function, renal cysts, unicornuate uterus, and diabetic ketoacidosis at presentation. The patient in Case 3 (a 14-year-old boy) had a variation in the KCNJ11 gene (MODY 13) and presented with diabetic ketoacidosis; after initially being treated as having T1DM, he developed progressive weight gain, acanthosis nigricans, and decreased requirement of insulin. The patients in Cases 1 and 3 were subsequently treated with oral sulfonylureas and insulin was gradually tapered and interrupted, resulting in drastic improvement in glucose control. The patient in Case 2 remained on insulin, as this is the appropriate management for MODY 5. This case series demonstrates that atypical cases of MODY with ketoacidosis do occur, underscoring the potential for this complication within the phenotypic spectrum of MODY. In patients with atypical presentations, a thorough family history taking may reveal the diagnosis of MODY.

A Korean Family Presenting with Renal Cysts and Maturity-Onset Diabetes of the Young Caused by a Novel In-Frame Deletion of HNF1B.

Maturity-onset diabetes of the young (MODY; OMIM # 606391) comprises a cluster of inherited disorders within non-autoimmune diabetes mellitus (DM), typically emerging during adolescence or young adulthood. We report a novel in-frame deletion of HNF1B in a family with renal cysts and MODY, furthering our understanding of HNF1B-related phenotypes. We conducted sequential genetic testing to investigate the glucose intolerance, renal cysts, hepatic cysts, and agenesis of the dorsal pancreas observed in the proband. A comprehensive clinical exome sequencing approach using a Celemics G-Mendeliome Clinical Exome Sequencing Panel was employed. Considering the clinical manifestations observed in the proband, gene panel sequencing identified a heterozygous HNF1B variant, c.36_38delCCT/p.(Leu13del) (reference transcript ID: NM_000458.4), as the most likely cause of MODY in the proband. The patient's clinical presentation was consistent with MODY caused by the HNF1B variant, showing signs of glucose intolerance, renal cysts, hepatic cysts, and agenesis of the dorsal pancreas. Sanger sequencing confirmed the same HNF1B variant and established the paternally inherited autosomal dominant status of the heterozygous variant in the patient, as well as in his father and sister. The presence of early-onset diabetes, renal cysts, a family history of the condition, and nephropathy appearing before or after the diagnosis of diabetes mellitus (DM) suggests a diagnosis of HNF1B-MODY5. Early diagnosis is crucial for preventing complications of DM, enabling family screening, providing pre-conceptional genetic counseling, and monitoring kidney function decline.

Sexually dimorphic renal expression of mouse Klotho is directed by a kidney-specific distal enhancer responsive to HNF1b.

Transcription enhancers are genomic sequences regulating common and tissue-specific genes and their disruption can contribute to human disease development and progression. Klotho, a sexually dimorphic gene specifically expressed in kidney, is well-linked to kidney dysfunction and its deletion from the mouse genome leads to premature aging and death. However, the sexually dimorphic regulation of Klotho is not understood. Here, we characterize two candidate Klotho enhancers using H3K27ac epigenetic marks and transcription factor binding and investigate their functions, individually and combined, through CRISPR-Cas9 genome engineering. We discovered that only the distal (E1), but not the proximal (E2) candidate region constitutes a functional enhancer, with the double deletion not causing Klotho expression to further decrease. E1 activity is dependent on HNF1b transcription factor binding site within the enhancer. Further, E1 controls the sexual dimorphism of Klotho as evidenced by qPCR and RNA-seq. Despite the sharp reduction of Klotho mRNA, unlike germline Klotho knockouts, mutant mice present normal phenotype, including weight, lifespan, and serum biochemistry. Lastly, only males lacking E1 display more prominent acute, but not chronic kidney injury responses, indicating a remarkable range of potential adaptation to isolated Klotho loss, especially in female E1 knockouts, retaining renoprotection despite over 80% Klotho reduction.

Examining the clinical and genetic spectrum of maturity-onset diabetes of the young (MODY) in Iran.

Maturity-onset diabetes of the young (MODY) is an uncommon monogenic type of diabetes mellitus. Detecting genetic variants for MODY is a necessity for precise diagnosis and treatment. The majority of MODY genetic predisposition has been documented in European populations and a lack of information is present in Iranians which leads to misdiagnosis as a consequence of defects in unknown variants. In this study, using genetic variant information of 20,002 participants from the family-based TCGS (Tehran Cardiometabolic Genetic Study) cohort, we evaluated the genetic spectrum of MODY in Iran. We concentrated on previously discovered MODY-causing genes. Genetic variants were evaluated for their pathogenicity. We discovered 6 variants that were previously reported in the ClinVar as pathogenic/likely pathogenic (P/LP) for MODY in 45 participants from 24 families (INS in 21 cases, GCK in 13, HNF1B in 8, HNF4A, HNF1A, and CEL in 1 case). One potential MODY variant with Uncertain Risk Allele in ClinVar classification was also identified, which showed complete disease penetrance (100%) in four subjects from one family. This is the first family-based study to define the genetic spectrum and estimate the prevalence of MODY in Iran. The discovered variants need to be investigated by additional studies.

Challenges in the management of patients with HNF1B MODY and multisystem manifestations: the cases of two adolescent boys.

INTRODUCTION: Hepatocyte nuclear factor-1 beta (HNF1B) encodes a homeodomain-containing transcription factor, which is expressed early in embryogenesis and is involved in the development of multiple tissues and organs. HNF1B mutations cause complex multisystem disorders, with renal developmental disease and maturity onset diabetes of the young (HNF1B MODY), a rare cause of diabetes mellitus, being representative features. METHODS: We present two adolescent boys from different socioeconomic backgrounds who were diagnosed with genetically confirmed HNF1B MODY following hospitalization for diabetic ketoacidosis in the first case and after diagnostic work-up due to impaired glucose tolerance in the second case. Multisystem manifestations, including pancreatic hypoplasia and early-onset diabetes mellitus (DM), renal cysts, hypomagnesemia, hyperuricemia, liver and biliary impairment, genital tract malformations, and primary hyperparathyroidism were also present, strongly suggesting HNF1B MODY. RESULTS: The first patient was treated with subcutaneous insulin but was lost to follow-up due to social reasons. Conversely, early diagnosis in the second patient allowed the management of multisystem defects by a multidisciplinary team of experts. Moreover, manifestation of HNF1B MODY in the form of diabetic ketoacidosis was prevented and a structured diabetes training program has proven successful in regulating glycemic control, postponing the necessity for insulin treatment. CONCLUSION: Early genetic work-up of patients with dysglycemia associated with a specific phenotype suggestive of HNF1B MODY is extremely important in the care of children and adolescents with diabetes since it ensures that early and optimal management is initiated, thereby preventing the onset of life-threatening diabetic ketoacidosis and other multisystem complications and/or comorbidities.

Genetic insights into fetal kidney development: Variants in HNF1A and PKHD1 genes.

The orchestration of fetal kidney development involves the precise control of numerous genes, including HNF1A, HNF1B and PKHD1. Understanding the genetic factors influencing fetal kidney development is essential for unraveling the complexities of renal disorders. This study aimed to search for disease-causing variants in HNF1A, HNF1B, PKHD1 genes, among fetus and babies or via parental samples, using sanger sequencing, NGS technologie and MLPA. The study revealed an absence of gene deletions and disease-causing variants in the HNF1B gene. However, five previously SNPs in the HNF1A gene were identified in four patients (patients 1, 2, 3, and 4). These include c.51C > G (Exon1, p. Leu17=), c.79A > C (Exon1, p. Ile27Leu), c.1375C > T (Exon7, p. Leu459=), c.1460G > A (Exon7, p. Ser487Asn), and c.1501 + 7G > A (Intron7). Additionally, in addition to previously SNPs identified, a de novo heterozygous missense mutation (p.E508K) was detected in patient 4. Furthermore, a heterozygous mutation in exon 16 (p. Arg494*; c.1480C > T) was identified in both parents of patient 5, allowing predictions of fetal homozygosity. Bioinformatic analyses predicted the effects of the c.1522G > A mutation (p.E508K) on splicing processes, pre-mRNA structures, and protein instability and conformation. Similarly, the c.1480C > T mutation (p. Arg494*) was predicted to introduce a premature codon stop, leads to the production of a shorter protein with altered or impaired function. Identification of variants in the HNF1A and in PKHD1 genes provides valuable insights into the genetic landscape of renal abnormalities in affected patients. These findings underscore the heterogeneity of genetic variants contributing to renal disorders and emphasize the importance of genetic screening.

Variable phenotype and genotype of pediatric patients with HNF1B nephropathy.

AIMS: Hepatocyte nuclear factor 1ß (HNF1B) mutations are the most common monogenic cause of congenital anomalies of the kidney and urinary tract (CAKUT). We aimed to investigate clinical and genetic characteristics of patients with HNF1B nephropathy to expand its phenotypic and genetic spectrum. MATERIALS AND METHODS: This retrospective cohort study included 16 unrelated pediatric patients (6 females, 10 males) from 13 families with genetically confirmed HNF1B-related nephropathy. RESULTS: Abnormal prenatal kidney abnormalities were present in 13 patients (81.3%). The most common antenatal kidney abnormality was kidney cysts, which were observed in 8 patients (61.5%). Urinary system abnormalities (vesicoureteral reflux (VUR) and ureteropelvic junction obstruction (UPJO)) were present in 4 patients (25%). HNF1B analysis uncovered missense variants in 4 families (30.8%) as the most common genetic abnormality. In addition, 4 novel pathological variations have been defined. During follow-up, hypomagnesemia and hyperuricemia were observed in 7 (43.8%) and 5 patients (31.3%), respectively. None of the patients with a missense variant had hypomagnesemia. However, 7 out of 12 patients (58.3%) with a non-missense variant had hypomagnesemia (p = 0.09). None of the patients had an HNF1B score below 8, and the mean score was 15.3 ± 4.4. The mean follow-up period was 7.4 ± 5.0 years. While 100% of patients (n = 4) with missense variants were in various stages of CKD (CKD2: 2 patients, CKD3: 2 patients), 25% of those with non-missense variants had CKD (CKD2, 3, and 5; 1 patient, respectively) (p = 0.026). CONCLUSION: Patients with HNF1B-associated disease have concomitant urinary system abnormalities such as VUR or UPJO. Missense variants seem to be the most common pathological variations in HNF1B gene and have higher risk of CKD.

High prevalence of copy number variations in the Japanese participants with suspected MODY.

Maturity-Onset Diabetes of the Young (MODY) is a diabetes mellitus subtype caused by a single gene. The detection rate of the responsible gene is 27% in the United Kingdom, indicating that the causative gene remains unknown in the majority of clinically diagnosed MODY cases. To improve the detection rate, we applied comprehensive genetic testing using whole exome sequencing (WES) followed by Multiplex Ligation-dependent Probe Amplification (MLPA) and functional analyses. Twenty-one unrelated Japanese participants with MODY were enrolled in the study. To detect copy number variations (CNVs), WES was performed first, followed by MLPA analysis for participants who were negative on the basis of WES. Undetermined variants were analyzed according to their functional properties. WES identified 7 pathogenic and 3 novel likely pathogenic variants in the 21 participants. Functional analyses revealed that 1 in 3 variants was pathogenic. MLPA analysis applied to the remaining 13 undetermined samples identified 4 cases with pathogenic CNVs: 3 in HNF4A and 1 in HNF1B. Pathogenic variants were identified in 12 participants (12/21, 57.1%) - relatively high rate reported to date. Notably, one-third of the participants had CNVs in HNF4A or HNF1B, indicating a limitation of WES-only screening.

Human pluripotent stem cell-derived kidney organoids reveal tubular epithelial pathobiology of heterozygous HNF1B-associated dysplastic kidney malformations.

Hepatocyte nuclear factor 1B (HNF1B) encodes a transcription factor expressed in developing human kidney epithelia. Heterozygous HNF1B mutations are the commonest monogenic cause of dysplastic kidney malformations (DKMs). To understand their pathobiology, we generated heterozygous HNF1B mutant kidney organoids from CRISPR-Cas9 gene-edited human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) reprogrammed from a family with HNF1B-associated DKMs. Mutant organoids contained enlarged malformed tubules displaying deregulated cell turnover. Numerous genes implicated in Mendelian kidney tubulopathies were downregulated, and mutant tubules resisted the cyclic AMP (cAMP)-mediated dilatation seen in controls. Bulk and single-cell RNA sequencing (scRNA-seq) analyses indicated abnormal Wingless/Integrated (WNT), calcium, and glutamatergic pathways, the latter hitherto unstudied in developing kidneys. Glutamate ionotropic receptor kainate type subunit 3 (GRIK3) was upregulated in malformed mutant nephron tubules and prominent in HNF1B mutant fetal human dysplastic kidney epithelia. These results reveal morphological, molecular, and physiological roles for HNF1B in human kidney tubule differentiation and morphogenesis illuminating the developmental origin of mutant-HNF1B-causing kidney disease.

The Phenotypic Variability Associated with Hepatocyte Nuclear Factor 1B Genetic Defects Poses Challenges in Both Diagnosis and Therapy.

The evolving landscape of clinical genetics is becoming increasingly relevant in the field of nephrology. HNF1B-associated renal disease presents with a diverse array of renal and extrarenal manifestations, prominently featuring cystic kidney disease and diabetes mellitus. For the genetic analyses, whole exome sequencing (WES) and multiplex ligation-dependent probe amplification (MLPA) were performed. Bioinformatics analysis was performed with Ingenuity Clinical Insights software (Qiagen). The patient's electronic record was utilized after receiving informed consent. In this report, we present seven cases of HNF1B-associated kidney disease, each featuring distinct genetic abnormalities and displaying diverse extrarenal manifestations. Over 12 years, the mean decline in eGFR averaged -2.22 ± 0.7 mL/min/1.73 m2. Diabetes mellitus was present in five patients, kidney dysplastic lesions in six patients, pancreatic dysplasia, hypomagnesemia and abnormal liver function tests in three patients each. This case series emphasizes the phenotypic variability and the fast decline in kidney function associated with HNF-1B-related disease. Additionally, it underscores that complex clinical presentations may have a retrospectively straightforward explanation through the use of diverse genetic analytical tools.

In Vitro Functional Analysis Can Aid Precision Diagnostics of HNF1B-MODY.

Precision medicine relies on accurate and consistent classification of sequence variants. A correct diagnosis of hepatocyte nuclear factor (HNF) 1B maturity-onset diabetes of the young, caused by pathogenic variants in the HNF1B gene, is important for optimal disease management and prognosis, and it has implications for genetic counseling and follow-up of at-risk family members. We hypothesized that the functional characterization could provide valuable information to assist the interpretation of pathogenicity of HNF1B variants. Using different in vitro functional assays, variants identified among 313 individuals, suspected to have monogenic diabetes with or without kidney disease, were characterized. The data from the functional assays were subsequently conjugated with obtained clinical, biochemical, and in silico data. Two variants (p.A167P, p.H336Pfs∗22) showed severe loss of function due to impaired transactivation, reduced DNA binding (p.A167P), and mRNA instability (p.A167P). Although both these variant carriers were diagnosed with diabetes, the p.H336Pfs∗22 carrier also had congenital absence of a kidney, which is a characteristic trait for HNF1B maturity-onset diabetes of the young. Functional analysis of the p.A167P variant revealed damaging effects on HNF-1B protein function, which may warrant imaging of the kidneys and/or pancreas. In addition, the current study has generated important data, including evidence supporting the benign functional impact of five variants (p.D82N, p.T88A, p.N394D, p.V458G, and p.T544A), and piloting new approaches that will prove critical for the growth of HNF1B-diabetes diagnosis.

Semaglutide as a potential therapeutic alternative for HNF1B-MODY: a case study.

Maturity-onset diabetes of the young (MODY) is a grouping of monogenic disorders. It is characterized by dominantly inherited, non-insulin-dependent diabetes. MODY is relatively rare, encompassing up to 3.5% in those diagnosed under 30 years of age. Specific types are most commonly treated with sulfonylurea, particularly those identified as HNF4A-MODY and HNF1A-MODY. HNF1B-MODY is another type that is most frequently managed with insulin therapy but lacks a defined precision treatment. We present an 18-year-old, non-obese female patient diagnosed with HNF1B-MODY. She displays complete gene deletion, a renal cyst, and hypomagnesemia. Her treatment plan includes both long- and short-acting insulin, though she frequently encountered hypoglycemia and hyperglycemia. Semaglutide, a GLP-1RA, was administered weekly over 4 months. The patient's glucose level was continuously tracked using Dexcom's Continuous Glucose Monitoring system. The data suggested a notable improvement in her condition: time-in-range (TIR) increased from 70% to 88%, with some days achieving 100%, and the frequency of hypoglycemic episodes, indicated by time-below-range values, fell from 5% to 1%. The time-above-range values also dropped from 25% to 10%, and her HbA1c levels declined from 7% to 5.6%. During the semaglutide therapy, we were able to discontinue her insulin treatment. Additionally, her body mass index (BMI) was reduced from 24.1 to 20.1 kg/m2. However, the semaglutide treatment was halted after 4 months due to side effects such as nausea, vomiting, and reduced appetite. Other contributing factors included exam stress and a COVID-19 infection, which forced a switch back to insulin. Her last recorded HbA1c level under exclusive insulin therapy rose to 7.1%, and her BMI increased to 24.9 kg/m2. In conclusion, semaglutide could potentially replace insulin to improve glucose variability, TIR, and HbA1c in patients with HNF1B-MODY. However, more extensive studies are required to confirm its long-term safety and efficacy.

1H, 13C and 15N backbone resonance assignments of hepatocyte nuclear factor-1-beta (HNF1ß) POUS and POUHD.

Hepatocyte nuclear factor 1ß (HNF1ß) is a transcription factor that plays a key role in the development and function of the liver, pancreas, and kidney. HNF1ß plays a key role in early vertebrate development and the morphogenesis of these organs. In humans, heterozygous mutations in the HNF1B gene can result in organ dysplasia, making it the most common cause of developmental renal diseases, including renal cysts, renal malformations, and familial hypoplastic glomerular cystic kidney disease. Pathogenic variants in the HNF1B gene are known to cause various diseases, including maturity-onset diabetes of the young and developmental renal diseases. This study presents the backbone resonance assignments of HNF1ß POUS and POUHD domains, which are highly conserved domains required for the recognition of double-stranded DNA. Our data will be useful for NMR studies to verify the altered structures and functions of mutant HNF1B proteins that can induce developmental renal diseases, including renal cysts, renal malformations, and familial hypoplastic glomerular cystic kidney disease. This study will provide the structural basis for future studies to elucidate the molecular mechanisms underlying how mutations in HNF1ß cause diseases.

Prenatal diagnosis and perinatal findings of 17q12 microdeletion encompassing HNF1B in a fetus with bilateral hyperechogenic kidneys on fetal ultrasound and mild renal abnormality after birth, and a review of the literature of prenatal diagnosis of 17q12 microdeletion.

OBJECTIVE: We present prenatal diagnosis and perinatal findings of 17q12 microdeletion encompassing HNF1B in a fetus with bilateral hyperechogenic kidneys on fetal ultrasound and mild renal abnormality after birth, and a review of the literature. CASE REPORT: A 36-year-old, primigravid woman underwent amniocentesis at 17 weeks of gestation because of advanced maternal age. Simultaneous array comparative genomic hybridization (aCGH) analysis on the DNA extracted from uncultured amniocytes showed a de novo 1.38-Mb 17q12 microdeletion encompassing LHX1 and HNF1B. The parents did not have such a microdeletion. Prenatal ultrasound showed bilateral hyperechogenic kidneys with normal corticomedullary (CM) differentiation. The parents elected to continue the pregnancy, and a grossly normal 3180-g male baby was delivered at 39 weeks of gestation. aCGH analysis on the cord blood DNA revealed arr [GRCh37 (hg19)] 17q12 (34,856,055-36,248,918) × 1.0 with a 1.393-Mb microdeletion encompassing the genes of MYO19, PIGW, GGNBP2, DHRS11, MRM1, LHX1, AATF, ACACA, TADA2A, DUSP14, SYNRG, DDX52 and HNF1B. When follow-up at age 2 years and 4 months, the renal ultrasound revealed bilateral increased renal echogenicity with normal CM differentiation and small left renal cysts. The blood test revealed BUN = 28 mg/dL (normal: 5-18 mg/dL) and creatinine = 0.5 mg/dL (normal: 0.2-0.4 mg/dL). CONCLUSION: 17q12 microdeletion encompassing LHX1 and HNF1B at prenatal diagnosis may present variable clinical spectrum with bilateral hyperechogenic kidneys on fetal ultrasound and mild renal abnormality after birth. Prenatal diagnosis of fetal hyperechogenic kidneys should raise a suspicion of 17q12 microdeletion syndrome.

Development of a tool for predicting HNF1B mutations in children and young adults with congenital anomalies of the kidneys and urinary tract.

BACKGROUND: We aimed to develop a tool for predicting HNF1B mutations in children with congenital abnormalities of the kidneys and urinary tract (CAKUT). METHODS: The clinical and laboratory data from 234 children and young adults with known HNF1B mutation status were collected and analyzed retrospectively. All subjects were randomly divided into a training (70%) and a validation set (30%). A random forest model was constructed to predict HNF1B mutations. The recursive feature elimination algorithm was used for feature selection for the model, and receiver operating characteristic curve statistics was used to verify its predictive effect. RESULTS: A total of 213 patients were analyzed, including HNF1B-positive (mut + , n = 109) and HNF1B-negative (mut - , n = 104) subjects. The majority of patients had mild chronic kidney disease. Kidney phenotype was similar between groups, but bilateral kidney anomalies were more frequent in the mut + group. Hypomagnesemia and hypermagnesuria were the most common abnormalities in mut + patients and were highly selective of HNF1B. Hypomagnesemia based on age-appropriate norms had a better discriminatory value than the age-independent cutoff of 0.7 mmol/l. Pancreatic anomalies were almost exclusively found in mut + patients. No subjects had hypokalemia; the mean serum potassium level was lower in the HNF1B cohort. The abovementioned, discriminative parameters were selected for the model, which showed a good performance (area under the curve: 0.85; sensitivity of 93.67%, specificity of 73.57%). A corresponding calculator was developed for use and validation. CONCLUSIONS: This study developed a simple tool for predicting HNF1B mutations in children and young adults with CAKUT.

Evaluation of HNF1B, KLK3, ELAC2, TMPRSS2-ERG, and CTNNB1 polymorphisms associated with prostate cancer in samples of patients from HUPE-UERJ.

PURPOSE: Prostate cancer (PCa) is the leading cause of death among men in 48 countries. Genetic alterations play a significant role in PCa carcinogenesis. For the hypothesis of this research, five unique polymorphisms (SNP) were investigated in different genes that showed to be associated in different ways with PCa: rs4430796, rs2735839, rs4792311, rs12329760, and rs28931588, respectively for the genes HNF1B, KLK3, ELAC2, TMPRSS2-ERG, and CTNNB1. PATIENTS AND METHODS: Blood samples from 426 subjects were evaluated: 290 controls (161 females and 129 males) and 136 PCa patients. SNP were determined by real-time polymerase chain reaction. TaqMan SNP genotyping assay. In the control samples, the SNPs were defined in association with the self-reported ethnicity, and in 218 control samples with markers with ancestry indicators. The genes were in Hardy-Weinberg equilibrium. One hundred and seventy control samples were matched by ethnicity for comparison with the PCa samples. RESULTS: The G allele at rs28931588 was monomorphic in both patients and controls studied. Significant differences were observed in allelic and genotypic frequencies between the control and Pca samples in rs2735839 (KLK3; p = 0.002 and χ2 = 8.73 and p = 0.01, respectively), by the global frequency and in the dominant model rs2735839_GG (odds ratio [OR] = 0.51, p = 0.02). AA and GA genotypes at rs4792311 (ELAC2) were more frequent in patients with Gleason 7(4 + 3), 8, and 9 (n = 37%-59.7%) compared to patients with Gleason 6 and 7(3 + 4) (n = 26%-40.0%) conferring a protective effect on the GG genotype (OR = 0.45, p = 0.02). The same genotype showed an OR = 2.71 (p = 0.01) for patients with low severity. The HNF1B-KLK3-ELAC2-TMPRSS2-ERG haplotypes: GAAT, AAAT, GAGT, and AAGT were more frequent in patients with Pca with OR ranging from 4.65 to 2.48. CONCLUSIONS: Higher frequencies of risk alleles were confirmed in the SNPs, KLK3 rs2735839_A, ELAC2 rs4792311_A, and TMPRSS2 rs12329760_T in patients with Pca. Rs2735839_A was associated with risk of Pca and rs4792311_A with severity and Gleason score of 7(4 + 3) or greater. There is a need for careful observation of rs2735839 and rs4792311 in association with the prostatic biopsy due to the increased risk of Pca.

Characterization of the prenatal renal phenotype associated with 17q12, HNF1B, microdeletions.

OBJECTIVE: Recurrent deletions involving 17q12 are associated with a variety of clinical phenotypes, including congenital abnormalities of the kidney and urinary tract (CAKUT), maturity onset diabetes of the young, type 5, and neurodevelopmental disorders. Structural and/or functional renal disease is the most common phenotypic feature, although the prenatal renal phenotypes and the postnatal correlates have not been well characterized. METHOD: We reviewed pre- and postnatal medical records of 26 cases with prenatally or postnatally identified 17q12/HNF1B microdeletions (by chromosomal microarray or targeted gene sequencing), obtained through a multicenter collaboration. We specifically evaluated 17 of these cases (65%) with reported prenatal renal ultrasound findings. RESULTS: Heterogeneous prenatal renal phenotypes were noted, most commonly renal cysts (41%, n = 7/17) and echogenic kidneys (41%), although nonspecific dysplasia, enlarged kidneys, hydronephrosis, pelvic kidney with hydroureter, and lower urinary tract obstruction were also reported. Postnatally, most individuals developed renal cysts (73%, 11/15 live births), and there were no cases of end-stage renal disease during childhood or the follow-up period. CONCLUSION: Our findings demonstrate that copy number variant analysis to assess for 17q12 microdeletion should be considered for a variety of prenatally detected renal anomalies. It is important to distinguish 17q12 microdeletion from other etiologies of CAKUT as the prognosis for renal function and presence of associated findings are distinct and may influence pregnancy and postnatal management.