Background | Recessive RPE65-retinopathy is an inherited retinal disease (IRD) that is a well-known target for gene therapy. Dominant RPE65-retinopathy, however, due to the Irish founder variant p.(D477G), is very rare. Here, we present the discovery of a novel dominant RPE65-retinopathy caused by ultrarare variant c.1555G>A, p.(Glu519Lys), hereafter named p.(E519K). Methods | In addition to genome (n=3), exome (n=28), or targeted sequencing (index: n=14; segregation: n=30) to identify the p.(E519K) variant, patients underwent extensive ophthalmological examinations. Haplotype phasing was based on long-read genome sequencing data in four individuals, combined with microsatellite analysis of six markers in all index cases. The p.(E519K) variant was functionally assessed using an enzymatic RPE65 assay, western blotting, co-immunoprecipitation, cellular thermal shift assay (CETSA), minigene assays and protein modelling (AlphaFold). Results | Using genome, exome, or targeted sequencing in Belgian IRD cases (discovery cohort, n=2,873) and interrogating genomic IRD databases from France, the Netherlands, Germany, United Kingdom, Scotland, Ireland, and Canada (replication cohort, n=18,798) we identified 83 monoallelic p.(E519K)-IRD cases of Flemish ancestry. Long-read sequencing-based haplotyping revealed a shared region of 464 kb, confirming a founder effect. p.(E519K) affects a highly conserved amino acid and lowers RPE65 enzymatic activity to ~56%, in line with reduced protein expression. While no increased interaction with wild type RPE65 or aberrant splicing could be demonstrated in vitro, protein modelling and CETSA supports a shift in protein stability. Segregation analysis revealed dominant inheritance with complete penetrance and phenotypic variability, hallmarked by a characteristic late-onset macula-predominant IRD with two main subtypes. The milder phenotype is characterized by subtle, diffuse mottling of the posterior pole, while the more severe phenotype manifests as a macular pattern dystrophy with chorioretinal atrophy as a hallmark. Conclusions | The discovery of a dominant RPE65-IRD due to the ultrarare Flemish founder variant p.(E519K) reduces the diagnostic gap in dominant IRD and highlights a novel target for therapy.

Purpose:Recessive RPE65-associated retinopathy is a well-known target for gene therapy, whereas dominant RPE65-associated retinopathy, due to the Irish founder variant p.(D477G), has been reported only once until now and is very rare. Here, we present the discovery of a novel, second dominant RPE65-associated retinopathy caused by variant c.1555G>A, p.(E519K). Methods:Genomic data was investigated in a Belgian discovery cohort (n = 2873) and an international replication cohort (n = 18,796) with inherited retinal disease (IRD). Heterozygous p.(E519K) individuals underwent extensive phenotyping. Haplotype phasing was based on long-read sequencing and microsatellite analysis. Variant p.(E519K) was assessed in vitro using an enzymatic assay, Western blotting, co-immunoprecipitation, cellular thermal shift assay (CETSA), minigene assays, and in silico using protein modeling (AlphaFold). Results:The monoallelic p.(E519K) variant was found in 83 affected individuals from Belgium, the Netherlands, France, and Canada, all of European ancestry. A shared region of 464 kilobases (kb) confirmed a founder effect. Variant p.(E519K) lowers RPE65 protein expression and enzymatic activity, with altered protein stability predicted and experimentally confirmed. Genotype-phenotype data support dominant inheritance and phenotypic variability, respectively, characterized by late-onset macular dystrophy with two main subtypes. Conclusions:The discovery of a dominant RPE65-IRD due to founder variant p.(E519K) reduces the diagnostic gap in dominant IRD and highlights a novel target for therapy.

Atypical hemolytic uremic syndrome (aHUS) usually results from an overactivation of the alternative complement pathway. As large clinical trials are scarce, patient registries can partially fill the knowledge gap on patient characteristics, management, and outcomes. We here describe the baseline clinical and genetic characteristics as well as the management of all Belgian patients enrolled in the Global aHUS Registry at data cut-off. This observational study prospectively and retrospectively collected data (data cut-off: December 26, 2022) from patients of all ages with a clinical diagnosis of aHUS, irrespective of treatment. A total of 121 Belgian patients were registered in the Global aHUS Registry, resulting in a prevalence of 10.4 aHUS patients per million inhabitants, with a higher proportion of females affected (57.9

Background: Autosomal dominant polycystic kidney disease (ADPKD) is a common, inherited nephropathy often resulting in kidney failure. It is genetically heterogeneous; along with the major genes, PKD1 and PKD2 , at least 8 others have been suggested. ALG8 pathogenic variants have been associated with autosomal dominant polycystic liver disease and implicated in ADPKD, while ALG9 has been suggested as an ADPKD gene, but details of the phenotypes and penetrance are unclear. Methods: We screened >3900 families with cystic kidneys and/or livers using global approaches to detect ALG8 or ALG9 pathogenic variants. In addition, population cohorts with sequence data (Genomics England 100kGP (100kGP), UK Biobank (UKBB), and Mayo Clinic Biobank (MCBB)), were screened for ALG8 / ALG9 pathogenic variants. Results: Multicenter screening of individuals with polycystic kidney and/or liver disease identified 51 (1.3%) ALG8 (7 multiplex) and 23 (0.6%) ALG9 (5 multiplex) families; frequencies that were ∼10x and ∼24x greater than non-polycystic kidney disease (PKD) controls. Analysis of individuals with PKD phenotypes in 100kGP, UKBB, and MCBB identified 9 ALG8 (0.39%) and 9 ALG9 (0.39%) families, an enriched frequency over controls. Two individuals had PKD1 and ALG8 pathogenic changes. Eighty-nine percent of individuals with ALG8 mutations with imaging in the entire MCBB had kidney cysts (56%, >10 cysts), with greater median kidney and liver cyst numbers than controls. For ALG9, 78% had kidney cysts (27%, >10 cysts). Individuals with ALG8 mutations typically had mild cystic kidneys with limited enlargement. Liver cysts were common (71%) with enlarged livers (>2L) found in 11/62 patients although surgical intervention was rare. The ALG9 kidney phenotype was also of mild cystic kidneys but enlarged livers were rare; for both genes chronic kidney disease or kidney failure were rare. Conclusions: ALG8 and ALG9 are defined as cystic kidney/liver genes but with limited penetrance for lower eGFR.

In children, 15% of nephrotic syndromes are steroid-resistant (SRNS); approximately 30% of early onset SRNS have a genetic origin, with more than 100 causal genes described so far. SRNS can be syndromic, if associated with signs and symptoms affecting other organs or systems, such as the central nervous system, the heart or the eyes. Patients with SRNS are at high risk of chronic kidney disease and progressive renal failure, and as such need multidisciplinary care, centred on renal protection. Recently, K acetyltransferase 2B (KAT2B) loss of function was identified as a risk factor for morphological and functional defects in Drosophila nephrocytes; in vitro knockdown ofKAT2Balso impaired the adhesion and migration ability of human podocytes.Here we provide the first clinical description of a family affected by a loss of function mutation ofKAT2B. Clinically, both siblings presented with early onset SRNS and bilateral cataract, without neurological or heart defects. Renal function was maintained in the teenage years; nephrotic-range proteinuria was insensitive to immunosuppressive therapies. Therefore, mutations ofKAT2Bshould be sought in patients with unexplained syndromic SRNS affecting the eye.

Background The use of genetic testing in pediatric patients with chronic kidney diseases (CKD) has increased exponentially in the past few years, particularly with the emergence of novel sequencing techniques. However, the genetic yield remains unexpectedly low in nephrology, with an impact on diagnosis, prognosis and treatment. Moreover, the increasing diversity of genetic testing possibilities can be seen as an obstacle by clinicians, in the absence of a strong background in genetics. Here, we propose a step-by-step, multidisciplinary strategy for the diagnostic evaluation of pediatric patients with CKD, and appropriate genetic test selection to maximize the yield of genetic testing. Methods A total of 126 pediatric patients were enrolled in a retrospective file analysis. Genetic testing techniques used included phenotype-associated next-generation panel sequencing ( N = 41), Sanger and SNaPshot sequencing ( N = 3) and/or whole exome sequencing ( N = 2). Results Overall genetic yield reached 63% and genetic testing significantly impacted patient management in 70%. The distribution of kidney diseases among patients was balanced and matched previously described pediatric cohorts in terms of glomerulopathies, tubulopathies and ciliopathies. Genetic analyses led to significant treatment modifications, kidney biopsy sparing and personalized nephroprotection, as well as tailored genetic counseling. Of note, the evaluation of Human Phenotype Ontology term accuracy in the cohort showed that causal mutations were precisely identified in 85% of the patients at most. Conclusion Here we suggest a step-by-step, multidisciplinary strategy to maximize the yield of genetic testing in pediatric patients with CKD. This approach optimizes patient care while avoiding unnecessary treatments or procedures. Graphical Abstract A higher resolution version of the Graphical abstract is available as Supplementary information

A 23-year-old man with no relevant medical history or active medication presented with gross hematuria and hypogastric pain. Kidney ultrasound revealed medullary hyperechogenicity, suggestive of nephrocalcinosis, and bilateral cysts (Fig 1). A month later, he developed acute renal colic secondary to an obstructive 14 mm stone located in the right pyeloureteral junction, requiring placement of a double J stent. The stone was removed by ureterorenoscopy. Infrared spectroscopy showed the stone to be of mixed type: carbapatite, brushite, and calcium oxalate mono- and dihydrate. Metabolic work-up revealed mild hypercalcemia with suppressed parathyroid hormone (PTH), elevated 24-hour urinary calcium excretion, 25-hydroxyvitamin D level within the reference range, and high 1,25-dihydroxyvitamin D level (Table 1). Family history was negative for nephrolithiasis or cysts and the parents were not consanguineous. Kidney magnetic resonance imaging showed normal-sized kidneys, multiple renal cysts bilaterally, and the absence of liver cysts.•What is the differential diagnosis for this patient’s hypercalcemia, suppressed PTH, and nephrolithiasis?•What additional work-up may confirm this diagnosis?•What treatment options are possible for this patient?Table 1Laboratory FindingsValueReference RangeBlood Creatinine, mg/dL1.160.6-1.3 Calcium, mmol/L2.572.20-2.50 Ionized calcium, mg/dL5.84.44-4.80 Phosphorus, mmol/L1.180.81-1.45 iPTH, pg/mL<315-80 Total 25-hydroxyvitamin D, ng/mL54>30 1,25-hydroxyvitamin D, pg/mL10619.9-79Urine Volume, mL/d1,500 pH6.45.0-7.5 Creatinine, g/d1.860.81-2.01 Calcium, mmol/d8.9<7.5 Oxalate, mg/d38<45 Sodium, mmol/d18040-220Abbreviations: iPTH, intact parathyroid hormone. Open table in a new tab Abbreviations: iPTH, intact parathyroid hormone. This patient has non–parathyroid-related hypercalcemia, of which the most common cause is neoplasia. Both solid tumors and hematologic malignancies may increase bone resorption by various mechanisms: induction of osteolysis by bone metastases, release of osteoclast activating factor in multiple myeloma, secretion of PTH-related protein by some solid tumors (especially squamous cell carcinomas), or production of 1,25-dihydroxyvitamin D (usually by lymphomas).1Guise T.A. Wysolmerski J.J. Cancer-associated hypercalcemia.N Engl J Med. 2022; 386: 1443https://doi.org/10.1056/NEJMcp2113128Crossref PubMed Scopus (15) Google Scholar Nontumor etiologies of non–parathyroid-related hypercalcemia include excessive intake of vitamin D supplements or 1,25-dihydroxyvitamin D3 and increased endogenous production of 1,25-hydroxyvitamin D3 in patients with granulomatous disorders (especially sarcoidosis). Other rare causes of hypercalcemia include lithium therapy, thiazide diuretics, hypervitaminosis A, thyrotoxicosis, pheochromocytoma, adrenal insufficiency, milk-alkali syndrome, and prolonged immobilization. A rare additional cause of high vitamin D levels is a monogenic disorder caused by biallelic (or occasionally monoallelic) pathogenic variants in the gene encoding 25-hydroxyvitamin D3 24-hydroxylase. This enzyme, also known as CYP24A1, catalyzes the conversion of 1,25-dihydroxvitamin D3 and 25-hydroxyvitamin D3 into inactive 24-hydroxylated products that are excreted (Fig 2). CYP24A1 deficiency leads to persistently high levels of 1,25-dihydroxvitamin D3. Loss-of-function variants in CYP24A1 may lead to infantile hypercalcemia type 1 (OMIM 143880), also called hypersensitivity to vitamin D3. This hypersensitivity to vitamin D3 can be severe and potentially fatal in infants after prophylactic vitamin D3 supplementation for the prevention of rickets.2Schlingmann K.P. Kaufmann M. Weber S. et al.Mutations in CYP24A1 and idiopathic infantile hypercalcemia.N Engl J Med. 2011; 365: 410-421https://doi.org/10.1056/NEJMoa1103864Crossref PubMed Scopus (487) Google Scholar Adult patients may present with recurrent calcium kidney stones, with or without nephrocalcinosis. Recently, medullary and/or corticomedullary junction cysts (a mean of 5.3 cysts per patient) were reported in 16 patients with CYP24A1 deficiency (half of whom had nephrolithiasis as the presenting symptom).3Hanna C. Potretzke T.A. Cogal A.G. et al.High prevalence of kidney cysts in patients with CYP24A1 deficiency.Kidney Int Rep. 2021; 6: 1895-1903https://doi.org/10.1016/j.ekir.2021.04.030Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar The mechanisms of cystogenesis remain unknown, but sustained hypercalciuria and/or exposure to increased calcitriol levels could contribute to kidney cyst development. The diagnosis of CYP24A1 deficiency should be suspected in patients with bilateral kidney cysts, high levels of 1,25-dihydroxvitamin D3, nephrocalcinosis, and kidney stones composed of carbapatite, brushite, and/or oxalate calcium dihydrate, which are typically associated with hypercalciuria. Chest imaging, measurement of serum levels of angiotensin-converting enzyme, and eye examination were performed to rule out sarcoidosis. Genetic testing using a next-generation sequencing targeted gene panel revealed a homozygous variant in the CYP24A1 gene predicted to lead to a substitution of tryptophan for arginine at amino acid 396 (p.Arg396Trp); this variant has been previously reported to result in complete loss of function.2Schlingmann K.P. Kaufmann M. Weber S. et al.Mutations in CYP24A1 and idiopathic infantile hypercalcemia.N Engl J Med. 2011; 365: 410-421https://doi.org/10.1056/NEJMoa1103864Crossref PubMed Scopus (487) Google Scholar The patient’s parents were both heterozygous for the variant. The management of CYP24A1 deficiency remains challenging. The patient received dietary counseling on the need to increase water intake; reduce intake of salt, protein, and oxalate; and maintain a diet moderately rich in calcium to enhance bone formation. The patient was also counseled to avoid vitamin D supplements and sun exposure.4Figueres M.L. Linglart A. Bienaime F. et al.Kidney function and influence of sunlight exposure in patients with impaired 24-hydroxylation of vitamin D due to CYP24A1 mutations.Am J Kidney Dis. 2015; 65: 122-126https://doi.org/10.1053/j.ajkd.2014.06.037Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar Thiazide diuretics must be used with caution when treating hypercalciuria, as they may worsen or cause hypercalcemia. Use of imidazole derivatives such as ketoconazole or fluconazole to partially inhibit CYP27B1 (to decrease calcitriol levels) or rifampin (to increase CYP3A4 activity), has shown short-term benefits, but the long-term safety of such therapies remains uncertain.5Nguyen M. Boutignon H. Mallet E. et al.Infantile hypercalcemia and hypercalciuria: new insights into a vitamin D-dependent mechanism and response to ketoconazole treatment.J Pediatr. 2010; 157: 296-302https://doi.org/10.1016/j.jpeds.2010.02.025Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar, 6Sayers J. Hynes A.M. Srivastava S. et al.Successful treatment of hypercalcaemia associated with a CYP24A1 mutation with fluconazole.Clin Kidney J. 2015; 8: 453-455https://doi.org/10.1093/ckj/sfv028Crossref PubMed Scopus (58) Google Scholar, 7Brancatella A. Cappellani D. Kaufmann M. et al.Long-term efficacy and safety of rifampin in the treatment of a patient carrying a CYP24A1 loss-of-function variant.J Clin Endocrinol Metab. 2022; 107: e3159-e3166https://doi.org/10.1210/clinem/dgac315Crossref Scopus (4) Google Scholar CYP24A1 deficiency secondary to a homozygous pathogenic variant. Valentine Gillion, MD, Karin Dahan, MD, PhD, Cristina Anca Dragean, and Nathalie Demoulin, MD. None. The authors declare that they have no relevant financial interests. The authors declare that they have obtained written consent from the patient reported in this article for publication of the information about him that appears within this Quiz. Received October 19, 2022. Evaluated by an external reviewer, with direct editorial input from an Editorial Intern and the Engagement Editor. Accepted in revised form November 17, 2022.

BACKGROUND:The identification of complement defects as major drivers of primary atypical hemolytic uremic syndrome (HUS) has transformed the landscape of thrombotic microangiopathies (TMAs), leading to the development of targeted therapies and better patient outcomes. By contrast, little is known about the presentation, genetics, and outcomes of TMA associated with specific diseases or conditions, also referred to as secondary TMA. METHODS:In this study, we assessed the relative incidence, clinical and genetic spectra, and long-term outcomes of secondary TMA versus other TMAs in consecutive patients hospitalized with a first episode of TMA from 2009 to 2019 at two European reference centers. RESULTS:During the study period, 336 patients were hospitalized with a first episode of TMA. Etiologies included atypical HUS in 49 patients (15%), thrombotic thrombocytopenic purpura (TTP) in 29 (9%), shigatoxin-associated HUS in 70 (21%), and secondary TMA in 188 (56%). The main causes of secondary TMA were hematopoietic stem-cell transplantation ( n =56, 30%), solid-organ transplantation ( n =44, 23%), and malignant hypertension ( n =25, 13%). Rare variants in complement genes were identified in 32 of 49 patients (65%) with atypical HUS and eight of 64 patients (13%) with secondary TMA; pathogenic or likely pathogenic variants were found in 24 of 49 (49%) and two of 64 (3%) of them, respectively ( P < 0.001). After a median follow-up of 1157 days, death or kidney failure occurred in 14 (29%), eight (28%), five (7%), and 121 (64%) patients with atypical HUS, TTP, shigatoxin-associated HUS, and secondary TMA, respectively. Unadjusted and adjusted Cox regressions showed that patients with secondary TMA had the highest risk of death or kidney failure (unadjusted hazard ratio [HR], 3.35; 95% confidence interval [CI], 1.85 to 6.07; P < 0.001; adjusted HR, 4.11; 95% CI, 2.00 to 8.46; P < 0.001; considering atypical HUS as reference). CONCLUSIONS:Secondary TMAs represent the main cause of TMA and are independently associated with a high risk of death and progression to kidney failure.

The recent description of a cohort with both adults and children harboring biallelic pathogenic variants of CUBN changed the paradigm of the management of isolated proteinuria. Indeed, the detection of proteinuria in a patient, regardless of age, often leads to an exhaustive check-up including kidney biopsy but also the prescription of renin-angiotensin system (RAS) blockers to slow the progression of kidney disease. Patients with CUBN variants have nondetrimental proteinuria and are non-responsive to RAS blockers. We herein describe 2 siblings treated for isolated proteinuria for several years, eventually diagnosed with CUBN biallelic pathogenic variants (c.703 C > T and c.10363-3A > G). We review the physio-pathological mechanisms of this newly discovered disease and discuss implications for clinical management.

Autosomal dominant polycystic kidney disease (ADPKD) resulting from pathogenic variants in PKD1 and PKD2 is the most common form of PKD, but other genetic causes tied to primary cilia function have been identified. Biallelic pathogenic variants in the serine/threonine kinase NEK8 cause a syndromic ciliopathy with extra-kidney manifestations. Here we identify NEK8 as a disease gene for ADPKD in 12 families. Clinical evaluation was combined with functional studies using fibroblasts and tubuloids from affected individuals. Nek8 knockout mouse kidney epithelial (IMCD3) cells transfected with wild type or variant NEK8 were further used to study ciliogenesis, ciliary trafficking, kinase function, and DNA damage responses. Twenty-one affected monoallelic individuals uniformly exhibited cystic kidney disease (mostly neonatal) without consistent extra-kidney manifestations. Recurrent de novo mutations of the NEK8 missense variant p.Arg45Trp, including mosaicism, were seen in ten families. Missense variants elsewhere within the kinase domain (p.Ile150Met and p.Lys157Gln) were also identified. Functional studies demonstrated normal localization of the NEK8 protein to the proximal cilium and no consistent cilia formation defects in patient-derived cells. NEK8-wild type protein and all variant forms of the protein expressed in Nek8 knockout IMCD3 cells were localized to cilia and supported ciliogenesis. However, Nek8 knockout IMCD3 cells expressing NEK8-p.Arg45Trp and NEK8-p.Lys157Gln showed significantly decreased polycystin-2 but normal ANKS6 localization in cilia. Moreover, p.Arg45Trp NEK8 exhibited reduced kinase activity in vitro. In patient derived tubuloids and IMCD3 cells expressing NEK8-p.Arg45Trp, DNA damage signaling was increased compared to healthy passage-matched controls. Thus, we propose a dominant-negative effect for specific heterozygous missense variants in the NEK8 kinase domain as a new cause of PKD.

BACKGROUND & AIMS: Constitutional mismatch repair defi- ciency (CMMRD) is a rare recessive childhood cancer predis-position syndrome caused by germline mismatch repair variants. Constitutional microsatellite instability (cMSI) is a CMMRD diagnostic hallmark and may associate with cancer risk. We quantified cMSI in a large CMMRD patient cohort to explore genotype-phenotype correlations using novel MSI markers selected for instability in blood. METHODS: Three CMMRD, 1 Lynch syndrome, and 2 control blood samples were genome sequenced to >120x depth. A pilot cohort of 8 CMMRD and 38 control blood samples and a blinded cohort of 56 CMMRD, 8 suspected CMMRD, 40 Lynch syndrome, and 43 control blood samples were amplicon sequenced to 5000x depth. Sample cMSI score was calculated using a published method comparing microsatellite reference allele frequencies with 80 controls. RESULTS: Thirty-two mononucleotide re-peats were selected from blood genome and pilot amplicon sequencing data. cMSI scoring using these MSI markers ach-ieved 100% sensitivity (95% CI, 93.6%-100.0%) and speci-ficity (95% CI 97.9%-100.0%), was reproducible, and was superior to an established tumor MSI marker panel. Lower cMSI scores were found in patients with CMMRD with MSH6 deficiency and patients with at least 1 mismatch repair missense variant, and patients with biallelic truncating/copy number variants had higher scores. cMSI score did not correlate with age at first tumor. CONCLUSIONS: We present an inex-pensive and scalable cMSI assay that enhances CMMRD detec-tion relative to existing methods. cMSI score is associated with mismatch repair genotype but not phenotype, suggesting it is not a useful predictor of cancer risk.

Background It has been suggested that inactivation of p14 ARF , a tumor suppressor central to regulating p53 protein stability through interaction with the MDM2 oncoprotein, abrogates p53 activity in human tumors retaining the wild-type TP53 gene. Differences in expression of tumor suppressor genes are frequently associated with cancer. We previously reported on a pattern of restricted p53 immunohistochemical overexpression significantly associated with microsatellite instability (MSI), low TP53 mutation frequency, and MDM2 overexpression in colorectal cancers (CRCs). In this study, we investigated whether p14 ARF alterations could be a mechanism for disabling the p53 pathway in this subgroup of CRCs. Results Detailed maps of the alterations in the p14 ARF gene were determined in a cohort of 98 CRCs to detect both nucleotide and copy-number changes. Methylation-specific PCR combined with bisulfite sequencing was used to evaluate the prevalence and distribution of p14 ARF methylation. p14 ARF alterations were then correlated with MSI status, TP53 mutations, and immunohistochemical expression of p53 and MDM2. The frequency of p14 ARF mutations was extremely low (1/98; 1%), whereas coexistence of methylated and unmethylated alleles in both tumors and normal colon mucosa was common (91/98; 93%). Only seven of ninety-eight tumors (7%) had a distinct pattern of methylation compared with normal colon mucosa. Evaluation of the prevalence and distribution of p14 ARF promoter methylation in a region containing 27 CpG sites in 35 patients showed a range of methylated CpG sites in tumors (0 to 25 (95% CI 1 to 13) versus 0 to 17 (95% CI 0 to 2)) in adjacent colon mucosa ( P = 0.004). Hypermethylation of the p14 ARF promoter was significantly correlated with the restricted p53 overexpression pattern ( P = 0.03), and MDM2 overexpression (P = 0.02), independently of MSI phenotype. Although no significant correlation between p14 ARF methylation and TP53 mutational status was seen ( P = 0.23), methylation involving the proximal CpG sites within the 5′ CpG flanking exon 1β was present more frequently in tumors with restricted p53 overexpression than in those with diffuse p53 overexpression (range of methylated clones 17 to 36% (95% CI 24 to 36%) versus range 0 to 3% (95% CI 0 to 3%), P = 0. 0003). Conclusion p14 ARF epigenetic silencing may represent an important deregulating mechanism of the p53-MDM2-p14 ARF pathway in CRCs exhibiting a restricted p53 overexpression pattern.

Early detection of hypertension in children with autosomal polycystic kidney disease (ADPKD) may be beneficial, but screening children at risk of ADPKD remains controversial. We investigated determinants of hypertension in children with ADPKD to help identify a subgroup of children at risk of ADPKD for whom screening for the disease and/or its complications would be more relevant. In a retrospective study including consecutive children with ADPKD aged 5–18 years and followed at Saint-Luc Hospital Brussels between 2006 and 2020, we investigated the potential association between genotype, clinical characteristics and parental phenotype, and presence of hypertension. Hypertension was defined as blood pressure > P95 during 24-h ambulatory monitoring or anti-hypertensive therapy use. Parental phenotype was considered severe based on age at kidney failure, Mayo Clinic Imaging Classification and rate of eGFR decline. The study enrolled 55 children with ADPKD (mean age 9.9 ± 2.2 years, 45