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UNSTRUCTURED Previously, Thorleifsson et al. published a paper on Nature Genetics titled "Sequence variants in the CLDN14 gene associate with kidney stones and bone mineral density" which did not use standard HGVS nomenclature to report their data, causing confusion among the genetics community. In this paper, we proposed to re-represent the data complying with HGVS standards. More specifically, to report all variants using the forwards strand.

ObjectiveTo explore the frequency of occurrence of extra-renal manifestations associated with monogenic kidney stone diseases.MethodsA literature review was conducted to identify genes that are well-established monogenic causes of nephrolithiasis. The Online Mendelian Inheritance in Man (OMIM) and Human Protein Atlas (HPA) databases were used to identify associated diseases and their properties. Disease phenotypes were ascertained using OMIM clinical synopses and sorted into 24 different phenotype categories as classified in OMIM. Disease phenotypes caused by the same gene were merged into a single gene-associated phenotype (GAP) unit such that one GAP encompasses all related disease phenotypes for a specific gene. We measured the total number of GAPs involving each phenotype category and determined the median phenotype category. Phenotype categories were classified as overrepresented or underrepresented if the number of GAPs involving them was higher or lower than the median, respectively. A chi-square test was conducted to determine whether the number of GAPs affecting a given category significantly deviated from the median.ResultsFifty-five genes were identified as monogenic causes of nephrolithiasis. All GAPs comprised at least one extra-renal phenotype category. The median phenotype category was part of 10 (18%) unique GAPs. A total of 6 significantly overrepresented (growth, skeletal, neurologic, abdomen/gastrointestinal, muscle, metabolic features) and 5 significantly underrepresented (mouth, voice, neck, immunology, neoplasia) phenotype categories were identified among our group of monogenic kidney stone diseases (pConclusionMonogenic nephrolithiasis is a multi-system disorder. Recognizing the extra-renal manifestations associated with monogenic causes of kidney stones is critical for earlier diagnosis and optimal prognosis in patients.

BackgroundCystine stone is a Mendelian genetic disease caused bySLC3A1orSLC7A9. In this study, we aimed to estimate the genetic prevalence of cystine stones and compare it with the clinical prevalence to better understand the disease etiology.MethodsWe analyzed genetic variants in the general population using the 1000 Genomes project and the Human Gene Mutation Database to extract allSLC3A1andSLC7A9pathogenic variants. All variants procured from both databases were intersected. Pathogenic allele frequency, carrier rate, and affected rate were calculated and estimated based on Hardy-Weinberg equilibrium.ResultsWe found that 9 uniqueSLC3A1pathogenic variants were carried by 26 people and 5 uniqueSLC7A9pathogenic variants were carried by 12 people, all of whom were heterozygote carriers. No homozygote, compound heterozygote, or double heterozygote was identified in the 1000 Genome database. Based on the Hardy-Weinberg equilibrium, the calculated genetic prevalence of cystine stone disease is 1 in 30,585.ConclusionThe clinical prevalence of cystine stone has been previously reported as 1 in 7,000, a notably higher figure than the genetic prevalence of 1 in 30,585 calculated in this study. This suggests that the etiology of cystine stone is more complex than what our current genetic knowledge can explain. Possible factors that may contribute to this difference include novel causal genes, undiscovered pathogenic variants, alternative inheritance models, founder effects, epigenetic modifications, environmental factors, or other modifying factors. Further investigation is needed to fully understand the etiology of cystine stone.

BackgroundCystinosis is a metabolic disease characterized by the accumulation of cystine most often presenting in an infantile nephropathic form caused by pathogenic variants in theCTNSgene. It is characterized by progressive loss of glomerular function leading to renal failure by the first decade of life, making early diagnosis crucial to improving outcomes. This study seeks to estimate the prevalence of cystinosis using a population genetics approach.MethodsThe Human Genome Mutation Database (HGMD) was used to identify known pathogenic variants inCTNS, and the 1000 Genomes (1KG) database was used to identifyCTNSvariants in a cohort representing a healthy population. These two databases were intersected to identify disease-causing variants and their carriers in the general population. The Hardy-Weinberg equilibrium was used to calculate expected carrier and affected rates for cystinosis.ResultsThe allele frequency for all disease-causing alleles was calculated to be 0.016. The predicted affected rate was calculated to be 0.00027 (approximately 1:3680), and the predicted carrier rate was 0.032 (approximately 1:30).ConclusionCompared to the reported clinical prevalence of between 1 in 100,000 to 1 in 200,000, the prevalence of cystinosis in this study was calculated to be 1 in 3,680. This significantly higher result may be due to the underdiagnosis of cystinosis or variable expressivity of variants presenting with a broad range of disease severity. These results support the proposal of newborn screening for early diagnosis and improved outcomes in infantile nephropathic cystinosis.

BACKGROUND: Spina bifida (SB) is the second most common nonlethal congenital malformation. The existence of monogenic SB mouse models and human monogenic syndromes with SB features indicate that human SB may be caused by monogenic genes. We hypothesized that whole exome sequencing (WES) allows identification of potential candidate genes by i) generating a list of 136 candidate genes for SB, and ii) by unbiased exome-wide analysis. METHODS: We generated a list of 136 potential candidate genes from three categories: and evaluated WES data of 50 unrelated SB cases for likely deleterious variants in 136 potential candidate genes, and for potential SB candidate genes exome-wide. RESULTS: We identified 6 likely deleterious variants in 6 of the 136 potential SB candidate genes in 6 of the 50 SB cases, whereof 4 genes were derived from mouse models, 1 gene was derived from human non-syndromic SB, and 1 gene was derived from candidate genes known to cause human syndromic SB. In addition, by unbiased exome-wide analysis, we identified 12 genes as potential candidates for SB. CONCLUSIONS: Identification of these 18 potential candidate genes in larger SB cohorts will help decide which ones can be considered as novel monogenic causes of human SB.

Nephrolithiasis (NL) affects 1 in 11 individuals worldwide, leading to significant patient morbidity. NL is associated with nephrocalcinosis (NC), a risk factor for chronic kidney disease. Causative genetic variants are detected in 11-28% of NL and/or NC, suggesting additional NL/NC-associated genetic loci await discovery. Therefore, we employed genomic approaches to discover novel genetic forms of NL/NC.Exome sequencing and directed sequencing of the OXGR1 locus were performed in a worldwide NL/NC cohort. Putatively deleterious rare OXGR1 variants were functionally characterized.Exome sequencing revealed a heterozygous OXGR1 missense variant (c.371TG, p.L124R) co-segregating with calcium oxalate NL and/or NC disease in an autosomal dominant inheritance pattern within a multi-generational family with five affected individuals. OXGR1 encodes 2-oxoglutarate (α-ketoglutarate) receptor 1 in the distal nephron. In response to its ligand α-ketoglutarate (AKG), OXGR1 stimulates the chloride-bicarbonate exchanger Pendrin, which also regulates transepithelial calcium transport in cortical connecting tubules. Strong amino acid conservation in orthologues and paralogues, severe in silico prediction scores, and extreme rarity in exome population databases suggested the variant was deleterious. Interrogation of the OXGR1 locus in 1107 additional NL/NC families identified five additional deleterious dominant variants in five families with calcium oxalate NL/NC. Rare, potentially deleterious OXGR1 variants were enriched in NL/NC subjects relative to ExAC controls (ΧRare, dominant loss-of-function OXGR1 variants are associated with recurrent calcium oxalate NL/NC disease.

The contribution of genetic factors to the presence of an overactive bladder is recognized. This study aimed to (1) assemble and synthesize available data from studies assessing differential gene expression in patients with overactive bladder vs controls without overactive bladder and (2) determine possible correlations and functional pathways between genes.We searched PubMed, Ovid or Medline, and Wiley Cochrane Central Register of Controlled Trials databases between January 1, 2000, and December 15, 2021.Studies were included if gene expression was detected and quantified using molecular approaches performed on human bladder tissue specimens directly and excluded if the gene expression analysis was carried out from blood and urine specimens alone.A systematic review was completed to identify publications that reported differently expressed gene candidates among patients with overactive bladder vs healthy individuals. Gene networking connections and pathway analysis were performed employing Metascape software, where inputs were identified from our systematic review of differentially expressed genes in overactive bladder.A total of 9 studies were included in the final analysis and 11 genes were identified as being up-regulated (purinergic receptor P2X 2 [P2RX2], smoothelin [SMTN], growth-associated protein 43 [GAP43], transient receptor potential cation channel subfamily M member 8 [TRPM8], cadherin 11 [CDH1], gap junction protein gamma 1 [GJC1], cholinergic receptor muscarinic 2 [CHRM2], cholinergic receptor muscarinic 3 [CHRM3], and transient receptor potential cation channel subfamily V member 4 [TRPV4]) or down-regulated (purinergic receptor P2X 2 [P2RX3] and purinergic receptor P2X 5 [P2RX5]) in patients with overactive bladder. Gene network analysis showed that genes are involved in chemical synaptic transmission, smooth muscle contraction, blood circulation, and response to temperature stimulus. Network analysis demonstrated a significant genetic interaction between TRPV4, TRPM8, P2RX3, and PR2X2 genes.Outcomes of this systematic review highlighted potential biomarkers for treatment efficacy and have laid the groundwork for developing future gene therapies for overactive bladder in clinical settings.

BackgroundCongenital anomalies of the kidneys and urinary tract (CAKUT) constitute the most common cause of chronic kidney disease in the first three decades of life. Variants in four Forkhead box (FOX) transcription factors have been associated with CAKUT. We hypothesized that other FOX genes, if highly expressed in developing kidneys, may also represent monogenic causes of CAKUT.MethodsWe here performed whole-exome sequencing (WES) in 541 families with CAKUT and generated four lists of CAKUT candidate genes: (A) 36 FOX genes showing high expression during renal development, (B) 4 FOX genes known to cause CAKUT to validate list A, (C) 80 genes that we identified as unique potential novel CAKUT candidate genes when performing WES in 541 CAKUT families and (D) 175 genes identified from WES as multiple potential novel CAKUT candidate genes.ResultsTo prioritize potential novel CAKUT candidates in the FOX gene family, we overlapped 36 FOX genes (list A) with lists C and D of WES-derived CAKUT candidates. Intersection with list C identified a de novo FOXL2 in-frame deletion in a patient with eyelid abnormalities and ureteropelvic junction obstruction, and a homozygous FOXA2 missense variant in a patient with horseshoe kidney. Intersection with list D identified a heterozygous FOXA3 missense variant in a CAKUT family with multiple affected individuals.ConclusionsWe hereby identified FOXL2, FOXA2 and FOXA3 as novel monogenic candidate genes of CAKUT, supporting the utility of a paralog-based approach to discover mutated genes associated with human disease.

International audience; Congenital anomalies of the kidney and urinary tract (CAKUT) constitute one of the most frequent birth defects and represent the most common cause of chronic kidney disease in the first three decades of life. Despite the discovery of dozens of monogenic causes of CA-KUT, most pathogenic pathways remain elusive. We performed whole-exome sequencing (WES) in 551 individuals with CAKUT and identified a heterozygous de novo stop-gain variant in ZMYM2 in two different families with CAKUT. Through collaboration, we identified in total 14 different heterozygous loss-of-function mutations in ZMYM2 in 15 unrelated families. Most mutations occurred de novo, indicating possible interference with reproductive function. Human disease features are replicated in X. tropicalis larvae with morpho-lino knockdowns, in which expression of truncated ZMYM2 proteins, based on individual mutations, failed to rescue renal and cranio-facial defects. Moreover, heterozygous Zmym2-deficient mice recapitulated features of CAKUT with high penetrance. The ZMYM2 protein is a component of a transcriptional corepressor complex recently linked to the silencing of developmentally regulated endoge-nous retrovirus elements. Using protein-protein interaction assays, we show that ZMYM2 interacts with additional epigenetic silencing complexes, as well as confirming that it binds to FOXP1, a transcription factor that has also been linked to CAKUT. In summary, our findings establish that loss-of-function mutations of ZMYM2, and potentially that of other proteins in its interactome, as causes of human CAKUT, offering new routes for studying the pathogenesis of the disorder.

Purpose Congenital anomalies of the kidneys and urinary tract (CAKUT) constitute the leading cause of chronic kidney disease in children. In total, 174 monogenic causes of isolated or syndromic CAKUT are known. However, syndromic features may be overlooked when the initial clinical diagnosis of CAKUT is made. We hypothesized that the yield of a molecular genetic diagnosis by exome sequencing (ES) can be increased by applying reverse phenotyping, by re-examining the case for signs/symptoms of the suspected clinical syndrome that results from the genetic variant detected by ES. Methods We conducted ES in an international cohort of 731 unrelated families with CAKUT. We evaluated ES data for variants in 174 genes, in which variants are known to cause isolated or syndromic CAKUT. In cases in which ES suggested a previously unreported syndromic phenotype, we conducted reverse phenotyping. Results In 83 of 731 (11.4%) families, we detected a likely CAKUT-causing genetic variant consistent with an isolated or syndromic CAKUT phenotype. In 19 of these 83 families (22.9%), reverse phenotyping yielded syndromic clinical findings, thereby strengthening the genotype–phenotype correlation. Conclusion We conclude that employing reverse phenotyping in the evaluation of syndromic CAKUT genes by ES provides an important tool to facilitate molecular genetic diagnostics in CAKUT.

PURPOSE: Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of chronic kidney disease in childhood and adolescence. We aim to identify novel monogenic causes of CAKUT. METHODS: Exome sequencing was performed in 550 CAKUT-affected families. RESULTS: We discovered seven FOXC1 heterozygous likely pathogenic variants within eight CAKUT families. These variants are either never reported, or present in