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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.

Background Nephrolithiasis (NL) affects 1 in 11 individuals worldwide and causes significant morbidity and cost. Common variants in the calcium sensing receptor gene (CaSR) have been associated with NL. Rare inactivating CaSR variants classically cause hyperparathyroidism, hypercalcemia and hypocalciuria. However, NL and familial hypercalciuria have been paradoxically associated with select inactivating CaSR variants in three kindreds from Europe and Australia. Methods To discover novel NL-associated CaSR variants from a geographically distinct cohort, 57 Pakistani families presenting with pediatric onset NL were recruited. The CaSR locus was analyzed by directed or exome sequencing. Results We detected a heterozygous and likely pathogenic splice variant (GRCh37 Chr3:122000958A>G; GRCh38 Chr3:12228211A>G; NM_000388:c.1609-2A>G) in CaSR in one family with recurrent calcium oxalate stones. This variant would be predicted to cause exon skipping and premature termination (p.Val537Metfs*49). Moreover, a splice variant of unknown significance in an alternative CaSR transcript (GRCh37 Chr3:122000929G>C; GRCh38 Chr3:122282082G >C NM_000388:c.1609-31G >C NM_001178065:c.1609-1G >C) was identified in two additional families. Conclusions Sequencing of the CaSR locus in Pakistani stone formers reveals a novel loss-of-function variant, expanding the connection between the CaSR locus and nephrolithiasis.

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