The genetic architecture of membranous nephropathy and its potential to improve non-invasive diagnosis Jingyuan Xie et al. # Membranous Nephropathy (MN) is a rare autoimmune cause of kidney failure. Here we report a genome-wide association study (GWAS) for primary MN in 3,782 cases and 9,038 controls of East Asian and European ancestries. We discover two previously unreported loci, NFKB1

Background/Aims: Calcium homeostasis requires regulated cellular and interstitial systems interacting to modulate the activity and movement of this ion. Disruption of these systems in the kidney results in nephrocalcinosis and nephrolithiasis, important medical problems whose pathogenesis is incompletely understood. Methods: We investigated 25 patients from 16 families with unexplained nephrocalcinosis and characteristic dental defects (amelogenesis imperfecta, gingival hyperplasia, impaired tooth eruption). To identify the causative gene, we performed genome-wide linkage analysis, exome capture, next-generation sequencing, and Sanger sequencing. Results: All patients had bi-allelic FAM20A mutations segregating with the disease; 20 different mutations were identified. Conclusions: This au-tosomal recessive disorder, also known as enamel renal syndrome, of FAM20A causes nephrocalcinosis and amelogenesis imperfecta. We speculate that all individuals with biallelic FAM20A mutations will eventually show nephrocalcinosis.

General rightsThis document is made available in accordance with publisher policies. Please cite only the published version using the reference above. We propose that the promoter mutation alters tissue-specific chromatin loop formation with consequent organ-specific deficiency of PMM2 leading to the restricted phenotype of HIPKD. Our findings extend the spectrum of genetic 5 causes for both HI and PKD and provide insights into gene regulation and PMM2 pleiotropy.6

BackgroundSteroid-sensitive nephrotic syndrome (SSNS), the most common form of nephrotic syndrome in childhood, is considered an autoimmune disease with an established classic HLA association. However, the precise etiology of the disease is unclear. In other autoimmune diseases, the identification of loci outside the classic HLA region by genome-wide association studies (GWAS) has provided critical insights into disease pathogenesis. Previously conducted GWAS of SSNS have not identified non-HLA loci achieving genome-wide significance.MethodsIn an attempt to identify additional loci associated with SSNS, we conducted a GWAS of a large cohort of European ancestry comprising 422 ethnically homogeneous pediatric patients and 5642 ethnically matched controls.ResultsThe GWAS found three loci that achieved genome-wide significance, which explain approximately 14% of the genetic risk for SSNS. It confirmed the previously reported association with the HLA-DR/DQ region (lead single-nucleotide polymorphism [SNP] rs9273542, P=1.59×10−43; odds ratio [OR], 3.39; 95% confidence interval [95% CI], 2.86 to 4.03) and identified two additional loci outside the HLA region on chromosomes 4q13.3 and 6q22.1. The latter contains the calcium homeostasis modulator family member 6 gene CALHM6 (previously called FAM26F). CALHM6 is implicated in immune response modulation; the lead SNP (rs2637678, P=1.27×10−17; OR, 0.51; 95% CI, 0.44 to 0.60) exhibits strong expression quantitative trait loci effects, the risk allele being associated with lower lymphocytic expression of CALHM6.ConclusionsBecause CALHM6 is implicated in regulating the immune response to infection, this may provide an explanation for the typical triggering of SSNS onset by infections. Our results suggest that a genetically conferred risk of immune dysregulation may be a key component in the pathogenesis of SSNS.

BackgroundWhilst still rare, the incidence of paediatric stone disease is increasing in developed countries and it is important to evaluate the aetiology. We set up a dedicated renal stone service for children combining medical and surgical expertise in 1993 and now have a large case series of children to investigate the epidemiology.MethodsA retrospective hospital note review of children presenting with kidney stones during the last 22 years (1993–2015) was conducted. All patients had a comprehensive infective and metabolic screen and were classified as metabolic, infective or idiopathic stone disease.ResultsFive hundred eleven patients (322 male) were reviewed. The median age of presentation was 4.4y for males (1 m-16.6y) and 7.3y (1–18.5y) for females with a median height and weight on the 25th centile for male and on 10th and 25th for female, respectively. One hundred seventy five (34%) had an underlying metabolic abnormality, 112 (22%) had infective stones and 224 (44%) were classified as idiopathic.Of the 175 patients with a metabolic abnormality: 91 (52%) had hypercalciuria (76 persistent and 15 transient), 37 (21%) hyperoxaluria, 38 (22%) cystinuria, 3 (2%) abnormalities in the purine metabolism and the remainder other metabolic abnormalities. Bilateral stones occurred in 27% of the metabolic group compared to 16% in the non-metabolic group (OR 0.2, p < 0.05). Urinary tract infection was a common complication (27%) in the metabolic group.ConclusionsIn this paper, we present the largest cohort of paediatric stone disease reported from a developed country giving details on both, clinical and laboratory data. We show that in the majority of the patients there is an identifiable underlying metabolic and/or infective aetiology emphasizing the importance of a full work up to provide adequate treatment and prevent recurrence. Moreover, we show that stone disease in children, in contrast to the adult population, does not seem to be associated with obesity, as children have a weight below average at presentation.