Persistent Disease Activity in Patients With Long-Standing Glomerular Disease

Introduction: Glomerular diseases are characterized by variable disease activity over many years. We aimed to analyze the relationship between clinical disease activity and duration of glomerular disease. Methods: Disease activity in adults with chronic minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, and IgA nephropathy (IgAN; first diagnostic biopsy >5 years before enrollment; Of Longstanding Disease [OLD] cohort, n = 256) followed at Columbia University Medical Center (CUMC), was compared with disease activity of an internal and external cohort of patients with first diagnostic biopsy <5 years before enrollment drawn from the Cure Glomerulonephropathy Network (CureGN cohort, n = 1182; CUMC-CureGN cohort, n = 362). Disease activity was defined by (i) Kidney Disease: Improving Global Outcomes–recommended threshold criteria for initiation of immunosuppression in primary glomerulonephropathy (GN) and (ii) CureGN's Disease Activity Working Group definitions for activity. Results: No significant differences were detected among the 3 cohorts in terms of age, sex, serum creatinine, and urinary protein-to-creatinine ratio. For each GN subtype, disease activity in the OLD cohort was comparable with disease activity in the entire CureGN and the CUMC-CureGN cohort. When limiting our comparisons to disease activity in incident CUMC-CureGN patients (first diagnostic biopsy within 6 months of enrollment), OLD patients demonstrated similar activity rates as incident patients. Conclusion: Disease activity did not differ among patients with shorter versus longer duration of disease. Such survivor patients, with long-term but persistent disease, are potentially highly informative for understanding the clinical course and pathogenesis of GN and may help identify factors mediating more chronic subtypes of disease

Genetic drivers of kidney defects in the digeorge syndrome

BACKGROUND The DiGeorge syndrome, the most common of the microdeletion syndromes, affects multiple organs, including the heart, the nervous system, and the kidney. It is caused by deletions on chromosome 22q11.2; the genetic driver of the kidney defects is unknown. METHODS We conducted a genomewide search for structural variants in two cohorts: 2080 patients with congenital kidney and urinary tract anomalies and 22,094 controls. We performed exome and targeted resequencing in samples obtained from 586 additional patients with congenital kidney anomalies. We also carried out functional studies using zebrafish and mice. RESULTS We identified heterozygous deletions of 22q11.2 in 1.1% of the patients with congenital kidney anomalies and in 0.01% of population controls (odds ratio, 81.5; P = 4.5×1014). We localized the main drivers of renal disease in the DiGeorge syndrome to a 370-kb region containing nine genes. In zebrafish embryos, an induced loss of function in snap29, aifm3, and crkl resulted in renal defects; the loss of crkl alone was sufficient to induce defects. Five of 586 patients with congenital urinary anomalies had newly identified, heterozygous protein-Altering variants, including a premature termination codon, in CRKL. The inactivation of Crkl in the mouse model induced developmental defects similar to those observed in patients with congenital urinary anomalies. CONCLUSIONS We identified a recurrent 370-kb deletion at the 22q11.2 locus as a driver of kidney defects in the DiGeorge syndrome and in sporadic congenital kidney and urinary tract anomalies. Of the nine genes at this locus, SNAP29, AIFM3, and CRKL appear to be critical to the phenotype, with haploinsufficiency of CRKL emerging as the main genetic driver

Cerebral changes during exercise in the heat

Copy number variations associate with different developmental phenotypes and represent a major cause of congenital anomalies of the kidney and urinary tract (CAKUT). Because rare pathogenic copy number variations are often large and contain multiple genes, identification of the underlying genetic drivers has proven to be difficult. Here we studied the role of rare copy number variations in 80 patients from the KIMONO study cohort for which pathogenic mutations in three genes commonly implicated in CAKUT were excluded. In total, 13 known or novel genomic imbalances in 11 of 80 patients were absent or extremely rare in 23,362 population controls. To identify the most likely genetic drivers for the CAKUT phenotype underlying these rare copy number variations, we used a systematic in silico approach based on frequency in a large data set of controls, annotation with publicly available databases for developmental diseases, tolerance and haploinsufficiency scores, and gene expression profile in the developing kidney and urinary tract. Five novel candidate genes for CAKUT were identified that showed specific expression in the human and mouse developing urinary tract. Among these genes, DLG1 and KIF12 are likely novel susceptibility genes for CAKUT in humans. Thus, there is a significant role of genomic imbalance in the determination of kidney developmental phenotypes. Additionally, we defined a systematic strategy to identify genetic drivers underlying rare copy number variations

Localization of a gene for nonsyndromic renal hypodysplasia to chromosome 1p32-33.

Nonsyndromic defects in the urinary tract are the most common cause of end-stage renal failure in children and account for a significant proportion of adult nephropathy. The genetic basis of these disorders is not fully understood. We studied seven multiplex kindreds ascertained via an index case with a nonsyndromic solitary kidney or renal hypodysplasia. Systematic ultrasonographic screening revealed that many family members harbor malformations, such as solitary kidneys, hypodysplasia, or ureteric abnormalities (in a total of 29 affected individuals). A genomewide scan identified significant linkage to a 6.9-Mb segment on chromosome 1p32-33 under an autosomal dominant model with reduced penetrance (peak LOD score 3.5 at D1S2652 in the largest kindred). Altogether, three of the seven families showed positive LOD scores at this interval, demonstrating heterogeneity of the trait (peak HLOD 3.9, with 45% of families linked). The chromosome 1p32-33 interval contains 52 transcription units, and at least 23 of these are expressed at stage E12.5 in the murine ureteric bud and/or metanephric mesenchyme. These data show that autosomal dominant nonsyndromic renal hypodysplasia and associated urinary tract malformations are genetically heterogeneous and identify a locus for this common cause of human kidney failure

Medical Records-Based Genetic Studies of the Complement System

Background Genetic variants in complement genes have been associated with a wide range of human disease states, but well-powered genetic association studies of complement activation have not been performed in large multiethnic cohorts. Methods We performed medical records?based genome-wide and phenome-wide association studies for plasma C3 and C4 levels among participants of the Electronic Medical Records and Genomics (eMERGE) network. Results In a GWAS for C3 levels in 3949 individuals, we detected two genome-wide significant loci: chr.1q31.3 (CFH locus; rs3753396-A; ?=0.20; 95% CI, 0.14 to 0.25; P=1.52x10(-11)) and chr.19p13.3 (C3 locus; rs11569470-G; ?=0.19; 95% CI, 0.13 to 0.24; P=1.29x10(-8)). These two loci explained approximately 2% of variance in C3 levels. GWAS for C4 levels involved 3998 individuals and revealed a genome-wide significant locus at chr.6p21.32 (C4 locus; rs3135353-C; ?=0.40; 95% CI, 0.34 to 0.45; P=4.58x10(-35)). This locus explained approximately 13% of variance in C4 levels. The multiallelic copy number variant analysis defined two structural genomic C4 variants with large effect on blood C4 levels: C4-BS (?=?0.36; 95% CI, ?0.42 to ?0.30; P=2.98x10(-22)) and C4-AL-BS (?=0.25; 95% CI, 0.21 to 0.29; P=8.11x10(-23)). Overall, C4 levels were strongly correlated with copy numbers of C4A and C4B genes. In comprehensive phenome-wide association studies involving 102,138 eMERGE participants, we cataloged a full spectrum of autoimmune, cardiometabolic, and kidney diseases genetically related to systemic complement activation. Conclusions We discovered genetic determinants of plasma C3 and C4 levels using eMERGE genomic data linked to electronic medical records. Genetic variants regulating C3 and C4 levels have large effects and multiple clinical correlations across the spectrum of complement-related diseases in humans.Significance Statement The complement pathway represents one of the critical arms of the innate immune system. We combined genome-wide and phenome-wide association studies using medical records data for C3 and C4 levels to discover common genetic variants controlling systemic complement activation. Three genome-wide significant loci had large effects on complement levels. These loci encode three critical complement genes: CFH, C3, and C4. We performed detailed functional annotations of the significant loci, including multiallelic copy number variant analysis of the C4 locus to define two structural genomic variants with large effects on C4 levels. Blood C4 levels were strongly correlated with the copy number of C4A and C4B genes. Lastly, using genome-wide genetic correlations and electronic health records?based phenome-wide association studies in 102,138 participants, we catalogued a spectrum of human diseases genetically related to systemic complement activation, including inflammatory, autoimmune, cardiometabolic, and kidney diseases.Pathophysiology and treatment of rheumatic disease

Exome sequencing identified MYO1E and NEIL1 as candidate genes for human autosomal recessive steroid-resistant nephrotic syndrome

To identify gene loci associated with steroid-resistant nephrotic syndrome (SRNS), we utilized homozygosity mapping and exome sequencing in a consanguineous pedigree with three affected siblings. High-density genotyping identified three segments of homozygosity spanning 33.6\u2009Mb on chromosomes 5, 10, and 15 containing 296 candidate genes. Exome sequencing identified two homozygous missense variants within the chromosome 15 segment; an A159P substitution in myosin 1E (MYO1E), encoding a podocyte cytoskeletal protein; and an E181K substitution in nei endonuclease VIII-like 1 (NEIL1), encoding a base-excision DNA repair enzyme. Both variants disrupt highly conserved protein sequences and were absent in public databases, 247 healthy controls, and 286 patients with nephrotic syndrome. The MYO1E A159P variant is noteworthy, as it is expected to impair ligand binding and actin interaction in the MYO1E motor domain. The predicted loss of function is consistent with the previous demonstration that Myo1e inactivation produces nephrotic syndrome in mice. Screening 71 additional patients with SRNS, however, did not identify independent NEIL1 or MYO1E mutations, suggesting larger sequencing efforts are needed to uncover which mutation is responsible for the phenotype. Our findings demonstrate the utility of exome sequencing for rapidly identifying candidate genes for human SRNS

Mutations in DSTYK

BACKGROUND: Congenital abnormalities of the kidney and the urinary tract are the most common cause of pediatric kidney failure. These disorders are highly heterogeneous, and the etiologic factors are poorly understood. METHODS: We performed genomewide linkage analysis and whole-exome sequencing in a family with an autosomal dominant form of congenital abnormalities of the kidney or urinary tract (seven affected family members). We also performed a sequence analysis in 311 unrelated patients, as well as histologic and functional studies. RESULTS: Linkage analysis identified five regions of the genome that were shared among all affected family members. Exome sequencing identified a single, rare, deleterious variant within these linkage intervals, a heterozygous splice-site mutation in the dual serine–threonine and tyrosine protein kinase gene (DSTYK). This variant, which resulted in aberrant splicing of messenger RNA, was present in all affected family members. Additional, independent DSTYK mutations, including nonsense and splice-site mutations, were detected in 7 of 311 unrelated patients. DSTYK is highly expressed in the maturing epithelia of all major organs, localizing to cell membranes. Knockdown in zebrafish resulted in developmental defects in multiple organs, which suggested loss of fibroblast growth factor (FGF) signaling. Consistent with this finding is the observation that DSTYK colocalizes with FGF receptors in the ureteric bud and metanephric mesenchyme. DSTYK knockdown in human embryonic kidney cells inhibited FGF-stimulated phosphorylation of extracellular-signal-regulated kinase (ERK), the principal signal downstream of receptor tyrosine kinases. CONCLUSIONS: We detected independent DSTYK mutations in 2.3% of patients with congenital abnormalities of the kidney or urinary tract, a finding that suggests that DSTYK is a major determinant of human urinary tract development, downstream of FGF signaling. (Funded by the National Institutes of Health and others.