Systemic lupus erythematosus (SLE) is the prototypic systemic autoimmune disease. It is thought that many common variant gene loci of weak effect act additively to predispose to common autoimmune ...diseases, while the contribution of rare variants remains unclear. Here we describe that rare coding variants in lupus-risk genes are present in most SLE patients and healthy controls. We demonstrate the functional consequences of rare and low frequency missense variants in the interacting proteins BLK and BANK1, which are present alone, or in combination, in a substantial proportion of lupus patients. The rare variants found in patients, but not those found exclusively in controls, impair suppression of IRF5 and type-I IFN in human B cell lines and increase pathogenic lymphocytes in lupus-prone mice. Thus, rare gene variants are common in SLE and likely contribute to genetic risk.
Congenital anomalies of the kidney and urinary tract (CAKUT) account for approximately half of children with chronic kidney disease. CAKUT can be caused by monogenic mutations; however, data are ...lacking on their frequency. Genetic diagnosis has been hampered by genetic heterogeneity and lack of genotype–phenotype correlation. To determine the percentage of cases with CAKUT that can be explained by mutations in known CAKUT genes, we analyzed the coding exons of the 17 known dominant CAKUT-causing genes in a cohort of 749 individuals from 650 families with CAKUT. The most common phenotypes in this CAKUT cohort were vesicoureteral reflux in 288 patients, renal hypodysplasia in 120 patients, and unilateral renal agenesis in 90 patients. We identified 37 different heterozygous mutations (33 novel) in 12 of the 17 known genes in 47 patients from 41 of the 650 families (6.3%). These mutations include (number of families): BMP7 (1), CDC5L (1), CHD1L (5), EYA1 (3), GATA3 (2), HNF1B (6), PAX2 (5), RET (3), ROBO2 (4), SALL1 (9), SIX2 (1), and SIX5 (1). Furthermore, several mutations previously reported to be disease-causing are most likely benign variants. Thus, in a large cohort over 6% of families with isolated CAKUT are caused by a mutation in 12 of 17 dominant CAKUT genes. Our report represents one of the most in-depth diagnostic studies of monogenic causes of isolated CAKUT in children.
We present eight cases of the homozygous MCPggaac haplotype, which is considered to increase the likelihood and severity of atypical hemolytic uremic syndrome (aHUS), especially in combination with ...additional risk aHUS mutations. Complement blockade (CBT) was applied at a median age of 92 months (IQR 36–252 months). The median number of relapses before CBT initiation (Eculizumab) was two. Relapses occurred within an average of 22.16 months (median 17.5, minimum 8 months, and maximum 48 months) from the first subsequent onset of the disease (6/8 patients). All cases were treated with PI/PEX, and rarely with renal replacement therapy (RRT). When complement blockade was applied, children had no further disease relapses. Children with MCPggaac haplotype with/without additional gene mutations can achieve remission through renal replacement therapy without an immediate need for complement blockade. If relapse of aHUS occurs soon after disease onset or relapses are repeated frequently, a permanent complement blockade is required. However, the duration of such a blockade remains uncertain. If complement inhibition is not applied within 4–5 relapses, proteinuria and chronic renal failure will eventually occur.
This letter discusses therapeutic disparities between developing countries and developed countries for patients with nephropathic cystinosis, one of a number of rare diseases for which therapy exists ...but is unevenly distributed.
To the Editor:
Nephropathic cystinosis is a rare autosomal recessive lysosomal storage disease that, if untreated, leads to end-stage renal disease (ESRD) in the first decade of life because of intracellular accumulation of cystine caused by mutant cystinosin, the transporter of cystine.
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Since 1979, most patients in developed countries have received cysteamine, which enables the transport of cystine from cells and thus lowers the amount of intracellular cystine. Cysteamine has postponed ESRD and extrarenal manifestations until patients are in their teens or beyond.
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In contrast, patients in developing nations have remained largely untreated, mainly because of limited access . . .
Abstract
Distal renal tubular acidosis (dRTA) is characterized by an impaired ability of the distal tubule to excrete acid, leading to metabolic acidosis. Associated complications include bone ...disease, growth failure, urolithiasis and hypokalaemia. Due to its rarity, there is limited evidence to guide diagnosis and management; however, available data strongly suggest that metabolic control of the acidosis by alkali supplementation can halt or revert almost all complications. Despite this, cohort studies show that adequate metabolic control is present in only about half of patients, highlighting problems with treatment provision or adherence. With these clinical practice points the authors, part of the working groups tubulopathies in the European Rare Kidney Disease Reference network and inherited kidney diseases of the European Society for Paediatric Nephrology, aim to provide guidance for the management of patients with dRTA to facilitate adequate treatment and establish an initial best practice standard against which treatment of patients can be audited.
Although over 50 genes are known to cause renal malformation if mutated, the underlying genetic basis, most easily identified in syndromic cases, remains unsolved in most patients. In search of novel ...causative genes, whole-exome sequencing in a patient with renal, i.e., crossed fused renal ectopia, and extrarenal, i.e., skeletal, eye, and ear, malformations yielded a rare heterozygous variant in the GDF6 gene encoding growth differentiation factor 6, a member of the BMP family of ligands. Previously, GDF6 variants were reported to cause pleiotropic defects including skeletal, e.g., vertebral, carpal, tarsal fusions, and ocular, e.g., microphthalmia and coloboma, phenotypes. To assess the role of GDF6 in the pathogenesis of renal malformation, we performed targeted sequencing in 193 further patients identifying rare GDF6 variants in two cases with kidney hypodysplasia and extrarenal manifestations. During development, gdf6 was expressed in the pronephric tubule of Xenopus laevis, and Gdf6 expression was observed in the ureteric tree of the murine kidney by RNA in situ hybridization. CRISPR/Cas9-derived knockout of Gdf6 attenuated migration of murine IMCD3 cells, an effect rescued by expression of wild-type but not mutant GDF6, indicating affected variant function regarding a fundamental developmental process. Knockdown of gdf6 in Xenopus laevis resulted in impaired pronephros development. Altogether, we identified rare heterozygous GDF6 variants in 1.6% of all renal anomaly patients and 5.4% of renal anomaly patients additionally manifesting skeletal, ocular, or auricular abnormalities, adding renal hypodysplasia and fusion to the phenotype spectrum of GDF6 variant carriers and suggesting an involvement of GDF6 in nephrogenesis.
National service systems in child healthcare are characterized by diversity and complexity. Primary, secondary, tertiary and quaternary healthcare services create complex networks covering pediatric ...subspecialties, psychology, sociology, economics and politics. Can pediatrics exist without philosophy? Does the absence of integrating philosophical perspectives during conceptualization of pediatric care contribute to deficiencies in the service systems structuring child healthcare? Philosophy offers new ways of complex systems thinking in scientific and clinical pediatrics. Philosophy could improve coping strategies on different levels when dealing with ethics of research projects, individual child healthcare and crises of healthcare service systems. Boundary and ultimate situations experienced by severely sick children require help, hope and resilience. Patients and families as well as pediatricians and other caregivers must act in concert. All of them may benefit from consulting with philosophers. The aim of this article is to point out the risks of a strict separation of scientific insight and sensory experience affecting child healthcare in our modern society, which is dominated by technology, competition and lack of equity and time.
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.
...Exome sequencing was performed in 550 CAKUT-affected families.
We discovered seven FOXC1 heterozygous likely pathogenic variants within eight CAKUT families. These variants are either never reported, or present in <5 alleles in the gnomAD database with ~141,456 controls. FOXC1 is a causal gene for Axenfeld–Rieger syndrome type 3 and anterior segment dysgenesis 3. Pathogenic variants in FOXC1 have not been detected in patients with CAKUT yet. Interestingly, mouse models for Foxc1 show severe CAKUT phenotypes with incomplete penetrance and variable expressivity. The FOXC1 variants are enriched in the CAKUT cohort compared with the control. Genotype–phenotype correlations showed that Axenfeld–Rieger syndrome or anterior segment dysgenesis can be caused by both truncating and missense pathogenic variants, and the missense variants are located at the forkhead domain. In contrast, for CAKUT, there is no truncating pathogenic variant, and all variants except one are located outside the forkhead domain.
We thereby expanded the phenotype of FOXC1 pathogenic variants toward involvement of CAKUT, which can potentially be explained by allelism.
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