ABSTRACT
Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of chronic kidney disease (~ 45%) that manifests before 30 years of age. The genetic locus containing COL4A1 (13q33-34) has been implicated in vesicoureteral reflux (VUR), but mutations in COL4A1 have not been reported in CAKUT. We hypothesized that COL4A1 mutations cause CAKUT in humans. We performed whole exome sequencing (WES) in 550 families with CAKUT. As negative control cohorts we used WES sequencing data from patients with nephronophthisis (NPHP) with no genetic cause identified (n = 257) and with nephrotic syndrome (NS) due to monogenic causes (n = 100). We identified a not previously reported heterozygous missense variant in COL4A1 in three siblings with isolated VUR. When examining 549 families with CAKUT, we identified nine additional different heterozygous missense mutations in COL4A1 in 11 individuals from 11 unrelated families with CAKUT, while no COL4A1 mutations were identified in a control cohort with NPHP and only one in the cohort with NS. Most individuals (12/14) had isolated CAKUT with no extrarenal features. The predominant phenotype was VUR (9/14). There were no clinical features of the COL4A1-related disorders (e.g., HANAC syndrome, porencephaly, tortuosity of retinal arteries). Whereas COL4A1-related disorders are typically caused by glycine substitutions in the collagenous domain (84.4% of variants), only one variant in our cohort is a glycine substitution within the collagenous domain (1/10). We identified heterozygous COL4A1 mutations as a potential novel autosomal dominant cause of CAKUT that is allelic to the established COL4A1-related disorders and predominantly caused by non-glycine substitutions.
Subject(s)
Collagen Type IV/genetics , Congenital Abnormalities/diagnosis , Congenital Abnormalities/genetics , Kidney/abnormalities , Mutation , Phenotype , Urinary Tract/abnormalities , Alleles , Amino Acid Substitution , Computational Biology/methods , DNA Mutational Analysis , Databases, Genetic , Evolution, Molecular , Female , Genetic Association Studies , Genetic Loci , Genomics/methods , Heterozygote , Humans , Kidney Diseases, Cystic/diagnosis , Kidney Diseases, Cystic/genetics , Male , Nephrotic Syndrome/diagnosis , Nephrotic Syndrome/genetics , Web Browser , Exome SequencingABSTRACT
BACKGROUND: Congenital anomalies of the kidney and urinary tract (CAKUT) are the most prevalent cause of kidney disease in the first three decades of life. Previous gene panel studies showed monogenic causation in up to 12% of patients with CAKUT. METHODS: We applied whole-exome sequencing to analyze the genotypes of individuals from 232 families with CAKUT, evaluating for mutations in single genes known to cause human CAKUT and genes known to cause CAKUT in mice. In consanguineous or multiplex families, we additionally performed a search for novel monogenic causes of CAKUT. RESULTS: In 29 families (13%), we detected a causative mutation in a known gene for isolated or syndromic CAKUT that sufficiently explained the patient's CAKUT phenotype. In three families (1%), we detected a mutation in a gene reported to cause a phenocopy of CAKUT. In 15 of 155 families with isolated CAKUT, we detected deleterious mutations in syndromic CAKUT genes. Our additional search for novel monogenic causes of CAKUT in consanguineous and multiplex families revealed a potential single, novel monogenic CAKUT gene in 19 of 232 families (8%). CONCLUSIONS: We identified monogenic mutations in a known human CAKUT gene or CAKUT phenocopy gene as the cause of disease in 14% of the CAKUT families in this study. Whole-exome sequencing provides an etiologic diagnosis in a high fraction of patients with CAKUT and will provide a new basis for the mechanistic understanding of CAKUT.
Subject(s)
Exome Sequencing/methods , Genetic Predisposition to Disease/epidemiology , Pedigree , Urogenital Abnormalities/genetics , Vesico-Ureteral Reflux/genetics , Animals , Humans , Incidence , Kidney/abnormalities , Mice , Phenotype , Prognosis , Risk Assessment , Sensitivity and Specificity , Sex Distribution , Urinary Tract/abnormalities , Urogenital Abnormalities/epidemiology , Vesico-Ureteral Reflux/epidemiologyABSTRACT
We investigated the value of genetic, histopathologic, and early treatment response information in prognosing long-term renal outcome in children with primary steroid-resistant nephrotic syndrome. From the PodoNet Registry, we obtained longitudinal clinical information for 1354 patients (disease onset at >3 months and <20 years of age): 612 had documented responsiveness to intensified immunosuppression (IIS), 1155 had kidney biopsy results, and 212 had an established genetic diagnosis. We assessed risk factors for ESRD using multivariate Cox regression models. Complete and partial remission of proteinuria within 12 months of disease onset occurred in 24.5% and 16.5% of children, respectively, with the highest remission rates achieved with calcineurin inhibitor-based protocols. Ten-year ESRD-free survival rates were 43%, 94%, and 72% in children with IIS resistance, complete remission, and partial remission, respectively; 27% in children with a genetic diagnosis; and 79% and 52% in children with histopathologic findings of minimal change glomerulopathy and FSGS, respectively. Five-year ESRD-free survival rate was 21% for diffuse mesangial sclerosis. IIS responsiveness, presence of a genetic diagnosis, and FSGS or diffuse mesangial sclerosis on initial biopsy as well as age, serum albumin concentration, and CKD stage at onset affected ESRD risk. Our findings suggest that responsiveness to initial IIS and detection of a hereditary podocytopathy are prognostic indicators of favorable and poor long-term outcome, respectively, in children with steroid-resistant nephrotic syndrome. Children with multidrug-resistant sporadic disease show better renal survival than those with genetic disease. Furthermore, histopathologic findings may retain prognostic relevance when a genetic diagnosis is established.
Subject(s)
Immunosuppressive Agents/therapeutic use , Kidney Failure, Chronic/etiology , Nephrotic Syndrome/congenital , Adolescent , Child , Child, Preschool , Follow-Up Studies , Humans , Infant , Nephrotic Syndrome/complications , Nephrotic Syndrome/drug therapy , Survival AnalysisABSTRACT
The health care system in Serbia is based on a network of public health institutions funded by the National Health Insurance and from the state budget. Access to public health institutions is free. Preventive and curative services are provided at the local level in primary health care centers. Over the past 5-7 years, the number of pediatricians in primary health care centers decreased because of reduced number of applicants for pediatric training, which endangers the maintenance of the traditional model of pediatric care. Secondary medical care is offered in pediatric departments of local and regional general hospitals or outpatient clinics, and in specialized hospitals for children or adults. Tertiary medical care is provided by inpatient or outpatient subspecialty services in 5 major university children's clinics. The health reforms undertaken in the recent 10 years have aimed at strengthening preventive health care and reducing the overall costs for pediatric care. Current initiatives of the Ministry of Health and national pediatric associations are aimed at reestablishing and strengthening the capacity of the primary pediatric health care model by increasing the number of physicians and developing new processes of care.
Subject(s)
Child Health Services , Child Health , Adolescent , Child , Child, Preschool , Female , Humans , Male , SerbiaABSTRACT
AIM: This studied reviewed renovascular hypertension (RVH) due to renal artery stenosis (RAS) in two Serbian paediatric centres from 2001 to 2013. METHODS: The patients' demographic data, underlying syndromes, blood pressure (BP), antihypertensive treatments and outcomes were reviewed. RESULTS: The incidence of RVH was 1.9 per million children per year during the study period, and there were 25 patients with RAS, aged 10.4 ± 5.2 years. At presentation, their mean blood pressure (BP) standard deviation scores were 6.9 ± 3.4 systolic and 5.2 ± 2.6 diastolic. BP loads on 24-hour ambulatory BP were 88 ± 14% systolic and 80 ± 29% diastolic. We found that 72% had fibromuscular dysplasia and 28% had underlying syndromes. RAS was unilateral in 64% and bilateral in 28%, and 8% had RAS of a single kidney. Antihypertensive treatment included antihypertensive drugs (100%), percutaneous transluminal angioplasty (92%), renal auto-transplantation (16%), surgical revascularisation (12%) and nephrectomy (12%). After 4.4 ± 3.6 years of follow-up, high BP was cured in 40% of the patients and 39.4% of the kidneys and improved in 48% (75.7%), with BP decreases of 20.3 ± 3.7% systolic and 16.3 ± 6.2% diastolic. CONCLUSION: Fibromuscular dysplasia was the most common cause of RVH in this study, and hypertension was cured or improved in 88% of the patients.
Subject(s)
Fibromuscular Dysplasia/complications , Hypertension, Renovascular/therapy , Renal Artery Obstruction/complications , Adolescent , Antihypertensive Agents/therapeutic use , Child , Child, Preschool , Combined Modality Therapy , Female , Fibromuscular Dysplasia/diagnosis , Follow-Up Studies , Humans , Hypertension, Renovascular/diagnosis , Hypertension, Renovascular/epidemiology , Hypertension, Renovascular/etiology , Kidney Transplantation , Male , Nephrectomy , Renal Artery Obstruction/diagnosis , Retrospective Studies , Serbia/epidemiology , Treatment OutcomeABSTRACT
Schimke immuno-osseous dysplasia (SIOD) is an autosomal recessive, fatal childhood disorder associated with skeletal dysplasia, renal dysfunction, and T-cell immunodeficiency. This disease is linked to biallelic loss-of-function mutations of the SMARCAL1 gene. Although recurrent infection, due to T-cell deficiency, is a leading cause of morbidity and mortality, the etiology of the T-cell immunodeficiency is unclear. Here, we demonstrate that the T cells of SIOD patients have undetectable levels of protein and mRNA for the IL-7 receptor alpha chain (IL7Rα) and are unresponsive to stimulation with IL-7, indicating a loss of functional receptor. No pathogenic mutations were detected in the exons of IL7R in these patients; however, CpG sites in the IL7R promoter were hypermethylated in SIOD T cells. We propose therefore that the lack of IL7Rα expression, associated with hypermethylation of the IL7R promoter, in T cells and possibly their earlier progenitors, restricts T-cell development in SIOD patients.
Subject(s)
Arteriosclerosis/genetics , Immunologic Deficiency Syndromes/genetics , Nephrotic Syndrome/genetics , Osteochondrodysplasias/genetics , Pulmonary Embolism/genetics , Receptors, Interleukin-7/genetics , T-Lymphocytes/metabolism , Adolescent , Adult , Arteriosclerosis/metabolism , Arteriosclerosis/pathology , Cells, Cultured , Child , Child, Preschool , DNA Helicases/genetics , DNA Methylation , Flow Cytometry , Gene Expression , Humans , Immunohistochemistry , Immunologic Deficiency Syndromes/metabolism , Immunologic Deficiency Syndromes/pathology , Interleukin-17/pharmacology , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/metabolism , Mutation , Nephrotic Syndrome/metabolism , Nephrotic Syndrome/pathology , Osteochondrodysplasias/metabolism , Osteochondrodysplasias/pathology , Primary Immunodeficiency Diseases , Promoter Regions, Genetic/genetics , Pulmonary Embolism/metabolism , Pulmonary Embolism/pathology , Receptors, Interleukin-7/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Sequence Analysis, DNA , Young AdultABSTRACT
Congenital anomalies of the kidney and urinary tract (CAKUT) account for 40-50% of chronic kidney disease that manifests in the first two decades of life. Thus far, 31 monogenic causes of isolated CAKUT have been described, explaining ~12% of cases. To identify additional CAKUT-causing genes, we performed whole-exome sequencing followed by a genetic burden analysis in 26 genetically unsolved families with CAKUT. We identified two heterozygous mutations in SRGAP1 in 2 unrelated families. SRGAP1 is a small GTPase-activating protein in the SLIT2-ROBO2 signaling pathway, which is essential for development of the metanephric kidney. We then examined the pathway-derived candidate gene SLIT2 for mutations in cohort of 749 individuals with CAKUT and we identified 3 unrelated individuals with heterozygous mutations. The clinical phenotypes of individuals with mutations in SLIT2 or SRGAP1 were cystic dysplastic kidneys, unilateral renal agenesis, and duplicated collecting system. We show that SRGAP1 is expressed in early mouse nephrogenic mesenchyme and that it is coexpressed with ROBO2 in SIX2-positive nephron progenitor cells of the cap mesenchyme in developing rat kidney. We demonstrate that the newly identified mutations in SRGAP1 lead to an augmented inhibition of RAC1 in cultured human embryonic kidney cells and that the SLIT2 mutations compromise the ability of the SLIT2 ligand to inhibit cell migration. Thus, we report on two novel candidate genes for causing monogenic isolated CAKUT in humans.
Subject(s)
GTPase-Activating Proteins , Intercellular Signaling Peptides and Proteins , Mutation , Nerve Tissue Proteins , Receptors, Immunologic , Signal Transduction/genetics , Urogenital Abnormalities , Vesico-Ureteral Reflux , Animals , Exome , GTPase-Activating Proteins/biosynthesis , GTPase-Activating Proteins/genetics , HEK293 Cells , Humans , Intercellular Signaling Peptides and Proteins/biosynthesis , Intercellular Signaling Peptides and Proteins/metabolism , Mesoderm/metabolism , Mice , Nerve Tissue Proteins/biosynthesis , Nerve Tissue Proteins/metabolism , Rats , Receptors, Immunologic/biosynthesis , Receptors, Immunologic/genetics , Receptors, Immunologic/metabolism , Risk Factors , Urogenital Abnormalities/embryology , Urogenital Abnormalities/genetics , Vesico-Ureteral Reflux/embryology , Vesico-Ureteral Reflux/geneticsABSTRACT
BACKGROUND: Schimke immuno-osseous dysplasia (SIOD) is an autosomal recessive disorder caused by mutations in SMARCAL1. A frequent complication is arteriosclerosis associated with reduced elastin expression; however, the mechanism underlying the reduced elastin expression remains unknown. METHODS: Expression of transcriptional regulators of elastin (ELN) and microRNA (miRNA) regulators of ELN messenger RNA (mRNA), ELN promoter methylation, and ELN mRNA poly(A) tail length were assessed by quantitative RT-PCR, bisulfite Sanger sequencing, and the Poly(A) Tail Length Assay Kit, respectively, in unaffected developing human aortae and in an SIOD aorta. RESULTS: Comparing unaffected fetal and adult aortae, ELN precursor mRNA (pre-mRNA) levels remained nearly constant, whereas mRNA levels declined by ~10(2)-fold. This corresponded with a reduction in poly(A) tail length but not with changes in the other parameters. In contrast, compared to the unaffected fetal aortae, the SIOD aorta had 18-fold less ELN pre-mRNA and 10(4)-fold less mRNA. This corresponded with increased expression of miRNA regulators and shorter ELN mRNA poly(A) tail lengths but not with altered expression of ELN transcriptional regulators or ELN promoter methylation. CONCLUSION: Posttranscriptional mechanisms account for the reduction in ELN mRNA levels in unaffected aortae, whereas transcriptional and posttranscriptional mechanisms reduce elastin expression in SIOD aorta and predispose to arteriosclerosis.
Subject(s)
Aorta/metabolism , Arteriosclerosis/genetics , Elastin/genetics , Immunologic Deficiency Syndromes/genetics , Nephrotic Syndrome/genetics , Osteochondrodysplasias/genetics , Pulmonary Embolism/genetics , RNA Precursors/genetics , RNA Processing, Post-Transcriptional , RNA, Messenger/genetics , Transcription, Genetic , Adolescent , Adult , Aorta/embryology , Aorta/pathology , Arteriosclerosis/embryology , Arteriosclerosis/metabolism , Arteriosclerosis/pathology , Case-Control Studies , Cells, Cultured , Child , Child, Preschool , DNA Methylation , Down-Regulation , Elastin/metabolism , Female , Gestational Age , Humans , Immunologic Deficiency Syndromes/embryology , Immunologic Deficiency Syndromes/metabolism , Immunologic Deficiency Syndromes/pathology , Male , MicroRNAs/genetics , MicroRNAs/metabolism , Middle Aged , Nephrotic Syndrome/embryology , Nephrotic Syndrome/metabolism , Nephrotic Syndrome/pathology , Osteochondrodysplasias/embryology , Osteochondrodysplasias/metabolism , Osteochondrodysplasias/pathology , Primary Immunodeficiency Diseases , Promoter Regions, Genetic , Pulmonary Embolism/embryology , Pulmonary Embolism/metabolism , Pulmonary Embolism/pathology , RNA Precursors/metabolism , RNA, Messenger/metabolism , Transcription Factors/genetics , Transcription Factors/metabolismABSTRACT
BACKGROUND: A high prevalence of chronic kidney disease among children with focal segmental glomerulosclerosis (FSGS) leads to a permanent quest for good predictors of kidney dysfunction. Thus, we carried out a retrospective cohort study in order to examine known clinical and morphological predictors of adverse outcome, as well as to investigate glomerular nestin expression as a potential new early predictor of kidney dysfunction in children with FSGS. Relationships between nestin expression and clinical and morphological findings were also investigated. METHODS: Among 649 renal biopsy samples, obtained from two children's hospitals, FSGS was diagnosed in 60 children. Thirty-eight patients, who met the criteria for this study, were followed up for 9.0 ± 5.2 years. Using Kaplan-Meier and Cox's regression analysis, potential clinical and morphological predictors were applied in two models of prediction: after disease onset and after the biopsy. RESULTS: The present study revealed the following significant predictors of kidney dysfunction: patients' ages at disease onset, as well as age at biopsy, resistance to corticosteroid treatment, serum creatinine level, urine protein/creatinine ratio, vascular involvement, tubular atrophy, interstitial fibrosis, and decreased glomerular nestin expression. CONCLUSIONS: The most important finding of our study is that nestin can be used as a potential new early morphological predictor of kidney dysfunction in childhood onset of FSGS, since nestin has been obviously decreased in both sclerotic and normal glomeruli seen by light microscopy.
Subject(s)
Glomerulosclerosis, Focal Segmental/metabolism , Kidney Glomerulus/metabolism , Nestin/analysis , Adolescent , Biomarkers/analysis , Child , Child, Preschool , Cohort Studies , Female , Glomerulosclerosis, Focal Segmental/complications , Humans , Infant , Kidney Failure, Chronic/epidemiology , Male , Retrospective Studies , Young AdultABSTRACT
Congenital anomalies of the kidney and urinary tract (CAKUT) account for approximately 40% of children with ESRD in the United States. Hitherto, mutations in 23 genes have been described as causing autosomal dominant isolated CAKUT in humans. However, >90% of cases of isolated CAKUT still remain without a molecular diagnosis. Here, we hypothesized that genes mutated in recessive mouse models with the specific CAKUT phenotype of unilateral renal agenesis may also be mutated in humans with isolated CAKUT. We applied next-generation sequencing technology for targeted exon sequencing of 12 recessive murine candidate genes in 574 individuals with isolated CAKUT from 590 families. In 15 of 590 families, we identified recessive mutations in the genes FRAS1, FREM2, GRIP1, FREM1, ITGA8, and GREM1, all of which function in the interaction of the ureteric bud and the metanephric mesenchyme. We show that isolated CAKUT may be caused partially by mutations in recessive genes. Our results also indicate that biallelic missense mutations in the Fraser/MOTA/BNAR spectrum genes cause isolated CAKUT, whereas truncating mutations are found in the multiorgan form of Fraser syndrome. The newly identified recessive biallelic mutations in these six genes represent the molecular cause of isolated CAKUT in 2.5% of the 590 affected families in this study.
Subject(s)
Carrier Proteins/genetics , Extracellular Matrix Proteins/genetics , Fraser Syndrome/genetics , Integrin alpha Chains/genetics , Intercellular Signaling Peptides and Proteins/genetics , Kidney/abnormalities , Mutation , Nerve Tissue Proteins/genetics , Receptors, Interleukin/genetics , Urinary Tract/abnormalities , Vesico-Ureteral Reflux/genetics , Animals , Congenital Abnormalities/genetics , Disease Models, Animal , Female , Genes, Recessive , Humans , Kidney Diseases/congenital , Kidney Diseases/genetics , Male , Mice , Mice, Mutant Strains , Urogenital AbnormalitiesABSTRACT
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.
Subject(s)
Genes, Dominant , Mutation , Vesico-Ureteral Reflux/genetics , DNA Mutational Analysis , Female , Genetic Predisposition to Disease , Genetic Testing/methods , Heredity , Heterozygote , Humans , Male , Pedigree , Phenotype , Predictive Value of Tests , Risk Factors , Urogenital AbnormalitiesABSTRACT
WT1 mutations cause a wide spectrum of renal and extrarenal manifestations. Here we evaluated disease prevalence, phenotype spectrum, and genotype-phenotype correlations of 61 patients with WT1-related steroid-resistant nephrotic syndrome relative to 700 WT1-negative patients, all with steroid-resistant nephrotic syndrome. WT1 patients more frequently presented with chronic kidney disease and hypertension at diagnosis and exhibited more rapid disease progression. Focal segmental glomerulosclerosis was equally prevalent in both cohorts, but diffuse mesangial sclerosis was largely specific for WT1 disease and was present in 34% of cases. Sex reversal and/or urogenital abnormalities (52%), Wilms tumor (38%), and gonadoblastoma (5%) were almost exclusive to WT1 disease. Missense substitutions affecting DNA-binding residues were associated with diffuse mesangial sclerosis (74%), early steroid-resistant nephrotic syndrome onset, and rapid progression to ESRD. Truncating mutations conferred the highest Wilms tumor risk (78%) but typically late-onset steroid-resistant nephrotic syndrome. Intronic (KTS) mutations were most likely to present as isolated steroid-resistant nephrotic syndrome (37%) with a median onset at an age of 4.5 years, focal segmental glomerulosclerosis on biopsy, and slow progression (median ESRD age 13.6 years). Thus, there is a wide range of expressivity, solid genotype-phenotype associations, and a high risk and significance of extrarenal complications in WT1-associated nephropathy. We suggest that all children with steroid-resistant nephrotic syndrome undergo WT1 gene screening.
Subject(s)
Glomerulosclerosis, Focal Segmental/genetics , Mutation , Nephrotic Syndrome/congenital , Renal Insufficiency, Chronic/genetics , WT1 Proteins/genetics , Age of Onset , Child , Child, Preschool , DNA Mutational Analysis , Disease Progression , Female , Genetic Association Studies , Genetic Predisposition to Disease , Genetic Testing/methods , Glomerulosclerosis, Focal Segmental/diagnosis , Glomerulosclerosis, Focal Segmental/epidemiology , Glomerulosclerosis, Focal Segmental/therapy , Humans , Incidence , Infant , Male , Nephrotic Syndrome/diagnosis , Nephrotic Syndrome/epidemiology , Nephrotic Syndrome/genetics , Nephrotic Syndrome/therapy , Phenotype , Prevalence , Prognosis , Registries , Renal Insufficiency, Chronic/diagnosis , Renal Insufficiency, Chronic/epidemiology , Renal Insufficiency, Chronic/therapy , Risk Factors , Time FactorsABSTRACT
Congenital abnormalities of the kidney and urinary tract (CAKUT) account for approximately half of children with chronic kidney disease and they are the most frequent cause of end-stage renal disease in children in the US. However, its genetic etiology remains mostly elusive. VACTERL association is a rare disorder that involves congenital abnormalities in multiple organs including the kidney and urinary tract in up to 60% of the cases. By homozygosity mapping and whole-exome resequencing combined with high-throughput mutation analysis by array-based multiplex PCR and next-generation sequencing, we identified recessive mutations in the gene TNF receptor-associated protein 1 (TRAP1) in two families with isolated CAKUT and three families with VACTERL association. TRAP1 is a heat-shock protein 90-related mitochondrial chaperone possibly involved in antiapoptotic and endoplasmic reticulum stress signaling. Trap1 is expressed in renal epithelia of developing mouse kidney E13.5 and in the kidney of adult rats, most prominently in proximal tubules and in thick medullary ascending limbs of Henle's loop. Thus, we identified mutations in TRAP1 as highly likely causing CAKUT or VACTERL association with CAKUT.
Subject(s)
Anal Canal/abnormalities , DNA Mutational Analysis , Esophagus/abnormalities , Exosomes , Genetic Testing , HSP90 Heat-Shock Proteins , Heart Defects, Congenital/genetics , Kidney/abnormalities , Limb Deformities, Congenital/genetics , Mutation , Spine/abnormalities , Trachea/abnormalities , Vesico-Ureteral Reflux/genetics , Age Factors , Animals , DNA Mutational Analysis/methods , Europe , Female , Gene Expression Regulation, Developmental , Genetic Predisposition to Disease , Genetic Testing/methods , Gestational Age , HSP90 Heat-Shock Proteins/genetics , HSP90 Heat-Shock Proteins/metabolism , Heart Defects, Congenital/diagnosis , High-Throughput Nucleotide Sequencing , Homozygote , Humans , Kidney/embryology , Kidney/metabolism , Limb Deformities, Congenital/diagnosis , Male , Mice , Multiplex Polymerase Chain Reaction , Pedigree , Predictive Value of Tests , Risk Factors , United States , Urogenital Abnormalities , Vesico-Ureteral Reflux/diagnosisABSTRACT
Ciliopathies are genetically heterogeneous disorders characterized by variable expressivity and overlaps between different disease entities. This is exemplified by the short rib-polydactyly syndromes, Jeune, Sensenbrenner, and Mainzer-Saldino chondrodysplasia syndromes. These three syndromes are frequently caused by mutations in intraflagellar transport (IFT) genes affecting the primary cilia, which play a crucial role in skeletal and chondral development. Here, we identified mutations in IFT140, an IFT complex A gene, in five Jeune asphyxiating thoracic dystrophy (JATD) and two Mainzer-Saldino syndrome (MSS) families, by screening a cohort of 66 JATD/MSS patients using whole exome sequencing and targeted resequencing of a customized ciliopathy gene panel. We also found an enrichment of rare IFT140 alleles in JATD compared with nonciliopathy diseases, implying putative modifier effects for certain alleles. IFT140 patients presented with mild chest narrowing, but all had end-stage renal failure under 13 years of age and retinal dystrophy when examined for ocular dysfunction. This is consistent with the severe cystic phenotype of Ift140 conditional knockout mice, and the higher level of Ift140 expression in kidney and retina compared with the skeleton at E15.5 in the mouse. IFT140 is therefore a major cause of cono-renal syndromes (JATD and MSS). The present study strengthens the rationale for IFT140 screening in skeletal ciliopathy spectrum patients that have kidney disease and/or retinal dystrophy.
Subject(s)
Biological Transport/genetics , Cilia/metabolism , Kidney Diseases/genetics , Mutation , Animals , Cerebellar Ataxia/genetics , Child , Cohort Studies , Disease Progression , Exome , Humans , Kidney Diseases/pathology , Male , Mice , Retinitis Pigmentosa/geneticsABSTRACT
Genetic screening paradigms for congenital and infantile nephrotic syndrome are well established; however, screening in adolescents has received only minor attention. To help rectify this, we analyzed an unselected adolescent cohort of the international PodoNet registry to develop a rational screening approach based on 227 patients with nonsyndromic steroid-resistant nephrotic syndrome aged 10-20 years. Of these, 21% had a positive family history. Autosomal dominant cases were screened for WT1, TRPC6, ACTN4, and INF2 mutations. All other patients had the NPHS2 gene screened, and WT1 was tested in sporadic cases. In addition, 40 sporadic cases had the entire coding region of INF2 tested. Of the autosomal recessive and the sporadic cases, 13 and 6%, respectively, were found to have podocin-associated nephrotic syndrome, and 56% of them were compound heterozygous for the nonneutral p.R229Q polymorphism. Four percent of the sporadic and 10% of the autosomal dominant cases had a mutation in WT1. Pathogenic INF2 mutations were found in 20% of the dominant but none of the sporadic cases. In a large cohort of adolescents including both familial and sporadic disease, NPHS2 mutations explained about 7% and WT1 4% of cases, whereas INF2 proved relevant only in autosomal dominant familial disease. Thus, screening of the entire coding sequence of NPHS2 and exons 8-9 of WT1 appears to be the most rational and cost-effective screening approach in sporadic juvenile steroid-resistant nephrotic syndrome.
Subject(s)
DNA Mutational Analysis , Genetic Testing/methods , Intracellular Signaling Peptides and Proteins/genetics , Membrane Proteins/genetics , Mutation , Nephrotic Syndrome/congenital , Actinin/genetics , Adolescent , Age of Onset , Child , Exons , Female , Formins , Genetic Predisposition to Disease , Humans , Male , Microfilament Proteins/genetics , Nephrotic Syndrome/genetics , Nephrotic Syndrome/therapy , Pedigree , Phenotype , Predictive Value of Tests , Prognosis , Registries , TRPC Cation Channels/genetics , TRPC6 Cation Channel , WT1 Proteins/genetics , Young AdultABSTRACT
BACKGROUND: Pulmonary renal syndrome (PRS), denoting the presence of diffuse alveolar hemorrhage and glomerulonephritis as manifestations of systemic autoimmune disease, is very rare in childhood. The coexistence of circulating anti-neutrophil cytoplasmic antibody (ANCA) and anti-glomerular basement membrane (GBM) disease in children affected by this syndrome is exceptional, with unfavorable outcome in five out of seven patients reported to date. We describe a child with PRS associated with both circulating anti-myeloperoxidase (anti-MPO) ANCA and anti-GBM disease on renal biopsy who was successfully treated with immunosuppressive therapy. CASE PRESENTATION: A 10-year old girl presented with fever, fatigue, malaise, and pallor followed by hemoptysis and severe anemia. Diffuse alveolar hemorrhage was revealed on fiberoptic bronchoscopy. Renal findings consisted of microscopic hematuria, moderate proteinuria, and anti-GBM disease on renal biopsy. ANCA with anti-MPO specificity were present whereas anti-GBM antibodies were on borderline for positivity. Methyl-prednisolone pulses followed by prednisone led to cessation of hemoptysis, marked improvement of lung fuction, and normal finding on chest x-ray within 10 days. An immunosuppressive regimen was then given consisting of prednisone daily for 4 weeks with subsequent taper on alternate day, i.v. cyclophosphamide pulses monthly for 6 doses, followed by mycophenolate mofetil that resulted in normal lung function tests, hemoglobin concentration, and anti-MPO level within four subsequent weeks. During 10-months of follow-up she remained well, her blood pressure and renal function tests were normal, and proteinuria and hematuria gradually resolved. CONCLUSION: We report a child with an exceptionally rare coexistence of circulating ANCA and anti-GBM disease manifesting as PRS in whom renal disease was not the prominent part of clinical presentation, contrary to other reported pediatric patients. A review of literature on disease with double positive antibodies is also presented. Evaluation of a patient with PRS should include testing for presence of different antibodies. An early diagnosis and rapid institution of aggressive immunosuppressive therapy can induce remission and preserve renal function. Renal prognosis depends on the extent of kidney injury at diagnosis and appropriate treatment.
Subject(s)
Anti-Glomerular Basement Membrane Disease/complications , Anti-Glomerular Basement Membrane Disease/diagnosis , Antibodies, Antineutrophil Cytoplasmic , Glomerulonephritis/complications , Glomerulonephritis/diagnosis , Hemorrhage/complications , Hemorrhage/diagnosis , Lung Diseases/complications , Lung Diseases/diagnosis , Anti-Glomerular Basement Membrane Disease/blood , Antibodies, Antineutrophil Cytoplasmic/blood , Child , Female , Glomerulonephritis/blood , Hemorrhage/blood , Humans , Lung Diseases/bloodABSTRACT
Granulomatosis with polyangiitis (GPA), also known as Wegener's granulomatosis, is a rare disease in childhood. Of 39 GPA patients that we diagnosed during a 20-year period, only 3 (7.7%) were younger than 18 years. We report the course of GPA in three girls whose disease started at the ages of 16, 11, and 6 years. All had cutaneous manifestations: the first had necrotizing vasculitis, the second had palpable purpura, and the third had right upper-eyelid edema and infiltration and proptosis caused by extraocular pseudotumor, initially histologically misdiagnosed as orbital immunoglobulin G4 (IgG4)-related disease. Unlike with skin vasculitis and glomerulonephritis, upper-airway and orbital inflammation were resistant to immunosuppressive therapy. Our report emphasizes that children presenting with cutaneous vasculitis, chronic eyelid swelling, sinusitis, or hoarseness should be tested for antineutrophil cytoplasmic antibodies. We emphasize that the upper-eyelid edema and infiltration, with histologic characteristics of orbital IgG4-related disease, may be the initial presentation of localized GPA in children, a feature that, until now, has been described only in adults.
Subject(s)
Antibodies, Antineutrophil Cytoplasmic/blood , Granulomatosis with Polyangiitis/immunology , Granulomatosis with Polyangiitis/pathology , Skin/pathology , Adolescent , Age of Onset , Child , Female , HumansABSTRACT
Schimke immuno-osseous dysplasia (SIOD, MIM 242900) is an autosomal-recessive pleiotropic disorder with the diagnostic features of spondyloepiphyseal dysplasia, renal dysfunction and T-cell immunodeficiency. Using genome-wide linkage mapping and a positional candidate approach, we determined that mutations in SMARCAL1 (SWI/SNF2-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1), are responsible for SIOD. Through analysis of data from persons with SIOD in 26 unrelated families, we observed that affected individuals from 13 of 23 families with severe disease had two alleles with nonsense, frameshift or splicing mutations, whereas affected individuals from 3 of 3 families with milder disease had a missense mutation on each allele. These observations indicate that some missense mutations allow retention of partial SMARCAL1 function and thus cause milder disease.
Subject(s)
DNA Helicases/genetics , Immunologic Deficiency Syndromes/genetics , Mutation , Osteochondrodysplasias/genetics , Adolescent , Adult , Alleles , Amino Acid Sequence , Animals , Base Sequence , Child , Child, Preschool , Consanguinity , Conserved Sequence , DNA/genetics , DNA Mutational Analysis , Female , Genes, Recessive , Humans , Male , Molecular Sequence Data , Mutation, Missense , Pedigree , Phenotype , Renal Insufficiency/genetics , Sequence Homology, Amino Acid , Species Specificity , T-Lymphocytes/immunologyABSTRACT
Renal tubular acidosis (RTA) is common in adults with primary Sjogren syndrome (pSS) but to date this condition has only been identified in 12 pediatric cases of pSS. Here we present the case of a 13-year-old, otherwise asymptomatic girl in whom the search for the etiology of incidentally found nephrocalcinosis led to diagnosis of distal RTA and nephrogenic diabetes insipidus secondary to SS-associated tubulointerstitial nephritis. Immunosupressive treatment and alkali/electrolyte supplementation resulted in stable renal function over the 6-year follow-up. A review of the literature focuses on two aspects of pSS: (1) the difficulties in diagnosing pSS in childhood and (2) clinical-pathological features, treatment and outcome of renal tubulointerstitial disease in childhood pSS. SS should be considered in older children, particularly females with otherwise unexplained RTA. A careful search for other renal dysfunctions is necessary, and renal biopsy may be of value in assessing the extent of renal damage and the need for immunomodulatory therapy.
Subject(s)
Acidosis, Renal Tubular/diagnosis , Nephrocalcinosis/diagnosis , Sjogren's Syndrome/pathology , Acidosis, Renal Tubular/complications , Acidosis, Renal Tubular/therapy , Adolescent , Electrolytes/administration & dosage , Female , Humans , Immunosuppressive Agents/therapeutic use , Incidental Findings , Nephritis, Interstitial/complications , Nephritis, Interstitial/pathology , Nephritis, Interstitial/therapy , Nephrocalcinosis/complications , Sjogren's Syndrome/complications , Sjogren's Syndrome/therapy , Sodium Bicarbonate/administration & dosage , Treatment OutcomeABSTRACT
BACKGROUND: The epidemiological information from well-defined populations regarding childhood chronic kidney disease (CKD), particularly those concerning non-terminal stages, are scanty. The epidemiology of CKD in children is often based on renal replacement therapy (RRT) data, which means that a considerable number of children in earlier stages of CKD are missed as they will reach end-stage renal disease (ESRD) in adulthood. Here, we report the basic epidemiological data on childhood CKD in Serbia, gathered over the 10-year period of activity of the Serbian Pediatric Registry of Chronic Kidney Disease. METHODS: Since 2000-09, data on incidence, prevalence, aetiology, treatment modalities and outcome of children aged 0-18 years, with CKD Stages 2-4 and CKD Stage 5, were collected by reporting index cases from paediatric centres. RESULTS: Three hundred and thirty-six children were registered (211 boys, 125 girls, male/female ratio 1.7). The median age at registration was 9.0 years [interquartile range (IQR) 3-13]. Median follow-up was 4.0 years (IQR, 1-9). The median glomerular filtration rate (GFR) at the time of the registration was 39.6 mL/min/1.73m(2) (IQR, 13.8-65.4). Median annual incidence of CKD 2-5 stages was 14.3 per million age-related population (p.m.a.r.p.), while those of CKD 2-4 or CKD 5 were 9.1 and 5.7 p.m.a.r.p., respectively. The median prevalence of CKD 2-5 was 96.1 p.m.a.r.p., 52.8 p.m.a.r.p. in CKD 2-4 and 62.2 p.m.a.r.p. in CKD 5. The main causes of CKD were congenital anomalies of kidney and urinary tract and hereditary nephropathies. Kidney survival was the worst in children with glomerular diseases and in those with advanced CKD. Haemodialysis was the most common first modality of RRT. Mortality rate was 4.5%, mainly due to cardiovascular and infectious complications. CONCLUSIONS: Epidemiology of paediatric CKD in Serbia is similar to that reported from developed European countries. The knowledge of the epidemiology of earlier stages of CKD is essential for both institution of renoprotective therapy and planning of RRT, a fact of paramount importance in countries with limited resources.