RESUMO
Individualized pre-pregnancy counseling and antenatal care for women with chronic kidney disease (CKD) require disease-specific data. Here, we investigated pregnancy outcomes and long-term kidney function in women with COL4A3-5 related disease (Alport Syndrome, (AS)) in a large multicenter cohort. The ALPART-network (mAternaL and fetal PregnAncy outcomes of women with AlpoRT syndrome), an international collaboration of 17 centers, retrospectively investigated COL4A3-5 related disease pregnancies after the 20th week. Outcomes were stratified per inheritance pattern (X-Linked AS (XLAS)), Autosomal Dominant AS (ADAS), or Autosomal Recessive AS (ARAS)). The influence of pregnancy on estimated glomerular filtration rate (eGFR)-slope was assessed in 192 pregnancies encompassing 116 women (121 with XLAS, 47 with ADAS, and 12 with ARAS). Median eGFR pre-pregnancy was over 90ml/min/1.73m2. Neonatal outcomes were favorable: 100% live births, median gestational age 39.0 weeks and mean birth weight 3135 grams. Gestational hypertension occurred during 23% of pregnancies (reference: 'general' CKD G1-G2 pregnancies incidence is 4-20%) and preeclampsia in 20%. The mean eGFR declined after pregnancy but remained within normal range (over 90ml/min/1.73m2). Pregnancy did not significantly affect eGFR-slope (pre-pregnancy ß=-1.030, post-pregnancy ß=-1.349). ARAS-pregnancies demonstrated less favorable outcomes (early preterm birth incidence 3/11 (27%)). ARAS was a significant independent predictor for lower birth weight and shorter duration of pregnancy, next to the classic predictors (pre-pregnancy kidney function, proteinuria, and chronic hypertension) though missing proteinuria values and the small ARAS-sample hindered analysis. This is the largest study to date on AS and pregnancy with reassuring results for mild AS, though inheritance patterns could be considered in counseling next to classic risk factors. Thus, our findings support personalized reproductive care and highlight the importance of investigating kidney disease-specific pregnancy outcomes.
Assuntos
Nefrite Hereditária , Complicações na Gravidez , Nascimento Prematuro , Insuficiência Renal Crônica , Feminino , Humanos , Gravidez , Recém-Nascido , Lactente , Resultado da Gravidez/epidemiologia , Nefrite Hereditária/genética , Peso ao Nascer , Estudos Retrospectivos , Nascimento Prematuro/etiologia , Complicações na Gravidez/epidemiologia , Complicações na Gravidez/genética , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/genética , Proteinúria , AconselhamentoRESUMO
Autosomal dominant polycystic kidney disease (ADPKD) resulting from pathogenic variants in PKD1 and PKD2 is the most common form of PKD, but other genetic causes tied to primary cilia function have been identified. Biallelic pathogenic variants in the serine/threonine kinase NEK8 cause a syndromic ciliopathy with extra-kidney manifestations. Here we identify NEK8 as a disease gene for ADPKD in 12 families. Clinical evaluation was combined with functional studies using fibroblasts and tubuloids from affected individuals. Nek8 knockout mouse kidney epithelial (IMCD3) cells transfected with wild type or variant NEK8 were further used to study ciliogenesis, ciliary trafficking, kinase function, and DNA damage responses. Twenty-one affected monoallelic individuals uniformly exhibited cystic kidney disease (mostly neonatal) without consistent extra-kidney manifestations. Recurrent de novo mutations of the NEK8 missense variant p.Arg45Trp, including mosaicism, were seen in ten families. Missense variants elsewhere within the kinase domain (p.Ile150Met and p.Lys157Gln) were also identified. Functional studies demonstrated normal localization of the NEK8 protein to the proximal cilium and no consistent cilia formation defects in patient-derived cells. NEK8-wild type protein and all variant forms of the protein expressed in Nek8 knockout IMCD3 cells were localized to cilia and supported ciliogenesis. However, Nek8 knockout IMCD3 cells expressing NEK8-p.Arg45Trp and NEK8-p.Lys157Gln showed significantly decreased polycystin-2 but normal ANKS6 localization in cilia. Moreover, p.Arg45Trp NEK8 exhibited reduced kinase activity in vitro. In patient derived tubuloids and IMCD3 cells expressing NEK8-p.Arg45Trp, DNA damage signaling was increased compared to healthy passage-matched controls. Thus, we propose a dominant-negative effect for specific heterozygous missense variants in the NEK8 kinase domain as a new cause of PKD.
Assuntos
Doenças Renais Policísticas , Rim Policístico Autossômico Dominante , Animais , Humanos , Recém-Nascido , Camundongos , Proteínas de Transporte/metabolismo , Cílios/patologia , Rim/metabolismo , Mutação , Quinases Relacionadas a NIMA/genética , Quinases Relacionadas a NIMA/metabolismo , Doenças Renais Policísticas/genética , Rim Policístico Autossômico Dominante/patologia , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Serina/genética , Serina/metabolismo , Canais de Cátion TRPP/genética , Canais de Cátion TRPP/metabolismoRESUMO
BACKGROUND: Gitelman syndrome is the most frequent hereditary salt-losing tubulopathy characterized by hypokalemic alkalosis and hypomagnesemia. Gitelman syndrome is caused by biallelic pathogenic variants in SLC12A3, encoding the Na+-Cl- cotransporter (NCC) expressed in the distal convoluted tubule. Pathogenic variants of CLCNKB, HNF1B, FXYD2, or KCNJ10 may result in the same renal phenotype of Gitelman syndrome, as they can lead to reduced NCC activity. For approximately 10 percent of patients with a Gitelman syndrome phenotype, the genotype is unknown. METHODS: We identified mitochondrial DNA (mtDNA) variants in three families with Gitelman-like electrolyte abnormalities, then investigated 156 families for variants in MT-TI and MT-TF, which encode the transfer RNAs for phenylalanine and isoleucine. Mitochondrial respiratory chain function was assessed in patient fibroblasts. Mitochondrial dysfunction was induced in NCC-expressing HEK293 cells to assess the effect on thiazide-sensitive 22Na+ transport. RESULTS: Genetic investigations revealed four mtDNA variants in 13 families: m.591C>T (n=7), m.616T>C (n=1), m.643A>G (n=1) (all in MT-TF), and m.4291T>C (n=4, in MT-TI). Variants were near homoplasmic in affected individuals. All variants were classified as pathogenic, except for m.643A>G, which was classified as a variant of uncertain significance. Importantly, affected members of six families with an MT-TF variant additionally suffered from progressive chronic kidney disease. Dysfunction of oxidative phosphorylation complex IV and reduced maximal mitochondrial respiratory capacity were found in patient fibroblasts. In vitro pharmacological inhibition of complex IV, mimicking the effect of the mtDNA variants, inhibited NCC phosphorylation and NCC-mediated sodium uptake. CONCLUSION: Pathogenic mtDNA variants in MT-TF and MT-TI can cause a Gitelman-like syndrome. Genetic investigation of mtDNA should be considered in patients with unexplained Gitelman syndrome-like tubulopathies.
Assuntos
DNA Mitocondrial/genética , Síndrome de Gitelman/genética , Mutação , Adolescente , Adulto , Idoso , Sequência de Bases , Criança , Pré-Escolar , Feminino , Genótipo , Síndrome de Gitelman/metabolismo , Síndrome de Gitelman/patologia , Células HEK293 , Humanos , Lactente , Rim/metabolismo , Rim/ultraestrutura , Masculino , Pessoa de Meia-Idade , Mitocôndrias/metabolismo , Modelos Biológicos , Conformação de Ácido Nucleico , Linhagem , Fenótipo , Polimorfismo de Nucleotídeo Único , RNA de Transferência de Isoleucina/química , RNA de Transferência de Isoleucina/genética , RNA de Transferência de Fenilalanina/química , RNA de Transferência de Fenilalanina/genética , Membro 3 da Família 12 de Carreador de Soluto/genética , Adulto JovemRESUMO
Genetic kidney disease comprises a diverse group of disorders. These can roughly be divided in the phenotype groups congenital anomalies of the kidney and urinary tract, ciliopathies, glomerulopathies, stone disorders, tubulointerstitial kidney disease, and tubulopathies. Many etiologies can lead to chronic kidney disease that can progress to end-stage kidney disease. Despite each individual disease being rare, together these genetic disorders account for a large proportion of kidney disease cases. With the introduction of massively parallel sequencing, genetic testing has become more accessible, but a comprehensive analysis of the diagnostic yield is lacking. This review gives an overview of the diagnostic yield of genetic testing across and within the full range of kidney disease phenotypes through a systematic literature search that resulted in 115 included articles. Patient, test, and cohort characteristics that can influence the diagnostic yield are highlighted. Detection of copy number variations and their contribution to the diagnostic yield is described for all phenotype groups. Also, the impact of a genetic diagnosis for a patient and family members, which can be diagnostic, therapeutic, and prognostic, is shown through the included articles. This review will allow clinicians to estimate an a priori probability of finding a genetic cause for the kidney disease in their patients.
Assuntos
Variações do Número de Cópias de DNA , Insuficiência Renal Crônica , Humanos , Variações do Número de Cópias de DNA/genética , Testes Genéticos/métodos , Fenótipo , Rim , Sequenciamento de Nucleotídeos em Larga Escala/métodos , NucleotídeosRESUMO
Congenital anomalies of the kidney and urinary tract (CAKUT) represent the most common cause of chronic kidney failure in children. Despite growing knowledge of the genetic causes of CAKUT, the majority of cases remain etiologically unsolved. Genetic alterations in roundabout guidance receptor 1 (ROBO1) have been associated with neuronal and cardiac developmental defects in living individuals. Although Slit-Robo signaling is pivotal for kidney development, diagnostic ROBO1 variants have not been reported in viable CAKUT to date. By next-generation-sequencing methods, we identified six unrelated individuals and two non-viable fetuses with biallelic truncating or combined missense and truncating variants in ROBO1. Kidney and genitourinary manifestation included unilateral or bilateral kidney agenesis, vesicoureteral junction obstruction, vesicoureteral reflux, posterior urethral valve, genital malformation, and increased kidney echogenicity. Further clinical characteristics were remarkably heterogeneous, including neurodevelopmental defects, intellectual impairment, cerebral malformations, eye anomalies, and cardiac defects. By in silico analysis, we determined the functional significance of identified missense variants and observed absence of kidney ROBO1 expression in both human and murine mutant tissues. While its expression in multiple tissues may explain heterogeneous organ involvement, variability of the kidney disease suggests gene dosage effects due to a combination of null alleles with mild hypomorphic alleles. Thus, comprehensive genetic analysis in CAKUT should include ROBO1 as a new cause of recessively inherited disease. Hence, in patients with already established ROBO1-associated cardiac or neuronal disorders, screening for kidney involvement is indicated.
Assuntos
Proteínas do Tecido Nervoso/genética , Receptores Imunológicos/genética , Sistema Urinário , Anormalidades Urogenitais , Refluxo Vesicoureteral , Animais , Criança , Feminino , Humanos , Rim/patologia , Masculino , Camundongos , Sistema Urinário/patologia , Anormalidades Urogenitais/diagnóstico , Anormalidades Urogenitais/genética , Refluxo Vesicoureteral/diagnóstico , Proteínas RoundaboutRESUMO
BACKGROUND: Often only chronic kidney disease (CKD) patients with high likelihood of genetic disease are offered genetic testing. Early genetic testing could obviate the need for kidney biopsies, allowing for adequate prognostication and treatment. To test the viability of a 'genetics-first' approach for CKD, we performed genetic testing in a group of kidney transplant recipients aged <50 years, irrespective of cause of transplant. METHODS: From a cohort of 273 transplant patients, we selected 110 that were in care in the University Medical Center Utrecht, had DNA available and were without clear-cut non-genetic disease. Forty patients had been diagnosed with a genetic disease prior to enrollment; in 70 patients, we performed a whole-exome sequencing-based 379 gene panel analysis. RESULTS: Genetic analysis yielded a diagnosis in 51%. Extrapolated to the 273 patient cohort, who did not all fit the inclusion criteria, the diagnostic yield was still 21%. Retrospectively, in 43% of biopsied patients, the kidney biopsy would not have had added diagnostic value if genetic testing had been performed as a first-tier diagnostic. CONCLUSIONS: The burden of monogenic disease in transplant patients with end-stage kidney disease (ESKD) of any cause prior to the age of 50 years is between 21% and 51%. Early genetic testing can provide a non-invasive diagnostic, impacting prognostication and treatment, and obviating the need for an invasive biopsy. We conclude that in patients who expect to develop ESKD prior to the age of 50 years, genetic testing should be considered as first mode of diagnostics.
Assuntos
Falência Renal Crônica , Insuficiência Renal Crônica , Estudos de Coortes , Testes Genéticos , Humanos , Falência Renal Crônica/diagnóstico , Falência Renal Crônica/genética , Pessoa de Meia-Idade , Insuficiência Renal Crônica/complicações , Estudos RetrospectivosRESUMO
Monoallelic mutations of DNAJB11 were recently described in seven pedigrees with atypical clinical presentations of autosomal dominant polycystic kidney disease. DNAJB11 encodes one of the main cofactors of the endoplasmic reticulum chaperon BiP, a heat-shock protein required for efficient protein folding and trafficking. Here we conducted an international collaborative study to better characterize the DNAJB11-associated phenotype. Thirteen different loss-of-function variants were identified in 20 new pedigrees (54 affected individuals) by targeted next-generation sequencing, whole-exome sequencing or whole-genome sequencing. Amongst the 77 patients (27 pedigrees) now in total reported, 32 reached end stage kidney disease (range, 55-89 years, median age 75); without a significant difference between males and females. While a majority of patients presented with non-enlarged polycystic kidneys, renal cysts were inconsistently identified in patients under age 45. Vascular phenotypes, including intracranial aneurysms, dilatation of the thoracic aorta and dissection of a carotid artery were present in four pedigrees. We accessed Genomics England 100,000 genomes project data, and identified pathogenic variants of DNAJB11 in nine of 3934 probands with various kidney and urinary tract disorders. The clinical diagnosis was cystic kidney disease for eight probands and nephrocalcinosis for one proband. No additional pathogenic variants likely explaining the kidney disease were identified. Using the publicly available GnomAD database, DNAJB11 genetic prevalence was calculated at 0.85/10.000 individuals. Thus, establishing a precise diagnosis in atypical cystic or interstitial kidney disease is crucial, with important implications in terms of follow-up, genetic counseling, prognostic evaluation, therapeutic management, and for selection of living kidney donors.
Assuntos
Rim Policístico Autossômico Dominante , Canais de Cátion TRPP , Idoso , Inglaterra , Feminino , Proteínas de Choque Térmico HSP40 , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Rim Policístico Autossômico Dominante/diagnóstico , Rim Policístico Autossômico Dominante/epidemiologia , Rim Policístico Autossômico Dominante/genética , Prevalência , Prognóstico , Canais de Cátion TRPP/genéticaRESUMO
Background Nephronophthisis (NPH) is the most prevalent genetic cause for ESRD in children. However, little is known about the prevalence of NPH in adult-onset ESRD. Homozygous full gene deletions of the NPHP1 gene encoding nephrocystin-1 are a prominent cause of NPH. We determined the prevalence of NPH in adults by assessing homozygous NPHP1 full gene deletions in adult-onset ESRD.Methods Adult renal transplant recipients from five cohorts of the International Genetics and Translational Research in Transplantation Network (iGeneTRAiN) underwent single-nucleotide polymorphism genotyping. After quality control, we determined autosomal copy number variants (such as deletions) on the basis of median log2 ratios and B-allele frequency patterns. The findings were independently validated in one cohort. Patients were included in the analysis if they had adult-onset ESRD, defined as start of RRT at ≥18 years old.Results We included 5606 patients with adult-onset ESRD; 26 (0.5%) showed homozygous NPHP1 deletions. No donor controls showed homozygosity for this deletion. Median age at ESRD onset was 30 (range, 18-61) years old for patients with NPH, with 54% of patients age ≥30 years old. Notably, only three (12%) patients were phenotypically classified as having NPH, whereas most patients were defined as having CKD with unknown etiology (n=11; 42%).Conclusions Considering that other mutation types in NPHP1 or mutations in other NPH-causing genes were not analyzed, NPH is a relatively frequent monogenic cause of adult-onset ESRD. Because 88% of patients had not been clinically diagnosed with NPH, wider application of genetic testing in adult-onset ESRD may be warranted.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Doenças Renais Císticas/epidemiologia , Doenças Renais Císticas/genética , Falência Renal Crônica/genética , Proteínas de Membrana/genética , Adolescente , Adulto , Fatores Etários , Proteínas do Citoesqueleto , Feminino , Deleção de Genes , Dosagem de Genes , Homozigoto , Humanos , Incidência , Doenças Renais Císticas/complicações , Falência Renal Crônica/terapia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Prevalência , Adulto JovemRESUMO
Congenital abnormalities of the kidney and the urinary tract (CAKUT) belong to the most common birth defects in human, but the molecular basis for the majority of CAKUT patients remains unknown. Here we show that the transcription factor SOX11 is a crucial regulator of kidney development. SOX11 is expressed in both mesenchymal and epithelial components of the early kidney anlagen. Deletion of Sox11 in mice causes an extension of the domain expressing Gdnf within rostral regions of the nephrogenic cord and results in duplex kidney formation. On the molecular level SOX11 directly binds and regulates a locus control region of the protocadherin B cluster. At later stages of kidney development, SOX11 becomes restricted to the intermediate segment of the developing nephron where it is required for the elongation of Henle's loop. Finally, mutation analysis in a cohort of patients suffering from CAKUT identified a series of rare SOX11 variants, one of which interferes with the transactivation capacity of the SOX11 protein. Taken together these data demonstrate a key role for SOX11 in normal kidney development and may suggest that variants in this gene predispose to CAKUT in humans.
Assuntos
Rim/anormalidades , Mutação , Fatores de Transcrição SOXC/genética , Ureter/anormalidades , Anormalidades Urogenitais/genética , Refluxo Vesicoureteral/genética , Animais , Caderinas/genética , Caderinas/metabolismo , Proliferação de Células , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Estudos de Associação Genética , Predisposição Genética para Doença , Fator Neurotrófico Derivado de Linhagem de Célula Glial/genética , Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Humanos , Rim/metabolismo , Masculino , Camundongos Knockout , Morfogênese , Fenótipo , Fatores de Risco , Fatores de Transcrição SOXC/deficiência , Ureter/metabolismo , Anormalidades Urogenitais/metabolismo , Anormalidades Urogenitais/patologia , Refluxo Vesicoureteral/metabolismo , Refluxo Vesicoureteral/patologiaRESUMO
BACKGROUND: Nephronophthisis is an autosomal recessive ciliopathy and important cause of end-stage renal disease (ESRD) in children and young adults. Diagnostic delay is frequent. This study investigates clinical characteristics, initial symptoms, and genetic defects in a cohort with nephronophthisis-related ciliopathy, to improve early detection and genetic counseling. METHODS: Forty patients from 36 families with nephronophthisis-related ciliopathy were recruited at university medical centers and online. Comprehensive clinical and genotypic data were recorded. Patients without molecular diagnosis were offered genetic analysis. RESULTS: Of 40 patients, 45% had isolated nephronophthisis, 48% syndromic diagnosis, and 7% nephronophthisis with extrarenal features not constituting a recognizable syndrome. Patients developed ESRD at median 13 years (range 5-47). Median age of symptom onset was 9 years in both isolated and syndromic forms (range 5-26 vs. 5-33). Common presenting symptoms were fatigue (42%), polydipsia/polyuria (33%), and hypertension (21%). Renal ultrasound showed small-to-normal-sized kidneys, increased echogenicity (65%), cysts (43%), and abnormal corticomedullary differentiation (32%). Renal biopsies in eight patients showed nonspecific signs of chronic kidney disease (CKD). Twenty-three patients (58%) had genetic diagnosis upon inclusion. Thirteen of those without a genetic diagnosis gave consent for genetic testing, and a cause was identified in five (38%). CONCLUSIONS: Nephronophthisis is genetically and phenotypically heterogeneous and should be considered in children and young adults presenting with persistent fatigue and polyuria, and in all patients with unexplained CKD. As symptom onset can occur into adulthood, presymptomatic monitoring of kidney function in syndromic ciliopathy patients should continue until at least age 30.
Assuntos
Ciliopatias/diagnóstico , Aconselhamento Genético , Testes Genéticos , Doenças Renais Císticas/congênito , Falência Renal Crônica/prevenção & controle , Proteínas Adaptadoras de Transdução de Sinal/genética , Adolescente , Adulto , Idade de Início , Biópsia , Criança , Ciliopatias/complicações , Ciliopatias/genética , Ciliopatias/patologia , Proteínas do Citoesqueleto , Diagnóstico Tardio/prevenção & controle , Feminino , Humanos , Rim/diagnóstico por imagem , Rim/patologia , Doenças Renais Císticas/complicações , Doenças Renais Císticas/diagnóstico , Doenças Renais Císticas/genética , Doenças Renais Císticas/patologia , Falência Renal Crônica/etiologia , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Países Baixos , Sistema de Registros/estatística & dados numéricos , Fatores de Tempo , Ultrassonografia , Sequenciamento do Exoma , Adulto JovemRESUMO
Genetic testing in kidney disease has been gaining more attention in recent years as an important diagnostic tool. Especially in selected cases, genetic testing can be a first mode of diagnostics in various renal diseases. Mallett et al. are the first to report on the overall diagnostic yield of targeted gene panel testing in familial kidney disease, both in pediatric and adult cases. In this commentary we discuss the importance of a clear gene panel design, with an up-to-date enrichment offering sufficient coverage for each gene, and a validated pipeline for variant calling. We also emphasize the necessity of detailed phenotyping, including a pedigree, as a critical factor for gene panel selection and variant interpretation.
Assuntos
Testes Genéticos , Linhagem , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , NefropatiasRESUMO
The leading cause of end-stage renal disease in children is attributed to congenital anomalies of the kidney and urinary tract (CAKUT). Familial clustering and mouse models support the presence of monogenic causes. Genetic testing is insufficient as it mainly focuses on HNF1B and PAX2 mutations that are thought to explain CAKUT in 515% of patients. To identify novel, potentially pathogenic variants in additional genes, we designed a panel of genes identified from studies on familial forms of isolated or syndromic CAKUT and genes suggested by in vitro and in vivo CAKUT models. The coding exons of 208 genes were analyzed in 453 patients with CAKUT using next-generation sequencing. Rare truncating, splice-site variants, and non-synonymous variants, predicted to be deleterious and conserved, were prioritized as the most promising variants to have an effect on CAKUT. Previously reported disease-causing mutations were detected, but only five were fully penetrant causal mutations that improved diagnosis. We prioritized 148 candidate variants in 151 patients, found in 82 genes, for follow-up studies. Using a burden test, no significant excess of rare variants in any of the genes in our cohort compared with controls was found. Thus, in a study representing the largest set of genes analyzed in CAKUT patients to date, the contribution of previously implicated genes to CAKUT risk was significantly smaller than expected, and the disease may be more complex than previously assumed.
Assuntos
Anormalidades Urogenitais/genética , Éxons , Deleção de Genes , Humanos , Análise de Sequência de DNARESUMO
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.
Assuntos
Proteínas Ativadoras de GTPase , Peptídeos e Proteínas de Sinalização Intercelular , Mutação , Proteínas do Tecido Nervoso , Receptores Imunológicos , Transdução de Sinais/genética , Anormalidades Urogenitais , Refluxo Vesicoureteral , Animais , Exoma , Proteínas Ativadoras de GTPase/biossíntese , Proteínas Ativadoras de GTPase/genética , Células HEK293 , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/biossíntese , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Mesoderma/metabolismo , Camundongos , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/metabolismo , Ratos , Receptores Imunológicos/biossíntese , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo , Fatores de Risco , Anormalidades Urogenitais/embriologia , Anormalidades Urogenitais/genética , Refluxo Vesicoureteral/embriologia , Refluxo Vesicoureteral/genéticaRESUMO
Muckle-Wells syndrome (MWS) is a genetic periodic fever syndrome characterised by urticaria, fever and malaise starting in childhood with the development of perceptive hearing loss and risk of amyloidosis later in life.Patient A, in his 60s, was referred to a nephrologist because of glomerular haematuria and elevated erythrocyte sedimentation rate. He appeared to have periodic fevers since childhood, skin changes in cold circumstances and progressive deafness since he was 30 years of age. Genetic analysis revealed a pathogenic variant in the NLRP3 gene compatible with MWS. Treatment with anakinra (interleukin 1 antagonist) improved his symptoms, but only mild episodic arthralgia remained. Glomerular erythrocyturia diminished during treatment, supposing a relation between MWS and haematuria.This case report shows that rare genetic fever syndromes starting from early childhood can still be diagnosed in adult patients, with important therapeutic consequences. Symptoms can be relieved and amyloidosis with potential renal failure may be prevented.
Assuntos
Amiloidose , Síndrome Antifosfolipídica , Síndromes Periódicas Associadas à Criopirina , Nefropatias , Pré-Escolar , Adulto , Masculino , Humanos , Hematúria/etiologia , Síndromes Periódicas Associadas à Criopirina/complicações , Síndromes Periódicas Associadas à Criopirina/diagnóstico , Síndromes Periódicas Associadas à Criopirina/tratamento farmacológico , Febre , Amiloidose/complicações , Amiloidose/diagnósticoRESUMO
Medullary sponge kidney (MSK) is a description of radiographic features. However, the pathogenesis of MSK remains unclear. MSK is supposed to be the cause of secondary distal renal tubular acidosis (dRTA), although there are case reports suggesting that MSK is a complication of primary dRTA. In addition to these reports, we report 3 patients with metabolic acidosis and MSK, in whom primary dRTA is confirmed by molecular genetic analyses of SLC4A1 and ATP6V1B1 genes. With a comprehensive genetics-first approach using the 100,000 Genomes Rare Diseases Project dataset, the association between MSK and primary dRTA is examined. We showed that many patients with MSK phenotypes are genetically tested with a gene panel which does not contain dRTA-associated genes, revealing opportunities for missed genetic diagnosis. Our cases highlight that the radiological description of MSK is not a straightforward disease or clinical phenotype. Therefore, when an MSK appearance is noted, a broader set of causes should be considered including genetic causes of primary dRTA as the underlying reason for medullary imaging abnormalities.
Assuntos
Acidose Tubular Renal , Rim em Esponja Medular , Humanos , Rim em Esponja Medular/genética , Rim em Esponja Medular/complicações , Acidose Tubular Renal/genética , Feminino , Masculino , ATPases Vacuolares Próton-Translocadoras/genética , Adulto , Proteína 1 de Troca de Ânion do Eritrócito/genética , Pessoa de Meia-IdadeRESUMO
Four European Reference Networks (ERN-EYE, ERKNet, Endo-ERN, ERN-ITHACA) have teamed up to establish a consensus statement and recommendations for Bardet-Biedl syndrome (BBS). BBS is an autosomal recessive ciliopathy with at least 26 genes identified to date. The clinical manifestations are pleiotropic, can be observed in utero and will progress with age. Genetic testing has progressively improved in the last years prompting for a revision of the diagnostic criteria taking into account clinical Primary and Secondary features, as well as positive or negative molecular diagnosis. This consensus statement also emphasizes on initial diagnosis, monitoring and lifelong follow-up, and symptomatic care that can be provided to patients and family members according to the involved care professionals. For paediatricians, developmental anomalies can be at the forefront for diagnosis (such as polydactyly) but can require specific care, such as for associated neuro developmental disorders. For ophthalmology, the early onset retinal degeneration requires ad hoc functional and imaging technologies and specific care for severe visual impairment. For endocrinology, among other manifestations, early onset obesity and its complications has benefited from better evaluation of eating behaviour problems, improved lifestyle programs, and from novel pharmacological therapies. Kidney and urinary track involvements warrants lifespan attention, as chronic kidney failure can occur and early management might improve outcome. This consensus recommends revised diagnostic criteria for BBS that will ensure certainty of diagnosis, giving robust grounds for genetic counselling as well as in the perspective of future trials for innovative therapies.
RESUMO
Variants in the CNNM2 gene are causative for hypomagnesaemia, seizures and intellectual disability, although the phenotypes can be variable. This study aims to understand the genotype-phenotype relationship in affected individuals with CNNM2 variants by phenotypic, functional and structural analysis of new as well as previously reported variants. This results in the identification of seven variants that significantly affect CNNM2-mediated Mg2+ transport. Pathogenicity of these variants is further supported by structural modelling, which predicts CNNM2 structure to be affected by all of them. Strikingly, seizures and intellectual disability are absent in 4 out of 7 cases, indicating these phenotypes are caused either by specific CNNM2 variant only or by additional risk factors. Moreover, in line with sporadic observations from previous reports, CNNM2 variants might be associated with disturbances in parathyroid hormone and Ca2+ homeostasis.
Assuntos
Proteínas de Transporte de Cátions , Deficiência Intelectual , Humanos , Deficiência Intelectual/genética , Magnésio/metabolismo , Convulsões/genética , Fenótipo , Proteínas de Transporte de Cátions/genéticaRESUMO
Introduction: Hepatocyte nuclear factor 1-beta (HNF1B) gene variants or the chromosome 17q12 deletion (17q12del) represent the most common monogenic cause of developmental kidney disease. Although neurodevelopmental disorders have been associated with the 17q12del, specific genotype-phenotype associations with respect to kidney function evolution have not yet been fully defined. Here, we aimed to determine whether 17q12del or specific HNF1B variants were associated with kidney survival in a large patient population with HNF1B disease. Methods: This was a retrospective observational study involving 521 patients with HNF1B disease from 14 countries using the European Reference Network for rare kidney diseases with detailed information on the HNF1B genotype (HNF1B variants or the 17q12del). Median follow-up time was 11 years with 6 visits per patient. The primary end point was progression to chronic kidney disease (CKD) stage 3 (estimated glomerular filtration rate [eGFR] < 60 ml/min per 1.73 m2). Secondary end points were the development of hypomagnesemia or extrarenal disorders, including hyperuricemia and hyperglycemia. Results: Progression toward CKD stage 3 was significantly delayed in patients with the 17q12del compared to patients with HNF1B variants (hazard ratio [HR]: 0.29, 95% confidence interval [CI]: 0.19-0.44, P < 0.001). Progression toward CKD stage 3 was also significantly delayed when HNF1B variants involved the HNF1B Pit-1, Oct-1, and Unc-86 homeodomain (POUh) DNA-binding and transactivation domains rather than the POU-specific domain (POUs) DNA-binding domain (HR: 0.15 [95% CI: 0.06-0.37), P < 0.001 and HR: 0.25 (95% CI: 0.11-0.57), P = 0.001, respectively). Finally, the 17q12del was positively associated with hypomagnesemia and negatively associated with hyperuricemia, but not with hyperglycemia. Conclusion: Patients with the 17q12del display a significantly better kidney survival than patients with other HNF1B variants; and for the latter, variants in the POUs DNA-binding domain lead to the poorest kidney survival. These are clinically relevant HNF1B kidney genotype-phenotype correlations that inform genetic counseling.
RESUMO
Genetic testing in patients with suspected hereditary kidney disease may not reveal the genetic cause for the disorder as potentially pathogenic variants can reside in genes that are not yet known to be involved in kidney disease. We have developed KidneyNetwork, that utilizes tissue-specific expression to inform candidate gene prioritization specifically for kidney diseases. KidneyNetwork is a novel method constructed by integrating a kidney RNA-sequencing co-expression network of 878 samples with a multi-tissue network of 31,499 samples. It uses expression patterns and established gene-phenotype associations to predict which genes could be related to what (disease) phenotypes in an unbiased manner. We applied KidneyNetwork to rare variants in exome sequencing data from 13 kidney disease patients without a genetic diagnosis to prioritize candidate genes. KidneyNetwork can accurately predict kidney-specific gene functions and (kidney disease) phenotypes for disease-associated genes. The intersection of prioritized genes with genes carrying rare variants in a patient with kidney and liver cysts identified ALG6 as plausible candidate gene. We strengthen this plausibility by identifying ALG6 variants in several cystic kidney and liver disease cases without alternative genetic explanation. We present KidneyNetwork, a publicly available kidney-specific co-expression network with optimized gene-phenotype predictions for kidney disease phenotypes. We designed an easy-to-use online interface that allows clinicians and researchers to use gene expression and co-regulation data and gene-phenotype connections to accelerate advances in hereditary kidney disease diagnosis and research. TRANSLATIONAL STATEMENT: Genetic testing in patients with suspected hereditary kidney disease may not reveal the genetic cause for the patient's disorder. Potentially pathogenic variants can reside in genes not yet known to be involved in kidney disease, making it difficult to interpret the relevance of these variants. This reveals a clear need for methods to predict the phenotypic consequences of genetic variation in an unbiased manner. Here we describe KidneyNetwork, a tool that utilizes tissue-specific expression to predict kidney-specific gene functions. Applying KidneyNetwork to a group of undiagnosed cases identified ALG6 as a candidate gene in cystic kidney and liver disease. In summary, KidneyNetwork can aid the interpretation of genetic variants and can therefore be of value in translational nephrogenetics and help improve the diagnostic yield in kidney disease patients.