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RATIONALE & OBJECTIVE: Genetic etiologies have been identified among approximately 10% of adults with chronic kidney disease (CKD). However, data are lacking regarding the prevalence of monogenic etiologies especially among members of minority groups. This study characterized the genetic markers among members of an Israeli minority group with end-stage kidney disease (ESKD). STUDY DESIGN: A national-multicenter cross-sectional study of Israeli Druze patients (an Arabic-speaking Near-Eastern transnational population isolate) who are receiving maintenance dialysis for ESKD. All study participants underwent exome sequencing. SETTING & PARTICIPANTS: We recruited 94 adults with ESKD, comprising 97% of the total 97 Druze individuals throughout Israel being treated with dialysis during the study period. PREDICTORS: Demographics and clinical characteristics of kidney disease. OUTCOME: Genetic markers. ANALYTICAL APPROACH: Whole-exome sequencing and the relationship of markers to clinical phenotypes. RESULTS: We identified genetic etiologies in 17 of 94 participants (18%). None had a previous molecular diagnosis. A novel, population-specific, WDR19 homozygous pathogenic variant (p.Cys293Tyr) was the most common genetic finding. Other monogenic etiologies included PKD1, PKD2, type IV collagen mutations, and monogenic forms of noncommunicable diseases. The pre-exome clinical diagnosis corresponded to the final molecular diagnosis in fewer than half of the participants. LIMITATIONS: This study was limited to Druze individuals, so its generalizability may be limited. CONCLUSIONS: Exome sequencing identified a genetic diagnosis in approximately 18% of Druze individuals with ESKD. These results support conducting genetic analyses in minority populations with high rates of CKD and for whom phenotypic disease specificity may be low. PLAIN-LANGUAGE SUMMARY: Chronic kidney disease (CKD) affects many people worldwide and has multiple genetic causes. However, there is limited information on the prevalence of genetic etiologies, especially among minority populations. Our national-multicenter study focused on Israeli Druze patients. Using exome-sequencing, we identified previously undetected genetic causes in nearly 20% of patients, including a new and population-specific WDR19 homozygous pathogenic variant. This mutation has not been previously described; it is extremely rare globally but is common among the Druze, which highlights the importance of studying minority populations with high rates of CKD. Our findings provide insights into the genetic basis of end-stage kidney disease in the Israeli Druze, expand the WDR19 phenotypic spectrum, and emphasize the potential value of genetic testing in such populations.
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Falência Renal Crônica , Insuficiência Renal Crônica , Adulto , Humanos , Grupos Minoritários , Israel/epidemiologia , Marcadores Genéticos , Estudos Transversais , Falência Renal Crônica/epidemiologia , Falência Renal Crônica/genética , Falência Renal Crônica/terapia , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/diagnóstico , Minorias Desiguais em Saúde e Populações VulneráveisRESUMO
BACKGROUND: About 40 disease genes have been described to date for isolated CAKUT, the most common cause of childhood CKD. However, these genes account for only 20% of cases. ARHGEF6, a guanine nucleotide exchange factor that is implicated in biologic processes such as cell migration and focal adhesion, acts downstream of integrin-linked kinase (ILK) and parvin proteins. A genetic variant of ILK that causes murine renal agenesis abrogates the interaction of ILK with a murine focal adhesion protein encoded by Parva , leading to CAKUT in mice with this variant. METHODS: To identify novel genes that, when mutated, result in CAKUT, we performed exome sequencing in an international cohort of 1265 families with CAKUT. We also assessed the effects in vitro of wild-type and mutant ARHGEF6 proteins, and the effects of Arhgef6 deficiency in mouse and frog models. RESULTS: We detected six different hemizygous variants in the gene ARHGEF6 (which is located on the X chromosome in humans) in eight individuals from six families with CAKUT. In kidney cells, overexpression of wild-type ARHGEF6 -but not proband-derived mutant ARHGEF6 -increased active levels of CDC42/RAC1, induced lamellipodia formation, and stimulated PARVA-dependent cell spreading. ARHGEF6-mutant proteins showed loss of interaction with PARVA. Three-dimensional Madin-Darby canine kidney cell cultures expressing ARHGEF6-mutant proteins exhibited reduced lumen formation and polarity defects. Arhgef6 deficiency in mouse and frog models recapitulated features of human CAKUT. CONCLUSIONS: Deleterious variants in ARHGEF6 may cause dysregulation of integrin-parvin-RAC1/CDC42 signaling, thereby leading to X-linked CAKUT.
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Sistema Urinário , Anormalidades Urogenitais , Humanos , Camundongos , Animais , Cães , Anormalidades Urogenitais/genética , Rim/anormalidades , Sistema Urinário/anormalidades , Integrinas/metabolismo , Proteínas Mutantes/metabolismo , Fatores de Troca de Nucleotídeo Guanina Rho/genéticaRESUMO
Congenital anomalies of the kidney and urinary tract (CAKUT) constitute one of the most frequent birth defects and represent the most common cause of chronic kidney disease in the first three decades of life. Despite the discovery of dozens of monogenic causes of CAKUT, most pathogenic pathways remain elusive. We performed whole-exome sequencing (WES) in 551 individuals with CAKUT and identified a heterozygous de novo stop-gain variant in ZMYM2 in two different families with CAKUT. Through collaboration, we identified in total 14 different heterozygous loss-of-function mutations in ZMYM2 in 15 unrelated families. Most mutations occurred de novo, indicating possible interference with reproductive function. Human disease features are replicated in X. tropicalis larvae with morpholino knockdowns, in which expression of truncated ZMYM2 proteins, based on individual mutations, failed to rescue renal and craniofacial defects. Moreover, heterozygous Zmym2-deficient mice recapitulated features of CAKUT with high penetrance. The ZMYM2 protein is a component of a transcriptional corepressor complex recently linked to the silencing of developmentally regulated endogenous retrovirus elements. Using protein-protein interaction assays, we show that ZMYM2 interacts with additional epigenetic silencing complexes, as well as confirming that it binds to FOXP1, a transcription factor that has also been linked to CAKUT. In summary, our findings establish that loss-of-function mutations of ZMYM2, and potentially that of other proteins in its interactome, as causes of human CAKUT, offering new routes for studying the pathogenesis of the disorder.
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Proteínas de Ligação a DNA/genética , Epigênese Genética , Fatores de Transcrição Forkhead/genética , Mutação , Proteínas Repressoras/genética , Fatores de Transcrição/genética , Sistema Urinário/metabolismo , Anormalidades Urogenitais/genética , Proteínas de Anfíbios/antagonistas & inibidores , Proteínas de Anfíbios/genética , Proteínas de Anfíbios/metabolismo , Animais , Estudos de Casos e Controles , Criança , Pré-Escolar , Proteínas de Ligação a DNA/metabolismo , Família , Feminino , Fatores de Transcrição Forkhead/metabolismo , Heterozigoto , Humanos , Lactente , Larva/genética , Larva/crescimento & desenvolvimento , Larva/metabolismo , Masculino , Camundongos , Camundongos Knockout , Morfolinos/genética , Morfolinos/metabolismo , Linhagem , Ligação Proteica , Proteínas Repressoras/metabolismo , Fatores de Transcrição/metabolismo , Sistema Urinário/anormalidades , Anormalidades Urogenitais/metabolismo , Anormalidades Urogenitais/patologia , Sequenciamento do Exoma , XenopusRESUMO
BACKGROUND: Kaposiform lymphangiomatosis (KLA) is a complex lymphatic anomaly involving most commonly the mediastinum, lung, skin and bones with few effective treatments. In recent years, RAS-MAPK pathway mutations were shown to underlie the pathogenesis of several complex lymphatic anomalies. Specifically, an activating NRAS mutation (p.Q61R) was found in the majority of KLA patients. Recent reports demonstrated promising results of treatment with the MEK inhibitor, Trametinib, in patients with complex lymphatic anomalies harboring gain of function mutations in ARAF and SOS1, as well as loss of function mutation in the CBL gene, a negative regulator of the RAS-MAPK pathway. We present a 9-year-old child with a severe case of KLA harboring the typical NRAS (p.Q61R) mutation detected by plasma-derived cell free DNA, responsive to trametinib therapy. METHODS: The NRAS somatic mutation was detected from plasma cfDNA using droplet digital PCR. Concurrent in-vitro studies of trametinib activity on mutant NRAS affected lymphatic endothelial cells were performed using a three-dimensional spheroid sprouting assay. RESULTS: Trametinib treatment lead to resolution of lifelong thrombocytopenia, improvement of pulmonary function tests and wellbeing, as well as weaning from prolonged systemic steroid treatment. Concurrent studies of mutant NRAS-expressing cells showed enhanced lymphangiogenic capacity along with over activation of the RAS-MAPK and PI3K-AKT-mTOR pathways, both reversed by trametinib. CONCLUSIONS: Trametinib treatment can substantially change the prognosis of patients with RAS pathway associated lymphatic anomalies. IMPACT: This is the first description of successful trametinib treatment of a patient with KLA harboring the most characteristic NRAS p.Q61R mutation. Treatment can significantly change the prognosis of patients with RAS pathway-associated lymphatic anomalies. We devised an in vitro model of KLA enabling a reproducible method for the continued study of disease pathogenesis. Mutated NRAS p.Q61R cells demonstrated increased lymphangiogenic capacity.
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Células Endoteliais , Anormalidades Linfáticas , Criança , Humanos , Fosfatidilinositol 3-Quinases , Mutação , Resultado do Tratamento , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Proteínas de Membrana/genética , GTP Fosfo-Hidrolases/genéticaRESUMO
BACKGROUND: The molecular basis of heterotaxy and congenital heart malformations associated with disruption of left-right asymmetry is broad and heterogenous, with over 25 genes implicated in its pathogenesis thus far. OBJECTIVE: We sought to elucidate the molecular basis of laterality disorders and associated congenital heart defects in a cohort of 30 unrelated probands of Arab-Muslim descent, using next-generation sequencing techniques. METHODS: Detailed clinical phenotyping followed by whole-exome sequencing (WES) was pursued for each of the probands and their parents (when available). Sanger sequencing was used for segregation analysis of disease-causing mutations in the families. RESULTS: Using WES, we reached a molecular diagnosis for 17 of the 30 probands (56.7%). Genes known to be associated with heterotaxy and/or primary ciliary dyskinesia, in which homozygous pathogenic or likely pathogenic variants were detected, included CFAP53 (CCDC11), CFAP298 (C21orf59), CFAP300, LRRC6, GDF1, DNAAF1, DNAH5, CCDC39, CCDC40, PKD1L1 and TTC25. Additionally, we detected a homozygous disease causing mutation in DAND5, as a novel recessive monogenic cause for heterotaxy in humans. Three additional probands were found to harbour variants of uncertain significance. These included variants in DNAH6, HYDIN, CELSR1 and CFAP46. CONCLUSIONS: Our findings contribute to the current knowledge regarding monogenic causes of heterotaxy and its associated congenital heart defects and underscore the role of next-generation sequencing techniques in the diagnostic workup of such patients, and especially among consanguineous families.
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Cardiopatias Congênitas , Síndrome de Heterotaxia , Estudos de Coortes , Cardiopatias Congênitas/genética , Síndrome de Heterotaxia/genética , Homozigoto , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Proteínas de Membrana/genética , Mutação/genética , Sequenciamento do ExomaRESUMO
PURPOSE: The clinical spectrum of motile ciliopathies includes laterality defects, hydrocephalus, and infertility as well as primary ciliary dyskinesia when impaired mucociliary clearance results in otosinopulmonary disease. Importantly, approximately 30% of patients with primary ciliary dyskinesia lack a genetic diagnosis. METHODS: Clinical, genomic, biochemical, and functional studies were performed alongside in vivo modeling of DAW1 variants. RESULTS: In this study, we identified biallelic DAW1 variants associated with laterality defects and respiratory symptoms compatible with motile cilia dysfunction. In early mouse embryos, we showed that Daw1 expression is limited to distal, motile ciliated cells of the node, consistent with a role in left-right patterning. daw1 mutant zebrafish exhibited reduced cilia motility and left-right patterning defects, including cardiac looping abnormalities. Importantly, these defects were rescued by wild-type, but not mutant daw1, gene expression. In addition, pathogenic DAW1 missense variants displayed reduced protein stability, whereas DAW1 loss-of-function was associated with distal type 2 outer dynein arm assembly defects involving axonemal respiratory cilia proteins, explaining the reduced cilia-induced fluid flow in particle tracking velocimetry experiments. CONCLUSION: Our data define biallelic DAW1 variants as a cause of human motile ciliopathy and determine that the disease mechanism involves motile cilia dysfunction, explaining the ciliary beating defects observed in affected individuals.
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Transtornos da Motilidade Ciliar , Ciliopatias , Proteínas do Citoesqueleto , Animais , Humanos , Camundongos , Axonema/genética , Cílios/metabolismo , Transtornos da Motilidade Ciliar/genética , Transtornos da Motilidade Ciliar/metabolismo , Transtornos da Motilidade Ciliar/patologia , Ciliopatias/genética , Ciliopatias/metabolismo , Ciliopatias/patologia , Proteínas do Citoesqueleto/genética , Mutação , Proteínas/genética , Peixe-Zebra/genéticaRESUMO
We compare cases of familial Mediterranean fever-related protracted febrile myalgia and poststreptococcal myalgia, both rare disorders presenting with fever, myalgia, and inflammatory biomarkers. Although clinical symptoms may be undistinguishable, steroids are usually required in protracted febrile myalgia syndrome and poststreptococcal myalgia most often respond to nonsteroidal anti-inflammatory drugs. Awareness of poststreptococcal myalgia and preceding history may prevent unnecessary tests or overtreatment.
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Febre Familiar do Mediterrâneo , Mialgia , Anti-Inflamatórios não Esteroides/uso terapêutico , Febre Familiar do Mediterrâneo/complicações , Febre Familiar do Mediterrâneo/diagnóstico , Febre Familiar do Mediterrâneo/tratamento farmacológico , Febre/diagnóstico , Febre/tratamento farmacológico , Febre/etiologia , Humanos , Mialgia/diagnóstico , Mialgia/etiologia , SobretratamentoRESUMO
During the past decades, remarkable progress has been made in our understanding of the molecular basis of kidney diseases, as well as in the ability to pinpoint disease-causing genetic changes. Congenital anomalies of the kidney and urinary tract (CAKUT) are remarkably diverse, and may be either isolated to the kidney or involve other systems, and are notorious in their variable genotype-phenotype correlations. Genetic conditions underlying CAKUT are individually rare, but collectively contribute to disease etiology in ~ 16% of children with CAKUT. In this review, we will discuss basic concepts of kidney development and genetics, common causes of monogenic CAKUT, and the approach to diagnosing and managing a patient with suspected monogenic CAKUT. Altogether, the concepts presented herein represent an introduction to the emergence of nephrogenetics, a fast-growing multi-disciplinary field that is focused on deciphering the causes and manifestations of genetic kidney diseases as well as providing the framework for managing patients with genetic forms of CAKUT.
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Nefropatias , Sistema Urinário , Anormalidades Urogenitais , Humanos , Rim/anormalidades , Nefropatias/diagnóstico , Nefropatias/genética , Sistema Urinário/anormalidades , Anormalidades Urogenitais/diagnóstico , Anormalidades Urogenitais/genética , Refluxo VesicoureteralRESUMO
BACKGROUND: Genetic kidney diseases contribute a significant portion of kidney diseases in children and young adults. Nephrogenetics is a rapidly evolving subspecialty; however, in the clinical setting, increased use of genetic testing poses implementation challenges. Consequently, we established a national nephrogenetics clinic to apply a multidisciplinary model. METHODS: Patients were referred from different pediatric or adult nephrology units across the country if their primary nephrologist suspected an undiagnosed genetic kidney disease. We determined the diagnostic rate and observed the effect of diagnosis on medical care. We also discuss the requirements of a nephrogenetics clinic in terms of logistics, recommended indications for referral, and building a multidisciplinary team. RESULTS: Over 24 months, genetic evaluation was completed for a total of 74 unrelated probands, with an age range of 10 days to 72 years. The most common phenotypes included congenital anomalies of the kidneys and urinary tract, nephrotic syndrome or unexplained proteinuria, nephrocalcinosis/nephrolithiasis, tubulopathies, and unexplained kidney failure. Over 80% of patients were referred due to clinical suspicion of an undetermined underlying genetic diagnosis. A molecular diagnosis was reached in 42/74 probands, yielding a diagnostic rate of 57%. Of these, over 71% of diagnoses were made via next generation sequencing (gene panel or exome sequencing). CONCLUSIONS: We identified a substantial fraction of genetic kidney etiologies among previously undiagnosed individuals which influenced subsequent clinical management. Our results support that nephrogenetics, a rapidly evolving field, may benefit from well-defined multidisciplinary co-management administered by a designated team of nephrologist, geneticist, and bioinformatician. A higher resolution version of the Graphical abstract is available as Supplementary information.
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Testes Genéticos , Nefropatias , Criança , Humanos , Nefropatias/genética , Fenótipo , Encaminhamento e Consulta , Sequenciamento do Exoma/métodosRESUMO
BACKGROUND: Increasing cancer incidence among children alongside improved treatments has resulted in a growing number of pediatric cancer survivors. Despite childhood cancer survivors' exposure to various factors that compromise kidney function, few studies have investigated the association between childhood cancer and future kidney disease. METHODS: To assess the risk of ESKD among childhood cancer survivors, we conducted a nationwide, population-based, retrospective cohort study that encompassed all Israeli adolescents evaluated for mandatory military service from 1967 to 1997. After obtaining detailed histories, we divided the cohort into three groups: participants without a history of tumors, those with a history of a benign tumor (nonmalignant tumor with functional impairment), and those with a history of malignancy (excluding kidney cancer). This database was linked to the Israeli ESKD registry to identify incident ESKD cases. We used Cox proportional hazards models to estimate the hazard ratio (HR) of ESKD. RESULTS: Of the 1,468,600 participants in the cohort, 1,444,345 had no history of tumors, 23,282 had a history of a benign tumor, and 973 had a history of malignancy. During a mean follow-up of 30.3 years, 2416 (0.2%) participants without a history of tumors developed ESKD. Although a history of benign tumors was not associated with an increased ESKD risk, participants with a history of malignancy exhibited a substantially elevated risk for ESKD compared with participants lacking a history of tumors, after controlling for age, sex, enrollment period, and paternal origin (adjusted HR, 3.2; 95% confidence interval, 1.3 to 7.7). CONCLUSIONS: Childhood cancer is associated with an increased risk for ESKD, suggesting the need for tighter and longer nephrological follow-up.
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Falência Renal Crônica/epidemiologia , Neoplasias/complicações , Adolescente , Adulto , Criança , Estudos de Coortes , Feminino , Humanos , Incidência , Israel , Falência Renal Crônica/diagnóstico , Masculino , Pessoa de Meia-Idade , Neoplasias/patologia , Modelos de Riscos Proporcionais , Fatores de Risco , Adulto JovemRESUMO
BACKGROUND: Coronavirus disease 2019 (COVID-19) and dengue fever are difficult to distinguish given shared clinical and laboratory features. Failing to consider COVID-19 due to false-positive dengue serology can have serious implications. We aimed to assess this possible cross-reactivity. METHODS: We analyzed clinical data and serum samples from 55 individuals with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. To assess dengue serology status, we used dengue-specific antibodies by means of lateral-flow rapid test, as well as enzyme-linked immunosorbent assay (ELISA). Additionally, we tested SARS-CoV-2 serology status in patients with dengue and performed in-silico protein structural analysis to identify epitope similarities. RESULTS: Using the dengue lateral-flow rapid test we detected 12 positive cases out of the 55 (21.8%) COVID-19 patients versus zero positive cases in a control group of 70 healthy individuals (P = 2.5E-5). This includes 9 cases of positive immunoglobulin M (IgM), 2 cases of positive immunoglobulin G (IgG), and 1 case of positive IgM as well as IgG antibodies. ELISA testing for dengue was positive in 2 additional subjects using envelope protein directed antibodies. Out of 95 samples obtained from patients diagnosed with dengue before September 2019, SARS-CoV-2 serology targeting the S protein was positive/equivocal in 21 (22%) (16 IgA, 5 IgG) versus 4 positives/equivocal in 102 controls (4%) (P = 1.6E-4). Subsequent in-silico analysis revealed possible similarities between SARS-CoV-2 epitopes in the HR2 domain of the spike protein and the dengue envelope protein. CONCLUSIONS: Our findings support possible cross-reactivity between dengue virus and SARS-CoV-2, which can lead to false-positive dengue serology among COVID-19 patients and vice versa. This can have serious consequences for both patient care and public health.
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COVID-19 , Vírus da Dengue , Anticorpos Antivirais , Reações Cruzadas , Humanos , SARS-CoV-2Assuntos
Diabetes Mellitus , Doenças Renais Císticas , Humanos , Masculino , Adulto Jovem , Cistos , Rim/diagnóstico por imagemRESUMO
BACKGROUND: The long-term risk associated with childhood kidney disease that had not progressed to chronic kidney disease in childhood is unclear. We aimed to estimate the risk of future end-stage renal disease (ESRD) among adolescents who had normal renal function and a history of childhood kidney disease. METHODS: We conducted a nationwide, population-based, historical cohort study of 1,521,501 Israeli adolescents who were examined before compulsory military service in 1967 through 1997; data were linked to the Israeli ESRD registry. Kidney diseases in childhood included congenital anomalies of the kidney and urinary tract, pyelonephritis, and glomerular disease; all participants included in the primary analysis had normal renal function and no hypertension in adolescence. Cox proportional-hazards models were used to estimate the hazard ratio for ESRD associated with a history of childhood kidney disease. RESULTS: During 30 years of follow-up, ESRD developed in 2490 persons. A history of any childhood kidney disease was associated with a hazard ratio for ESRD of 4.19 (95% confidence interval [CI], 3.52 to 4.99). The associations between each diagnosis of kidney disease in childhood (congenital anomalies of the kidney and urinary tract, pyelonephritis, and glomerular disease) and the risk of ESRD in adulthood were similar in magnitude (multivariable-adjusted hazard ratios of 5.19 [95% CI, 3.41 to 7.90], 4.03 [95% CI, 3.16 to 5.14], and 3.85 [95% CI, 2.77 to 5.36], respectively). A history of kidney disease in childhood was associated with younger age at the onset of ESRD (hazard ratio for ESRD among adults <40 years of age, 10.40 [95% CI, 7.96 to 13.59]). CONCLUSIONS: A history of clinically evident kidney disease in childhood, even if renal function was apparently normal in adolescence, was associated with a significantly increased risk of ESRD, which suggests that kidney injury or structural abnormality in childhood has long-term consequences.
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Nefropatias/complicações , Falência Renal Crônica/etiologia , Sistema Urinário/anormalidades , Adolescente , Adulto , Estudos de Coortes , Feminino , Seguimentos , Humanos , Incidência , Israel/epidemiologia , Rim/anormalidades , Falência Renal Crônica/epidemiologia , Tábuas de Vida , Masculino , Pielonefrite/complicações , Sistema de Registros , Risco , Sistema Urinário/cirurgia , Adulto JovemRESUMO
OBJECTIVES: FMF results from mutations in the Mediterranean fever (MEFV) gene. The p. E148Q protein alternation is one of the most frequent in the MEFV gene, yet the exact E148Q genotype-phenotype correlation remains unclear. The aim of this study was to examine clinical significance of heterozygous E148Q variant in a paediatric FMF cohort. METHODS: We compared the clinical manifestations and disease severity score of four genetic subgroups: (group 1) patients harbouring a single heterozygous p. E148Q variant (n = 6); (group 2) patients harbouring a single p. M694V heterozygous variant (n = 88); (group 3) patients harbouring compound heterozygous p. M694V and p. E148Q variants (n = 36); and (group 4) homozygotes for p. M694V variant (n = 160). RESULTS: Of 646 FMF children from our centre, only 1% (six patients) of our genetically characterized FMF cohort had a single E148Q variant, most presenting with recurrent fevers and abdominal pain. None of the participants was found to harbour homozygous E148Q. Overall, M694V/E148Q compound heterozygosity did not exhibit a more severe phenotype compared with patients with a single M694V variant. The former group were less likely to have abdominal pain and exertional leg pain (P < 0.004 and P < 0.001, respectively) and more likely to have chest pain (P < 0.01). Both subgroups showed milder clinical phenotype compared with patients with M694V homozygosity. CONCLUSION: Our findings demonstrate that a single heterozygous E148Q variant is unlikely to cause FMF in children and that E148Q/M694V is clinically indistinguishable from a single M694V variant. Thus, E148Q heterozygosity does not result in clinically meaningful phenotype in children.
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Febre Familiar do Mediterrâneo/genética , Pirina/genética , Substituição de Aminoácidos , Criança , Pré-Escolar , Feminino , Heterozigoto , Humanos , Masculino , Estudos RetrospectivosRESUMO
Chronic kidney disease (CKD) is a major public health challenge, affecting as much as 8 to 18% of the world population. Identifying childhood risk factors for future CKD may help clinicians make early diagnoses and initiation of preventive interventions for CKD and its attendant comorbidities as well as monitoring for complications. The purpose of this review is to describe childhood risk factors that may predict development of overt kidney disease later in life. Currently, there are multiple childhood risk factors associated with future onset and progression of CKD. These risk factors can be grouped into five categories: genetic factors (e.g., monogenic or risk alleles), perinatal factors (e.g., low birth weight and prematurity), childhood kidney diseases (e.g., congenital anomalies, glomerular diseases, and renal cystic ciliopathies), childhood onset of chronic conditions (e.g., cancer, diabetes, hypertension, dyslipidemia, and obesity), and different lifestyle factors (e.g., physical activity, diet, and factors related to socioeconomic status). The available published information suggests that the lifelong risk for CKD can be attributed to multiple factors that appear already during childhood. However, results are conflicting on the effects of childhood physical activity, diet, and dyslipidemia on future renal function. On the other hand, there is consistent evidence to support follow-up of high-risk groups.
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Insuficiência Renal Crônica , Adulto , Criança , Progressão da Doença , Humanos , Recém-Nascido de Baixo Peso , Recém-Nascido , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/etiologia , Fatores de Risco , Classe SocialRESUMO
BACKGROUND: Kabuki syndrome (KS) is a genetic disorder caused mainly by de novo pathogenic variants in KMT2D or KDM6A, characterized by recognizable facial features, intellectual disability, and multi-systemic involvement, including short stature, microcephaly, hearing loss, cardiac defects, and additional congenital anomalies. While congenital anomalies of the kidneys and urinary tract (CAKUT) are known manifestations of this disorder, studies focused solely on kidney involvement are scarce, and its prevalence is most likely underestimated. This study aimed to describe the prevalence and nature of CAKUT and other renal manifestations, in a cohort of KS patients followed at a single tertiary center. METHODS: All patients who were evaluated at the Sheba Medical Center and received a clinical and/or molecular diagnosis of KS, over a 16-year period (2004-2020), were included. Digital medical records, including ultrasound studies, were reviewed by a team of pediatric nephrologists. RESULTS: Thirteen patients were included in the study, at ages ranging from the neonatal period to 20 years. In eight patients, a pathogenic variant in KMT2D was established. CAKUT were detected in 8/13 (61.5%) of patients and varied from hypospadias, hydronephrosis, or double collecting systems to pelvic kidney, kidney asymmetry, horseshoe kidney, or kidney agenesis. One patient experienced kidney failure necessitating transplantation at 20 years of age. CONCLUSIONS: Our findings underscore the high prevalence of CAKUT and genitourinary involvement in patients with KS and suggest that assessment by pediatric nephrology specialists is warranted as part of the routine multidisciplinary evaluation of newly diagnosed patients. A higher resolution version of the Graphical abstract is available as Supplementary information.
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Anormalidades Múltiplas , Face/anormalidades , Doenças Hematológicas , Sistema Urinário , Doenças Vestibulares , Adolescente , Criança , Pré-Escolar , Humanos , Lactente , Recém-Nascido , Rim/diagnóstico por imagem , Masculino , Sistema Urinário/diagnóstico por imagem , Anormalidades Urogenitais , Refluxo Vesicoureteral , Adulto JovemRESUMO
BACKGROUND: Diabetic kidney disease (DKD) is becoming increasingly common among children. We aimed to estimate the risk of end-stage renal disease (ESKD) and mortality among adolescents with type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM) and normal renal function compared with non-diabetics. We hypothesized that childhood onset T1DM vs. T2DM would be associated with a different risk profile for developing ESKD and its complications. METHODS: A nationwide, population-based, retrospective cohort study, including 1,500,522 adolescents examined for military service between 1967 and 1997, which were classified according to the presence and type of diabetes. Data were linked to the Israeli ESKD registry. Cox proportional-hazards models were used to estimate the hazard ratio (HR) for ESKD. RESULTS: At study enrolment, 1183 adolescents had T1DM and 196 had T2DM. ESKD developed in 2386 non-diabetic individuals (0.2%) compared with 72 individuals (6.1%) with T1DM and 8 individuals (4.1%) with T2DM. Participants with T1DM were younger at ESKD onset than participants with T2DM (median age, 36.0 vs. 40.5 years, P < 0.05). In a multivariate model adjusted for age, sex, paternal origin, enrollment year, BMI, and blood pressure, T1DM and T2DM were associated with HR of 36.4 (95% CI 28.3-46.9) and 19.3 (95% CI 9.6-38.8) for ESKD, respectively. Stratification according to sex, ethnicity, immigration, and socioeconomic status did not materially change the HR. During the follow-up period, mortality rates were higher in T2DM as compared with T1DM and controls (8.7 %, 2.2%, and 2.7% respectively). CONCLUSIONS: T1DM and T2DM in adolescents with normal renal function confer a significantly increased risk for ESKD. T1DM is associated with younger age at ESKD onset while T2DM is associated with higher mortality rate.
Assuntos
Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Falência Renal Crônica , Adolescente , Adulto , Criança , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Nefropatias Diabéticas/epidemiologia , Nefropatias Diabéticas/etiologia , Humanos , Falência Renal Crônica/epidemiologia , Falência Renal Crônica/etiologia , Estudos Retrospectivos , Fatores de RiscoRESUMO
INTRODUCTION: Chronic kidney disease (CKD) in children arises from heterogeneous disease etiologies. A large portion is caused by monogenic diseases, which are also known as single-gene disorders or Mendelian diseases. Understanding the genetic underpinnings of childhood and young adulthood, CKD has increased significantly over the last decade due to increased availability of genetic testing as well as clinician's awareness. This led to the discovery of numerous genes that, if mutated, may lead to early onset CKD. So far, hundreds of CKD-causing genes have been reported, explaining ~30% of cases among children and ~10% in adults. Nonetheless, the genetic diagnostic yield varies markedly across different study cohorts, depending on clinical presentation, geographic region and ethnicity. In clinical practice, the diagnosis of genetic kidney diseases may be challenging due to variable expressivity, incomplete penetrance, low index of suspicion, lack of overt symptoms at early disease stages and insufficient availability of next generation sequencing methods. Detection of monogenic causes of CKD provides definitive diagnosis that might end a long distressing odyssey. It enables personalized surveillance and treatments, spares unnecessary diagnostic procedures such as kidney biopsies, prevents the use of inappropriate therapies, and might also prevent incompatible transplantation from an affected relative. Additionally, it allows family genetic consulting and early diagnosis of asymptomatic family members. The notable progress in the field of genetics in addition to the diagnostic challenges of genetic kidney disease led to the emergence of nephrogenetics - a rapidly evolving subspecialty of nephrology and genetics. Preferably, the management of patients with genetic kidney disease should be multi-disciplinary and include collaboration between nephrologists, geneticists and additional consultants as needed. We anticipate that a routine use of genetic testing for CKD patients, as well as additional advancements in genetic discoveries, will further lead to understanding of genetic CKD patho-mechanisms and to the development of novel gene-based therapies. In this review, we will discuss the genetic basis of CKD in children and young adults. We will also discuss the clinical approach to patients with suspected genetic kidney disease.
Assuntos
Insuficiência Renal Crônica , Adulto , Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Rim , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/etiologia , Adulto JovemRESUMO
Despite the accelerated discovery of genes associated with syndromic traits, the majority of families affected by such conditions remain undiagnosed. Here, we employed whole-exome sequencing in two unrelated consanguineous kindreds with central nervous system (CNS), cardiac, renal, and digit abnormalities. We identified homozygous truncating mutations in TMEM260, a locus predicted to encode numerous splice isoforms. Systematic expression analyses across tissues and developmental stages validated two such isoforms, which differ in the utilization of an internal exon. The mutations in both families map uniquely to the long isoform, raising the possibility of an isoform-specific disorder. Consistent with this notion, RT-PCR of lymphocyte cell lines from one of the kindreds showed reduced levels of only the long isoform, which could be ameliorated by emetine, suggesting that the mutation induces nonsense-mediated decay. Subsequent in vivo testing supported this hypothesis. First, either transient suppression or CRISPR/Cas9 genome editing of zebrafish tmem260 recapitulated key neurological phenotypes. Second, co-injection of morphants with the long human TMEM260 mRNA rescued CNS pathology, whereas the short isoform was significantly less efficient. Finally, immunocytochemical and biochemical studies showed preferential enrichment of the long TMEM260 isoform to the plasma membrane. Together, our data suggest that there is overall reduced, but not ablated, functionality of TMEM260 and that attenuation of the membrane-associated functions of this protein is a principal driver of pathology. These observations contribute to an appreciation of the roles of splice isoforms in genetic disorders and suggest that dissection of the functions of these transcripts will most likely inform pathomechanism.