Genetic Markers Among the Israeli Druze Minority Population With End-Stage Kidney Disease.

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.

Adolescent Body Mass Index and Early Chronic Kidney Disease in Young Adulthood.

Importance: Despite increasing obesity rates in adolescents, data regarding early kidney sequelae are lacking. Objective: To assess the association between adolescent body mass index (BMI) and early chronic kidney disease (CKD) in young adulthood (<45 years of age). Design, Setting, and Participants: This cohort study linked screening data of mandatory medical assessments of Israeli adolescents to data from a CKD registry of a national health care system. Adolescents who were aged 16 to 20 years; born since January 1, 1975; medically evaluated for mandatory military service through December 31, 2019; and insured by Maccabi Healthcare Services were assessed. Individuals with kidney pathology, albuminuria, hypertension, dysglycemia, or missing blood pressure or BMI data were excluded. Body mass index was calculated as weight in kilograms divided by height in meters squared and categorized by age- and sex-matched percentiles according to the US Centers for Disease Control and Prevention. Follow-up started at the time of medical evaluation or January 1, 2000 (whichever came last), and ended at early CKD onset, death, the last day insured, or August 23, 2020 (whichever came first). Data analysis was performed from December 19, 2021, to September 11, 2023. Main Outcomes and Measures: Early CKD, defined as stage 1 to 2 CKD by moderately or severely increased albuminuria, with an estimated glomerular filtration rate of 60 mL/min/1.73 m2 or higher. Results: Of 629 168 adolescents evaluated, 593 660 (mean [SD] age at study entry, 17.2 [0.5] years; 323 293 [54.5%] male, 270 367 [45.5%] female) were included in the analysis. During a mean (SD) follow-up of 13.4 (5.5) years for males and 13.4 (5.6) years for females, 1963 adolescents (0.3%) developed early CKD. Among males, the adjusted hazard ratios were 1.8 (95% CI, 1.5-2.2) for adolescents with high-normal BMI, 4.0 (95% CI, 3.3-5.0) for those with overweight, 6.7 (95% CI, 5.4-8.4) for those with mild obesity, and 9.4 (95% CI, 6.6-13.5) for those with severe obesity. Among females, the hazard ratios were 1.4 (95% CI, 1.2-1.6) for those with high-normal BMI, 2.3 (95% CI, 1.9-2.8) for those with overweight, 2.7 (95% CI, 2.1-3.6) for those with mild obesity, and 4.3 (95% CI, 2.8-6.5) for those with severe obesity. The results were similar when the cohort was limited to individuals who were seemingly healthy as adolescents, individuals surveyed up to 30 years of age, or those free of diabetes and hypertension at the end of the follow-up. Conclusions and Relevance: In this cohort study, high BMI in late adolescence was associated with early CKD in young adulthood. The risk was also present in seemingly healthy individuals with high-normal BMI and before 30 years of age, and a greater risk was seen among those with severe obesity. These findings underscore the importance of mitigating adolescent obesity rates and managing risk factors for kidney disease in adolescents with high BMI.

Diagnostic Utility of Exome Sequencing Among Israeli Children With Kidney Failure.

Introduction: Genetic etiologies are estimated to account for a large portion of chronic kidney diseases (CKD) in children. However, data are lacking regarding the true prevalence of monogenic etiologies stemming from an unselected population screen of children with advanced CKD. Methods: We conducted a national multicenter prospective study of all Israeli pediatric dialysis units to provide comprehensive "real-world" evidence for the genetic basis of childhood kidney failure in Israel. We performed exome sequencing and assessed the genetic diagnostic yield. Results: Between 2019 and 2022, we recruited approximately 88% (n = 79) of the children on dialysis from all 6 Israeli pediatric dialysis units. We identified genetic etiologies in 36 of 79 (45%) participants. The most common subgroup of diagnostic variants was in congenital anomalies of the kidney and urinary tract causing genes (e.g., EYA1, HNF1B, PAX2, COL4A1, and NFIA) which together explain 28% of all monogenic etiologies. This was followed by mutations in genes causing renal cystic ciliopathies (e.g., NPHP1, NPHP4, PKHD1, and BBS9), steroid-resistant nephrotic syndrome (e.g., LAGE3, NPHS1, NPHS2, LMX1B, and SMARCAL1) and tubulopathies (e.g., CTNS and AQP2). The genetic diagnostic yield was higher among Arabs compared to Jewish individuals (55% vs. 29%) and in children from consanguineous compared to nonconsanguineous families (63% vs. 29%). In 5 participants (14%) with genetic diagnoses, the molecular diagnosis did not correspond with the pre-exome diagnosis. Genetic diagnosis has a potential influence on clinical management in 27 of 36 participants (75%). Conclusion: Exome sequencing in an unbiased Israeli nationwide dialysis-treated kidney failure pediatric cohort resulted in a genetic diagnostic yield of 45% and can often affect clinical decision making.

Dialysis in Israeli Children between 1990 and 2020: Trends and International Comparisons.

BACKGROUND: Childhood kidney failure is a rare condition with worldwide clinical variability. We used a nationwide multicenter analysis to study the pretransplant course of the entire Israeli pediatric kidney failure population over 30 years. METHODS: In this nationwide, population-based, historical cohort study, we analyzed medical and demographic data of all children treated with KRT and reported to the Israeli kidney failure registry in 1990-2020. Statistical analysis was performed with incidence rate corrected for age, ethnicity, and calendar year, using the appropriate age-related general population as denominator. RESULTS: During the last 30 years, childhood incidence of kidney failure decreased. Average incidence in 2015-2019 was 9.1 cases per million age-related population (pmarp). Arab and Druze children exhibited higher kidney failure incidence rates than Jewish children (18.4 versus 7.0 cases pmarp for minorities versus Jews). The most common kidney failure etiologies among Arab and Jewish children were congenital anomalies of the kidney and urinary tract (approximately 27%), followed by cystic kidney diseases among Arab children (13%) and glomerulonephritis among Jewish children (16%). The most common etiology among Druze children was primary hyperoxaluria type 1 (33%). Israel's national health insurance provides access to primary health care to all citizens. Accordingly, waiting time for deceased-donor transplantation was equal between all ethnicities. Living-donor kidney transplantation rates among minority populations remained low in comparison with Jews over the entire study period. Although all patient groups demonstrated improvement in survival, overall survival rates were mainly etiology dependent. CONCLUSIONS: In Israel, Arab and Druze children had a higher incidence of kidney failure, a unique etiological distribution, and a lower rate of living-donor kidney transplantations compared with Jewish children.

Effect of interleukin-1 antagonist on growth of children with colchicine resistant or intolerant FMF.

INTRODUCTION: Familial Mediterranean Fever (FMF) is the most common monogentic autoinflammatory disease. FMF results from mutations in MEFV, which lead to a pro-inflammatory state and increased production of Interleukin 1 beta subunit (IL-1b) by myeloid cells. Despite the overall positive results obtained with anti-IL-1 agents in FMF patients, little is known about the long-term growth impact of these drugs in the pediatric population. OBJECTIVES: To assess the long-term body weight and height trajectories in children with FMF treated with anti-IL-1 agents. METHODS: We conducted a retrospective analysis of 646 pediatric FMF patients followed in our center, of whom 22 were treated with either anakinra (36.3%) and/or canakinumab (90.9%). Patients were assessed for demographic, clinical and genetic characteristics and were followed for a mean of 3.05 ± 1.75 years. Data of height and weight percentiles were recorded before and after treatment. RESULTS: The most common indication for IL-1 blockers treatment was colchicine resistance (66.6%). Ninety percent of those patients had a moderate or severe disease according to the Pras score and had higher proportion of M694V homozygosity compared with patients who did not require anti IL-1 agents (95.2% vs. 30.5%, p < 0.001). Overall, anakinra and canakinumab resulted in a complete response in 80% of patients and exhibited low rates of adverse effects. We found a significant increase in height and body weight percentiles following treatment (19.6 ± 16% vs. 30.8 ± 23%, p = 0.007, and 29.5 ± 30% vs. 39.1 ± 36%, p = 0.043, respectively). CONCLUSION: Treatment with anti-IL-1 agents in children with FMF is effective and safe and may potentiate long-term growth.

Colchicine treatment can be discontinued in a selected group of pediatric FMF patients.

OBJECTIVES: Familial Mediterranean Fever (FMF) patients are required to adhere to a life-long treatment with colchicine, primarily for preventing amyloidosis. As some patients may be asymptomatic for long periods of time, it remains unclear whether it is possible to discontinue colchicine treatment in a selective group of patients. We aimed to identify predictive characteristics for a successful cessation of colchicine therapy. METHODS: Out of 646 FMF pediatric patients followed in our referral FMF clinic, colchicine treatment was discontinued in 51 patients. In this study we compared the genetic, demographic, and clinical characteristics between patients for whom a successful cessation of therapy was made (Group 1; n = 21) and patients for whom cessation of therapy was deemed a failure (Group 2; n = 30) and consequently had to resume colchicine therapy. RESULTS: Patients for whom a successful cessation of therapy was achieved had no biallelic pathogenic MEFV mutations, were less likely to have "severe attacks" (two or more FMF characteristic symptoms) (24% vs 80%; P = 0.000067) and did not require higher than 1 mg/day of colchicine, prior to the drug cessation. Remission duration under colchicine treatment was significantly higher in group 1 compared with group 2 (4.36 years ±2.12 vs 2.53 years ±2; P = 0.0036). CONCLUSION: This study supports the concept of colchicine free remission in a minority of FMF patients (3%). Holding treatment, under close monitoring, may be reasonable when selecting the appropriate patients.

Treatment of severe Kaposiform lymphangiomatosis positive for NRAS mutation by MEK inhibition.

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.

Genetic Variants in ARHGEF6 Cause Congenital Anomalies of the Kidneys and Urinary Tract in Humans, Mice, and Frogs.

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.

Biallelic DAW1 variants cause a motile ciliopathy characterized by laterality defects and subtle ciliary beating abnormalities.

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.

Persistent Asymptomatic Isolated Microscopic Hematuria in Adolescents is not Associated With an Increased Risk for Early Onset Urinary Tract Cancer.

OBJECTIVE: To elucidate the association between adolescent microscopic hematuria and early onset urothelial carcinoma and renal cell carcinoma. METHODS: Nationwide, population-based, retrospective cohort study using medical data of 970,366 adolescents aged 16 through 19 years (58.6% male) examined for fitness for military service between 1980 and 1997. Diagnoses of persistent isolated microscopic hematuria were given after thorough work up process excluding any other renal abnormalities. Incident cases of urothelial carcinoma and renal cell carcinoma diagnosed during the years of 1982-2012 were retrieved from the Israeli National Cancer Registry. Cox proportional hazards models were used to estimate the hazard ratio (HR) separately for urothelial carcinoma and renal cell carcinoma. RESULTS: During a cumulative follow-up of 22,115,629 person-years (median follow-up, 22.8), persistent isolated microscopic hematuria was diagnosed among 5509 (0.6%) adolescents. Urothelial carcinoma and renal cell carcinoma developed in 332 (3 among those with persistent isolated microscopic hematuria) and 292 (2) individuals, respectively. The adjusted HR for incident urothelial carcinoma among adolescents with isolated microscopic hematuria was 1.17 (95% CI, 0.38-3.66) and the adjusted HR for renal cell carcinoma was 1.02 (95% CI, 0.25-4.12). CONCLUSION: Persistent asymptomatic isolated microscopic hematuria at adolescence was not associated with increased risk for urothelial carcinoma nor renal cell carcinoma.

Hereditary neuropathy with liability to pressure palsies (HNPP): Intrafamilial phenotypic variability and early childhood refusal to walk as the presenting symptom.

BACKGROUND: Limping and/or refusal to walk is a common complaint in the setting of the pediatric department, with a widely diverse differential diagnosis. An unusual etiology, is that of a hereditary neuropathy. Hereditary neuropathy with liability to pressure palsies (HNPP) is a recurrent, episodic demyelinating neuropathy, most commonly caused by a 17p11.2 chromosomal deletion encompassing the PMP22 gene. METHODS: We pursued chromosomal microarray analysis (CMA) in multiple affected individuals of a single extended family, manifesting a range of phenotypic features consistent with HNPP. RESULTS: A 4.5 years-old boy presented for in-patient evaluation due to refusal to walk. Initial investigations including spine MRI and bone scan failed to yield a conclusive diagnosis. Following family history, which implied an autosomal dominant mode of inheritance, CMA was pursued and confirmed a 17p11.2 deletion in the proband consistent with HNPP. Importantly, following this diagnosis, four additional affected family members were demonstrated to harbor the deletion. Their variable phenotypic features, ranging from a prenatal diagnosis of a 6 months-old sibling, to recurrent paresthesias manifesting in the fourth decade of life, are discussed. CONCLUSIONS: Our experience with the family reported herein demonstrates how a thorough anamnesis can lead to a rare genetic etiology with a favorable prognosis and prevent unnecessary investigations, and underscores HNPP as an uncommon diagnostic possibility in the limping child.

Poststreptococcal Myalgia and Protracted Febrile Myalgia Syndrome: Similar Yet Different.

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.

Adolescent Blood Pressure and the Risk for Early Kidney Damage in Young Adulthood.

BACKGROUND: Recent guidelines classified blood pressure above 130/80 mm Hg as hypertension. However, outcome data were lacking. OBJECTIVE: To determine the association between blood pressure in adolescence and the risk for early kidney damage in young adulthood. METHODS: In this nationwide cohort study, we included 629 168 adolescents aged 16 to 20 who underwent medical examinations before mandatory military service in Israel. We excluded 30 466 adolescents with kidney pathology, hypertension, or missing blood pressure or anthropometric data at study entry. Blood pressure measurements at study entry were categorized according to the Clinical Practice Guideline for Screening and Management of High Blood Pressure in Children and Adolescents: group A (<120/<80 mm Hg; Reference group), group B (120/<80-129/<80 mm Hg), group C (130/80-139/89 mm Hg), and group D (≥140/90 mm Hg). Early kidney damage in young adulthood was defined as albuminuria of ≥30 mg/g with an estimated glomerular filtration rate of 60 mL/(min·1.73 m2) or over. RESULTS: Of 598 702 adolescents (54% men), 2004 (0.3%) developed early kidney damage during a mean follow-up of 15.1 (7.2) years. The adjusted hazard ratios for early kidney damage in blood pressure group C were 1.17 (1.03-1.32) and 1.51 (1.22-1.86) among adolescents with lean (body mass index <85th percentile) and high body mass index (body mass index ≥85th percentile), respectively. Corresponding hazard ratios for kidney disease in group D were 1.49 (1.15-1.93) and 1.79 (1.35-2.38) among adolescents with lean and high body mass index, respectively. CONCLUSIONS: Blood pressure of ≥130/80 mm Hg was associated with early kidney damage in young adulthood, especially in adolescents with overweight and obesity.

The genetic basis of congenital anomalies of the kidney and urinary tract.

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.

A multidisciplinary nephrogenetic referral clinic for children and adults-diagnostic achievements and insights.

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.