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Chronic kidney disease (CKD) is a major health problem, with steadily increasing incidence and prevalence and the threat of a true "epidemic". Converging evidence suggests a high prevalence of genetic etiology in rare kidney diseases and the list of new disease-causing genes is constantly updated. Recent advances in next-generation sequencing (NGS) technologies have prompted a significant improvement in the diagnosis of rare kidney diseases. Notwithstanding this, NGS generates high numbers of information that need to be properly analysed by the joint efforts of geneticists, nephrologists and bioinformatics in order to integrate clinical and genetic information in a personalized manner. In addition, in selected cases, the contribution of researchers proves essential for the development of experimental models of the disease to study and understand the pathogenic features and propose a personalized therapeutic approach. Such an innovative, integrated diagnostic paradigm is currently available in few centers all over the world and cannot be easily translated in daily clinical practice.
The aim of the study is to set-up an integrated diagnostic algorithm to extend the newest personalized diagnostic and treatment strategies for rare kidney diseases to all patients in the Tuscany region, under 40 years of age with kidney disease. This algorithm will be based on a constant cross-talk between participating centers and a dedicated multidisciplinary team. Diagnostic and therapeutic performances will be validated at European level.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Pathogenic variants | Experimental | Variants fitting bioinformatic prioritization criteria for pathogenicity according to ACMG guidelines and the clinical phenotype, and variants already reported in the literature will be defined as pathogenic variants |
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| Potentially Pathogenic Variants | Experimental | Variants fitting bioinformatic prioritization criteria but apparently do not correlate with the clinical phenotype and have not been previously reported in the literature will be defined as potentially pathogenic variants |
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| Variants of Unknown Significance (VUS) | Experimental | Variants fitting the phenotype but not fitting bioinformatic prioritization criteria will be defined as variants of uncertain clinical significance (VUS) |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Conclusive genetic testing | Diagnostic Test | Patients will be referred for genetic counseling at the study coordinating center. This will lead to a conclusive genetic diagnosis. |
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| Measure | Description | Time Frame |
|---|---|---|
| Validation of genetic diagnosis | The investigators will assess the role of potentially pathogenic variants and variants of uncertain clinical significance (VUS) in determining a conclusive genetic diagnosis by patient reassessment (reverse phenotyping) or in vitro functional studies. In detail, after the results of ES, a multidisciplinary team will evaluate the results of sequencing and will eventually request additional investigations (e.g., laboratory or imaging tests, specific consultations, etc) to the patient and/or family member in order to look for previously undetected/overlooked signs of the genetic diseases suggested by ES (reverse phenotyping). In vitro functional studies on u-RPC will be requested in a subset of patients. The number of patients with a conclusive diagnosis obtained trough these strategies will contribute to the overall diagnostic rate of the workflow (number of conclusive genetic diagnosis/number of patients enrolled in the study). | From enrollment (genetic testing) until the date of returning of genetic testing results (up to 6 months) |
| Measure | Description | Time Frame |
|---|---|---|
| Identification of molecular pathways | The investigators aim to o identify molecular pathways that could represent potential therapeutic targets in a selection of patients carrying potentially pathogenic variants. To this goal, the investigators will perform single-cell RNA sequencing on kidney biopsy fragments of patients who have undergone a diagnostic kidney biopsy. After obtaining intracellular transcriptome of individual cells carrying the potentially pathogenic variants, the investigators will compare their RNA expression profile to the same type of cells obtained from non-mutated patients. |
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Inclusion Criteria:
Exclusion Criteria:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Azienda Ospedaliero Universitaria Careggi | Florence | Italy | ||||
| Meyer Children's Hospital IRCCS |
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Patients selected based on the inclusion criteria will be evaluated by a multidisciplinary team of experts. All the selected patients will undergo genetic testing by clinical exome sequencing and in silico filtering for a panel of genes described as causing or in association with CKD. Identified variants will be classified according to the American College of Medical Genetics and Genomics (ACMG) guidelines. Reverse phenotyping will be performed according to the results of genetic testing. The results of the diagnostic work-up will be evaluated by a multi-disciplinary team of experts in order to establish conclusive diagnosis.
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| Genotype-phenotype correlation for personalized diagnosis | Diagnostic Test | Patients and their family members will undergo a thorough clinical reassessment at the study coordinating center to identify diagnostic handles of the suspected disease based on the genetic test result (reverse phenotyping). The clinical reassessment could include the performance of additional clinical and instrumental tests, as well as other specialized consultations. This will lead to a conclusive genetic diagnosis in a substantial proportion of cases, cases, who will then be provided with genetic counselling. |
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| Personalized study of variants of uncertain clinical significance (VUS) through functional studies on 3D organ-on-a-chip | Diagnostic Test | The investigators will perform functional assessment trough urine derived Renal Progenitor Cells (u-RPC) to establish the role of variants in determining the clinical phenotype. |
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| From enrollment (genetic testing) until the last patient last visit, estimated up to 12 months |
| Explore the applicability of gene editing in rare kidney diseases | The investigators will explore the applicability of CRISPR/Cas9 gene editing in rare kidney diseases through u-RPCs obtained from patients carrying pathogenic mutations. In order to achieve the rescue of disease causative variants, the investigators will perform a stable correction of genetic variants identified through CRISPR/Cas9 gene editing approach, in u-RPC isolated from patients carrying pathogenic variants. | From enrollment (genetic testing) until the last patient last visit, estimated up to 12 months |
| Florence |
| Italy |
| USL Toscana Centro | Florence | Italy |
| Azienda Ospedaliero Universitaria Pisana | Pisa | Italy |
| ID | Term |
|---|---|
| D051436 | Renal Insufficiency, Chronic |
| ID | Term |
|---|---|
| D051437 | Renal Insufficiency |
| D007674 | Kidney Diseases |
| D014570 | Urologic Diseases |
| D052776 | Female Urogenital Diseases |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
| D000091642 | Urogenital Diseases |
| D052801 | Male Urogenital Diseases |
| D002908 | Chronic Disease |
| D020969 | Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
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