Exome sequencing is increasingly being used for clinical diagnostics, with an impetus to expand reporting of incidental findings across a wide range of disorders. Analysis of population cohorts can ...help reduce risk for genetic variant misclassification and resultant unnecessary referrals to subspecialists.
To examine the burden of candidate pathogenic variants for kidney and genitourinary disorders emerging from exome sequencing.
Secondary analysis of genetic data.
A tertiary care academic medical center.
A convenience sample of exome sequence data from 7974 self-declared healthy adults.
Assessment of the prevalence of candidate pathogenic variants in 625 genes associated with Mendelian kidney and genitourinary disorders.
Of all participants, 23.3% carried a candidate pathogenic variant, most of which were attributable to previously reported variants that had implausibly high allele frequencies. In particular, 25 genes (discovered before the creation of the Exome Aggregation Consortium, a genetic database comprising data from a large control population) accounted for 67.7% of persons with candidate pathogenic variants. After stringent filtering based on allele frequency, 1.4% of persons still had a candidate pathogenic variant, an excessive rate given the prevalence of monogenic kidney and genitourinary disorders. Manual annotation of a subset of variants showed that the majority would be classified as nonbenign under current guidelines for clinical sequence interpretation and could prompt subspecialty referrals if returned.
Limited access to health record data prevented comprehensive assessment of the phenotypic concordance with genetic diagnoses.
Widespread reporting of incidental genetic findings related to kidney and genitourinary disorders will require stringent curation of clinical variant databases and detailed case-level review to avoid genetic misdiagnosis and unnecessary referrals. These findings motivate similar analyses for genes relevant to other medical subspecialties.
National Institute of Diabetes and Digestive and Kidney Diseases and National Human Genome Research Institute.
Between 15-20% of patients with end stage renal disease (ESRD) do not know the cause of the primary kidney disease and can develop complications after kidney transplantation. We performed a genetic ...screening in 300 patients with kidney transplantation, or undiagnosed primary renal disease, in order to identify the primary disease cause and discriminate between overlapping phenotypes. We used a custom-made panel for next-generation sequencing (Agilent technology, Santa Clara, CA, USA), including genes associated with Fabry disease, podocytopaties, complement-mediated nephropathies and Alport syndrome-related diseases. We detected candidate diagnostic variants in genes associated with nephrotic syndrome and Focal Segmental Glomerulosclerosis (FSGS) in 29 out of 300 patients, solving about 10% of the probands. We also identified the same genetic cause of the disease (
: c.1266dupC) in three family members with different clinical diagnoses. Interestingly we also found one female patient carrying a novel missense variant, c.1259C>A (p.Thr420Lys), in the
gene not previously associated with Fabry disease, which is in silico defined as a likely pathogenic and destabilizing, and associated with a mild alteration in GLA enzymatic activity. The identification of the specific genetic background may provide an opportunity to evaluate the risk of recurrence of the primary disease, especially among patient candidates living with a donor kidney transplant.
The Complement System is an evolutionarily conserved component of immunity that plays a key role in host defense against infections and tissue homeostasis. However, the dysfunction of the Complement ...System can result in tissue damage and inflammation, thereby contributing to the development and progression of various renal diseases, ranging from atypical Hemolytic Uremic Syndrome to glomerulonephritis. Therapeutic interventions targeting the complement system have demonstrated promising results in both preclinical and clinical studies. Currently, several complement inhibitors are being developed for the treatment of complement-mediated renal diseases. This review aims to summarize the most recent insights into complement activation and therapeutic inhibition in renal diseases. Furthermore, it offers potential directions for the future rational use of complement inhibitor drugs in the context of renal diseases.
Focal segmental glomerulosclerosis (FSGS) is a complex disease which describes different kinds of kidney defects, not exclusively linked with podocyte defects. Since nephrin mutation was first ...described in association with early-onset nephrotic syndrome (NS), many advancements have been made in understanding genetic patterns associated with FSGS. New genetic causes of FSGS have been discovered, displaying unexpected genotypes, and recognizing possible site of damage. Many recent large-scale sequencing analyses on patients affected by idiopathic chronic kidney disease (CKD), kidney failure (KF) of unknown origin, or classified as FSGS, have revealed collagen alpha IV genes, as one of the most frequent sites of pathogenic mutations. Also, recent interest in complex and systemic lysosomal storage diseases, such as Fabry disease, has highlighted
GLA
mutations as possible causes of FSGS. Tubulointerstitial disease, recently classified by KDIGO based on genetic subtypes, when associated with
UMOD
variants, may phenotypically gain FSGS features, as well as ciliopathy genes or others, otherwise leading to completely different phenotypes, but found carrying pathogenic variants with associated FSGS phenotype. Thus, glomerulosclerosis may conceal different heterogeneous conditions. When a kidney biopsy is performed, the principal objective is to provide an accurate diagnosis. The broad spectrum of phenotypic expression and genetic complexity is demonstrating that a combined path of management needs to be applied. Genetic investigation should not be reserved only to selected cases, but rather part of medical management, integrating with clinical and renal pathology records. FSGS heterogeneity should be interpreted as an interesting opportunity to discover new pathways of CKD, requiring prompt genotype–phenotype correlation. In this review, we aim to highlight how FSGS represents a peculiar kidney condition, demanding multidisciplinary management, and in which genetic analysis may solve some otherwise unrevealed idiopathic cases. Unfortunately there is not a uniform correlation between specific mutations and FSGS morphological classes, as the same variants may be identified in familial cases or sporadic FSGS/NS or manifest a variable spectrum of the same disease. These non-specific features make diagnosis challenging. The complexity of FSGS genotypes requires new directions. Old morphological classification does not provide much information about the responsible cause of disease and misdiagnoses may expose patients to immunosuppressive therapy side effects, mistaken genetic counseling, and misguided kidney transplant programs.
The utility of exome sequencing for most constitutional disorders in adults is unclear. In this study, exome sequencing in 3315 patients with chronic kidney disease yielded a genetic diagnosis in 307 ...cases (9.3%), with clinically important management implications for 89% of those reviewed.
The utility of whole-exome sequencing (WES) for the diagnosis and management of adult-onset constitutional disorders has not been adequately studied. Genetic diagnostics may be advantageous in adults ...with chronic kidney disease (CKD), in whom the cause of kidney failure often remains unknown.
To study the diagnostic utility of WES in a selected referral population of adults with CKD.
Observational cohort.
A major academic medical center.
92 adults with CKD of unknown cause or familial nephropathy or hypertension.
The diagnostic yield of WES and its potential effect on clinical management.
Whole-exome sequencing provided a diagnosis in 22 of 92 patients (24%), including 9 probands with CKD of unknown cause and encompassing 13 distinct genetic disorders. Among these, loss-of-function mutations were identified in PARN in 2 probands with tubulointerstitial fibrosis. PARN mutations have been implicated in a short telomere syndrome characterized by lung, bone marrow, and liver fibrosis; these findings extend the phenotype of PARN mutations to renal fibrosis. In addition, review of the American College of Medical Genetics actionable genes identified a pathogenic BRCA2 mutation in a proband who was diagnosed with breast cancer on follow-up. The results affected clinical management in most identified cases, including initiation of targeted surveillance, familial screening to guide donor selection for transplantation, and changes in therapy.
The small sample size and recruitment at a tertiary care academic center limit generalizability of findings among the broader CKD population.
Whole-exome sequencing identified diagnostic mutations in a substantial number of adults with CKD of many causes. Further study of the utility of WES in the evaluation and care of patients with CKD in additional settings is warranted.
New York State Empire Clinical Research Investigator Program, Renal Research Institute, and National Human Genome Research Institute of the National Institutes of Health.
Abstract
BACKGROUND AND AIMS
Percutaneous kidney biopsy (PRB) is an invasive procedure performed under local anaesthesia that often creates anxiety, stress and pain in the patient before, during and ...after the procedure. Music therapy (MT), defined as the clinical- and evidence-based use of music, is administered by a trained professional to achieve individualized goals within a therapeutic relationship between patient, music and music therapist. MT can be used as a complementary non-drug intervention to prevent and treat emotional distress and pain. The main objectives of the study were
1. evaluate the effectiveness of MT in managing anxiety, pain and satisfaction in patients undergoing PRB.
2. investigate the effect of MTI on heart rate variability (HRV).
METHOD
This study was a two-arm, single-centre, parallel-group and pre–post PRB randomized controlled trial. Patients programmed for PRB were enrolled (n = 80) and assigned to the MT intervention group (MG, n = 40) or standard treatment control group (CG), n = 40. MG received, from a FAMI-certified music therapist, a personalized playlist administered during the PRB, adapted to the individual patient. Patient anxiety was assessed before and after PRB using the State Y-1 Trait Anxiety Inventory (STAI-Y1). A visual analog scale (VAS) was used for self-assessment of pain (VAS-P) and satisfaction (VAS-S). Physiological stress parameters (PRE–POST) were assessed using HRV (SDNN, RMSSD, LH/HF, SD1, SD2) from E4 wristbands—Empatica Inc.1. The bracelet was placed 5 min before the patient entered the operating room for the procedure and removed after the completion of the PRB. The data of each session were divided into two segments: (1) pre, before the administration of the local anesthetic and (2) post, after the conclusion of the biopsy.
RESULTS
A statistically significant difference in anxiety levels was observed between the MG and CG groups (35.35 ± 6.208 versus 42.83 ± 9.027; P < 0.001, Fig. 1). The MG group showed significantly lower VAS-P values (4.95 ± 1.377 versus 6.28 ± 1.281; P < 0.001, Fig. 2) and higher VAS-S values (7.75 ± 0.981 versus 6.03 ± 0.800; P < 0.001) after PRB compared with the CG group (Fig. 3). The SDNN (P < 0.034), RMSDD (P < 0.04) and SD2 (P < 0.027) measurements of HRV were significantly higher in MG than in CG, while LF/HF decreased (P < 0.033).
CONCLUSION
This study supports the efficacy of MT in reducing anxiety and pain and improving satisfaction in patients undergoing PRB. MT modulates the autonomic nervous system, reducing sympathetic activity, increasing parasympathetic activity and inducing physiological relaxation.
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