The utility of a genetic kidney disease clinic employing a broad range of genomic testing platforms: experience of the Irish Kidney Gene Project.

BACKGROUND AND AIMS: Genetic testing presents a unique opportunity for diagnosis and management of genetic kidney diseases (GKD). Here, we describe the clinical utility and valuable impact of a specialized GKD clinic, which uses a variety of genomic sequencing strategies. METHODS: In this prospective cohort study, we undertook genetic testing in adults with suspected GKD according to prespecified criteria. Over 7 years, patients were referred from tertiary centres across Ireland to an academic medical centre as part of the Irish Kidney Gene Project. RESULTS: Among 677 patients, the mean age was of 37.2 ± 13 years, and 73.9% of the patients had family history of chronic kidney disease (CKD). We achieved a molecular diagnostic rate of 50.9%. Four genes accounted for more than 70% of identified pathogenic variants: PKD1 and PKD2 (n = 186, 53.4%), MUC1 (8.9%), and COL4A5 (8.3%). In 162 patients with a genetic diagnosis, excluding PKD1/PKD2, the a priori diagnosis was confirmed in 58% and in 13% the diagnosis was reclassified. A genetic diagnosis was established in 22 (29.7%) patients with CKD of uncertain aetiology. Based on genetic testing, a diagnostic kidney biopsy was unnecessary in 13 (8%) patients. Presence of family history of CKD and the underlying a priori diagnosis were independent predictors (P < 0.001) of a positive genetic diagnosis. CONCLUSIONS: A dedicated GKD clinic is a valuable resource, and its implementation of various genomic strategies has resulted in a direct, demonstrable clinical and therapeutic benefits to affected patients.

Polygenic risk score of non-melanoma skin cancer predicts post-transplant skin cancer across multiple organ types.

Polygenic risk scores (PRSs) calculated from genome-wide association studies (GWASs) of non-melanoma skin cancer (NMSC) in a general, non-transplant setting have recently been shown to predict risk of and time to post-renal transplant skin cancer. In this study, we set out to test these findings in a cohort of heart, lung, and liver transplant patients to see whether these scores could be applied across different organ transplant types. Using the PRS from Stapleton et al (2018), PRS was calculated for each sample across a European ancestry heart, lung, and liver transplant cohorts (n = 523) and tested as predictor of time to NMSC post-transplant. The top PRS, squamous cell carcinoma (SCC) pT1 x 10-5 , (n SNPs = 1953), SCC pT1 x 10-6 , and SCC pT1 x 10-6 (n SNPs = 1061) were significantly predictive in the time to NMSC, SCC, and basal cell carcinoma (BCC) analysis across organ (P = .006, .02, and .02, respectively). We observed here a similar direction of effect and effect size [NMSC HR = 1.31(1.08-1.59)] to that in the original discovery study with increased polygenic burden leading to a faster time to developing NMSC. In summary, we found that PRS of NMSC calculated from GWAS of NMSC in non-transplant populations independently replicated in this cohort of heart, lung, and liver transplant.

Utility of Genomic Testing after Renal Biopsy.

BACKGROUND: Renal biopsy is the mainstay of renal pathological diagnosis. Despite sophisticated diagnostic techniques, it is not always possible to make a precise pathological diagnosis. Our aim was to identify a genetic cause of disease in patients who had undergone renal biopsy and determine if genetic testing altered diagnosis or treatment. METHODS: Patients with suspected familial kidney disease underwent a variety of next-generation sequencing (NGS) strategies. The subset of these patients who had also undergone native kidney biopsy was identified. Histological specimens were reviewed by a consultant pathologist, and genetic and pathological diagnoses were compared. RESULTS: Seventy-five patients in 47 families underwent genetic sequencing and renal biopsy. Patients were grouped into 5 diagnostic categories based on pathological diagnosis: tubulointerstitial kidney disease (TIKD; n = 18); glomerulonephritis (GN; n = 15); focal segmental glomerulosclerosis and Alport Syndrome (n = 11); thrombotic microangiopathy (TMA; n = 17); and nonspecific pathological changes (n = 14). Thirty-nine patients (52%) in 21 families (45%) received a genetic diagnosis; 13 cases (72%) with TIKD, 4 (27%) with GN, 6 (55%) with focal segmental glomerulosclerosis/Alport syndrome, and 10 (59%) with TMA and 6 cases (43%) with nonspecific features. Genetic testing resulted in changes in understanding of disease mechanism in 21 individuals (54%) in 12 families (57%). Treatment would have been altered in at least 26% of cases (10/39). CONCLUSIONS: An accurate genetic diagnosis can result in changes in clinical diagnosis, understanding of pathological mechanism, and treatment. NGS should be considered as a complementary diagnostic technique to kidney biopsy in the evaluation of patients with kidney disease.

An Exome Sequencing Study of 10 Families with IgA Nephropathy.

BACKGROUND: Immunoglobulin A nephropathy (IgAN) is a heterogeneous disorder with a strong genetic component. The advent of whole exome sequencing (WES) has accelerated the discovery of genetic risk factors underlying familial disorders. OBJECTIVES: We set out to test whether damaging variants in known kidney disease genes explain a proportion of IgAN cases recruited in Ireland. METHODS: We performed WES in 10 Irish families with multiple affected members having kidney disease where at least one member had biopsy confirmed IgAN. Candidate variants were identified based on being shared between affected family members, minor allele frequency, function and predicted pathogenicity. Pathogenicity of variants was determined according to American College of Medical Genetics and Genomics guidelines. RESULTS: We detected candidate variants in 3 of 10 families. We identified a likely pathogenic variant in COL4A5 in one family and a variant of unknown significance (VUS) in COL4A3 in another. Variants in COL4A5 and COL4A3 are known to cause Alport syndrome. In the third family, we identified a VUS in LMX1B, a gene associated with Nail-patella syndrome. CONCLUSIONS: We identified a number of cases of familial IgAN where the families harbored variants in known kidney disease-related genes indicating that potentially a number of cases of familial IgAN are mistaken for other familial kidney disorders. However, the majority of families studied did not carry a candidate variant in a known kidney disease causing gene indicating that there may be >1 underlying genetic mechanism present in these families.

Polygenic risk score as a determinant of risk of non-melanoma skin cancer in a European-descent renal transplant cohort.

Renal transplant recipients have an increased risk of non-melanoma skin cancer (NMSC) compared to in the general population. Here, we show polygenic risk scores (PRS) calculated from genome-wide association studies (GWAS) of NMSC in a general, nontransplant setting, can predict risk of, and time to posttransplant skin cancer. Genetic variants, reaching predefined P-value thresholds were chosen from published squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) nontransplant GWAS. Using these GWAS, BCC and SCC PRS were calculated for each sample across three European ancestry renal transplant cohorts (n = 889) and tested as predictors of case:control status and time to NMSC posttransplant. BCC PRS calculated at P-value threshold 1 × 10-5 was the most significant predictor of case:control status of NMSC posttransplant (OR = 1.61; adjusted P = .0022; AUC [full model adjusted for clinical predictors and PRS] = 0.81). SCC PRS at P-value threshold 1 × 10-5 was the most significant predictor of time to posttransplant NMSC (adjusted P = 9.39 × 10-7 ; HR = 1.41, concordance [full model] = 0.74). PRS of nontransplant NMSC is predictive of case:control status and time to NMSC posttransplant. These results are relevant to how genomics can risk stratify patients to help develop personalized treatment regimens.

NPHP1 (Nephrocystin-1) Gene Deletions Cause Adult-Onset ESRD.

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.

Clinical Heterogeneity in Familial IgA Nephropathy.

BACKGROUND: IgA nephropathy is the most common primary glomerulonephritis worldwide and a significant cause of end-stage renal disease (ESRD). While most cases of IgA nephropathy are considered sporadic, familial cases have been reported. METHODS: We performed a national audit of 1,809 patients attending renal clinics and dialysis units to identify a family history among patients with kidney disease. We reviewed all renal biopsies performed at our institution spanning a 30-year period. Paediatric cases were not included. RESULTS: We identified 14 families involving 41 affected individuals with biopsy-proven IgA nephropathy and at least one other member with either biopsy-proven IgA nephropathy or ESRD. Detailed family histories were obtained, medical records reviewed and family pedigrees constructed. Retrospective application of the MESTC criteria to all familial IgA biopsies was performed. Seven families had 2 or more members with biopsy-proven IgA nephropathy, equating to 23 (1.8%) of 1,283 biopsies with IgA nephropathy over the last 30 years. A complex inheritance pattern was observed, with autosomal dominant and autosomal recessive families identified with varying penetrance. There was a male preponderance (68%), and a complex heterogeneity in the clinical and histopathological features of familial IgA patients (age range 16-60 years; creatinine range 60-350 µmol/L). We observed a high rate (66%) of progression to ESRD, with a mean time to progression of 5.13 years (SD 1.8 years; range 2-8 years). Among those patients who had undergone transplantation, recurrence of disease was reported in 5 (50%) cases. CONCLUSION: These data suggests familial aggregation of IgA nephropathy, confirm the clinical and histopathological heterogeneity and raise the possibility of monogenic inheritance.

Using omics to explore complications of kidney transplantation.

The importance of genetic and biochemical variation in renal transplant outcomes has been clear since the discovery of the HLA in the 1950s. Since that time, there have been huge advancements in both transplantation and omics. In recent years, there has seen an increased number of genome-, proteome- and transcriptome-wide studies in the field of transplantation moving away from the earlier candidate gene/protein approaches. These areas have the potential to lead to the development of personalized treatment depending on individual molecular risk profiles. Here, we discuss recent progress and the current literature surrounding omics and renal transplant complications.