• Citalopram
• Cortisol
• Gene expression
• Migraine
• Neuroendocrine
• RNA sequencing
• Stress response

• genetic counseling
• genetic diagnosis
• genetic kidney disease
• genetic testing
• nephrogenetics
• next-generation sequencing

• Humans
• High-Throughput Nucleotide Sequencing/methods
• Sequence Analysis, DNA/methods

• Bioinformatics
• Genetic diseases
• Genetics
• Molecular genetics
• Nephrology

• Humans
• Male
• Female
• Whole Genome Sequencing
• Kidney Diseases, Cystic/genetics
• Collagen Type IV/genetics
• Genetic Variation
• Gene Frequency
• Case-Control Studies
• Genetic Predisposition to Disease
• Autoantigens
• Receptors, Cell Surface

• Wellcome Trust

• gene therapy
• crispr–cas
• genome editing
• kidney disease

• Minigene
• Non-canonical splicing
• Polycystic kidney disease
• Variants

• Humans
• Female
• Male
• Pedigree
• Polycystic Kidney Diseases/genetics
• Adult
• RNA Splicing
• TRPP Cation Channels/genetics
• Receptors, Cell Surface/genetics
• Middle Aged
• Exome Sequencing/methods
• Mutation
• Genetic Predisposition to Disease

• Humans
• Connexin 26/genetics
• DNA Copy Number Variations
• Founder Effect
• Female
• Male
• Hearing Loss, Sensorineural/genetics
• Hearing Loss, Sensorineural/diagnosis
• Connexins/genetics
• Sequence Deletion
• Hearing Loss/genetics
• Genetic Predisposition to Disease
• Adult
• Whole Genome Sequencing
• Child
• Pedigree
• Haplotypes

Twenty-five percent of those with unexplained kidney failure have a monogenic cause. Whole genome sequencing with broad gene panel analysis is a feasible diagnostic approach in nephrology.

The cause of kidney failure is unknown in approximately 10% of patients with stage 5 chronic kidney disease (CKD). For those who first present to nephrology care with kidney failure, standard investigations of serology, imaging, urinalysis, and kidney biopsy are limited differentiators of etiology. We aimed to determine the diagnostic utility of whole genome sequencing (WGS) with analysis of a broad kidney gene panel in patients with kidney failure of unknown cause.

We prospectively recruited 100 participants who reached CKD stage 5 at the age of ≤50 years and had an unknown cause of kidney failure after standard investigation. Clinically accredited WGS was performed in this national cohort after genetic counseling. The primary analysis was targeted to 388 kidney-related genes with second-tier, genome-wide, and mitochondrial analysis.

The cohort was 61% male and the average age of participants at stage 5 CKD was 32 years (9 months to 50 years). A genetic diagnosis was made in 25% of participants. Disease-causing variants were identified across autosomal dominant tubulointerstitial kidney disease (6), glomerular disorders (4), ciliopathies (3), tubular disorders (2), Alport syndrome (4), and mitochondrial disease (1). Most diagnoses (80%) were in autosomal dominant, X-linked, or mitochondrial conditions (UMOD ; COL4A5 ; INF2 ; CLCN5 ; TRPC6 ; COL4A4 ; EYA1 ; HNF1B ; WT1 ; NBEA ; m.3243A>G ). Participants with a family history of CKD were more likely to have a positive result (odds ratio, 3.29; 95% confidence interval, 1.10 to 11.29). Thirteen percent of participants without a CKD family history had a positive result. In those who first presented in stage 5 CKD, WGS with broad analysis of a curated kidney disease gene panel was diagnostically more informative than kidney biopsy, with biopsy being inconclusive in 24 of the 25 participants.

In this prospectively ascertained Australian cohort, we identified a genetic diagnosis in 25% of patients with kidney failure of unknown cause.

• eskd

• Humans
• Australia
• Genetic Testing
• Male
• Female
• Middle Aged
• Renal Insufficiency/genetics
• Renal Insufficiency/diagnosis
• Aged
• Adult

• GNT1113531 National Health and Medical Research Council
• GNT2000001 National Health and Medical Research Council
• MRF2008820 National Health and Medical Research Council
• MRF2008249 National Health and Medical Research Council

• Humans
• Polycystic Kidney, Autosomal Dominant/genetics
• Polycystic Kidney, Autosomal Dominant/diagnosis
• TRPP Cation Channels/genetics
• High-Throughput Nucleotide Sequencing
• Multiplex Polymerase Chain Reaction/methods
• Female

• genetic counseling
• genetic testing
• neurogenetics
• neuromuscular

• ADPKD
• ARPKD
• PKD
• cystic kidney disease
• polycystic kidney disease

• Adult
• Pregnancy
• Female
• Child
• Humans
• Polycystic Kidney, Autosomal Recessive/diagnosis
• Polycystic Kidney, Autosomal Recessive/genetics
• Polycystic Kidney, Autosomal Recessive/therapy
• Kidney
• Polycystic Kidney, Autosomal Dominant/complications
• Polycystic Kidney, Autosomal Dominant/diagnosis
• Polycystic Kidney, Autosomal Dominant/genetics
• Kidney Neoplasms
• Cysts/diagnosis
• Cysts/genetics
• Cysts/therapy

• Autosomal dominant polycystic kidney disease
• Multiple ligation-dependent probe amplification
• Mutation
• PKD1
• PKD2

• Adolescent
• Adult
• Aged
• Child
• Female
• Humans
• Male
• Middle Aged
• Young Adult
• Cohort Studies
• DNA Mutational Analysis
• Gene Rearrangement
• Italy
• Mutation
• Polycystic Kidney, Autosomal Dominant/genetics
• TRPP Cation Channels/genetics

• IKBKG/NEMO
• NFκB pathway
• genotype-phenotype
• incontinentia pigmenti
• molecular diagnosis
• pathophysiology

• next-generation sequencing
• medical genetics

• Exome
• Genome, Human
• High-Throughput Nucleotide Sequencing/methods
• Humans
• Polymorphism, Single Nucleotide
• Rare Diseases/diagnosis
• Rare Diseases/genetics
• Whole Genome Sequencing

• MR/V037307/1 Medical Research Council

Monogenic forms of heritable kidney disease account for a significant proportion of chronic kidney disease (CKD) across both pediatric and adult patient populations and up to 11% of patients under 40 years reaching end-stage kidney failure (KF) and awaiting kidney transplant. Diagnostic genomics in the field of nephrology is ever evolving and now plays an important role in assessment and management of kidney transplant recipients and their related donor pairs. Genomic testing can help identify the cause of KF in kidney transplant recipients and assist in prognostication around graft survival and rate of recurrence of primary kidney disease. If a gene variant has been identified in the recipient, at-risk related donors can be assessed for the same and excluded if affected. This paper aims to address the indications for genomic testing in the context for kidney transplantation, the technologies available for testing, the conditions and groups in which testing should be most often considered, and the role for the renal genetics multidisciplinary team in this process.

The definition of a rare disease in the European Union describes genetic disorders that affect less than 1 in 2,000 people per individual disease; collectively these numbers amount to millions of individuals globally, who usually manifest a rare disease early on in life. At present, there are at least 8,000 known rare conditions, of which only some are clearly molecularly defined. Over the recent years, the use of genetic diagnosis is gaining ground into informing clinical practice, particularly in the field of rare diseases, where diagnosis is difficult. To demonstrate the complexity of genetic diagnosis for rare diseases, we focus on Ciliopathies as an example of a group of rare diseases where an accurate diagnosis has proven a challenge and novel practices driven by scientists are needed to help bridge the gap between clinical and molecular diagnosis. Current diagnostic difficulties lie with the vast multitude of genes associated with Ciliopathies and trouble in distinguishing between Ciliopathies presenting with similar phenotypes. Moreover, Ciliopathies such as Autosomal Recessive Polycystic Kidney Disease (ARPKD) and Meckel-Gruber syndrome (MKS) present with early phenotypes and may require the analysis of samples from foetuses with a suspected Ciliopathy. Advancements in Next Generation Sequencing (NGS) have now enabled assessing a larger number of target genes, to ensure an accurate diagnosis. The aim of this review is to provide an overview of current diagnostic techniques relevant to Ciliopathies and discuss the applications and limitations associated with these techniques.

• Ciliary Motility Disorders/diagnosis
• Ciliary Motility Disorders/genetics
• Ciliopathies/diagnosis
• Ciliopathies/genetics
• Humans
• Pathology, Molecular
• Polycystic Kidney Diseases/diagnosis
• Polycystic Kidney Diseases/genetics
• Rare Diseases/diagnosis
• Rare Diseases/genetics

Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic kidney disorder. Half of the patients would slowly progress to end-stage renal disease. However, the potential target for ADPKD treatment is still lacking.

Four ADPKD patients and two healthy family members were included in this study. The peripheral blood samples were obtained and tested by the whole exome sequencing (WES). The autosomal mutations in ADPKD patients were retained as candidate sites. The Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, and protein–protein interaction network (PPI) analyses were performed by clusterProfiler R package. A dataset containing 18 ADPKD patients and three normal samples were downloaded from the Gene Expression Omnibus (GEO) database and analyzed using the limma R package.

A total of six mutant genes were identified based on the dominant genetic pattern and most of them had not been reported to be associated with ADPKD. Furthermore, 19 harmful genes were selected according to the harmfulness of mutation. GO and KEGG enrichment analyses showed that the processes of single-organism cellular process, response to stimulus, plasma membrane, cell periphery, and anion binding as well as cyclic adenosine monophosphate (cAMP) signaling pathway and pathways in cancer were significantly enriched. Through integrating PPI and gene expression analyses, acyl-CoA thioesterase 13 (ACOT13), which has not been reported to be related to ADPKD, and prostaglandin E receptor 2 (PTGER2) were identified as potential genes associated with ADPKD.

Through combination of WES, gene expression, and PPI network analyses, we identified ACOT13 and PTGER2 as potential ADPKD-related genes.

The online version contains supplementary material available at 10.1186/s40001-021-00613-8.

• ACOT13
• Gene mutations
• PTGER2
• Polycystic kidney disease
• Whole exome sequencing

• genetic renal disease
• adpkd
• cystic kidney
• end-stage renal disease
• polycystic kidney disease
• polycystic kidney
• autosomal dominant
• whole genome sequencing
• epithelial cells
• cysts

• Humans
• Polycystic Kidney, Autosomal Dominant/genetics
• Mutation
• Epithelial Cells
• TRPP Cation Channels/genetics
• Cysts

• UL1 TR002384 NCATS NIH HHS
• Vertex Pharmaceuticals

The overall diagnostic yield of massively parallel sequencing–based tests in patients with chronic kidney disease (CKD) is 30% for paediatric cases and 6–30% for adult cases. These figures should encourage nephrologists to frequently use genetic testing as a diagnostic means for their patients. However, in reality, several barriers appear to hinder the implementation of massively parallel sequencing–based diagnostics in routine clinical practice. In this article we aim to support the nephrologist to overcome these barriers. After a detailed discussion of the general items that are important to genetic testing in nephrology, namely genetic testing modalities and their indications, clinical information needed for high-quality interpretation of genetic tests, the clinical benefit of genetic testing and genetic counselling, we describe each of these items more specifically for the different groups of genetic kidney diseases and for CKD of unknown origin.

• chronic kidney disease
• clinical benefit
• genetic counselling
• genetic testing
• massively parallel sequencing
• monogenic diseases

• genetics research
• polycystic kidney disease
• genetic testing

• Basic Science
• Genetics
• Iran
• Kidney Diseases
• Pathogenic variants
• Whole-Exome Sequencing
• genetic diagnosis

Genetic testing in nephrology clinical practice has moved rapidly from a rare specialized test to routine practice both in pediatric and adult nephrology. However, clear information pertaining to the likely outcome of testing is still missing. Here we describe the experience of the accredited Australia and New Zealand Renal Gene Panels clinical service, reporting on sequencing for 552 individuals from 542 families with suspected kidney disease in Australia and New Zealand. An increasing number of referrals have been processed since service inception with an overall diagnostic rate of 35%. The likelihood of identifying a causative variant varies according to both age at referral and gene panel. Although results from high throughput genetic testing have been primarily for diagnostic purposes, they will increasingly play an important role in directing treatment, genetic counseling, and family planning.

• Clinical genome
• Copy number variation
• Microarray
• Rare disease
• Structural variation
• Whole genome sequencing

• DNA Copy Number Variations/genetics
• Gene Frequency/genetics
• Humans
• Molecular Sequence Annotation
• Mutation/genetics
• Reproducibility of Results
• Software
• Whole Genome Sequencing

• Kinghorn Foundation
• Cancer Institute NSW
• NSW Health

• Adult
• Alleles
• Cameroon/epidemiology
• Case-Control Studies
• Child
• Collagen Type IX/genetics
• Female
• Hearing Loss/epidemiology
• Hearing Loss/genetics
• Hearing Loss/pathology
• Humans
• Male
• Mutation
• Myosin Heavy Chains/genetics
• Myosin Type III/genetics
• Myosins/genetics
• Phenotype
• Exome Sequencing/methods

• Wellcome Trust
• U01 HG009716 NHGRI NIH HHS
• U24 HL135600 NHLBI NIH HHS
• South African Medical Research Council
• National Health Laboratory Services
• National Institutes of Health

• Gene Expression Regulation
• Genetic Predisposition to Disease
• Genetic Variation
• Genome-Wide Association Study
• Humans
• Kidney Diseases/genetics
• Precision Medicine
• Quantitative Trait Loci

• DP3 DK108220 NIDDK NIH HHS
• R01 DK087635 NIDDK NIH HHS
• R01 DK132630 NIDDK NIH HHS
• R01 DK076077 NIDDK NIH HHS
• R01 DK105821 NIDDK NIH HHS

• Association
• Epac2
• Major depressive disorder
• Polymorphism
• rs3769219

To determine the diagnostic yield and clinical impact of exome sequencing (ES) in patients with suspected monogenic kidney disease.

We performed clinically accredited singleton ES in a prospectively ascertained cohort of 204 patients assessed in multidisciplinary renal genetics clinics at four tertiary hospitals in Melbourne, Australia.

ES identified a molecular diagnosis in 80 (39%) patients, encompassing 35 distinct genetic disorders. Younger age at presentation was independently associated with an ES diagnosis (p < 0.001). Of those diagnosed, 31/80 (39%) had a change in their clinical diagnosis. ES diagnosis was considered to have contributed to management in 47/80 (59%), including negating the need for diagnostic renal biopsy in 10/80 (13%), changing surveillance in 35/80 (44%), and changing the treatment plan in 16/80 (20%). In cases with no change to management in the proband, the ES result had implications for the management of family members in 26/33 (79%). Cascade testing was subsequently offered to 40/80 families (50%).

In this pragmatic pediatric and adult cohort with suspected monogenic kidney disease, ES had high diagnostic and clinical utility. Our findings, including predictors of positive diagnosis, can be used to guide clinical practice and health service design.

• chronic kidney disease
• exome sequencing
• genetic kidney disease

Newborn screening programs are an integral part of public health systems aiming to save lives and improve the quality of life for infants with treatable disorders. Technological advancements have driven the expansion of newborn screening programs in the last two decades and the development of fast, accurate next-generation sequencing technology has opened the door to a range of possibilities in the field. However, technological challenges with short-read next-generation sequencing technologies remain significant in highly homologous genomic regions such as pseudogenes or paralogous genes and need to be considered when implemented in screening programs. Here, we simulate 50 genomes from populations around the world to test the extent to which high homology regions affect short-read mapping of genes related to newborn screening disorders and the impact of differential read lengths and ethnic backgrounds. We examine a 158 gene screening panel directly relevant to newborn screening and identify gene regions where read mapping is affected by homologous genomic regions at different read lengths. We also determine that the patient’s ethnic background does not have a widespread impact on mapping accuracy or coverage. Additionally, we identify newborn screening genes where alternative forms of sequencing or variant calling pipelines should be considered and demonstrate that alterations to standard variant calling can retrieve some formerly uncalled variants.

• Genetic testing
• Paediatrics

• chronic kidney disease
• genetic testing
• kidney disease of unknown etiology

• Counseling
• Genetic Counseling
• Genetic Testing
• Humans
• Renal Insufficiency, Chronic/diagnosis
• Renal Insufficiency, Chronic/genetics

• F30 DK116473 NIDDK NIH HHS
• R01 DK080099 NIDDK NIH HHS
• R01 DK082753 NIDDK NIH HHS
• T32 DK108741 NIDDK NIH HHS
• R01 MD009223 NIMHD NIH HHS

• PKD1
• PKD2
• Polycystic kidney disease
• Sequence analysis

• Association
• Depression
• Fractalkine
• Single nucleotide polymorphism
• Transcriptional activity

• genetic testing
• next-generation sequencing
• polycystic kidney disease

• diagnostic utility
• end-stage renal disease
• exome sequencing
• genetic testing
• kidney disease

• GWAS
• genomics
• kidney disease
• whole exome sequencing analyses
• whole genome sequencing

• Ciliopathy
• Molecular genetics
• PKD
• Primary cilia
• Renal cyst

• Bevacizumab
• Biomarkers
• Glioblastoma
• Immunohistochemistry
• Whole genome sequencing

• Adult
• Aged
• Antineoplastic Agents/therapeutic use
• Bevacizumab/therapeutic use
• Biomarkers, Tumor/analysis
• Biomarkers, Tumor/genetics
• Brain Neoplasms/drug therapy
• Brain Neoplasms/metabolism
• Chromosomes, Human, Pair 19/genetics
• Clinical Trials, Phase II as Topic
• Cohort Studies
• Female
• Glioblastoma/drug therapy
• Glioblastoma/metabolism
• Humans
• Male
• Middle Aged
• Randomized Controlled Trials as Topic
• Retrospective Studies