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.

Revolutions in genetics, epigenetics, and bioinformatics are currently changing the outline of diagnostics and clinical medicine. From a nephrologist’s perspective, individuals with congenital anomalies of the kidney and urinary tract (CAKUT) are an important patient category: not only is CAKUT the predominant cause of kidney failure in children and young adults, but the strong phenotypic and genotypic heterogeneity of kidney and urinary tract malformations has hampered standardization of clinical decision making until now. However, patients with CAKUT may benefit from precision medicine, including an integrated diagnostics trajectory, genetic counseling, and personalized management to improve clinical outcomes of developmental kidney and urinary tract defects. In this review, we discuss the present understanding of the molecular etiology of CAKUT and the currently available genome diagnostic modalities in the clinical care of patients with CAKUT. Finally, we discuss how clinical integration of findings from large-scale genetic, epigenetic, and gene-environment interaction studies may improve the prognosis of all individuals with CAKUT.

Congenital nephrogenic diabetes insipidus (NDI; also known as arginine vasopressin resistance) is a rare inherited disorder of water homeostasis, caused by insensitivity of the distal nephron to arginine vasopressin. Consequently, the kidney loses its ability to concentrate urine, which leads to polyuria, polydipsia and the risk of hypertonic dehydration. The diagnosis and management of NDI are very challenging and require an integrated, multidisciplinary approach. Here, we present 36 recommendations for diagnosis, treatment and follow-up in both children and adults, as well as emergency management, genetic counselling and family planning, for patients with NDI. These recommendations were formulated and graded by an international group of experts in NDI from paediatric and adult nephrology, urology and clinical genetics from the European Rare Kidney Disease Reference Network and the European Society of Paediatric Nephrology, as well as patient advocates, and were validated by a voting panel in a Delphi process. The goal of these recommendations is to provide guidance to health care professionals who care for patients with NDI and to patients and their families. In addition, we emphasize the need for further research on different aspects of this potentially life-threatening disorder to support the development of evidence-based guidelines in the future.

Mounting evidence indicates that monogenic disorders are the underlying cause in a significant proportion of patients with CKD. In recent years, the diagnostic yield of genetic testing in these patients has increased significantly as a result of revolutionary developments in genetic sequencing techniques and sequencing data analysis. Identification of disease-causing genetic variant(s) in patients with CKD may facilitate prognostication and personalized management, including nephroprotection and decisions around kidney transplantation, and is crucial for genetic counseling and reproductive family planning. A genetic diagnosis in a patient with CKD allows for screening of at-risk family members, which is also important for determining their eligibility as kidney transplant donors. Despite evidence for clinical utility, increased availability, and data supporting the cost-effectiveness of genetic testing in CKD, especially when applied early in the diagnostic process, many nephrologists do not use genetic testing to its full potential because of multiple perceived barriers. Our aim in this article was to empower nephrologists to (further) implement genetic testing as a diagnostic means in their clinical practice, on the basis of the most recent insights and exemplified by patient vignettes. We stress why genetic testing is of significant clinical benefit to many patients with CKD, provide recommendations for which patients to test and which test(s) to order, give guidance about interpretation of genetic testing results, and highlight the necessity for and essential components of pretest and post-test genetic counseling.

Epidermolysis bullosa is a group of genetic skin conditions characterized by abnormal skin (and mucosal) fragility caused by pathogenic variants in various genes. The disease severity ranges from early childhood mortality in the most severe types to occasional acral blistering in the mildest types. The subtype and severity of EB is linked to the gene involved and the specific variants in that gene, which also determine its mode of inheritance. Current treatment is mainly focused on symptomatic relief such as wound care and blister prevention, because truly curative treatment options are still at the preclinical stage. Given the current level of understanding, the broad spectrum of genes and variants underlying EB makes it impossible to develop a single treatment strategy for all patients. It is likely that many different variant-specific treatment strategies will be needed to ultimately treat all patients. Antisense-oligonucleotide (ASO)-mediated exon skipping aims to counteract pathogenic sequence variants by restoring the open reading frame through the removal of the mutant exon from the pre-messenger RNA. This should lead to the restored production of the protein absent in the affected skin and, consequently, improvement of the phenotype. Several preclinical studies have demonstrated that exon skipping can restore protein production in vitro, in skin equivalents, and in skin grafts derived from EB-patient skin cells, indicating that ASO-mediated exon skipping could be a viable strategy as a topical or systemic treatment. The potential value of exon skipping for EB is supported by a study showing reduced phenotypic severity in patients who carry variants that result in natural exon skipping. In this article, we review the substantial progress made on exon skipping for EB in the past 15 years and highlight the opportunities and current challenges of this RNA-based therapy approach. In addition, we present a prioritization strategy for the development of exon skipping based on genomic information of all EB-involved genes.

Congenital anomalies of the kidney and urinary tract form a spectrum of congenital structural disorders that are generally known under the term CAKUT. The term CAKUT was introduced 20 years ago and has been used extensively in literature since. Prof. Woolf has made a plea for abandoning this term in his “case for the prosecution.” Here, I advocate for the continued use of CAKUT as an umbrella term for these related congenital kidney and urinary tract abnormalities. I explain why the term CAKUT accurately and usefully defines this group of related structural disorders with prenatal origin and why it makes sense to continue grouping these disorders given accumulating evidence for shared etiology of CAKUT phenotypes and the importance of grouping CAKUT phenotypes in genetic counseling.