The term CAKUT has outlived its usefulness:the case for the defense

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

Inherited Disorders of Water Handling

Under normal circumstances, about 90% of the 180 L/day glomerular filtrate is constitutively reabsorbed in the proximal tubule and descending limb of Henle’s loop. According to the needs, the remaining 10% of the fluid is reabsorbed in the collecting duct by a tightly regulated process under control of arginine vasopressin (AVP). After binding of AVP to arginine vasopressin type 2 receptors (AVPR2) in the basolateral membrane of collecting duct cells, aquaporin-2 (AQP2) water channels are inserted into the luminal membrane of these cells, allowing water reabsorption and urine concentration. Disorders of water handling are characterized by disturbances of this AVP-regulated system. In congenital nephrogenic diabetes insipidus (NDI), the kidney cannot concentrate urine in response to AVP, as a result of loss-of-function mutations in genes encoding AVPR2 and AQP2, resulting in polyuria and polydipsia. In recent years, extensive research has led to increased understanding of the cellular defects in NDI, with important implications for future development of targeted treatment of the disorder, with hope for better outcomes in comparison to the conventional symptomatic therapy. The very rare nephrogenic syndrome of inappropriate antidiuresis (NSIAD), caused by gain-of-function mutations in the gene encoding AVPR2, is the mirror image of NDI. In this disorder, urinary dilution is impaired, independent of the presence or absence of AVP. In this chapter, the focus will be on the physiology of water handling in the collecting duct and on its disturbances in congenital NDI. The clinical details, differential diagnosis, genetics, and conventional and possible future therapies of NDI will be discussed in detail.</p

Clinical versus research genomics in kidney disease

Key differences exist between clinical and research genomics. As genomic testing is adopted in nephrology clinical care, we propose focusing on clinical genomics approaches to obtain genetic diagnoses in order to ensure optimal use of resources and maximum patient benefit

Clinical Integration of Genome Diagnostics for Congenital Anomalies of the Kidney and Urinary Tract

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

Drug Repurposing for Rare Diseases

Currently, there are about 7000 identified rare diseases, together affecting 10% of the population. However, fewer than 6% of all rare diseases have an approved treatment option, highlighting their tremendous unmet needs in drug development. The process of repurposing drugs for new indications, compared with the development of novel orphan drugs, is a time-saving and cost-efficient method resulting in higher success rates, which can therefore drastically reduce the risk of drug development for rare diseases. Although drug repurposing is not novel, new strategies have been developed in recent years to do it in a systematic and rational way. Here, we review applied methodologies, recent accomplished progress, and the challenges associated in drug repurposing for rare diseases

Author's Reply:The Subcellular Localization of RRAGD

peer reviewe

Diagnostic Yield of Next-Generation Sequencing in Patients With Chronic Kidney Disease of Unknown Etiology

Advances in next-generation sequencing (NGS) techniques, including whole exome sequencing, have facilitated cost-effective sequencing of large regions of the genome, enabling the implementation of NGS in clinical practice. Chronic kidney disease (CKD) is a major contributor to global burden of disease and is associated with an increased risk of morbidity and mortality. CKD can be caused by a wide variety of primary renal disorders. In about one in five CKD patients, no primary renal disease diagnosis can be established. Moreover, recent studies indicate that the clinical diagnosis may be incorrect in a substantial number of patients. Both the absence of a diagnosis or an incorrect diagnosis can have therapeutic implications. Genetic testing might increase the diagnostic accuracy in patients with CKD, especially in patients with unknown etiology. The diagnostic utility of NGS has been shown mainly in pediatric CKD cohorts, while emerging data suggest that genetic testing can also be a valuable diagnostic tool in adults with CKD. In addition to its implications for unexplained CKD, NGS can contribute to the diagnostic process in kidney diseases with an atypical presentation, where it may lead to reclassification of the primary renal disease diagnosis. So far, only a few studies have reported on the diagnostic yield of NGS-based techniques in patients with unexplained CKD. Here, we will discuss the potential diagnostic role of gene panels and whole exome sequencing in pediatric and adult patients with unexplained and atypical CKD

Simulating the Genetics Clinic of the Future - whether undergoing whole-genome sequencing shapes professional attitudes

Whole-genome sequencing (WGS) can provide valuable health insight for research participants or patients. Opportunities to be sequenced are increasing as direct-to- consumer (DTC) testing becomes more prevalent, but it is still fairly unusual to have been sequenced. We offered WGS to fourteen professionals with pre-existing familiarity with an interest in human genetics - healthcare, science, policy and art. Participants received a hard drive containing their personal sequence data files (.BAM,. gvcf), without further explanation or obligation, to consider how experiencing WGS firsthand might influence their professional attitudes. We performed semi-structured pre- and post-sequencing interviews with each participant to identify key themes that they raised after being sequenced. To evaluate how their experience of the procedure evolved over time, we also conducted a questionnaire to gather their views 3 years after receiving their genomic data. Participants were generally satisfied with the experience (all 14 participants would choose to participate again). They mostly decided to participate out of curiosity (personal) and to learn from the experience (professional). Whereas most participants slightly developed their original perspective on genetic data, a small selection of them radically changed their views over the course of the project. We conclude that personal experience of sequencing provides an interesting alternative perspective for experts involved in leading, planning, implementing or researching genome sequencing services. Moreover, the personal experience may provide professionals with a better understanding of the challenges visitors of the Genetics Clinic of the Future may face.Peer reviewe

Uncertain futures and unsolicited findings in pediatric genomic sequencing:guidelines for return of results in cases of developmental delay

Background: Massively parallel sequencing techniques, such as whole exome sequencing (WES) and whole genome sequencing (WGS), may reveal unsolicited findings (UFs) unrelated to the diagnostic aim. Such techniques are frequently used for diagnostic purposes in pediatric cases of developmental delay (DD). Yet policy guidelines for informed consent and return of UFs are not well equipped to address specific moral challenges that may arise in these children’s situations. Discussion: In previous empirical studies conducted by our research group, we found that it is sometimes uncertain how children with a DD will develop and whether they could come to possess capacities for autonomous decision-making in the future. Parents sometimes felt this brought them into a Catch-22 like situation when confronted with choices about UFs before undergoing WES in trio-analysis (both the parents’ and child’s DNA are sequenced). An important reason for choosing to consent to WES was to gain more insight into how their child might develop. However, to make responsible choices about receiving or declining knowledge of UFs, some idea of their child’s future development of autonomous capacities is needed. This undesirable Catch-22 situation was created by the specific policy configuration in which parents were required to make choices about UFs before being sequencing (trio-analysis). We argue that this finding is relevant for reconfiguring current policies for return of UFs for WES/WGS and propose guidelines that encompass two features. First, the informed consent process ought to be staged. Second, differing guidelines are required for withholding/disclosing a UF in cases of DD appropriate to the level of confidence there is about the child’s future developmental of autonomous capacities. Conclusion: When combined with a dynamic consent procedure, these two features of our guidelines could help overcome significant moral challenges that present themselves in the situations of children undergoing genomic sequencing for clarifying a DD.</p