Exploring the genetic basis of early-onset chronic kidney disease

Abstract

The primary causes of chronic kidney disease (CKD) in children differ from those of adult onset CKD. In the United States the most common diagnostic groups of CKD that manifests before 25 years of age are: i) congenital anomalies of the kidneys and urinary tract (CAKUT) (49.1%), ii) steroid-resistant nephrotic syndrome (SRNS) (10.4%), iii) chronic glomerulonephritis (8.1%), and iv) renal cystic ciliopathies (5.3 %), encompassing >70% of CKD together. Recent findings suggest that early-onset CKD is caused by mutations in any one of over 200 different monogenic genes. High-throughput sequencing has very recently rendered identification of causative mutations in this high number of genes feasible. Molecular genetic diagnostics in early onset-CKD (before the age of 25 years) will, i) provide patients and families with a molecular genetic diagnosis, ii) generate new insights into diseases mechanisms, iii) allow etiology-based classification of patient cohorts for clinical studies and, iv) may have consequences for personalized treatment and prevention of CKD. In this review, we will discuss the implications of next-generation sequencing for clinical genetic diagnostics and discovery of novel genes in early-onset CKD. We also delineate the resulting opportunities for deciphering disease mechanisms and therapeutic implications.

Juvenile nephronophthisis and dysthyroidism: a rare association

“…The power of NGS has proven itself in research laboratories, and in the coming years this technology will be implemented in DNA diagnostics laboratories throughout the world. Whereas disease genes are currently stepwise the Sanger sequenced in diagnostics based on an educated guess at the best candidate gene, whereby clinical phenotype, mutation frequency, and ethnic origin are considered, unbiased mutation screening through NGS is expected to be much more effective [24][25][26]. Whole exome resequencing establishes an efficient, non-invasive approach towards early detection and causation-based diagnosis of recessive disease genes [27].…”

The status quo and challenges of genetic diagnosis in children with steroid-resistant nephrotic syndrome

“…Therefore, assignment of variants as disease causing identified by NGS and Sanger sequencing should be validated by the following approaches [28]:…”

Whole-Exome Sequencing Reveals FAT4 Mutations in a Clinically Unrecognizable Patient with Syndromic CAKUT: A Case Report

“…Congenital anomalies of the kidney and urinary tract (CAKUT) are the main causes of chronic kidney disease in the first 3 decades of life [Vivante and Hildebrandt, 2016]. Despite the high prevalence and clinical significance only approximately 17% of isolated CAKUT cases can currently be explained by monogenic mutations in about 38 different genes [Sanna-Cherchi et al, 2012;Kohl et al, 2014;Vivante et al, 2017].…”

“…Despite the high prevalence and clinical significance only approximately 17% of isolated CAKUT cases can currently be explained by monogenic mutations in about 38 different genes [Sanna-Cherchi et al, 2012;Kohl et al, 2014;Vivante et al, 2017]. However, more than 200 monogenic syndromes are known to date that comprise CAKUT as part of their distinctive phenotype [Vivante and Hildebrandt, 2016].…”