Accelerating nephrogenetics: from gene discovery to clinical application

Abstract

This thesis aimed to advance nephrogenetics research from fundamental discoveries to clinical applications. First, it provides an overview of the current knowledge on genetic testing in monogenic kidney disease with a specific focus on copy number variants (CNVs). This thesis further highlights the importance of CNV analysis, which contributed to 10.5% of the diagnostic yield from genetic testing in patients with suspected monogenic kidney disease at the University Medical Centre Utrecht over an eight-year period. To improve the Dutch infrastructure for research on genetic kidney disease, the data- and biobank GeNepher was established, in which patients give broad consent for future research. Furthermore, to accelerate research into kidney gene discovery, a kidney-specific co-expression network was developed. This is an innovative tool that can predict and prioritize genes involved in kidney disease. With these resources in place, three (potential) new genetic causes of kidney disease were identified. The gene-disease association of heterozygous NEK8 variants with cystic kidney disease was discovered and TMEM72 and ALG6 were identified as novel ciliopathy candidate genes. Finally, this thesis demonstrates the benefits of adopting a genetics-first approach, exemplified by patients with medullary sponge kidneys who were diagnosed with primary distal renal tubular acidosis (dRTA), resulting in a genetic diagnosis that modified their treatment, and highlighting this underrecognized gene-disease association.