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

Abstract

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.

Keywords: chronic kidney disease; clinical decision-making; clinical nephrology; computational biology; epigenesis; gene-environment interaction; genetic; genetic counseling; genetics and development; kidney development; molecular genetics; precision medicine; prognosis; renal insufficiency; urogenital abnormalities; vesico-ureteral reflux.

Figure 1.

Overview of CAKUT phenotypes, discerning parenchymal defects of the kidney, ureteral abnormalities, and posterior urethral valves as a lower urinary tract abnormality.

Figure 2.

Multiomics approach to define CAKUT etiology. Integration of data on genetic variation, gene expression and regulation, and environmental factors with clinical information on phenotype, imaging, and lab values will help to shape the genomic landscape of CAKUT and determine which DNA variants are involved in disease etiology and prognosis. AD, autosomal dominant; AR, autosomal recessive; CAKUT, congenital anomalies of the kidney and urinary tract; NICU, neonatal intensive care unit; lncRNA, long noncoding RNA; miRNA, micro-RNA; SNP, single nucleotide polymorphism; XL, X-linked.