Contribution of Genomic Imbalance in Prenatal Congenital Anomalies of the Kidney and Urinary Tract: A Multi‐Center Cohort Study

ABSTRACT Objectives To investigate the diagnostic utility of copy‐number variant (CNV) detection by chromosomal microarray analysis (CMA) and genotype‐phenotype associations in prenatal congenital anomalies of the kidney and urinary tract (CAKUT). Methods This is a retrospective multi‐center study of CNV analysis in 457 fetuses with ultrasound‐detected CAKUT and normal karyotypes. Cohorts from published studies were included for further pooled analyses ( N = 2746). A literature review of single‐nucleotide variant (SNV) and small insertions and deletions (Indel) analysis by whole‐exome sequencing was performed to investigate monogenic causes. Results In our multi‐center cohort, 5.3% (24/457) of fetuses had pathogenic CNVs (pCNV); 3.9% (14/359) and 10.2% (10/98) in isolated and non‐isolated CAKUT, respectively. Fetuses with isolated hyperechogenic kidneys (HEK) had the highest incidence of having pCNVs. In the literature review, 6.6% (180/2746) of fetuses carried pCNVs; 6.1% and 7.5% in isolated and non‐isolated CAKUT, respectively. SNV/Indel analysis provided at least 16.5% (63/381) additional diagnostic yield beyond CNV analysis; 12.8% and 23.8% in isolated and non‐isolated CAKUT, respectively. Conclusion pCNVs comprise a significant proportion of genetic diagnostic findings in prenatal CAKUT, most commonly detected in fetuses with isolated HEK, MCDK, renal agenesis, and non‐isolated CAKUT. Monogenic causes should be considered when karyotyping and CMA are nondiagnostic.