Molecular diagnostic in fetuses with isolated congenital anomalies of the kidney and urinary tract by whole‐exome sequencing

Background In prenatal care, accumulating evidences has demonstrated that whole‐exome sequencing (WES) expedites the genetic diagnosis of fetal structural anomalies. However, the clinical value of WES in the diagnosis of prenatal isolated congenital anomalies of the kidney and urinary tract (CAKUT) is unknown. Methods Forty‐one fetuses with unexplained isolated CAKUT, normal karyotype and negative chromosomal microarray analysis (CMA) results, underwent WES and were accordingly grouped as (a) Group 1: complex cases with bilateral renal abnormalities (N = 19); and (b) Group 2: cases with isolated unilateral fetal renal abnormalities (N = 22). Results The detection rate of WES for pathogenic variants and incidental variants was 7.32% (3/41) and 2.4% (1/41), respectively. The three pathogenic variants were identified in the genes ACTA2 (multisystem smooth muscle dysfunction syndrome), PKHD1 (autosomal recessive form of polycystic kidney disease), and PKD1 (autosomal dominant polycystic kidney disease type 1). The incidental variants were detected in genes PPM1D (syndromic neurodevelopmental disorders). Furthermore, all above fetuses carrying pathogenic variants came from bilateral kidney anomalies. Thus, the detection rate was 0 for fetuses with unilateral fetal renal abnormalities and 15.7% (3/19) for bilateral renal abnormalities. Conclusion This cohort shows that prenatal WES is a supplementary approach for the etiologic diagnosis of unexplained isolated CAKUT with negative CMA, especially for fetuses with bilateral renal abnormality.
Flowchart of characteristic of pregnant women and diagnostic finding from WES (analysis of fetuses with isolated CAKUT). Forty‐one cases with isolated CAKUT and prenatal diagnosis results available (WES) were selected. Detail results are described in the main text. CAKUT: congenital anomalies of the kidney and urinary tract WES: whole‐exome sequencing.