Whole-exome sequencing for prenatal diagnosis of fetuses with congenital anomalies of the kidney and urinary tract

Nephrol Dial Transplant. 2017 Oct 1;32(10):1665-1675. doi: 10.1093/ndt/gfx031.


Background: In the absence of cytogenetic abnormality, fetuses with congenital anomalies of the kidney and urinary tract (CAKUT) with/without other structural anomalies show a higher likelihood of monogenic causes; however, defining the underlying pathology can be challenging. Here, we investigate the value of whole-exome sequencing (WES) in fetuses with CAKUT but normal findings upon karyotyping and chromosome microarray analysis.

Methods: WES was performed on DNA from the cord blood of 30 fetuses with unexplained CAKUT with/without other structural anomalies. In the first 23 cases, sequencing was initially performed on fetal DNA only; for the remaining seven cases, the trio of fetus, mother and father was sequenced simultaneously.

Results: Of the 30 cases, pathogenic variants were identified in 4 (13%) (UMOD, NEK8, HNF1B and BBS2) and incidental variants in 2 (7%) (HSPD1 and GRIN2B). Furthermore, two of the above four cases had other anomalies in addition to CAKUT. Thus, the detection rate was only 2/22 (9.1%) for isolated CAKUT and 2/8 (25%) for CAKUT with other abnormalities.

Conclusions: Applying WES to the prenatal diagnostic approach in CAKUT fetuses with or without other anomalies allows for an accurate and early etiology-based diagnosis and improved clinical management. To expedite interpretation of the results, trio sequencing should be employed; however, interpretation may nevertheless be compromised by incomplete coverage of all relevant genes.

Keywords: BBS2; NEK8; UMOD; congenital anomalies of the kidney and urinary tract; monogenic causes.

MeSH terms

  • Adult
  • Amino Acid Sequence
  • Amniocentesis
  • Base Sequence
  • DNA Mutational Analysis
  • Exome*
  • Female
  • Fetus
  • Humans
  • Kidney / abnormalities
  • Kidney / diagnostic imaging
  • Molecular Diagnostic Techniques
  • Pregnancy
  • Ultrasonography, Prenatal
  • Urinary Tract / abnormalities
  • Urinary Tract / diagnostic imaging
  • Urogenital Abnormalities / diagnostic imaging
  • Urogenital Abnormalities / genetics*
  • Whole Exome Sequencing
  • Young Adult