Targeted gene sequencing and whole-exome sequencing in autopsied fetuses with prenatally diagnosed kidney anomalies

Clin Genet. 2018 Apr;93(4):860-869. doi: 10.1111/cge.13185. Epub 2018 Feb 23.


Identification of fetal kidney anomalies invites questions about underlying causes and recurrence risk in future pregnancies. We therefore investigated the diagnostic yield of next-generation sequencing in fetuses with bilateral kidney anomalies and the correlation between disrupted genes and fetal phenotypes. Fetuses with bilateral kidney anomalies were screened using an in-house-designed kidney-gene panel. In families where candidate variants were not identified, whole-exome sequencing was performed. Genes uncovered by this analysis were added to our kidney panel. We identified likely deleterious variants in 11 of 56 (20%) families. The kidney-gene analysis revealed likely deleterious variants in known kidney developmental genes in 6 fetuses and TMEM67 variants in 2 unrelated fetuses. Kidney histology was similar in the latter 2 fetuses-presenting a distinct prenatal form of nephronophthisis. Exome sequencing identified ROBO1 variants in one family and a GREB1L variant in another family. GREB1L and ROBO1 were added to our kidney-gene panel and additional variants were identified. Next-generation sequencing substantially contributes to identifying causes of fetal kidney anomalies. Genetic causes may be supported by histological examination of the kidneys. This is the first time that SLIT-ROBO signaling is implicated in human bilateral kidney agenesis.

Keywords: CAKUT; NGS; kidney agenesis; kidney anomalies; kidney dysplasia; prenatal screening.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autopsy
  • DNA Mutational Analysis
  • Female
  • Fetus
  • Genetic Predisposition to Disease
  • Humans
  • Intercellular Signaling Peptides and Proteins / genetics
  • Kidney Diseases / genetics*
  • Kidney Diseases / physiopathology
  • Male
  • Membrane Proteins / genetics
  • Mutation / genetics
  • Neoplasm Proteins / genetics*
  • Nerve Tissue Proteins / genetics*
  • Prenatal Diagnosis*
  • Receptors, Immunologic / genetics*
  • Whole Exome Sequencing


  • GREB1 protein, human
  • Intercellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Neoplasm Proteins
  • Nerve Tissue Proteins
  • ROBO2 protein, human
  • Receptors, Immunologic
  • TMEM67 protein, human
  • roundabout protein
  • Slit homolog 2 protein