Multidisciplinary approaches for elucidating genetics and molecular pathogenesis of urinary tract malformations

Kamal Khan, Dina F. Ahram, Yangfan P. Liu, Rik Westland, Rosemary V. Sampogna, Nicholas Katsanis*, Erica E. Davis*, Simone Sanna-Cherchi*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

11 Scopus citations


Advances in clinical diagnostics and molecular tools have improved our understanding of the genetically heterogeneous causes underlying congenital anomalies of kidney and urinary tract (CAKUT). However, despite a sharp incline of CAKUT reports in the literature within the past 2 decades, there remains a plateau in the genetic diagnostic yield that is disproportionate to the accelerated ability to generate robust genome-wide data. Explanations for this observation include (i) diverse inheritance patterns with incomplete penetrance and variable expressivity, (ii) rarity of single-gene drivers such that large sample sizes are required to meet the burden of proof, and (iii) multigene interactions that might produce either intra- (e.g., copy number variants) or inter- (e.g., effects in trans) locus effects. These challenges present an opportunity for the community to implement innovative genetic and molecular avenues to explain the missing heritability and to better elucidate the mechanisms that underscore CAKUT. Here, we review recent multidisciplinary approaches at the intersection of genetics, genomics, in vivo modeling, and in vitro systems toward refining a blueprint for overcoming the diagnostic hurdles that are pervasive in urinary tract malformation cohorts. These approaches will not only benefit clinical management by reducing age at molecular diagnosis and prompting early evaluation for comorbid features but will also serve as a springboard for therapeutic development.

Original languageEnglish (US)
Pages (from-to)473-484
Number of pages12
JournalKidney international
Issue number3
StatePublished - Mar 2022


  • copy number variant
  • embryonic development
  • genomics
  • kidney organoid
  • zebrafish

ASJC Scopus subject areas

  • Nephrology


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