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Kidney Week

Abstract: SA-PO754

"Genotype-First" Approach to Analyzing the Diversity and Prevalence of Genes in a Cohort of Cystic Disease Patients

Session Information

Category: Genetic Diseases of the Kidneys

  • 1201 Genetic Diseases of the Kidneys: Cystic


  • Clark, Dinah, Natera, Inc., Austin, Texas, United States
  • Zhang, Zhiji, Natera, Inc., Austin, Texas, United States
  • Burns, Robert T., Natera, Inc., Austin, Texas, United States
  • Baddar, Nour, Natera, Inc., Austin, Texas, United States
  • Bloom, Michelle, Natera, Inc., Austin, Texas, United States
  • Tabriziani, Hossein, Natera, Inc., Austin, Texas, United States
  • Punj, Sumit, Natera, Inc., Austin, Texas, United States

Cystic kidney diseases are one of the most prevalent forms of monogenic kidney diseases. Variants in PKD1 and PKD2 reportedly comprise 93% of genetic causes of cystic kidney diseases with variants in other genes (i.e. IFT140, GANAB, etc) accounting for a small proportion. As variants in these less common genes lead to milder or atypical presentations, a “phenotype-first” approach to identifying cases with cystic disease may lead to an underestimation of their contribution. Using comprehensive genetic testing, we present a “genotype-first” approach that identifies contributions of cystic kidney and/or liver disease, providing real-world insights.


A retrospective analysis of results from patients tested with a 385 renal gene panel (the Renasight™ test) was performed. Cases were selected based on having one pathogenic (P) or likely pathogenic (LP) variant in a gene associated with autosomal dominant cystic disease (PKD1/2, IFT140, HNF1B, UMOD, ALG9, GANAB, SEC63, PRKCSH).


Among 41,182 total cases reviewed, 3698 (9.0%) had positive results in a cystic gene, 23 of which (0.6%) had findings in more than one cystic gene. P/LP variants in PKD1/2 comprised the majority (74.0%, n=2,739) of the positive findings. A total of 1113 variants were identified in PKD1/2, of which 67% were private to a single case. Behind PKD1/2, variants in IFT140 (9.6%; n=357), HNF1B (8.2%, n=304) and UMOD (4.6%, n=171) comprised small but significant proportions of the positive cases. Findings in each of the remaining cystic genes (ALG9, GANAB, SEC63, PRKCSH) had prevalence < 1.0%.


This study, representing the largest real-world experience, provides new insight into estimates of the prevalence of cystic disease causing genes in a “genotype-first” approach. While our observation of private mutations in PKD1/2 is consistent with prior reports, we showed that PKD1/2 were etiologically implicated in a smaller proportion of cases than has previously been reported. These new insights into the genetic landscape of cystic disease will have important implications for clinical practice given the prognosis and implications for management differ greatly between PKD1/2 and the other genetic causes.