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Abstract: TH-PO659

A Genotype-First Approach Identifies Atypical PKD in DNAJB11 Mutation Carriers

Session Information

Category: Genetic Diseases of the Kidney

  • 1001 Genetic Diseases of the Kidney: Cystic

Authors

  • Luo, Jonathan Z., Geisinger, Danville, Pennsylvania, United States
  • Mooore, Bryn S., Geisinger, Danville, Pennsylvania, United States
  • Besse, Whitney E., Yale University, New Haven, Connecticut, United States
  • Somlo, Stefan, Yale University, New Haven, Connecticut, United States
  • Chang, Alex R., Geisinger, Danville, Pennsylvania, United States
  • Mirshahi, Tooraj, Geisinger, Danville, Pennsylvania, United States
  • Hartzel, Dustin N., Geisinger Health System, Danville, Pennsylvania, United States
Background

Approximately 7-8% of autosomal dominant polycystic kidney disease (ADPKD) cases remain genetically unresolved. Mutations in DNAJB11, an ER co-chaperone molecule with a significant role in polycystin-1 maturation and trafficking, were recently identified in ADPKD patients with non-enlarged, cystic kidneys in the absence of PKD1/2 mutations. Little is known about the association between putative loss of function (pLOF) DNAJB11 mutations with ADPKD in an unselected population.

Methods

We used whole exome sequencing (WES) from 91,365 patients in the Geisinger-Regeneron DiscovEHR cohort to identify patients with pLOF DNAJB11 mutations (early-termination, frameshifts and start-loss mutations). Electronic health record data (diagnostic billing codes, eGFR, imaging) were examined to determine clinical phenotype. Evidence for the presence of renal and liver cysts was determined using natural language processing and manual review of imaging reports.

Results

We found 7 DNAJB11 pLOF variants in 10 patients (median eGFR 60 mL/min/1.73m2) in our cohort, of whom 9 had renal imaging. Of the 2 younger patients (age 26 and 28) with renal imaging, 1 had a unilateral renal cyst, and 1 had bilateral hydronephrosis and right nephrolithiasis. Of the 7 older patients (age 49-72) with renal imaging, 3 had multiple, bilateral renal cysts, and 1 had multiple, unilateral renal cysts. One patient was diagnosed with ESRD at age 59. Two of the 7 patients were sisters carrying the same early termination mutation: a 61yo presenting with bilateral renal cysts, and a 55yo with multiple left renal cysts. Three patients carried rare PKD1 missense variants (MAF 0.01%-0.15%), all of which are classified as Likely Neutral in the Mayo PKDB. Three patients presented with nephrolithiasis. Only one patient was hypertensive.

Conclusion

Using WES in an unselected population, our findings provide further evidence that loss of function mutations in DNAJB11 could lead to normal-sized cystic kidneys and ESRD. Furthermore, we show the utility of a large-scale exome sequencing study combined with detailed EHR data in identifying rare genetic causes of kidney disease.

Funding

  • NIDDK Support