Kidney Week

Abstract: TH-PO661

The Genetic Complexity of ADPKD Is Illustrated in the HALT PKD Clinical Trial Cohort

Session Information

• ADPKD: Genetic and Model Studies
  October 25, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidney

• 1001 Genetic Diseases of the Kidney: Cystic

Authors

• Senum, Sarah R., Mayo Clinic, Rochester, Minnesota, United States

Sarah R. Senum,

• Cornec-Le Gall, Emilie, Centre Hospitalier Universitaire de Brest, BREST, France

Emilie Cornec-Le Gall,

• Brosnahan, Godela M., University of Colorado Denver, Aurora, Colorado, United States

Godela M. Brosnahan,

• Chapman, Arlene B., University of Chicago, Chicago, Illinois, United States

Arlene B. Chapman,

• Torres, Vicente E., Mayo Clinic, Rochester, Minnesota, United States

Vicente E. Torres,

• Perrone, Ronald D., Tufts Medical Center, Boston, Massachusetts, United States

Ronald D. Perrone,

• Yu, Alan S.L., University of Kansas Medical Center, Kansas City, Kansas, United States

Alan S.L. Yu,

• Steinman, Theodore I., Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States

Theodore I. Steinman,

• Braun, William E., Cleveland Clinic, Cleveland, Ohio, United States

William E. Braun,

• Abebe, Kaleab, University of Pittsburgh, Pittsburgh, Pennsylvania, United States

Kaleab Abebe,

• Bae, Kyongtae Ty, University of Pittsburgh, Pittsburgh, Pennsylvania, United States

Kyongtae Ty Bae,

• Harris, Peter C., Mayo Clinic, Rochester, Minnesota, United States

Peter C. Harris,

Group or Team Name

• HALT PKD Consortium

Background

The HALT PKD clinical trials consisted of hypertensive ADPKD patients, 15-49y with an eGFR >60 ml/min/1.73m² (Study A; n=558) or 18-64y with an eGFR 25-60 ml/min/1.73m² (Study B; n=486), but without total kidney volume requirements for recruitment. Hence, this population represents the cross-section of ADPKD seen by nephrologists and so provides an opportunity to characterize the genetics of a “typical” renal clinic population.

Methods

DNA samples were available from 970 patients from Study A and B that were screened by Sanger sequencing and MLPA for the PKD1 and PKD2 genes. Genetically unresolved cases were screened on a next generation sequencing (NGS) panel containing 65 known or candidate PKD genes. In some cases, further family analysis was performed to test segregation.

Results

Likely pathogenic mutations were detected in 95.1% of cases, 506 (52.2%) and 266 (27.4%), PKD1 truncating or PKD1 non-truncating, respectively, with 166 (15.2%) PKD2. The NGS revealed 23 mutations missed by the Sanger screen (21 PKD1, 2 PKD2), some due to allele drop out, with two others still being evaluated. A GANAB and a DNAJB11 family were identified, plus one with PKD2 and COL4A1 mutations. Five patients were PKD1 mosaics, detected due to family analysis (2x), MLPA (1x), or NGS (2x), with the mutant allele at ~20-40% of the wildtype level. One patient was digenic for a PKD1 (2 codon, inframe deletion) and a PKD2 (nonsense) mutation, with ESRD=43y. Two PKD1 mutations were likely gene conversions with the PKD1 pseudogenes, and in three other cases the pathogenic allele consisted of three weak PKD1 variants in cis shown in vitro to have additive effects. Two PKD2 patients co-inheriting hypomorphic PKD1 variants had move severe disease than expected.

Conclusion

While the majority of HALT PKD patients have ADPKD due to a monoallelic mutation to one of the two common genes, a total of five causative genes have now been identified. Mosaicism or complex inheritance were also characterized in >1% patients, likely an underestimate of the true complexity due to difficulty of detection and interpretation, in this “typical” ADPKD population.

Funding

• NIDDK Support