Predicted Mutation Strength of Nontruncating PKD1 Mutations Aids Genotype-Phenotype Correlations in Autosomal Dominant Polycystic Kidney Disease

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) often results in ESRD but with a highly variable course. Mutations to PKD1 or PKD2 cause ADPKD; both loci have high levels of allelic heterogeneity. We evaluated genotype-phenotype correlations in 1119 patients (945 families) from the HALT Progression of PKD Study and the Consortium of Radiologic Imaging Study of PKD Study. The population was defined as: 77.7% PKD1, 14.7% PKD2, and 7.6% with no mutation detected (NMD). Phenotypic end points were sex, eGFR, height-adjusted total kidney volume (htTKV), and liver cyst volume. Analysis of the eGFR and htTKV measures showed that the PKD1 group had more severe disease than the PKD2 group, whereas the NMD group had a PKD2-like phenotype. In both the PKD1 and PKD2 populations, men had more severe renal disease, but women had larger liver cyst volumes. Compared with nontruncating PKD1 mutations, truncating PKD1 mutations associated with lower eGFR, but the mutation groups were not differentiated by htTKV. PKD1 nontruncating mutations were evaluated for conservation and chemical change and subdivided into strong (mutation strength group 2 [MSG2]) and weak (MSG3) mutation groups. Analysis of eGFR and htTKV measures showed that patients with MSG3 but not MSG2 mutations had significantly milder disease than patients with truncating cases (MSG1), an association especially evident in extreme decile populations. Overall, we have quantified the contribution of genic and PKD1 allelic effects and sex to the ADPKD phenotype. Intrafamilial correlation analysis showed that other factors shared by families influence htTKV, with these additional genetic/environmental factors significantly affecting the ADPKD phenotype.

Keywords: ADPKD; Genotype/phenotype; Prognostic studies.

Figure 1.

Men have more severe renal disease in ADPKD. Comparison of men and women in terms of (A, C, and E) renal function measured by eGFR and (B and D) renal structure (htTKV; plotted on a natural log scale [log_e]) for the (A and B) total, (C and D) PKD1, and (E) PKD2 populations. Population numbers are indicated in Table 1, and details of the eGFR and htTKV differences and significance are shown in Table 2. Parallel regression lines are plotted for each variable in each comparison, and the data are corrected for age, gene, and mutation type, with the P value indicated.

Figure 2.

The mutated gene strongly influences the renal phenotype in ADPKD. The PKD1, PKD2, and NMD genic groups are compared in terms of (A) eGFR and (B) htTKV natural log scale (log_e), with overall P values indicated. Population numbers and details of the eGFR and htTKV differences and the individual significances are shown in Tables 1 and 2, respectively. (C) Residual analysis shows the relationship between the eGFR and htTKV measurements in the genic populations, with the corresponding number (percentage) of each population in each of the four quadrants (i–iv) shown in D. The zero point on the x and y axes is where the average age– and sex–corrected residual is equal to zero (no difference between the observed and predicted outcomes).

Figure 3.

Truncating PKD1 mutations are associated with worse renal function than nontruncating mutations. Mutations are divided into five different types—frameshifting indels, splicing, nonsense, missense, and in-frame indels (D/I)—and compared with (A) eGFR and (B) htTKV natural log scale (log_e), with overall P values indicated. Comparison of mutations predicted to truncate or nontruncate the protein with (C) eGFR and (D) htTKV (log_e). Population numbers and details of the eGFR and htTKV differences and the significance are shown in Tables 1 and 2, respectively.

Figure 4.

Strongly predicted nontruncating PKD1 mutations are associated with more severe disease than weak nontruncating mutations. PKD1 mutations are divided into three groups—truncating (MSG1), strongly predicted nontruncating (MSG2), and weakly predicted nontruncating (MSG3) (Supplemental Table 2)—and assayed for (A) eGFR and (B) htTKV natural log scale (log_e), with overall P values shown. Population numbers and details of the eGFR and htTKV differences and the significance are shown in Tables 1 and 2, respectively. (C) A plot of the residual analysis for the two phenotypic variables and (D) the frequency of each MSG in each quadrant show a significantly different distribution for the MSG3 group.

Figure 5.

Women and marginally PKD1 gene type are associated with larger liver cyst volumes. (A) htLCV plotted natural log scale (log_e) against age with the genic groups identified. (B) Analysis of sex shows that women have larger liver cyst volumes in the PKD1 population. Population numbers and details of the eGFR and htTKV differences and the significance are shown in Tables 1 and 3, respectively, with overall P values shown.