Refining Genotype-Phenotype Correlation in Autosomal Dominant Polycystic Kidney Disease

Abstract

Renal disease variability in autosomal dominant polycystic kidney disease (ADPKD) is strongly influenced by the gene locus (PKD1 versus PKD2). Recent studies identified nontruncating PKD1 mutations in approximately 30% of patients who underwent comprehensive mutation screening, but the clinical significance of these mutations is not well defined. We examined the genotype-renal function correlation in a prospective cohort of 220 unrelated ADPKD families ascertained through probands with serum creatinine ≤1.4 mg/dl at recruitment. We screened these families for PKD1 and PKD2 mutations and reviewed the clinical outcomes of the probands and affected family members. Height-adjusted total kidney volume (htTKV) was obtained in 161 affected subjects. Multivariate Cox proportional hazard modeling for renal and patient survival was performed in 707 affected probands and family members. Overall, we identified pathogenic mutations in 84.5% of our families, in which the prevalence of PKD1 truncating, PKD1 in-frame insertion/deletion, PKD1 nontruncating, and PKD2 mutations was 38.3%, 4.3%, 27.1%, and 30.3%, respectively. Compared with patients with PKD1 truncating mutations, patients with PKD1 in-frame insertion/deletion, PKD1 nontruncating, or PKD2 mutations have smaller htTKV and reduced risks (hazard ratio [95% confidence interval]) of ESRD (0.35 [0.14 to 0.91], 0.10 [0.05 to 0.18], and 0.03 [0.01 to 0.05], respectively) and death (0.31 [0.11 to 0.87], 0.20 [0.11 to 0.38], and 0.18 [0.11 to 0.31], respectively). Refined genotype-renal disease correlation coupled with targeted next generation sequencing of PKD1 and PKD2 may provide useful clinical prognostication for ADPKD.

Keywords: ADPKD; genetic renal disease; genetics and development.

Figure 1.

Mutation spectrum in TGESP. Percentage distribution of different mutation classes in study families. Overall, we identified 188 pathogenic mutations in 186 of 220 (i.e., 84.5%) families, including 2 families with cryptic bilineal ADPKD. Among 188 mutations identified, 38.3% (72 of 188) were PKD1 PT, 27.1% (51 of 188) were PKD1 NT, 4.3% (8 of 188) were PKD1 IF indel, and 30.3% (57 of 188) were PKD2 mutations (details in Supplemental Table 2).

Figure 2.

Cryptic bilineal ADPKD in TOR87 with marked intrafamilial renal disease variability. A and B show the two putative pathogenic PKD1 mutations (c.12389_12391delTGG, p.Val4130del; and c.12161C>T, p.Ser4054Phe) identified in this pedigree. C shows that p.Val4130del originated from II:3 and was also present in three of his five children. Follow-up screening of III:4, who was affected but did not carry p.Val4130del, identified a second PKD1 mutation (p.Ser4054Phe). p.Val4130del is a de novo mutation in II:3 that segregated with the disease in III:1, III:2, and III:5, whereas p.Ser4054Phe originated from II:4 segregated with the disease in III:3, III:4, and III:5. III:5 was transheterozygous for both mutations and suffered early and severe renal disease. By contrast, all other affected subjects carried only one hypomorphic PKD1 mutation and were mildly affected. The number in parentheses denotes the age at death or last follow-up.

Figure 3.

Effects of mutation class on htTKV. (A) Corrected for age, patients with PKD1 PT mutations generally have larger htTKV compared with those from other mutation classes. (B) Assuming exponential growth, the rate of htTKV expansion seems similar between patients with PKD1 PT, PKD1 IF indel, and PKD2 mutations; however, the absolute htTKV (y intercept) differed between the three mutation classes. By contrast, the rate of htTKV expansion associated with NT PKD1 mutations seemed to be significantly slower than the rates of the other three mutation classes. Two affected siblings from TOR264 displayed extreme discordance of their htTKV (denoted by stars; 455 and 2184 ml/m at 19 and 21 years of age, respectively), suggesting a modifier effect.

Figure 4.

Renal and patient survival in TGESP. Kaplan–Meier curves for (A) renal and (B) patient survival by mutation class. P value <0.001 by log-rank test.

Figure 5.

Renal disease severity in families with PKD1 nontruncating mutations. The age of affected relatives (denoted by circles) at ESRD or last follow-up is plotted for each family. White circles denote subjects who remained renal sufficient at their last follow-up, whereas black circles denote those who had reached ESRD. Families with one or more affected relatives with ESRD or renal sufficiency after age of 65 years old (top shaded area) are considered to have mild disease. By contrast, families with one or more affected relative who developed ESRD before age 50 years old are considered to have severe disease (bottom shaded area). Noninformative families are considered as indeterminate (middle shaded area). Nine families with probands but no other affected relatives were not included here.