Type of PKD1 Mutation Influences Renal Outcome in ADPKD

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Type of PKD1 Mutation Inﬂuences Renal Outcome in ADPKD

† †‡ †‡ Emilie Cornec-Le Gall,* Marie-Pierre Audrézet, Jian-Min Chen, Maryvonne Hourmant,§ | †† Marie-Pascale Morin, Régine Perrichot,¶ Christophe Charasse,** Bassem Whebe, ‡‡ || † Eric Renaudineau, Philippe Jousset,§§ Marie-Paule Guillodo, Anne Grall-Jezequel,* †‡ †‡ † Philippe Saliou, Claude Férec, and Yannick Le Meur*

*Nephrology Department, University Hospital, Brest, France; †Université de Bretagne Occidentale and European University of Brittany, Brest, France; ‡Molecular Genetic Department, INSERM U1078, University Hospital, EFS- Bretagne, Brest, France; §Nephrology Department, University Hospital, Nantes, France; |Nephrology Department, University Hospital, Rennes, France; ¶Nephrology Department, Vannes Hospital, Vannes, France; **Nephrology Department, Saint Brieuc Hospital, Saint Brieuc, France; ††Nephrology Department, Quimper Hospital, Quimper, France; ‡‡Nephrology Department, Broussais Hospital, Saint Malo, France; §§Nephrology Department, Pontivy Hospital, Pontivy, France; and ||Association des Urémiques de Bretagne, Brest, France

ABSTRACT Autosomal dominant polycystic kidney disease (ADPKD) is heterogeneous with regard to genic and allelic heterogeneity, as well as phenotypic variability. The genotype-phenotype relationship in ADPKD is not completely understood. Here, we studied 741 patients with ADPKD from 519 pedigrees in the Genkyst cohort and conﬁrmed that renal survival associated with PKD2 mutations was approximately 20 years longer than that associated with PKD1 mutations. The median age at onset of ESRD was 58 years for PKD1 carriers and 79 years for PKD2 carriers. Regarding the allelic effect on phenotype, in contrast to previous studies, we found that the type of PKD1 mutation, but not its position, correlated strongly with renal survival. The median age at onset of ESRD was 55 years for carriers of a truncating mutation and 67 years for carriers of a nontruncating mutation. This observation allows the integration of genic and allelic effects into a single scheme, which may have prognostic value.

J Am Soc Nephrol 24: 1006–1013, 2013. doi: 10.1681/ASN.2012070650

Autosomal dominant polycystic kidney disease patients with PKD1 than those with PKD2,6,7 (ADPKD) is the most common kidney disorder indicating a genic influence on the ADPKD pheno- with a Mendelian inheritance pattern, with a prev- type. Second, the position of the PKD1 mutation is alence ranging from 1/400 to 1/1000 worldwide.1 associated with the age at ESRD onset,8 suggesting ADPKD shows both locus and allelic heterogene- an allelic influence on ADPKD phenotype. How- ity. Two causative genes—PKD1, located at ever, these observations were made .10 years ago, 16p13.3,2 and PKD2, located at 4q213—have when mutational analysis of the PKD1 and PKD2 been identified, and the ADPKD mutation data- genes (particularly of the nonunique portion of the base (http://pkdb.mayo.edu/) describes .1000 PKD1 gene2,9) was substantially less comprehensive pathogenic mutations (929 in PKD1 and 167 in PKD2 as of June 5, 2012), not including our most recent data.4 Received July 5, 2012. Accepted January 7, 2013. ADPKD also shows high phenotypic variability, Published online ahead of print. Publication date available at as exemplified by the wide variation in the age at www.jasn.org. 5 fi onset of ESRD, which is de ned as the requirement Correspondence: Dr. Claude Férec, INSERM U1078 and EFS- of dialysis or transplantation. Genotype-phenotype Bretagne, 46 rue Félix Le Dantec, 29218 Brest, France. Email: correlation studies underscore two major issues. [email protected] First, on average, ESRD occurs 20 years earlier in Copyright © 2013 by the American Society of Nephrology

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Table 1. Patient characteristics Characteristic PKD1 Mutation Carriers PKD2 Mutation Carriers Mutation-Negative Patients Total Patients (pedigrees), n (n) 571 (392) 133 (95) 37 (32) 741 (519) Mean age (yr) 51.96 58.91 56.01 53.4 Sex (n) Male 254 50 21 325 Female 317 83 16 416 High BP Present, n (%) 474 (83) 107 (80.4) 31 (83.7) 612 Age at diagnosis (yr) 38.6 48.6 42.2 40.6 Absent (n) 92 26 6 124 Unknown (n)5005 CKD stage according to estimated GFR (MDRD formula) (n) I 74 21 4 90 (13.4) II 74 31 3 108 (14.6) III 91 38 8 137 (18.5) IV 61 12 4 77 (10.4) V Total 271 31 18 320 (43.2) Requiring dialysis (n) 51 15 4 70 (9.4) With kidney transplant (n) 192 11 7 210 (28.3) Unless otherwise noted, values in parentheses are percentages of patients. MDRD, Modification of Diet in Renal Disease. and sophisticated than it is currently,4,10 the methods for pre- Table 2. Distribution of pathogenic PKD1 and PKD2 dicting the potential pathogenicity of missense mutations mutations were in their infancy, and the studied patient cohorts were Gene/Mutation Type Pedigrees, n (%) fi relatively small. To con rm (or refute) these earlier observa- PKD1 392 tions, we performed a genotype and phenotype correlation Truncating mutations study using the Genkyst cohort, which comprises patients Total 255 (65.1) with ADPKD recruited from all private and public nephrol- Frameshift 130 (33.2) ogy centers in the Brittany region, namely, the western part of Nonsense 90 (22.9) France. Splice 32 (8.2) Large rearrangements 3 (0.8) Nontruncating mutations RESULTS Total 137 (34.9) Missense 110 (28) In-frame deletions or insertions 27 (6.9) Description of the Cohort and Distribution of the PKD1 PKD2 95 and PKD2 Mutations Truncating mutations This study included all 741 patients with ADPKD and Total 89 (93.7) molecular genetic analytic data (416 female and 325 male Frameshift 13 (13.7) patients; 519 pedigrees) registered in Genkyst between early Nonsense 41 (43.1) 2009 and July 2012. The mean age 6 SD at inclusion was Splice 20 (21.1) 53.4614.8 years (range, 5.45–89.5 years). Pathogenic muta- Large rearrangements 15 (15.8) tions in the PKD1 and PKD2 genes were found in 392 (75.5%) Nontruncating mutations 6 (6.3) and 95 (18.3%) of the 519 pedigrees, respectively (Table 1). No Total (all mutation positive pedigrees) 487 mutation was identified in the remaining 32 pedigrees (6.2%); the overall detection rate was thus 93.8%. The phenotypic characteristics of each patient group, including age, sex, BP different mutations were found in the 487 mutation-positive status with age at diagnosis of hypertension if available, and pedigrees (296 PKD1 mutations in 392 pedigrees and 46 PKD2 CKD stage in terms of estimated GFR (calculated using the mutations in 95 pedigrees). Approximately two thirds of the Modification of Diet in Renal Disease formula), are provided 342 PKD1 mutation–positive pedigrees and almost 95% of the in Table 1. 95 PKD2 mutation–positive pedigrees carry truncating muta- A large number of the pathogenic mutations in the current tions (i.e., nonsense mutations, frameshift mutations, splicing study were confined to single pedigrees. Thus, a total of 342 mutations, and large rearrangements) (Table 2).

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Genotype and Phenotype Correlations of the mutation and renal survival. Tothis end, we studied renal Sex Influence survival in two main categories of PKD1 mutations, defined by Using the Kaplan-Meier model, we found that male PKD1 their truncating effect on polycystin 1. As shown in Figure 1A, mutation carriers presented with a poorer renal survival the median age at ESRD onset in the truncating mutation than female ones (median age at ESRD onset, 56.1 years for group (i.e., frameshift, nonsense, splice mutations, and large male patients versus 59.5 years for female patients; P,0.04). rearrangements) was 55.6 years (95% CI, 53.6–57.7 years), This result was confirmed using Cox multivariate analysis and mutations with no truncating effect (i.e., in-frame muta- (P=0.03) (Table 3). However, we did not find any sex influence tions and missense events) were associated with a 12-year de- in the PKD2 mutation carriers. When the two datasets were lay in ESRD onset (median age, 67.9 years [95% CI, 62.4–73.4 combined, only a borderline significance was observed; the years]) (P,0.0001). This difference was also re flected by the median age at ESRD onset was 62.8 years for male patients proportion of truncating mutations in four groups of patients, versus 65.4 years for female patients (P=0.05). corresponding to the quartile of renal survival in patients with PKD1 (i.e.,quartile1,ESRDbefore50.5years;quartile2, Gene Influence ESRD between 50.5 and 58.2 years; quartile 3, ESRD between PKD1 mutation carriers had significantly poorer renal prognosis 58.2 and 68.4 years; and quartile 4, patients .68.4 years with- than their PKD2 counterparts, with respective median ages at out ESRD). In the mildest phenotype group (i.e.,quartile4), ESRD onset of 58.1 (95% confidence interval [CI], 56.5–59.9) the proportion of truncating mutations (46.6%) was signifi- and 79.7 (95% CI, 76.8–82.6) years (P,0.001). The mean age at cantly lower than in each of the other three quartiles (quartile diagnosis of hypertension was 10 years earlier for PKD1 muta- 1, 83.3%; quartile 2, 78.9%; and quartile 3, 74%; P,0.05) tion carriers (n=315; 38.6611.3 years) than for PKD2 mutation (Figure 2A). Moreover, we assessed the robustness of our sur- carriers (n=77; 48.6611.5 years) (P,0.001) (Table 1). vival analysis using a Cox multivariate model, taking into account age and sex. We found no effect of BP status, smoking, Allelic Influence of the PKD1 Gene hematuria, or mutation position on renal survival in the uni- To address the issue of allelic influence on phenotype in variate analysis (Table 3); therefore, these variables were not ADPKD, we first investigated the relationship between the type entered into the multivariate analysis. A strong effect of

Table 3. Details of univariate and multivariate Cox analysis for PKD1 mutation carriers Variable Patients (n) Univariate HR (95% CI) P Value Multivariate HR (95% CI) P Value Age ,45 yr 170 1 1 45–65 yr 306 2.75 (1.91–3.96) ,0.0001 2.7 (1.88–3.93) ,0.0001 .65 yr 89 11.5 (5.42–24.5) ,0.0001 11.48 (5.34–24.5) ,0.0001 Gender Female 227 1 1 Male 236 1.31 (1.01–1.68) 0.039 1.33 (1.03–1.72) 0.029 Mutation type Nontruncating 142 1 Truncating 321 2.6 (1.9–3.56) ,0.0001 2.74 (2–3.76) 0.0001 High BP Presence 474 Absence 92 0.872 (0.53–1.43) 0.40 Smoking (active or stopped) Yes 209 No 311 1.107 (0.84–1.44) 0.47 Macroscopic hematuria Yes 163 No 358 1.195 (0.91–1.57) 0.20 Mutation position 59 versus 39 end 59 end 281 39 end 289 1.113 (0.86–1.43) 0.41 Mutation position according to quartile of position 1st quartile 147 1 2nd quartile 138 1 (0.72–1.42) 0.72 3rd quartile 144 0.945 (0.67–1.34) 0.75 4th quartile 141 0.818 (0.57–1.17) 0.67

1008 Journal of the American Society of Nephrology J Am Soc Nephrol 24: 1006–1013, 2013 www.jasn.org CLINICAL RESEARCH

mutation type on renal survival was again observed; patients carrying a truncating PKD1 mutation were 2.74 times more likely to develop ESRD than those carrying a nontruncating PKD1 mutation (P,0.0001) (Table 3). Finally, the comparison of renal survival plots of male and female patients in the truncating mutation group showed that male patients with truncating mutations had significantly poorer prognoses than their female counterparts (respective median age at ESRD, 53.2 years [95% CI, 51.5–54.9 years] and 58.1 years [95% CI, 56.3–60 years]; P,0.001). How- ever, the same comparison in the nontruncating mutation group did not show any significant difference. Second, we evaluated the influence of mutation location along the PKD1 gene. Patients with PKD1 were separated into two groups according to the mutation position around the median: nucleotide 7815 within exon 19. Renal survival plots com- paring these two groups showed no significant difference between the 59 and the 39 end groups (P=0.69) (Figure 1B). In addition,weconductedthesameanalysis within four groups defined by the quartile of mutation position (quartile 1, 59 end to nucleotide 4617; quartile 2, nucleotide 4617–7815; quartile 3, nucleotide 7815– 10745; and quartile 4, nucleotide 10745– 39 end).Again,wefoundnosignificant differences in terms of renal survival. We further compared the median mutation positions in the four groups of patients corresponding to the quartile of renal survival in the PKD1 patients and found no significant differences (P=0.46) (Figure 2B). We also studied the position effect separately in the context of truncating and nontruncating mutations and, again, found no statis- tically significant differences (data not shown).

DISCUSSION Figure 1. PKD1 mutation type, but not its location, inﬂuences renal survival. Renal survival plots. (A) Signiﬁcant differences in renal survival between PKD1 truncating We report here our genotypic and pheno- mutation carriers, PKD1 nontruncating mutation carriers and PKD2 mutation carriers. typic analyses using data from Genkyst, (B) The absence of a position effect of PKD1 mutation on renal survival. one of the largest cohorts of patients with ADPKD worldwide. The Genkyst cohort is a valuable resource for investigating the role of genetic factors in renal disease evolution to ESRD because it aims to

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boundaries of PKD1 and PKD2 for both conventional mutations (i.e., single nucleotide substitutions, small insertions, and small deletions) and gross genomic rearrangements4 and (2)theidentification of a significant number of milder mutations. In addition, it may be possible that rare founder mutations have been considered as “recurrent” ones, thereby slightly increasing our mutation detection rate. We describe here a high level of private mutations (70.2%), which is consistent with previous findings.10–12 We cannot ex- clude the possibility that some recurrent mutations might in fact be due to the presence of a common ancestor. However, to date, we have not been able to establish any genealogic link between these families despite careful reanalysis of the pedigrees. A consequence of this putative misclassification would be the creation of some artificial mutational hotspots. Nonethe- less, this potential caveat is unlikely to have any undue influence on our main conclusions (see below) because our genotype and phenotype correlation was based on the number of included patients, irrespective of the number of families involved. Analysis of renal survival (Figure 1A) confirmed the previous observation that PKD2 mutations are associated with renal survival that is approximately 20 years longer than that seen with PKD1 mutations. However, our observed median ages at onset of ESRD for PKD1 and PKD2 mutation carriers (58.1 years versus 79.7 years) are 3.8 and 5.7 years older than the previously reported 54.3 and 74 years,7 respectively. This discrepancy may be attributed to the following reasons. First, the previous study7 was performed 13 years ago. Improvements in nephroprotective strategies over this period may have contributed to the increased renal survival. Second, all our patients were recruited from the same region in France and thus form a relatively homogeneous Figure 2. Patients with milder phenotypes are more likely to population. The presence of common protective genetic or en- harbor non-truncating mutations. Distribution of the patients ac- vironmental factors in these patients cannot be excluded. Third, PKD1 cording to the type and location of mutations in the four and perhaps most important, earlier studies typically analyzed quartiles of renal survival. Quartile 1, ESRD before 50.5 years; traditional, large families, which are often affected by severe quartile 2, ESRD between 50.5 and 58.2 years; quartile 3, ESRD fi fi . mutations. In contrast, our study identi ed a signi cant num- between 58.1 and 68.4 years; quartile 4, patients 68.4 years “ ” without ESRD or reaching ESRD after 68.4 years. The 258 PKD1 ber of mild or hypomorphic alleles. PKD1 mutation carriers presented in these figures have reached ESRD The sex effect reported in our study for the gene, with or are older than 68.4 years, corresponding to the lower limit of an earlier onset of ESRD in male patients, has previously been the last quartile. (A) Proportion of truncating mutations in patients described,13,14 but not unanimously.7,8 Nonetheless, this sex with milder renal phenotypes, represented by quartile 4, is sig- influence is moderate, both in our study and in previous ones, nificantly lower than that in patients with more severe diseases which may explain the conflicting results. (quartile 1, 2, or 3). (B) Median positions of mutations does not To our knowledge, this is the first study to show a strong differ in the four groups of renal survival. effect of PKD1 mutation type on renal phenotype, but we found no effect of mutation location at the population level. include all consenting patients followed in public and private Indeed, we showed a 12-year delay in ESRD onset in patients nephrology centers of a unique geographic region, no matter harboring a truncating mutation of PKD1 compared with pa- the CKD stage. Indeed, the preferential inclusion of patients tients with nontruncating mutation of PKD1. The risk of de- treated for ESRD (with dialysis or transplantation) could lead veloping ESRD was 2.74 times higher in patients with a trun- to the selection of only patients with severe phenotypes and cating mutation than in patients with a nontruncating may not take into account the milder forms of the disease. mutation of PKD1.WithinthePKD1 population, this aspect Our overall mutation detection rate, 93.8%, was higher than is, to our knowledge, the most effective predictive factor of the the previously reported 86%–89%.11,12 This improvement is evolution of ESRD ever reported. mainly due to the following two reasons: (1)thethorough In contrast to our conclusions, Rossetti et al. reported that analysis of the entire coding sequences and all the exon/intron thepositionbutnotthetypeofPKD1 mutation correlates with

1010 Journal of the American Society of Nephrology J Am Soc Nephrol 24: 1006–1013, 2013 www.jasn.org CLINICAL RESEARCH the severity of renal disease in ADPKD.8 Specifically, on the Beyond the demonstration of this allelic influence upon basis of the analysis of 324 patients with PKD1 from 80 dif- renal survival for PKD1,theidentification of modifier genes is ferent families, in whom the age at onset of ESRD was known an important goal, but studies to this end have remained in- for 152 patients, the authors concluded that “patients with conclusive to date.5 Nevertheless, case reports of early and mutations in the 59 region [i.e., 59 to the median position at severe ADPKD have recently highlighted the role of mutations nucleotide 7812; the full-length PKD1 mRNA sequence is in additional PKD genes (HNF1b, PKD1, PKD2,orPKHD1) ;14,000 bp] had significantly more severe disease than the in aggravating the phenotype.19 In the future, integrating the 39 group; median time to ESRD was 53 and 56 years, respec- different components of genetic heterogeneity in ADPKD, tively (P =0.025).” In contrast, the authors found no signifi- such as the gene involved, the type of PKD1 mutation, and cant differences among patients with truncating mutations, the coexistence of eventual modifier genes, will be complex in-frame changes, and missense mutations in PKD1. Thus, but may improve our ability to predict the severity of renal in terms of allelic influence, our findings are in direct oppo- disease. sition to previous ones.8 The three caveats mentioned in the introduction (i.e., the improvements in both molecular analyses and the scoring of missense events in the last 10 years and CONCISE METHODS the smaller size of the former study cohort) may certainly explain this discrepancy. Moreover, our findings are indirectly Patients supported by the literature. Although no similar observations Genkyst is a regional cohort involving up to 73 nephrologists working have been reported in autosomal dominant diseases, two studies in all 17 private and public nephrology centers in the Brittany region performed in the context of autosomal or X-linked recessive (Bretagne), France. It registers clinical and molecular genetic data of diseases have shown that truncating mutations are signifi- all consenting patients with ADPKD from this area. The ADPKD cantly more severe than nontruncating mutations (predom- diagnosis was based on renal ultrasonographic findings in accordance inantly missense mutations).15,16 Most of the nontruncating with previously described criteria.22 All 741 participating patients PKD1 mutations in our study are also missense mutations (from 519 pedigrees) with molecular genetic data were recruited be- (Table 2). It is tempting to speculate that some of these mis- tween early 2009 and July 2012, through nephrology consultation, sense mutations may represent “hypomorphic” alleles.17 In from dialysis centers, or during consultations or hospitalizations for fact, this hypothesis is well supported by recent publications. monitoring of kidney transplants. Repartition of the 741 patients Cases of milder ADPKD phenotypes have been reported in according to estimated GFR using the MDRD formula is available members of pedigrees harboring missense mutations com- in Table 1. All participants provided informed consent, and the local pared with relatives, co-inheriting the missense mutation ethics committee approved the study. with another mutation in PKD1 or PKD2.18–20 Moreover, the dosage dependence of cytogenesis has recently been high- Mutation Analysis lighted by a new PKD1 murine model.21 Most of the 741 participating patients had been included in our recent As illustrated in Figure 1A, our analysis led to a refinement of mutation report, which analyzed patients from both the Brittany region the genotypic and phenotypic relationship in ADPKD, with and other regions in France.4 For the newly recruited patients, mutation nontruncating PKD1 mutations identified as being associated detection and pathogenicity prediction for missense mutations were with an intermediate severity in terms of age at ESRD onset performed as previously described.4 Briefly, to assess the pathogenicity (67.9 years) between truncating PKD1 mutations (55.6 years) of missense variants, four different methods were combined: Grantham and PKD2 mutations (79.7 years). This new information, which matrix scoring system, Align Grantham Variation Grantham Devia- integrates the genic and allelic influences on phenotype into a tion;23 PolyPhen (http://genetics.bwh.harvard.edu/pph/);24,25 Sorting single scheme, may be of significant prognostic value. Moreover, Intolerant from Tolerant;26 and Mutation Taster.27 All missense muta- the costs of sequencing reactions and analyses are expected to tions predicted to be pathogenic (together with their predicted scores by decrease steadily in the coming years. Many factors have con- the different algorithms and the number of affected and unaffected tributed to this decrease, such as the automation of reaction members) are provided in Supplemental Table 1. preparations (i.e., for PCR reactions) and the development of next-generation sequencing technologies, as recently described Statistical Analyses for PKD1 and PKD2.10 In that setting, the molecular analysis of All statistical analyses were performed using SPSS software, version PKD1 and PKD2 could be more readily conducted for determin- 19 (SPSS, Inc., Armonk, NY). Renal survival was analyzed using the ing prognosis. In the context of emerging targeted therapies, this Kaplan-Meier method. The differences between the survival curves of new prognostic tool may help identify patients who could ben- the tested groups were assessed by means of a log-rank test with a 0.05 efit from treatment at a presymptomatic stage of the disease. significance level. The effects of age (,45 years, 45–65 years, .65 years), However, it is important to keep in mind that for each of the sex, and truncating versus nontruncating mutations on renal sur- two mutation type categories, extreme ESRD ages exist. Thus, vival were analyzed using the Cox proportional hazard model. Avariable taking into account the mutation type alone to predict renal was entered into the multivariate analysis when it was found to be outcome in PKD1 individual patients could be misleading. associated with the occurrence of ESRD in univariate analysis at a

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Hum Mutat 30: 264–273, 2009 Menoyo, Dr. Rifaat (ECHO, Vannes), Dr. Savoiu (ECHO, Saint 13. Gabow PA, Johnson AM, Kaehny WD, Kimberling WJ, Lezotte DC, Herblain), Dr. Bertheleme (Centre Héliomarin, Roscoff). Duley IT, Jones RH: Factors affecting the progression of renal disease in The authors wouldalso like toacknowledge the clinical researchteam autosomal-dominant polycystic kidney disease. Kidney Int 41: 1311– (Stéphanie Bouvier, Christelle Ratajczack, and Christelle Guillerm- 1319, 1992 14. Orskov B, Christensen KB, Feldt-Rasmussen B, Strandgaard S: Low Regost) and the molecular genetic laboratory (Joelle Creff, Isabelle birth weight is associated with earlier onset of end-stage renal disease Quéré, Sandrine Maestri, Caroline Benech, and Sylvia Redon). in Danish patients with autosomal dominant polycystic kidney disease. This study was conducted with the support of the National Plan for Kidney Int 81: 919–924, 2012 Clinical Research (PHRC regional 2010), the Société Française de 15. McEntagart M, Parsons G, Buj-Bello A, Biancalana V, Fenton I, Little M, Néphrologie, and the Institut National de la Santé et de la Recherche Krawczak M, Thomas N, Herman G, Clarke A, Wallgren-Pettersson C: Genotype-phenotype correlations in X-linked myotubular myopathy. Médicale (INSERM). Neuromuscul Disord 12: 939–946, 2002 Part of this work was presented as an oral communication at the 16. Snoeckx RL, Huygen PLM, Feldmann D, Marlin S, Denoyelle F, annual meeting of the American Society of Nephrology, November Waligora J, Mueller-Malesinska M, Pollak A, Ploski R, Murgia A, Orzan 2012, San Diego, California. E, Castorina P, Ambrosetti U, Nowakowska-Szyrwinska E, Bal J, Wiszniewski W, Janecke AR, Nekahm-Heis D, Seeman P, Bendova O, Kenna MA, Frangulov A, Rehm HL, Tekin M, Incesulu A, Dahl H-HM, du DISCLOSURES Sart D, Jenkins L, Lucas D, Bitner-Glindzicz M, Avraham KB, Brownstein Z, del Castillo I, Moreno F, Blin N, Pfister M, Sziklai I, Toth T, Kelley PM, None. Cohn ES, Van Maldergem L, Hilbert P, Roux A-F, Mondain M, Hoefsloot

1012 Journal of the American Society of Nephrology J Am Soc Nephrol 24: 1006–1013, 2013 www.jasn.org CLINICAL RESEARCH

LH, Cremers CWRJ, Löppönen T, Löppönen H, Parving A, Gronskov K, 22. Pei Y, Obaji J, Dupuis A, Paterson AD, Magistroni R, Dicks E, Parfrey P, Schrijver I, Roberson J, Gualandi F, Martini A, Lina-Granade G, Pallares- Cramer B, Coto E, Torra R, San Millan JL, Gibson R, Breuning M, Peters Ruiz N, Correia C, Fialho G, Cryns K, Hilgert N, Van de Heyning P, D, Ravine D: Uniﬁed criteria for ultrasonographic diagnosis of ADPKD. Nishimura CJ, Smith RJH, Van Camp G: GJB2 mutations and degree of JAmSocNephrol20: 205–212, 2009 hearing loss: A multicenter study. Am J Hum Genet 77: 945–957, 2005 23. Tavtigian SV, Byrnes GB, Goldgar DE, Thomas A: Classiﬁcation of 17. Vujic M, Heyer CM, Ars E, Hopp K, Markoff A, Orndal C, Rudenhed B, rare missense substitutions, using risk surfaces, with genetic- and Nasr SH, Torres VE, Torra R, Bogdanova N, Harris PC: Incompletely molecular-epidemiology applications. Hum Mutat 29: 1342–1354, penetrant PKD1 alleles mimic the renal manifestations of ARPKD. JAm 2008 Soc Nephrol 21: 1097–1102, 2010 24. Ramensky V, Bork P, Sunyaev S: Human non-synonymous SNPs: Server Nucleic Acids Res – 18. Pei Y, Lan Z, Wang K, Garcia-Gonzalez M, He N, Dicks E, Parfrey P, and survey. 30: 3894 3900, 2002 Germino G, Watnick T: A missense mutation in PKD1 attenuates the 25. Sunyaev S, Hanke J, Aydin A, Wirkner U, Zastrow I, Reich J, Bork P: severity of renal disease. Kidney Int 81: 412–417, 2012 Prediction of nonsynonymous single nucleotide polymorphisms JMolMed(Berl) – 19. Bergmann C, von Bothmer J, Ortiz Brüchle N, Venghaus A, Frank V, in human disease-associated genes. 77: 754 760, Fehrenbach H, Hampel T, Pape L, Buske A, Jonsson J, Sarioglu N, 1999 Santos A, Ferreira JC, Becker JU, Cremer R, Hoefele J, Benz MR, Weber 26. Sim N-L, Kumar P, Hu J, Henikoff S, Schneider G, Ng PC: SIFT web server: Predicting effects of amino acid substitutions on proteins. Nu- LT, Buettner R, Zerres K: Mutations in multiple PKD genes may explain cleic Acids Res 40[Web Server issue]: W452–457, 2012 early and severe polycystic kidney disease. J Am Soc Nephrol 22: 27. Schwarz JM, Rödelsperger C, Schuelke M, Seelow D: MutationTaster 2047–2056, 2011 evaluates disease-causing potential of sequence alterations. Nat 20. Rossetti S, Kubly VJ, Consugar MB, Hopp K, Roy S, Horsley SW, Methods 7: 575–576, 2010 Chauveau D, Rees L, Barratt TM, van’t Hoff WG, Niaudet P, Torres VE, Harris PC, Harris PC: Incompletely penetrant PKD1 alleles suggest a role for gene dosage in cyst initiation in polycystic kidney disease. Kidney Int 75: 848–855, 2009 See related editorial, “The Mutation, a Key Determinant of Phenotype in 21. Hopp K, Ward CJ, Hommerding CJ, Nasr SH, Tuan H-F, Gainullin VG, ADPKD,” on pages 868–870. Rossetti S, Torres VE, Harris PC: Functional polycystin-1 dosage gov- erns autosomal dominant polycystic kidney disease severity. JClinIn- This article contains supplemental material online at http://jasn.asnjournals. vest 122: 4257–4273, 2012 org/lookup/suppl/doi:10.1681/ASN.2012070650/-/DCSupplemental.

J Am Soc Nephrol 24: 1006–1013, 2013 PKD1 Mutation and Renal Outcome 1013 Supplemental materials, Table 1: Missense variants identified

Align GVGD Polyphen SIFT Mutation Taster Segregation Family Mutation Nucleotide Effect on Grantham Protein domain Exon affected/non Class Prediction Score Prediction Score Prediction Score Classification Reference number name change protein Distance affected Cystein-rich flanking PK10303 p.C51W c.153C>G p.Cys51Trp 1 2 / 0 215 C0 PoD 0.805 Deleterious 0.00 Polymorphism 0.817 Highly Likely Pathogenic Audrézet et al., 2012 region PK10642 p.I120T c.359T>C Ile120Thr LRR2 3 2 / 0 89 C0 B 0.03 Deleterious 0.01 Disease causing 0.987 Likely Pathogenic Audrézet et al., 2012 PK10242 p.C129R c.385T>C p.Cys129Arg LRR2 4 1 / 0 180 C0 B 0.050 Deleterious 0.00 Disease causing 0.983 Likely Pathogenic Audrézet et al., 2012 cysteine-rich flanking PK10526 p.C155Y c.464G>A p.Cys155Tyr 4 1 / 0 194 C0 B 0.195 Deleterious 0.00 Disease causing 0.986 Likely Pathogenic Audrézet et al., 2012 region PK10090 p.C183Y c.548G>A p.Cys183Tyr 5 1 / 0 194 C0 B 0.04 Deleterious 0.00 Disease causing 0.994 Likely Pathogenic Audrézet et al., 2012 PK10635 p.S225L c.674C>T p.Ser225Leu 5 1 / 0 145 C0 B 0.002 Deleterious 0.03 Polymorphism 0.848 Likely Pathogenic This Study PK10673 p.C232Y c.695G>A p.Cys232tyr 5 1 / 0 194 C0 B 0.003 Deleterious 0.00 Disease causing 0.994 Likely Pathogenic This Study PK10288 p.Y325C c.974A>G p.Tyr325cys PKDR1 5 2 / 0 194 C0 PD 0.998 Deleterious 0.00 Disease causing 0.999 Highly Likely Pathogenic Rossetti et al., 2007 PK10289 p.Y325C c.974A>G p.Tyr325cys PKDR1 5 2 / 0 194 C0 PD 0.998 Deleterious 0.00 Disease causing 0.999 Highly Likely Pathogenic Rossetti et al., 2007 PK10373 p.Y325C c.974A>G p.Tyr325cys PKDR1 5 2 / 0 194 C0 PD 0.998 Deleterious 0.00 Disease causing 0.999 Highly Likely Pathogenic Rossetti et al., 2007 PK10719 p.G515W c.1543G>T p.Gly515Trp 7 1 / 0 184 C0 PD 1 Deleterious 0.00 Disease causing 0.951 Likely Pathogenic This Study PK10653 p.H526D c.1576C>G p.His526Asp C-Lectin domain 7 1 / 0 81 C0 PD 0.999 Deleterious 0.00 Disease causing 0.732 Highly Likely Pathogenic Audrézet et al., 2012 PK10243 p.V577G c.1730T>G p.Val577Gly 9 1 / 1 109 C0 PoD 0.807 Deleterious 0.00 Disease causing 0.808 Likely Pathogenic Audrézet et al., 2012 PK10508 p.R611W c.1831C>T p.Arg611Trp 9 2 / 0 101 C0 PD 1 Deleterious 0.02 Disease causing 0.779 Likely Pathogenic Garcia-Gonzalez et al., 2007 PK10534 p.R611W c.1831C>T p.Arg611Trp 9 1 / 0 101 C0 PD 1 Deleterious 0.02 Disease causing 0.779 Likely Pathogenic Garcia-Gonzalez et al., 2007 PK10616 p.E685K c.2053G>A p.Glu685Lys 10 1 / 0 56 C0 PD 1 Deleterious 0.00 Disease causing 0.939 Likely Pathogenic Audrézet et al., 2012 PK10332 p.Y698D c.2092T>G p.Tyr698Asp 10 1 / 0 160 C0 PD 1 Deleterious 0.01 Disease causing 0.816 Likely Pathogenic Audrézet et al., 2012 PK10440 p.Y698D c.2092T>G p.Tyr698Asp 10 1 / 0 160 C0 PD 1 Deleterious 0.01 Disease causing 0.816 Likely Pathogenic Audrézet et al., 2012 PK10595 p.Y698D c.2092T>G p.Tyr698Asp 10 1 / 0 160 C0 PD 1 Deleterious 0.01 Disease causing 0.816 Likely Pathogenic Audrézet et al., 2012 PK10138 p.L727P c.2180T>C p.Leu727Pro 11 1 / 0 98 C0 PD 1 Deleterious 0.01 Disease causing 0.803 Highly Likely Pathogenic Rossetti et al., 2007 PK10284 p.L727P c.2180T>C p.Leu727Pro 11 1 / 0 98 C0 PD 1 Deleterious 0.01 Disease causing 0.803 Highly Likely Pathogenic Rossetti et al., 2007 PK10404 p.L727P c.2180T>C p.Leu727Pro 11 1 / 0 98 C0 PD 1 Deleterious 0.01 Disease causing 0.803 Highly Likely Pathogenic Rossetti et al., 2007 PK10530 p.L727P c.2180T>C p.Leu727Pro 11 1 / 0 98 C0 PD 1 Deleterious 0.01 Disease causing 0.803 Highly Likely Pathogenic Rossetti et al., 2007 PK10586 p.L727P c.2180T>C p.Leu727Pro 11 1 / 0 98 C0 PD 1 Deleterious 0.01 Disease causing 0.803 Highly Likely Pathogenic Rossetti et al., 2007 PK10623 p.L727P c.2180T>C p.Leu727Pro 11 1 / 0 98 C0 PD 1 Deleterious 0.01 Disease causing 0.803 Highly Likely Pathogenic Rossetti et al., 2007 PK10742 p.L727P c.2180T>C p.Leu727Pro 11 1 / 0 98 C0 PD 1 Deleterious 0.01 Disease causing 0.803 Highly Likely Pathogenic Rossetti et al., 2007 PK10205 p.V1206G c.3617T>G p.Val1206Gly PKDR5 15 1 / 0 109 C0 PoD 0.797 Deleterious 0.03 Polymorphism 0.998 Highly Likely Pathogenic Audrézet et al., 2012 PK10448 p.V1206G c.3617T>G p.Val1206Gly PKDR5 15 1 / 0 109 C0 PoD 0.797 Deleterious 0.03 Polymorphism 0.998 Highly Likely Pathogenic Audrézet et al., 2012 PK10579 p.V1206G c.3617T>G p.Val1206Gly PKDR5 15 1 / 0 109 C0 PoD 0.797 Deleterious 0.03 Polymorphism 0.998 Highly Likely Pathogenic Audrézet et al., 2012 PK10830 p.V1206G c.3617T>G p.Val1206Gly PKDR5 15 2 / 0 109 C0 PoD 0.797 Deleterious 0.03 Polymorphism 0.998 Highly Likely Pathogenic Audrézet et al., 2012 PK10581 p.I1241N c.3722T>A p.Ile1241Asn PKDR6 15 1 / 0 149 C0 PD 0.996 Deleterious 0.00 Disease causing 0.991 Likely Pathogenic Audrézet et al., 2012 PK10656 p.V1460G c.4379T>G p.Val1460Gly 15 2 / 0 109 C0 PD 1 Deleterious 0.00 Disease causing 0.897 Likely Pathogenic Audrézet et al., 2012 PK10633 p.P1727L c.5180C>T p.Pro1727Leu PKDR12 15 2 / 0 98 C0 PD 1 Deleterious 0.01 Disease causing 0.738 Highly Likely Pathogenic Audrézet et al., 2012 PK10812 p.P1727L c.5180C>T p.Pro1727Leu PKDR12 15 1 / 0 98 C0 PD 1 Deleterious 0.01 Disease causing 0.738 Highly Likely Pathogenic Audrézet et al., 2012 PK10785 p.C1979Y c.5936G>A p.Cys1979Tyr 15 1 / 0 194 C0 PoD 0.804 Deleterious 0.01 Disease causing 0.903 Likely Pathogenic This Study PK10747 p.G1987D c.5960G>A p.Gly1987Asp 15 1 / 0 94 C0 PD 1 Deleterious 0.00 Disease causing 0.993 Likely Pathogenic This Study PK10746 p.R1995C c.5983C>T p.Arg1995cys 15 1 / 0 80 C0 PD 1 Deleterious 0.01 Polymorphism 0.965 Likely Pathogenic This Study PK10707 p.S2000P c.5998T>C p.Ser2000Pro 15 1 / 0 74 C0 PD 0.999 Deleterious 0.05 Disease causing 0.67 Likely Pathogenic This Study PK10705 p.N2128H c.6382A>C p.Asn2128His 15 1 / 0 68 C0 PD 1 Deleterious 0.00 Disease causing 0.96 Likely Pathogenic This Study PK10576 p.R2166C c.6496C>T p.Arg2166cys 15 1 / 0 180 C0 PD 1 Deleterious 0.01 Disease causing 0.988 Likely Pathogenic Garcia-Gonzalez et al., 2007 PK10661 p.R2215W c.6643C>T p.Arg2215trp 15 1 / 0 101 C0 PD 0.999 Deleterious 0.00 Polymorphism 0.994 Likely Pathogenic This Study PK10720 p.L2216Q c.6647T>A p.Leu2216Gln 15 1 / 0 113 C0 PD 1 Deleterious 0.00 Disease causing 0.994 Likely Pathogenic This Study PK10614 p.Y2282C c.6845A>G p.Tyr2282Cys REJ 15 1 / 0 194 C0 PD 1 Deleterious 0.00 Disease causing 0.993 Likely Pathogenic This Study PK10256 p.W2298G c.6892T>G p.Trp2298Gly REJ 15 1 / 0 184 C0 PD 1 Deleterious 0.00 Disease causing 0.996 Likely Pathogenic Audrézet et al., 2012 PK10703 p.W2298G c.6892T>G p.Trp2298Gly REJ 15 1 / 0 184 C0 PD 1 Deleterious 0.00 Disease causing 0.996 Likely Pathogenic Audrézet et al., 2012 PK10583 p.R2329W c.6985C>T p.Arg2329Trp REJ 16 1 / 0 101 C0 PD 1 Deleterious 0.04 Polymorphism 0.978 Likely Pathogenic Perrichot et al., 2000 PK10316 p.S2372C c.7115C>G p.Ser2372Cys REJ 17 3 / 0 112 C0 PD 1 Deleterious 0.00 Disease causing 0.969 Highly Likely Pathogenic Audrézet et al., 2012 PK10136 p.Y2379C c.7136A>G p.Ser2379Cys REJ 17 2 / 0 194 C0 PD 1 Deleterious 0.00 Disease causing 0.993 Highly Likely Pathogenic Perrichot et al., 2000 PK10338 p.Y2379C c.7136A>G p.Ser2379Cys REJ 17 3 / 0 194 C0 PD 1 Deleterious 0.00 Disease causing 0.993 Highly Likely Pathogenic Perrichot et al., 2000 PK10400 p.G2391D c.7172G>A p.Gly2391Asp REJ 17 1 / 0 94 C0 PD 1 Deleterious 0.00 Disease causing 0.993 Likely Pathogenic Audrézet et al., 2012 PK10505 p.R2434W c.7300C>T p.Arg2434Trp REJ 18 1 / 0 101 C0 PD 1 Deleterious 0.00 Disease causing 0.992 Likely Pathogenic Audrézet et al., 2012 PK10706 p.R2434W c.7300C>T p.Arg2434Trp REJ 18 2 / 0 101 C0 PD 1 Deleterious 0.00 Disease causing 0.992 Likely Pathogenic Audrézet et al., 2012 PK10606 p.G2459D c.7376G>A p.Gly2459Asp REJ 18 1 / 0 94 C0 PD 1 Deleterious 0.00 Disease causing 0.993 Likely Pathogenic Audrézet et al., 2012 PK10441 p.C2476S c.7426T>A p.Cys2476Ser REJ 18 1 / 0 112 C0 PD 1 Deleterious 0.00 Disease causing 0.989 Likely Pathogenic Audrézet et al., 2012 PK10134 p.C2495R c.7483T>C p.Cys2495Arg REJ 18 1 / 0 180 C0 PD 1 Deleterious 0.00 Disease causing 0.990 Likely Pathogenic Audrézet et al., 2012 PK10296 p.R2516C c.7546C>T p.Arg2516Cys REJ 19 1 / 0 180 C0 PD 1 Deleterious 0.00 Disease causing 0.992 Highly Likely Pathogenic Rossetti et al., 2007 PK10831 p.R2516C c.7546C>T p.Arg2516Cys REJ 19 1 / 0 180 C0 PD 1 Deleterious 0.00 Disease causing 0.992 Highly Likely Pathogenic Rossetti et al., 2007 PK10225 p.R2767C c.8299C>T p.Arg2767Cys REJ 23 1 / 0 180 C0 PD 1 Deleterious 0.00 Disease causing 0.992 Highly Likely Pathogenic Garcia-Gonzalez et al., 2007 PK10442 p.R2767C c.8299C>T p.Arg2767Cys REJ 23 2 / 2 180 C0 PD 1 Deleterious 0 Disease causing 0.992 Highly Likely Pathogenic Garcia-Gonzalez et al., 2007 PK10189 p.R2767P c.8300G>C p.Arg2767Pro REJ 23 7 / 5 103 C0 PD 1 Deleterious 0.00 Disease causing 0.993 Highly Likely Pathogenic Audrézet et al., 2012 PK10385 p.N2770I c.8309A>T p.Asn2770Ile REJ 23 2 / 0 149 C0 PD 1 Deleterious 0.00 Disease causing 0.989 Highly Likely Pathogenic Audrézet et al., 2012 PK10130 p.E2771K c.8311G>A p.Glu2771Lys REJ 23 2 / 1 56 C0 PD 1 Deleterious 0.00 Disease causing 0.972 Highly Likely Pathogenic Rossetti et al., 2001 PK10366 p.E2771K c.8311G>A p.Glu2771Lys REJ 23 2 / 0 56 C0 PD 1 Deleterious 0.00 Disease causing 0.972 Highly Likely Pathogenic Rossetti et al., 2001 PK10546 p.E2771K c.8311G>A p.Glu2771Lys REJ 23 1 / 0 56 C0 PD 1 Deleterious 0.00 Disease causing 0.972 Highly Likely Pathogenic Rossetti et al., 2001 PK10551 p.E2771K c.8311G>A p.Glu2771Lys REJ 23 1 / 0 56 C0 PD 1 Deleterious 0.00 Disease causing 0.972 Highly Likely Pathogenic Rossetti et al., 2001 PK10650 p.E2771K c.8311G>A p.Glu2771Lys REJ 23 3 / 0 56 C0 PD 1 Deleterious 0.00 Disease causing 0.972 Highly Likely Pathogenic Rossetti et al., 2001 PK10528 p.L2816P c.8447T>C p.Leu2816Pro 23 1 / 0 98 C0 PD 0.997 Deleterious 0.00 Disease causing 0.901 Likely Pathogenic Rossetti et al., 2001 PK10675 p.T2846I c.8537C>T p.Thr2846Ile REJ 23 2 / 0 89 C0 PD 1 Deleterious 0.00 Disease causing 0.947 Likely Pathogenic This Study PK10708 p.F2978C c.8933T>G p.Phe2978Cys 24 1 / 0 205 C0 PD 1 Deleterious 0.00 Disease causing 0.997 Likely Pathogenic This Study PK10529 p.E3121K c.9361G>A p.Glu3121Lys 26 1 / 0 56 C0 PD 1 Deleterious 0.00 Disease causing 0.992 Likely Pathogenic This Study PK10496 p.T3126I c.9377C>T p.Thr3126Ile 26 1 / 0 89 C0 PD 1 Deleterious 0.00 Disease causing 0.992 Highly Likely Pathogenic Audrézet et al., 2012 PK10524 p.T3126I c.9377C>T p.Thr3126Ile 26 2 / 0 89 C0 PD 1 Deleterious 0.00 Disease causing 0.992 Highly Likely Pathogenic Audrézet et al., 2012 PK10748 p.S3132L c.9395C>T p.Ser3132Leu 26 1 / 0 145 C0 PD 0.994 Deleterious 0.00 Disease causing 0.983 Likely Pathogenic This Study PK10302 p.G3144W c.9430G>T p.Gly3144Trp 27 2 / 0 184 C0 PD 1 Deleterious 0.00 Disease causing 0.999 Highly Likely Pathogenic Audrézet et al., 2012 PK10413 p.R3162L c.9485G>T p.Arg3162Leu 27 1 / 0 102 C0 PD 1 Deleterious 0.00 Disease causing 0.998 Likely Pathogenic This Study PK10654 p.K3181N c.9543G>C p.Lys3181Asn 27 3 / 1 94 C0 PD 1 Deleterious O.00 Disease causing 0.926 Highly Likely Pathogenic Audrézet et al., 2012 PK10828 p.P3193S c.9577C>T p.Pro3193Ser 28 1 / 0 74 C0 PD 1 Deleterious 0.00 Disease causing 0.998 Likely Pathogenic This Study PK10038 p.P3193L c.9578C>T p.Pro3193Leu 28 6 / 1 98 C0 PD 1 Deleterious 0.00 Disease causing 0.999 Highly Likely Pathogenic Perrichot et al., 2000 PK10362 p.R3277C c.9829C>T p.Arg3277Cys 29 1 / 0 180 C0 PD 1 Deleterious 0.00 Disease causing 0.994 Highly Likely Pathogenic Rossetti et al., 2009 PK10655 p.G3300R c.9898G>A p.Gly3300Arg 29 1 / 0 125 C0 PD 0.972 Deleterious 0.00 Disease causing 0.939 Likely Pathogenic This Study PK10580 p.R3348Q c.10043G>A p.Arg3348Gln 30 1 / 0 43 C0 PD 1 Deleterious 0.00 Disease causing 0.969 Likely Pathogenic Bataille et al., 2011 PK10173 p.G3651S c.10951G>A p.Gly3651Ser 37 2 / 0 56 C55 PD 0,99 Deleterious 0.00 Disease causing 0.973 Highly Likely Pathogenic Zhang et al., 2005 PK10347 p.G3651S c.10951G>A p.Gly3651Ser 37 1 / 0 56 C55 PD 0,99 Deleterious 0.00 Disease causing 0.973 Highly Likely Pathogenic Zhang et al., 2005 PK10578 p.G3651S c.10951G>A p.Gly3651Ser 37 1 / 0 56 C55 PD 0,99 Deleterious 0.00 Disease causing 0.973 Highly Likely Pathogenic Zhang et al., 2005 PK10619 p.G3651S c.10951G>A p.Gly3651Ser 37 1 / 0 56 C55 PD 0,99 Deleterious 0.00 Disease causing 0.973 Highly Likely Pathogenic Zhang et al., 2005 PK10326 p.A3653V c.10958C>T p.Ala3653Val 37 2 / 0 64 C0 PD 0.997 Deleterious 0.02 Disease causing 0.942 Highly Likely Pathogenic Audrézet et al., 2012 PK10337 p.A3653V c.10958C>T p.Ala3653Val 37 1 / 0 64 C0 PD 0.997 Deleterious 0.02 Disease causing 0.942 Highly Likely Pathogenic Audrézet et al., 2012 PK10584 p.V3735D c.11204T>A p.Val3735Asp 39 1 / 0 152 C0 PD 0.996 Deleterious 0.01 Polymorphism 0.972 Likely Pathogenic This Study PK10663 p.R3750Q c.11249G>A p.Arg3750Gln 39 2 / 0 43 C0 PD 0.997 Deleterious 0.00 Disease causing 0.991 Likely Pathogenic Audrézet et al., 2012 PK10196 p.Q3751K c.11251C>A p.Gln3751Lys 39 4 / 0 53 C45 PD 0,999 Deleterious 0 Disease causing 0,995 Likely Pathogenic Audrézet et al., 2012 PK10339 p.R3753W c.11257C>T p.Arg3753Trp 39 2 / 0 101 C35 PD 1 Deleterious 0.00 Disease causing 0.885 Highly Likely Pathogenic Kim et al., 2000 PK10608 p.R3753W c.11257C>T p.Arg3753Trp 39 1 / 0 101 C35 PD 1 Deleterious 0.00 Disease causing 0.885 Highly Likely Pathogenic Kim et al., 2000 PK10818 p.R3753Q c.11258G>A p.Arg3753Gln 39 1 / 0 43 C35 PD 1 Deleterious 0.02 Disease causing 0.552 Highly Likely Pathogenic Kim et al., 2000 PK10462 p.L3823P c.11468T>C p.Leu3823Pro 41 1 / 0 98 C0 PD 1 Deleterious 0.00 Disease causing 0.992 Likely Pathogenic Audrézet et al., 2012 PK10319 p.E3872Q c.11614G>C p.Glu3872Gln 42 2 / 0 29 C0 PD 0.995 Deleterious 0.00 Disease causing 0.913 Highly Likely Pathogenic Audrézet et al., 2012 PK10327 p.E3872Q c.11614G>C p.Glu3872Gln 42 1 / 0 29 C0 PD 0.995 Deleterious 0.00 Disease causing 0.913 Highly Likely Pathogenic Audrézet et al., 2012 PK10692 p.S3904W c.11711C>G p.Ser3904Trp 42 1 / 0 177 C0 PD 0.999 Deleterious 0.02 Polymorphism 0.962 Likely Pathogenic This Study PK10285 p.R4150C c.12448C>T p.Arg4150Cys 46 1 / 0 180 C15 PD 1 Deleterious 0.00 Disease causing 0.982 Highly Likely Pathogenic Garcia-Gonzalez et al., 2007 PK10444 p.R4150C c.12448C>T p.Arg4150Cys 46 2 / 0 180 C15 PD 1 Deleterious 0.00 Disease causing 0.982 Highly Likely Pathogenic Garcia-Gonzalez et al., 2007 PK10575 p.R4150C c.12448C>T p.Arg4150Cys 46 2 / 0 180 C15 PD 1 Deleterious 0.00 Disease causing 0.982 Highly Likely Pathogenic Garcia-Gonzalez et al., 2007 PK10604 p.R4276W c.12826C>T p.Arg4276Trp 46 1 / 0 101 C0 PD 0.999 Deleterious 0.00 Polymorphism 0.882 Highly Likely Pathogenic Badenas et al., 1999 PK10609 p.R4276W c.12826C>T p.Arg4276Trp 46 1 / 1 101 C0 PD 0.999 Deleterious 0.00 Polymorphism 0.882 Highly Likely Pathogenic Badenas et al., 1999 PK10620 p.R4276W c.12826C>T p.Arg4276Trp 46 2 / 0 101 C0 PD 0.999 Deleterious 0.00 Polymorphism 0.882 Highly Likely Pathogenic Badenas et al., 1999 PK10648 p.R4276W c.12826C>T p.Arg4276Trp 46 1 / 0 101 C0 PD 0.999 Deleterious 0.00 Polymorphism 0.882 Highly Likely Pathogenic Badenas et al., 1999

References :

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Supplemental materials, Table 2: Details of the Kaplan-Meier analysis results

Median Mutational Number of Number of 75% 25% Gene Gender ages at P value Group patients events quartile quartile ESRD All 571 241 50.5 58.1 68.4 Total Male 254 118 49.2 56.1 65.5 P<0.05 Female 317 123 52.5 59.5 70.3 All 388 191 49.2 55.6 61.7 Truncating PKD1 Male 173 94 48.3 53.2 58.7 mutations P<0.001 Female 215 97 50.9 58.1 65.2 Non- All 183 50 56.0 67.9 NA truncating Male 81 24 54.5 68.4 NA ns mutations Female 102 81 56.2 63.9 NA All 133 26 66.6 79.7 NA PKD2 Total Male 50 10 66.6 79.7 NA ns Female 83 16 66.4 NA NA