Collagen IV Gene Mutations in Adults With Bilateral Renal Cysts and CKD (2019)

Bilateral renal cystic disease presenting as chronic kidney disease (CKD) in adults is most commonly due to autosomal dominant polycystic kidney disease (ADPKD). Genetic investigation of ADPKD cohorts identifies the underlying PKD1 (77%) or PKD2 mutation (15%) and up to 8% of cases remain as “no PKD mutation detected” (NMD).1Hwang Y.H. Conklin J. Chan W. et al.Refining genotype-phenotype correlation in autosomal dominant polycystic kidney disease.J Am Soc Nephrol. 2016; 27: 1861-1868Crossref PubMed Scopus (89) Google Scholar Molecular characterization of NMD-ADPKD cases by genome level sequencing such as whole exome sequencing (WES) may identify individuals misclassified as ADPKD based on clinical and imaging criteria. For example, HANAC (hereditary angiopathy, nephropathy, aneurysms, muscle cramps) syndrome caused by heterozygous COL4A1 mutations can cause bilateral kidney cysts that may phenocopy ADPKD.2Plaisier E. Gribouval O. Alamowitch S. et al.COL4A1 mutations and hereditary angiopathy, nephropathy, aneurysms, and muscle cramps.N Engl J Med. 2007; 357: 2687-2695Crossref PubMed Scopus (256) Google Scholar, 3Gulati A. Bae K.T. Somlo S. Watnick T. Genomic analysis to avoid misdiagnosis of adults with bilateral renal cysts.Ann Intern Med. 2018; 169: 130-131Crossref PubMed Scopus (5) Google Scholar, 4Cornec-Le Gall E. Chebib F.T. Madsen C.D. et al.The value of genetic testing in polycystic kidney diseases illustrated by a family with PKD2 and COL4A1 mutations.Am J Kidney Dis. 2018; 72: 302-308Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar Thin glomerular basement membrane (TBM) disease usually presents with persistent often familial microscopic hematuria with or without CKD progression. A few reports mention the finding of kidney cysts in patients with TBM disease but this association remains largely underrecognized.5Pierides A. Voskarides K. Athanasiou Y. et al.Clinico-pathological correlations in 127 patients in 11 large pedigrees, segregating one of three heterozygous mutations in the COL4A3/ COL4A4 genes associated with familial haematuria and significant late progression to proteinuria and chronic kidney disease from focal segmental glomerulosclerosis.Nephrol Dial Transplant. 2009; 24: 2721-2729Crossref PubMed Scopus (100) Google Scholar,6Sevillano A.M. Gutierrez E. Morales E. et al.Multiple kidney cysts in thin basement membrane disease with proteinuria and kidney function impairment.Clin Kidney J. 2014; 7: 251-256Crossref PubMed Scopus (10) Google Scholar Because TBM disease is attributed to heterozygous mutations in COL4A3 and COL4A4,5Pierides A. Voskarides K. Athanasiou Y. et al.Clinico-pathological correlations in 127 patients in 11 large pedigrees, segregating one of three heterozygous mutations in the COL4A3/ COL4A4 genes associated with familial haematuria and significant late progression to proteinuria and chronic kidney disease from focal segmental glomerulosclerosis.Nephrol Dial Transplant. 2009; 24: 2721-2729Crossref PubMed Scopus (100) Google Scholar we hypothesize that these cysts may be an additional incompletely penetrant consequence of a pathogenic mutation in these type IV collagen proteins. Heterozygous mutations in COL4A3 or COL4A4 may thus explain the presence of kidney cysts not due to ADPKD. We report the WES-based genetic investigation identifying type IV collagen mutations in patients with bilateral kidney cysts who were either NMD-ADPKD or were known to carry a diagnosis of TBM disease. A causal effect of these type IV collagen mutations or their modifier role in the progression of a cystic kidney phenotype remains to be established. We performed WES on 18 patients with findings of multiple bilateral kidney cysts that were either classified as NMD-ADPKD (13 patients) or carried a diagnosis of TBM disease (5 patients). The 13 patients with NMD-ADPKD were part of National Institutes of Health–sponsored longitudinal ADPKD studies and were known to be negative for underlying mutations in PKD1 or PKD2 (Supplementary MethodsS1–S17). Rare variants with an ethnicity-specific population minor allele frequency cutoff of 0.01% for heterozygous variants and 0.1% for recessive variants qualified as “pathogenic mutations” if they met the criteria of a predicted loss of function or as “likely pathogenic mutations” if they were missense variants deemed deleterious on bioinformatics predictions of MetaSVM and Mutation Taster (Supplementary Methods). WES identified heterozygous pathogenic COL4A4 mutations in 1 patient with NMD-ADPKD and 3 patients with TBM disease and cystic kidneys (Table 13Gulati A. Bae K.T. Somlo S. Watnick T. Genomic analysis to avoid misdiagnosis of adults with bilateral renal cysts.Ann Intern Med. 2018; 169: 130-131Crossref PubMed Scopus (5) Google Scholar,4Cornec-Le Gall E. Chebib F.T. Madsen C.D. et al.The value of genetic testing in polycystic kidney diseases illustrated by a family with PKD2 and COL4A1 mutations.Am J Kidney Dis. 2018; 72: 302-308Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar,S1,S3,S17,S18). In addition, 1 female patient with TBM disease and kidney cysts was a carrier for a COL4A5 likely pathogenic missense variant (Table 1). Finally, heterozygous pathogenic or likely pathogenic COL4A1 mutations that can cause kidney cysts as part of HANAC syndrome were present in 3 patients classified as NMD-ADPKD, 2 of whom have been previously reported in individual de-identified case reports.3Gulati A. Bae K.T. Somlo S. Watnick T. Genomic analysis to avoid misdiagnosis of adults with bilateral renal cysts.Ann Intern Med. 2018; 169: 130-131Crossref PubMed Scopus (5) Google Scholar,4Cornec-Le Gall E. Chebib F.T. Madsen C.D. et al.The value of genetic testing in polycystic kidney diseases illustrated by a family with PKD2 and COL4A1 mutations.Am J Kidney Dis. 2018; 72: 302-308Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar No mutations were found in other cystic kidney disease genes, including GANAB, DNAJB11, or in a panel of genes associated with polycystic liver disease or with monogenic nephropathy or CKD or focal segmental glomerulosclerosis (Supplementary Methods). There were no COL4A3 mutations in either patients with NMD-ADPKD or patients with TBM. In aggregate, heterozygous pathogenic or likely pathogenic mutations in COL4A1, COL4A4, or COL4A5 were found in 4 of the 13 NMD-ADPKD cases and 4 of the 5 TBM cases with bilateral kidney cysts.Table 1Clinical characteristics and type IV collagen gene mutations in patients with bilateral kidney cysts without PKD1 or PKD2 mutationsPatient no.CohortAgeaAge (yr) at clinical/imaging or histopathological diagnosis of ADPKD or TBM disease. (yr)/sex (ethnicity)eGFRbModification of Diet in Renal Disease eGFR in ml/min per 1.73 m2 or CKD stage recorded at the time of inclusion (and at 4-yr follow-up into ADPKD cohort) or at diagnosis of TBM./CKD stage/severity classcSeverity class–based age and height-adjusted total kidney volumeS3 at inclusion into CRISP study.S1Family historyType IV collagen gene mutation and predicted protein changeGenetic diagnosisType IV collagen variant detailsVariant typeMAFdPopulation minor allele frequency as listed in the genome aggregation database (http://gnomad.broadinstitute.org).Prior reportCOL4A4 variants1NMD-ADPKD25/M (Caucasian)eGFR:125 (85)/CKD stage 1(2)/class ICNot availableCOL4A4: exon28: c. G2383A: p. G795RCOL4A4-related renal diseaseSplice site; exon 28 skipping by minigene assay1 × 10–6None2TBM28/M (Caucasian)CKD stage 3ESRD in fatherCOL4A4:exon46:c.4503dupA:p.A1502Sfs*17COL4A4-related renal diseaseFrameshift and premature truncationNovelNone3TBM42/M (Caucasian)CKD stage 3Microhematuria in father; siblingCOL4A4: exon24: c.1697–1G>CCOL4A4-related renal diseaseCanonical splice site variantNot listedOne kindred with familial hematuriaS174TBM52/F (Caucasian)CKD stage 4Microhematuria in father; siblingCOL4A4: exon 39: c.3704delC: p. P1235Qfs*53COL4A4-related renal diseaseFrameshift and premature truncationNovelNoneCOL4A5 variant5TBM49/F (Caucasian)CKD stage 2Not availableCOL4A5: exon16:c.C899T: p. P300LCOL4A5 carrierMissense, likely pathogenic1 × 10–5NoneeThis particular variant has not been reported in the Alport syndrome database (http://www.arup.utah.edu). Proline substitutions at this third position of tripeptide repeating unit (G-X-Y) in the collagen triple-helical domain undergo post-translational modification and there are 5 proline substitutions listed as pathogenic in the Alport database.COL4A1 variant6NMD-ADPKDfTwo additional patients from this 17-patient NMD-ADPKD cohort have been previously reported as individual de-identified cases with HANAC syndrome; variant (COL4A1: exon25:c.C1612T: p. R538W)3; variant (COL4A1: exon13:c.C739T: p. Q247X).441/M (Caucasian)eGFR:77 (78)/ CKD stage 2 (2)/ class IBNot availableCOL4A1: exon31:c.C2351T: p. P784LHANAC-like syndromeMissense, likely pathogenic1 × 10–5NonegProline-to-lysine substitution at another residue 352 in COL4A1 is previously reported as pathogenic and tested in a cell culture–based secretion assay.S18CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; F, female; HANAC, hereditary angiopathy, nephropathy, aneurysms, muscle cramps; M, male; MAF, minor allele frequency; NMD-ADPKD, no PKD mutation detected–autosomal dominant polycystic kidney disease; TBM, thin glomerular basement membrane.a Age (yr) at clinical/imaging or histopathological diagnosis of ADPKD or TBM disease.b Modification of Diet in Renal Disease eGFR in ml/min per 1.73 m2 or CKD stage recorded at the time of inclusion (and at 4-yr follow-up into ADPKD cohort) or at diagnosis of TBM.c Severity class–based age and height-adjusted total kidney volumeS3 at inclusion into CRISP study.S1d Population minor allele frequency as listed in the genome aggregation database (http://gnomad.broadinstitute.org).e This particular variant has not been reported in the Alport syndrome database (http://www.arup.utah.edu). Proline substitutions at this third position of tripeptide repeating unit (G-X-Y) in the collagen triple-helical domain undergo post-translational modification and there are 5 proline substitutions listed as pathogenic in the Alport database.f Two additional patients from this 17-patient NMD-ADPKD cohort have been previously reported as individual de-identified cases with HANAC syndrome; variant (COL4A1: exon25:c.C1612T: p. R538W)3Gulati A. Bae K.T. Somlo S. Watnick T. Genomic analysis to avoid misdiagnosis of adults with bilateral renal cysts.Ann Intern Med. 2018; 169: 130-131Crossref PubMed Scopus (5) Google Scholar; variant (COL4A1: exon13:c.C739T: p. Q247X).4Cornec-Le Gall E. Chebib F.T. Madsen C.D. et al.The value of genetic testing in polycystic kidney diseases illustrated by a family with PKD2 and COL4A1 mutations.Am J Kidney Dis. 2018; 72: 302-308Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholarg Proline-to-lysine substitution at another residue 352 in COL4A1 is previously reported as pathogenic and tested in a cell culture–based secretion assay.S18 Open table in a new tab CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; F, female; HANAC, hereditary angiopathy, nephropathy, aneurysms, muscle cramps; M, male; MAF, minor allele frequency; NMD-ADPKD, no PKD mutation detected–autosomal dominant polycystic kidney disease; TBM, thin glomerular basement membrane. Patient 1 (Table 1) from the NMD-ADPKD group showed multiple bilateral kidney cysts and a relatively well-preserved kidney contour with little increase in total kidney volume (TKV) over time. The baseline height-adjusted TKV of 422 ml/m was stable at 461 ml/m at the time of 4-year follow-up (Figure 1a). WES showed a COL4A4 variant that was predicted to result in a glycine to arginine amino acid change at position 795. This variant is a guanine to adenine nucleotide change at the last base of exon 28, and in silico splice site prediction algorithms predicted the potential loss of the splice donor site for exon 28. We investigated this variant using an in vitro minigene splice assay (Supplementary Methods) and found that it resulted in aberrant splicing by this assay. Reverse-transcription polymerase chain reaction on the mRNA isolated from human embryonic kidney cells transfected with COL4A4 minigene carrying this patient’s mutation showed altered splicing and complete skipping of exon 28 in addition to inefficient splicing resulting in significant persistence of unspliced transcript (Figure 1b and c). Normal splicing pattern was observed with the expression of the wild-type COL4A4 minigene in this assay. WES analysis on 3 patients presenting with microscopic hematuria and TBM disease showed loss of function heterozygous COL4A4 mutations (Table 1, patients 2–4). Kidney biopsy showed TBM in patient 2 and focal segmental glomerulosclerosis in patient 4 and was not performed in patient 3. Imaging in all 3 individuals showed bilateral multiple well-formed kidney cysts without much increase in kidney size with right and left kidney lengths recorded as 11.8, 11.3 cm; 16.7, 17.0 cm; and 11.0, 10.5 cm for patients 2, 3, and 4, respectively. (Figure 2a–c). Patient 3 had large cysts located at the renal pole of each kidney contributing to the increased sagittal renal dimension. The clinical course, but not the genetic analysis, of patient 2 and patient 3 has been previously reported.6Sevillano A.M. Gutierrez E. Morales E. et al.Multiple kidney cysts in thin basement membrane disease with proteinuria and kidney function impairment.Clin Kidney J. 2014; 7: 251-256Crossref PubMed Scopus (10) Google Scholar A female patient (Table 1, patient 5) with persistent microscopic hematuria and TBM disease on kidney biopsy in addition to the imaging finding of bilateral kidney cysts with right and left kidney lengths of 10.5 and 9.5 cm each (Figure 2d) was a carrier for a rare COL4A5 variant that meets pathogenicity criteria (Supplementary Methods) and results in the substitution of a well-conserved proline to lysine at amino acid position 300 in the collagen triple-helical domain. Two patients from the NMD-ADPKD group have been previously reported to carry HANAC syndrome causing COL4A1 mutations.3Gulati A. Bae K.T. Somlo S. Watnick T. Genomic analysis to avoid misdiagnosis of adults with bilateral renal cysts.Ann Intern Med. 2018; 169: 130-131Crossref PubMed Scopus (5) Google Scholar,4Cornec-Le Gall E. Chebib F.T. Madsen C.D. et al.The value of genetic testing in polycystic kidney diseases illustrated by a family with PKD2 and COL4A1 mutations.Am J Kidney Dis. 2018; 72: 302-308Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar In the current study, we found a third NMD-ADPKD patient with a heterozygous COL4A1 missense mutation that results in a proline-to-lysine substitution that met criteria for being likely pathogenic (Table 1, patient 6; Supplementary Methods). A review of imaging for this patient after the molecular finding of a COL4A1 mutation showed minimally enlarged kidneys with height-adjusted TKV of 284 and 294 ml/m at enrollment and 4-year follow-up, respectively, with fewer cysts and well-preserved normal-appearing intervening renal parenchyma consistent with those seen in HANAC syndrome rather than ADPKD (Figure 2e). The 13-patient NMD-ADPKD cohort is composed of 9 Caucasian patients, 1 of whom had a COL4A4 mutation and 2 had COL4A1 mutations. Non-Caucasian patients with NMD-ADPKD include 3 African American individuals of whom 1 carries a COL4A1 mutation. The final individual with NMD-ADPKD has Mexican ethnicity. The COL4A4/COL4A5/COL4A1 mutations in the 161 PKD gene mutation–defined ADPKD cohort (Table 2S1,S3) were all present in the 140 Caucasian patients and none in the 16 African American, 4 Mexican, and 1 Asian individual.Table 2Type IV collagen gene mutations in 161 patients with ADPKD with an underlying PKD1 or PKD2 mutationPatient IDAgeaAge at ADPKD study entry. (yr)/sex (ethnicity)eGFRbModification of Diet in Renal Disease eGFR in ml/min per 1.73 m2 or CKD stage recorded at the time of inclusion (and at 4-yr follow-up into ADPKD cohort)./CKD stage/severity classcSeverity class–based age and height-adjusted total kidney volumeS3 at inclusion into CRISP study.S1ADPKD gene mutationType IV collagen gene variantType IV collagen variant detailsVariant typeMAFdPopulation minor allele frequency as listed in the genome aggregation database (http://gnomad.broadinstitute.org).COL4A4 variantCR89B334/M (Caucasian)100 (90)/CKD stage 1/class 1CPKD2 splice site exon12: c.2358+1G>ACOL4A4: exon46:c.C4513T: p. Q1505XPremature truncationNovelCOL4A1 variantsCR89C220/M (Caucasian)100 (79)/CKD stage 1(2)/class 1BPKD2 frameshift deletion exon1: c.424delG:p. G142fsCOL4A1: exon42: c. A3623G: p. E1208GMissense, likely pathogenic10–6CR90D1019/M (Caucasian)186 (113)/CKD stage 1(1)/class 1CPKD1 frameshift insertion exon 11: 2477_2478insCGGGT:Ile827fs72XCOL4A1: exon27:c.C1933T: p. P645SMissense, likely pathogenicNovelADPKD, autosomal dominant polycystic kidney disease; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; M, male; MAF, minor allele frequency.a Age at ADPKD study entry.b Modification of Diet in Renal Disease eGFR in ml/min per 1.73 m2 or CKD stage recorded at the time of inclusion (and at 4-yr follow-up into ADPKD cohort).c Severity class–based age and height-adjusted total kidney volumeS3 at inclusion into CRISP study.S1d Population minor allele frequency as listed in the genome aggregation database (http://gnomad.broadinstitute.org). Open table in a new tab ADPKD, autosomal dominant polycystic kidney disease; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; M, male; MAF, minor allele frequency. We tested and found no significant difference in the total burden of COL4A4/COL4A5/COL4A1 mutations in the 149 Caucasian patients from the ADPKD cohort that included 9 NMD patients and 140 patients with PKD mutation ADPKD versus those in the European (non-Finnish) individuals in the gnomAD v2.1.1 database: 6 of 292 versus 665 of 62,183 alleles, respectively (P = 0.14). However, in a subgroup analysis, we found of these mutations in 9 NMD-ADPKD patients of Caucasian with 140 PKD mutation–defined Caucasian patients with 3 of versus 3 of had type IV collagen respectively (P = or to the European (non-Finnish) individuals in the gnomAD v2.1.1 database: 3 of versus 665 of 62,183 in gnomAD (P = For value we deleterious of the total tested (Supplementary Methods). in type IV collagen that are an of the glomerular and basement in the kidney a of to kidney disease. of type IV collagen by their genes a with the and being the most in the human Y. et expression of type IV collagen in and Alport syndrome J Full Text Full Text PDF PubMed Scopus Google Scholar recessive or mutations in COL4A3 or COL4A4 or a for COL4A5 results in Alport syndrome with an nephropathy, the clinical of heterozygous COL4A3 or COL4A4 mutations or a COL4A5 female carrier is and Heterozygous COL4A3 or COL4A4 mutations may present with TBM disease. of Alport syndrome most commonly microscopic hematuria and an but of CKD progression. may of glomerular basement membrane and over et of the and in of and autosomal recessive J Kidney Dis. Full Text Full Text PDF PubMed Scopus Google Scholar The finding of kidney cysts has been in clinical reports of TBM A. Voskarides K. Athanasiou Y. et al.Clinico-pathological correlations in 127 patients in 11 large pedigrees, segregating one of three heterozygous mutations in the COL4A3/ COL4A4 genes associated with familial haematuria and significant late progression to proteinuria and chronic kidney disease from focal segmental glomerulosclerosis.Nephrol Dial Transplant. 2009; 24: 2721-2729Crossref PubMed Scopus (100) Google Scholar,6Sevillano A.M. Gutierrez E. Morales E. et al.Multiple kidney cysts in thin basement membrane disease with proteinuria and kidney function impairment.Clin Kidney J. 2014; 7: 251-256Crossref PubMed Scopus (10) Google Scholar Genetic investigation of these cases has been and none mutations in genes known to cause a polycystic kidney et A. Voskarides K. Athanasiou Y. et al.Clinico-pathological correlations in 127 patients in 11 large pedigrees, segregating one of three heterozygous mutations in the COL4A3/ COL4A4 genes associated with familial haematuria and significant late progression to proteinuria and chronic kidney disease from focal segmental glomerulosclerosis.Nephrol Dial Transplant. 2009; 24: 2721-2729Crossref PubMed Scopus (100) Google Scholar report multiple renal cysts in 4 presenting with persistent hematuria and focal segmental glomerulosclerosis with underlying heterozygous glycine substitution mutations in et A.M. Gutierrez E. Morales E. et al.Multiple kidney cysts in thin basement membrane disease with proteinuria and kidney function impairment.Clin Kidney J. 2014; 7: 251-256Crossref PubMed Scopus (10) Google Scholar bilateral kidney cysts in 9 of the 16 patients with TBM disease and no kidney cysts were reported in the 16 patients with TBM without none of the patients were Two patients with TBM with renal cystic disease from this are included in present report (Table 1, patients 2 and is to the finding of multiple kidney cysts in a female patient with the rare deletion syndrome that deletion of COL4A4 and COL4A3 were to be the most for the E. J. et with multiple renal cysts and J PubMed Scopus Google Scholar the cystic kidney phenotype may not the clinical of type IV collagen TBM this finding the likely association type IV collagen mutations and renal The that all 3 patients with TBM with kidney cysts had CKD, and the previously reported association of proteinuria with cystic kidneys in TBM disease by et A.M. Gutierrez E. Morales E. et al.Multiple kidney cysts in thin basement membrane disease with proteinuria and kidney function impairment.Clin Kidney J. 2014; 7: 251-256Crossref PubMed Scopus (10) Google Scholar is for cystic kidney phenotype as a of CKD progression and in TBM disease. is likely that collagen IV kidney cysts have a glomerular or a on the For example, the is the most of basement in the renal the is in the glomerular basement membrane with Y. et expression of type IV collagen in and Alport syndrome J Full Text Full Text PDF PubMed Scopus Google Scholar We found heterozygous loss of function COL4A4 mutations in 4 patients with CKD and bilateral multiple kidney cysts in the of other pathogenic mutation in genes known to with cystic The association of pathogenic COL4A4 mutations with renal cystic or is for The clinical is to of these patients as ADPKD, is the most genetic cause of polycystic kidneys and CKD in the renal imaging findings of patient 1 who was misclassified as ADPKD showed a and kidney progression than be in ADPKD due to either PKD1 or PKD2 mutation. TKV as a of kidney size was not for the patients with TBM, none of had a increase in kidney thus the imaging findings from that of a ADPKD. Because genetic testing for diagnosis is for a of ADPKD cases in clinical it may be to that or cases of ADPKD may be likely to has been previously renal cysts are a of HANAC syndrome caused by heterozygous mutations in COL4A1 for the that is in the renal and embryonic kidney basement E. Gribouval O. Alamowitch S. et al.COL4A1 mutations and hereditary angiopathy, nephropathy, aneurysms, and muscle cramps.N Engl J Med. 2007; 357: 2687-2695Crossref PubMed Scopus (256) Google Scholar Patient 6 in the present report in addition to the reported patients with HANAC syndrome from the NMD-ADPKD group that HANAC syndrome may phenocopy ADPKD. The of type IV collagen mutations in patients with cystic kidneys may thus an molecular for to of and for inclusion of these patients into clinical analysis an association type IV collagen mutations and kidney cysts of a causal in cohorts and investigation for underlying of rare variant pathogenicity included in silico predictions and a minigene assay that a variant listed as missense in the gnomAD database as a splice site variant based on an in vitro splice assay. analysis showed no significant of type IV collagen mutations in the ADPKD cohort NMD and patients) with population cohort are for there is a significant of type IV collagen mutations in patients with NMD-ADPKD with patients with ADPKD with an underlying PKD1 or PKD2 mutation or to population in the gnomAD ADPKD cohorts to be investigated to if patients with NMD-ADPKD to the of type IV collagen mutations in such The finding of a few pathogenic collagen IV gene variants in the PKD mutation–defined ADPKD group and the association of kidney cysts with collagen IV mutations is for these a gene modifier role in ADPKD that has been known for in carrying the PKD1 or PKD2 mutation. of much ADPKD cohorts of disease be for testing this is a and for previously reported have been in the the other no The the patients for their in the The are for the from the for Institutes of This was by Kidney Disease to and and and for the Kidney at and to and of The and from the CRISP and study by the CRISP and and by the National of and and Kidney were by the This was not in with of the CRISP study and not the or of the CRISP study, the or the with Supplementary