Matching clinical and genetic diagnoses in autosomal dominant polycystic kidney disease reveals novel phenocopies and potential candidate genes.
ADPKD
ALG9
Birt–Hogg–Dubé syndrome
FLCN
PKHD1
Journal
Genetics in medicine : official journal of the American College of Medical Genetics
ISSN: 1530-0366
Titre abrégé: Genet Med
Pays: United States
ID NLM: 9815831
Informations de publication
Date de publication:
08 2020
08 2020
Historique:
received:
27
12
2019
accepted:
17
04
2020
revised:
07
04
2020
pubmed:
14
5
2020
medline:
28
4
2021
entrez:
14
5
2020
Statut:
ppublish
Résumé
Autosomal dominant polycystic kidney disease (ADPKD) represents the most common hereditary nephropathy. Despite growing evidence for genetic heterogeneity, ADPKD diagnosis is still primarily based upon clinical imaging criteria established before discovery of additional PKD genes. This study aimed at assessing the diagnostic value of genetic verification in clinical ADPKD. In this prospective, diagnostic trial, 100 families with clinically diagnosed ADPKD were analyzed by PKD gene panel and multiplex ligation-dependent probe amplification (MLPA); exome sequencing (ES) was performed in panel/MLPA-negative families. Diagnostic PKD1/2 variants were identified in 81 families (81%), 70 of which in PKD1 and 11 in PKD2. PKD1 variants of unknown significance were detected in another 9 families (9%). Renal survival was significantly worse upon PKD1 truncation versus nontruncation and PKD2 alteration. Ten percent of the cohort were PKD1/2-negative, revealing alternative genetic diagnoses such as autosomal recessive PKD, Birt-Hogg-Dubé syndrome, and ALG9-associated PKD. In addition, among unsolved cases, ES yielded potential novel PKD candidates. By illustrating vast genetic heterogeneity, this study demonstrates the value of genetic testing in a real-world PKD cohort by diagnostic verification, falsification, and disease prediction. In the era of specific treatment for fast progressive ADPKD, genetic confirmation should form the basis of personalized patient care.
Identifiants
pubmed: 32398770
doi: 10.1038/s41436-020-0816-3
pii: S1098-3600(21)00697-3
pmc: PMC7394878
doi:
Substances chimiques
TRPP Cation Channels
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1374-1383Références
Lanktree MB, Haghighi A, Guiard E, et al. Prevalence estimates of polycystic kidney and liver disease by population sequencing. J Am Soc Nephrol. 2018;29:2593–2600.
pubmed: 30135240
pmcid: 6171271
Bae KT, Zhu F, Chapman AB, et al. Magnetic resonance imaging evaluation of hepatic cysts in early autosomal-dominant polycystic kidney disease: the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease cohort. Clin J Am Soc Nephrol. 2006;1:64–69.
pubmed: 17699192
Cornec-Le Gall E, Audrézet M-P, Chen J-M, et al. Type of PKD1 mutation influences renal outcome in ADPKD. J Am Soc Nephrol. 2013;24:1006–1013.
pubmed: 23431072
pmcid: 3665389
Cornec-Le Gall E, Audrézet M-P, Rousseau A, et al. The PROPKD score: a new algorithm to predict renal survival in autosomal dominant polycystic kidney disease. J Am Soc Nephrol. 2016;27:942–951.
pubmed: 26150605
Porath B, Gainullin VG, Cornec-Le Gall E, et al. Mutations in GANAB, encoding the glucosidase IIα subunit, cause autosomal-dominant polycystic kidney and liver disease. Am J Hum Genet. 2016;98:1193–1207.
pubmed: 27259053
pmcid: 4908191
Cornec-Le Gall E, Torres VE, Harris PC. Genetic complexity of autosomal dominant polycystic kidney and liver diseases. J Am Soc Nephrol. 2018;29:13–23.
pubmed: 29038287
Cornec-Le Gall E, Olson RJ, Besse W, et al. Monoallelic mutations to DNAJB11 cause atypical autosomal-dominant polycystic kidney disease. Am J Hum Genet. 2018;102:832–844.
pubmed: 29706351
pmcid: 5986722
Pei Y, Obaji J, Dupuis A, et al. Unified criteria for ultrasonographic diagnosis of ADPKD. J Am Soc Nephrol. 2009;20:205–212.
pubmed: 18945943
pmcid: 2615723
Pei Y, Hwang Y-H, Conklin J, et al. Imaging-based diagnosis of autosomal dominant polycystic kidney disease. J Am Soc Nephrol. 2015;26:746–753.
pubmed: 25074509
Irazabal MV, Rangel LJ, Bergstralh EJ, et al. Imaging classification of autosomal dominant polycystic kidney disease: a simple model for selecting patients for clinical trials. J Am Soc Nephrol. 2015;26:160–172.
pubmed: 24904092
Levey AS, Jong PE, de, Coresh J, et al. The definition, classification, and prognosis of chronic kidney disease: a KDIGO Controversies Conference report. Kidney Int. 2011;80:17–28.
pubmed: 21150873
Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–424.
pubmed: 25741868
pmcid: 25741868
Onuchic LF, Furu L, Nagasawa Y, et al. PKHD1, the polycystic kidney and hepatic disease 1 gene, encodes a novel large protein containing multiple immunoglobulin-like plexin-transcription-factor domains and parallel beta-helix 1 repeats. Am J Hum Genet. 2002;70:1305–1317.
pubmed: 11898128
pmcid: 447605
Furu L, Onuchic LF, Gharavi A, et al. Milder presentation of recessive polycystic kidney disease requires presence of amino acid substitution mutations. J Am Soc Nephrol. 2003;14:2004–2014.
pubmed: 12874454
Besse W, Chang AR, Luo JZ, et al. ALG9 mutation carriers develop kidney and liver cysts. J Am Soc Nephrol. 2019;30:2091–2102.
pubmed: 31395617
Toro JR, Wei M-H, Glenn GM, et al. BHD mutations, clinical and molecular genetic investigations of Birt–Hogg–Dubé syndrome: a new series of 50 families and a review of published reports. J Med Genet. 2008;45:321–331.
pubmed: 18234728
pmcid: 2564862
Silva LM, Jacobs DT, Allard BA, et al. Inhibition of Hedgehog signaling suppresses proliferation and microcyst formation of human autosomal dominant polycystic kidney disease cells. Sci Rep. 2018;8:4985
pubmed: 29563577
pmcid: 5862907
Tran PV, Talbott GC, Turbe-Doan A, et al. Downregulating hedgehog signaling reduces renal cystogenic potential of mouse models. J Am Soc Nephrol. 2014;25:2201–2212.
pubmed: 24700869
pmcid: 4178433
Kramann R, Fleig SV, Schneider RK, et al. Pharmacological GLI2 inhibition prevents myofibroblast cell-cycle progression and reduces kidney fibrosis. J Clin Invest. 2015;125:2935–2951.
pubmed: 26193634
pmcid: 4563736
Bolaños AL, Milla CM, Lira JC, et al. Role of Sonic Hedgehog in idiopathic pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol. 2012;303:L978–L990.
pubmed: 23023967
Besse W, Dong K, Choi J, et al. Isolated polycystic liver disease genes define effectors of polycystin-1 function. J Clin Invest. 2017;127:1772–1785.
pubmed: 28375157
pmcid: 5409105
Cnossen WR, te Morsche RHM, Hoischen A, et al. LRP5 variants may contribute to ADPKD. Eur J Hum Genet. 2016;24:237–242.
pubmed: 25920554
Carrera P, Calzavara S, Magistroni R, et al. Deciphering variability of PKD1 and PKD2 in an Italian cohort of 643 patients with autosomal dominant polycystic kidney disease (ADPKD). Sci Rep. 2016;6:30850.
pubmed: 27499327
pmcid: 4976333
Heyer CM, Sundsbak JL, Abebe KZ, et al. Predicted mutation strength of nontruncating PKD1 mutations aids genotype-phenotype correlations in autosomal dominant polycystic kidney disease. J Am Soc Nephrol. 2016;27:2872–2884.
pubmed: 26823553
pmcid: 5004648
Ali H, Al-Mulla F, Hussain N, et al. PKD1 duplicated regions limit clinical utility of whole exome sequencing for genetic diagnosis of autosomal dominant polycystic kidney disease. Sci Rep. 2019;9:4141.
pubmed: 30858458
pmcid: 6412018
Eisenberger T, Decker C, Hiersche M, et al. An efficient and comprehensive strategy for genetic diagnostics of polycystic kidney disease. PLoS One. 2015;10:e0116680.
pubmed: 25646624
pmcid: 4315576
Pandita S, Ramachandran V, Balakrishnan P, et al. Identification of PKD1 and PKD2 gene variants in a cohort of 125 Asian Indian patients of ADPKD. J Hum Genet. 2019;64:409–419.
pubmed: 30816285
Jin M, Xie Y, Chen Z, et al. System analysis of gene mutations and clinical phenotype in Chinese patients with autosomal-dominant polycystic kidney disease. Sci Rep. 2016;6:35945.
pubmed: 27782177
pmcid: 5080601
Kurashige M, Hanaoka K, Imamura M, et al. A comprehensive search for mutations in the PKD1 and PKD2 in Japanese subjects with autosomal dominant polycystic kidney disease. Clin Genet. 2015;87:266–272.
pubmed: 24611717
Fedeles SV, Tian X, Gallagher A-R, et al. A genetic interaction network of five genes for human polycystic kidney and liver diseases defines polycystin-1 as the central determinant of cyst formation. Nat Genet. 2011;43:639–647.
pubmed: 21685914
pmcid: 3547075
Sattler EC, Steinlein OK. Delayed diagnosis of Birt–Hogg–Dubé syndrome due to marked intrafamilial clinical variability: a case report. BMC Med Genet. 2018;19:45.
pubmed: 29548312
pmcid: 5857113
Nahorski MS, Reiman A, Lim DHK, et al. Birt Hogg-Dubé syndrome-associated FLCN mutations disrupt protein stability. Hum Mutat. 2011;32:921–929.
pubmed: 21538689
Hasumi H, Hasumi Y, Baba M, et al. H255Y and K508R missense mutations in tumour suppressor folliculin (FLCN) promote kidney cell proliferation. Hum Mol Genet. 2017;26:354–366.
pubmed: 28007907
Zhong M, Zhao X, Li J, et al. Tumor suppressor folliculin regulates mTORC1 through primary cilia. J Biol Chem. 2016;291:11689–11697.
pubmed: 27072130
pmcid: 4882437
Chapman AB, Devuyst O, Eckardt K-U, et al. Autosomal-dominant polycystic kidney disease (ADPKD): executive summary from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Kidney Int. 2015;88:17–27.
pubmed: 25786098
pmcid: 4913350
Groopman EE, Marasa M, Cameron-Christie S, et al. Diagnostic utility of exome sequencing for kidney disease. N Engl J Med. 2019;380:142–151.
pubmed: 30586318
Gast C, Pengelly RJ, Lyon M, et al. Collagen (COL4A) mutations are the most frequent mutations underlying adult focal segmental glomerulosclerosis. Nephrol Dial Transplant. 2016;31:961–970.
pubmed: 26346198
Lu H, Galeano MCR, Ott E, et al. Mutations in DZIP1L, which encodes a ciliary-transition-zone protein, cause autosomal recessive polycystic kidney disease. Nat Genet. 2017;49:1025–1034.
pubmed: 28530676
pmcid: 5687889
Hoff S, Halbritter J, Epting D, et al. ANKS6 is a central component of a nephronophthisis module linking NEK8 to INVS and NPHP3. Nat Genet. 2013;45:951–956.
pubmed: 23793029
pmcid: 3786259
Li M, Zhou Y, Chen C, et al. Efficacy and safety of mTOR inhibitors (rapamycin and its analogues) for tuberous sclerosis complex: a meta-analysis. Orphanet J Rare Dis. 2019;14:39.
pubmed: 30760308
pmcid: 6373010
Walz G, Budde K, Mannaa M, et al. Everolimus in patients with autosomal dominant polycystic kidney disease. N Engl J Med. 2010;363:830–840.
pubmed: 20581392
Sattler EC, Reithmair M, Steinlein OK. Kidney cancer characteristics and genotype-phenotype-correlations in Birt–Hogg–Dubé syndrome. PLoS One. 2018;13:e0209504.
pubmed: 30586397
pmcid: 6306193