Genomic diagnostics in polycystic kidney disease: an assessment of real-world use of whole-genome sequencing.
Adolescent
Adult
Aged
Child
Child, Preschool
Female
Gene Frequency
Genetic Testing
/ methods
Glucosidases
/ genetics
HSP40 Heat-Shock Proteins
/ genetics
Hepatocyte Nuclear Factor 1-alpha
/ genetics
Humans
Infant
Male
Middle Aged
Polycystic Kidney Diseases
/ diagnosis
Receptors, Cell Surface
/ genetics
Sensitivity and Specificity
TRPP Cation Channels
/ genetics
Tuberous Sclerosis Complex 2 Protein
/ genetics
Whole Genome Sequencing
/ methods
Journal
European journal of human genetics : EJHG
ISSN: 1476-5438
Titre abrégé: Eur J Hum Genet
Pays: England
ID NLM: 9302235
Informations de publication
Date de publication:
05 2021
05 2021
Historique:
received:
31
03
2020
accepted:
02
12
2020
revised:
03
11
2020
pubmed:
14
1
2021
medline:
18
1
2022
entrez:
13
1
2021
Statut:
ppublish
Résumé
Autosomal Dominant Polycystic Kidney Disease (ADPKD) is common, with a prevalence of 1/1000 and predominantly caused by disease-causing variants in PKD1 or PKD2. Clinical diagnosis is usually by age-dependent imaging criteria, which is challenging in patients with atypical clinical features, without family history, or younger age. However, there is increasing need for definitive diagnosis of ADPKD with new treatments available. Sequencing is complicated by six pseudogenes that share 97% homology to PKD1 and by recently identified phenocopy genes. Whole-genome sequencing can definitively diagnose ADPKD, but requires validation for clinical use. We initially performed a validation study, in which 42 ADPKD patients underwent sequencing of PKD1 and PKD2 by both whole-genome and Sanger sequencing, using a blinded, cross-over method. Whole-genome sequencing identified all PKD1 and PKD2 germline pathogenic variants in the validation study (sensitivity and specificity 100%). Two mosaic variants outside pipeline thresholds were not detected. We then examined the first 144 samples referred to a clinically-accredited diagnostic laboratory for clinical whole-genome sequencing, with targeted-analysis to a polycystic kidney disease gene-panel. In this unselected, diagnostic cohort (71 males :73 females), the diagnostic rate was 70%, including a diagnostic rate of 81% in patients with typical ADPKD (98% with PKD1/PKD2 variants) and 60% in those with atypical features (56% PKD1/PKD2; 44% PKHD1/HNF1B/GANAB/ DNAJB11/PRKCSH/TSC2). Most patients with atypical disease did not have clinical features that predicted likelihood of a genetic diagnosis. These results suggest clinicians should consider diagnostic genomics as part of their assessment in polycystic kidney disease, particularly in atypical disease.
Identifiants
pubmed: 33437033
doi: 10.1038/s41431-020-00796-4
pii: 10.1038/s41431-020-00796-4
pmc: PMC8110527
doi:
Substances chimiques
DNAJB11 protein, human
0
HNF1A protein, human
0
HSP40 Heat-Shock Proteins
0
Hepatocyte Nuclear Factor 1-alpha
0
PKHD1 protein, human
0
Receptors, Cell Surface
0
TRPP Cation Channels
0
TSC2 protein, human
0
Tuberous Sclerosis Complex 2 Protein
0
polycystic kidney disease 1 protein
0
polycystic kidney disease 2 protein
0
GANAB protein, human
EC 3.2.1.-
Glucosidases
EC 3.2.1.-
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
760-770Subventions
Organisme : NIDDK NIH HHS
ID : P30 DK090728
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK058816
Pays : United States
Références
Lanktree M, Haghighi A, Guiard E, Harris PC, Paterson AD, Pei Y. Prevalence Estimates of Polycystic Kidney and Liver Disease by Population Sequencing. J Am Soc Nephrol. 2018;29:2593–600.
doi: 10.1681/ASN.2018050493
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.
doi: 10.1681/ASN.2017050483
Pei Y, Obaji J, Dupuis A, Paterson AD, Magistroni R, Dicks E, et al. Unified Criteria for Ultrasonographic Diagnosis of ADPKD. J Am Soc Nephrol. 2009;20:205–12.
doi: 10.1681/ASN.2008050507
Iliuta I-A, Kalatharan V, Wang K, Cornec-Le Gall E, Conklin J, Pourafkari M, et al. Polycystic Kidney Disease without an Apparent Family History. J Am Soc Nephrol. 2017;28:2768–76.
doi: 10.1681/ASN.2016090938
Pei Y, Hwang YH, Conklin J, Sundsbak JL, Heyer CM, Chan W, et al. Imaging-Based Diagnosis of Autosomal Dominant Polycystic Kidney Disease. J Am Soc Nephrol. 2015;26:746–53.
doi: 10.1681/ASN.2014030297
Porath B, Gainullin VG, Gall EC-L, Dillinger EK, Heyer CM, Hopp K, et al. Mutations in GANAB, Encoding the Glucosidase IIα Subunit, Cause Autosomal-Dominant Polycystic Kidney and Liver Disease. Am J Hum Genet. 2016;98:1193–207.
doi: 10.1016/j.ajhg.2016.05.004
Cornec-Le Gall E, Olson RJ, Besse W, Heyer CM, Gainullin VG, Smith JM, et al. Monoallelic Mutations to DNAJB11 Cause Atypical Autosomal-Dominant Polycystic Kidney Disease. Am J Hum Genet. 2018;102:832–44.
doi: 10.1016/j.ajhg.2018.03.013
Clissold RL, Hamilton AJ, Hattersley AT, Ellard S, Bingham C. HNF1B-associated renal and extra-renal disease—an expanding clinical spectrum. Nat Rev Nephrol. 2014;11:102–12.
doi: 10.1038/nrneph.2014.232
Mallawaarachchi AC, Furlong TJ, Shine J, Harris PC, Cowley MJ. Population data improves variant interpretation in autosomal dominant polycystic kidney disease. Genet Med. 2019;21:1425–34.
Gansevoort RT, Arici M, Benzing T, Birn H, Capasso G, Covic A, et al. Recommendations for the use of tolvaptan in autosomal dominant polycystic kidney disease: a position statement on behalf of the ERA-EDTA Working Groups on Inherited Kidney Disorders and European Renal Best Practice. Nephrol Dial Transpl. 2016;31:337–48.
doi: 10.1093/ndt/gfv456
Cornec-Le Gall E, Audrezet MP, Rousseau A, Hourmant M, Renaudineau E, Charasse C, et al. The PROPKD Score: a New Algorithm to Predict Renal Survival in Autosomal Dominant Polycystic Kidney Disease. J Am Soc Nephrol. 2016;27:942–51.
doi: 10.1681/ASN.2015010016
Lanktree MB, Iliuta IA, Haghighi A, Song X, Pei Y. Evolving role of genetic testing for the clinical management of autosomal dominant polycystic kidney disease. Nephrol Dial Transpl. 2019;34:1453–60.
doi: 10.1093/ndt/gfy261
Rossetti S, Hopp K, Sikkink RA, Sundsbak JL, Lee YK, Kubly V, et al. Identification of Gene Mutations in Autosomal Dominant Polycystic Kidney Disease through Targeted Resequencing. J Am Soc Nephrol. 2012;23:915–33.
doi: 10.1681/ASN.2011101032
Bogdanova N, Markoff A, Gerke V, McCluskey M, Horst J, Dworniczak B. Homologues to the First Gene for Autosomal Dominant Polycystic Kidney Disease Are Pseudogenes. Genomics. 2001;74:333–41.
doi: 10.1006/geno.2001.6568
Ong ACM, Devuyst O, Knebelmann B, Walz G. Autosomal dominant polycystic kidney disease:the changing face of clinical management. Lancet. 2015;385:1993–2002.
doi: 10.1016/S0140-6736(15)60907-2
Mallawaarachchi AC, Hort Y, Cowley MJ, McCabe MJ, Minoche A, Dinger ME, et al. Whole-genome sequencing overcomes pseudogene homology to diagnose autosomal dominant polycystic kidney disease. Eur J Hum Genet. 2016;24:1584–90.
doi: 10.1038/ejhg.2016.48
Audrézet M-P, Cornec-Le Gall E, Chen J-M, Redon S, Quere I, Creff J, et al. Autosomal dominant polycystic kidney disease: comprehensive mutation analysis of PKD1 and PKD2 in 700 unrelated patients. Hum Mutat. 2012;33:1239–50.
doi: 10.1002/humu.22103
Trujillano D, Bullich G, Ossowski S, Ballarín J, Torra R, Estivill X, et al. Diagnosis of autosomal dominant polycystic kidney disease using efficient PKD1and PKD2 targeted next-generation sequencing. Mol Genet Genom Med. 2014;2:412–21.
doi: 10.1002/mgg3.82
Gayevskiy V, Roscioli T, Dinger ME, Cowley MJ. Seave: a comprehensive web platform for storing and interrogating human genomic variation. Bioinformatics. 2019;35:122–5.
doi: 10.1093/bioinformatics/bty540
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, 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;17:405–23.
doi: 10.1038/gim.2015.30
Layer RM, Chiang C, Quinlan AR, Hall IM. LUMPY: a probabilistic framework for structural variant discovery. Genome Biol. 2014;15:1–19.
doi: 10.1186/gb-2014-15-6-r84
Abyzov A, Urban AE, Snyder M, Gerstein M. CNVnator: an approach to discover, genotype, and characterize typical and atypical CNVs from family and population genome sequencing. Genome Res. 2011;21:974–84.
doi: 10.1101/gr.114876.110
Trost B, Walker S, Wang Z, Thiruvahindrapuram B, MacDonald JR, Sung WWL, et al. A Comprehensive Workflow for Read Depth-Based Identification of Copy-Number Variation from Whole-Genome Sequence Data. Am J Hum Genet. 2018;102:142–55.
doi: 10.1016/j.ajhg.2017.12.007
Gout AM, Martin NC, Brown AF, Ravine D. PKDB: Polycystic Kidney Disease Mutation Database-a gene variant database for autosomal dominant polycystic kidney disease. Hum Mutat. 2007;28:654–9. https://pkdb.mayo.edu/
doi: 10.1002/humu.20474
McLaughlin HM, Ceyhan-Birsoy O, Christensen K, Kohane I, Green RC, Rehm HL, et al. A systematic approach to the reporting of medically relevant findings from whole genome sequencing. BMC Med Genet. 2014;15:134–48.
doi: 10.1186/s12881-014-0134-1
Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int Supplements. 2013: 1–163.
Irazabal MV, Rangel LJ, Bergstralh EJ, Osborn SL, Harmon AJ, Sundsbak JL, et al. Imaging Classification of Autosomal Dominant Polycystic Kidney Disease: a Simple Model for Selecting Patients for Clinical Trials. J Am Soc Nephrol. 2015;26:160–72.
doi: 10.1681/ASN.2013101138
Cornec-Le Gall E, Audrezet MP, Chen JM, Hourmant M, Morin MP, Perrichot R, et al. Type of PKD1 Mutation Influences Renal Outcome in ADPKD. J Am Soc Nephrol. 2013;24:1006–13.
doi: 10.1681/ASN.2012070650
Rangan GK, Alexander SI, Campbell KL, Dexter MA, Lee VW, Lopez-Vargas P, et al. KHA-CARI guideline recommendations for the diagnosis and management of autosomal dominant polycystic kidney disease. Nephrology. 2016;21:705–16.
doi: 10.1111/nep.12658
De Rechter S, Breysem L, Mekahli D. Is Autosomal Dominant Polycystic Kidney Disease Becoming a Pediatric Disorder? Front Pediatrics. 2017;5:332.
doi: 10.3389/fped.2017.00272
Gimpel C, Bergmann C, Bockenhauer D, Breysem L, Cadnapaphornchai MA, Cetiner M, et al. International consensus statement on the diagnosis and management of autosomal dominant polycystic kidney disease in children and young people. Nat Rev Nephrol. 2019;15:713–26.
doi: 10.1038/s41581-019-0155-2
National Genomic Test Directory for rare and inherited disease https://www.england.nhs.uk/publication/national-genomic-test-directories/ . (Accessed: 2nd February 2020)
Ali H, Al-Mulla F, Hussain N, Naim M, Asbeutah AM, AlSahow A, 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.
doi: 10.1038/s41598-019-40761-w
Bullich G, Domingo-Gallego A, Vargas I, Ruiz P, Lorente-Grandoso L, Furlano M, et al. A kidney-disease gene panel allows a comprehensive genetic diagnosis of cystic and glomerular inherited kidney diseases. Kidney Int. 2018;94:363–71.
doi: 10.1016/j.kint.2018.02.027
Bayrak-Toydemir P, McDonald J, Mao R, Phansalkar A, Gedge F, Robles J, et al. Likelihood ratios to assess genetic evidence for clinical significance of uncertain variants: hereditary hemorrhagic telangiectasia as a model. Exp Mol Pathol. 2008;85:45–9.
doi: 10.1016/j.yexmp.2008.03.006
Miller NA, Farrow EG, Gibson M, Willig LK, Twist G, Yoo B, et al. A 26-hour system of highly sensitive whole genome sequencing for emergency management of genetic diseases. Genome Med. 2015;7:100–16.
doi: 10.1186/s13073-015-0221-8
Zhou X, Edmonson MN, Wilkinson MR, Patel A, Gang W, Liu Y, et al. Exploring genomic alteration in pediatric cancer using ProteinPaint. Nat Genet. 2016;48:4–6.
doi: 10.1038/ng.3466