Abstract
Wilson disease (WD) is a genetic disorder of copper metabolism caused by variants in the copper transporting P-type ATPase gene ATP7B. Estimates for WD population prevalence vary with 1 in 30,000 generally quoted. However, some genetic studies have reported much higher prevalence rates. The aim of this study was to estimate the population prevalence of WD and the pathogenicity/penetrance of WD variants by determining the frequency of ATP7B variants in a genomic sequence database. A catalogue of WD-associated ATP7B variants was constructed, and then, frequency information for these was extracted from the gnomAD data set. Pathogenicity of variants was assessed by (a) comparing gnomAD allele frequencies against the number of reports for variants in the WD literature and (b) using variant effect prediction algorithms. 231 WD-associated ATP7B variants were identified in the gnomAD data set, giving an initial estimated population prevalence of around 1 in 2400. After exclusion of WD-associated ATP7B variants with predicted low penetrance, the revised estimate showed a prevalence of around 1 in 20,000, with higher rates in the Asian and Ashkenazi Jewish populations. Reanalysis of other recent genetic studies using our penetrance criteria also predicted lower population prevalences for WD in the UK and France than had been reported. Our results suggest that differences in variant penetrance can explain the discrepancy between reported epidemiological and genetic prevalences of WD. They also highlight the challenge in defining penetrance when assigning causality to some ATP7B variants.
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Abdelghaffar TY, Elsayed SM, Elsobky E, Bochow B, Buttner J, Schmidt H (2008) Mutational analysis of ATP7B gene in Egyptian children with Wilson disease: 12 novel mutations. J Hum Genet 53:681–687. https://doi.org/10.1007/s10038-008-0298-7
Afgan E, Baker D, van den Beek M, Blankenberg D, Bouvier D, Cech M, Chilton J, Clements D, Coraor N, Eberhard C, Gruning B, Guerler A, Hillman-Jackson J, Von Kuster G, Rasche E, Soranzo N, Turaga N, Taylor J, Nekrutenko A, Goecks J (2016) The Galaxy platform for accessible, reproducible and collaborative biomedical analyses: 2016 update. Nucleic Acids Res 44:W3–W10. https://doi.org/10.1093/nar/gkw343
Aggarwal A, Chandhok G, Todorov T, Parekh S, Tilve S, Zibert A, Bhatt M, Schmidt HH (2013) Wilson disease mutation pattern with genotype-phenotype correlations from Western India: confirmation of p. C271* as a common Indian mutation and identification of 14 novel mutations. Ann Hum Genet 77:299–307. https://doi.org/10.1111/ahg.12024
Ala A, Walker AP, Ashkan K, Dooley JS, Schilsky ML (2007) Wilson's disease. Lancet 369:397–408. https://doi.org/10.1016/S0140-6736(07)60196-2
Bost M, Lachaux A, Accominotti M, Vandenberghe A (1999) Mutation screening and genotype-phenotype correlation in 32 families with Wilson disease. J Trace Elem Exp Med 12:321–329. https://doi.org/10.1002/(Sici)1520-670x(1999)12:4%3c321:Aid-Jtra5%3e3.0.Co;2-Y
Bost M, Piguet-Lacroix G, Parant F, Wilson CM (2012) Molecular analysis of Wilson patients: direct sequencing and MLPA analysis in the ATP7B gene and Atox1 and COMMD1 gene analysis. J Trace Elem Med Biol 26:97–101. https://doi.org/10.1016/j.jtemb.2012.04.024
Carter H, Douville C, Stenson PD, Cooper DN, Karchin R (2013) Identifying Mendelian disease genes with the variant effect scoring tool. BMC Genom 14(Suppl 3):S3. https://doi.org/10.1186/1471-2164-14-S3-S3
Chang IJ, Hahn SH (2017) The genetics of Wilson disease. Handb Clin Neurol 142:19–34. https://doi.org/10.1016/B978-0-444-63625-6.00003-3
Coffey AJ, Durkie M, Hague S, McLay K, Emmerson J, Lo C, Klaffke S, Joyce CJ, Dhawan A, Hadzic N, Mieli-Vergani G, Kirk R, Elizabeth Allen K, Nicholl D, Wong S, Griffiths W, Smithson S, Giffin N, Taha A, Connolly S, Gillett GT, Tanner S, Bonham J, Sharrack B, Palotie A, Rattray M, Dalton A, Bandmann O (2013) A genetic study of Wilson's disease in the United Kingdom. Brain 136:1476–1487. https://doi.org/10.1093/brain/awt035
Collet C, Laplanche JL, Page J, Morel H, Woimant F, Poujois A (2018) High genetic carrier frequency of Wilson's disease in France: discrepancies with clinical prevalence. BMC Med Genet 19:143. https://doi.org/10.1186/s12881-018-0660-3
Cox DW, Prat L, Walshe JM, Heathcote J, Gaffney D (2005) Twenty-four novel mutations in Wilson disease patients of predominantly European ancestry. Hum Mutat 26:280. https://doi.org/10.1002/humu.9358
Davies LP, Macintyre G, Cox DW (2008) New mutations in the Wilson disease gene, ATP7B: implications for molecular testing. Genet Test 12:139–145. https://doi.org/10.1089/gte.2007.0072
Dedoussis GV, Genschel J, Sialvera TE, Bochow B, Manolaki N, Manios Y, Tsafantakis E, Schmidt H (2005) Wilson disease: high prevalence in a mountainous area of Crete. Ann Hum Genet 69:268–274. https://doi.org/10.1046/j.1529-8817.2005.00171.x
Deguti MM, Genschel J, Cancado EL, Barbosa ER, Bochow B, Mucenic M, Porta G, Lochs H, Carrilho FJ, Schmidt HH (2004) Wilson disease: novel mutations in the ATP7B gene and clinical correlation in Brazilian patients. Hum Mutat 23:398. https://doi.org/10.1002/humu.9227
Ferenci P, Czlonkowska A, Stremmel W, Houwen R, Rosenberg W, Schilsky M, Jansen P, Moradpour D (2012) EASL Clinical Practice Guidelines: Wilson's disease. J Hepatol 56:671–685. https://doi.org/10.1016/j.jhep.2011.11.007
Ferenci P, Stremmel W, Czlonkowska A, Szalay F, Viveiros A, Stattermayer AF, Bruha R, Houwen R, Pop TL, Stauber R, Gschwantler M, Pfeiffenberger J, Yurdaydin C, Aigner E, Steindl-Munda P, Dienes HP, Zoller H, Weiss KH (2019) Age and sex but not ATP7B genotype effectively influence the clinical phenotype of Wilson disease. Hepatology 69:1464–1476. https://doi.org/10.1002/hep.30280
Gao J, Brackley S, Mann JP (2019) The global prevalence of Wilson disease from next-generation sequencing data. Genet Med 21:1155–1163. https://doi.org/10.1038/s41436-018-0309-9
Garcia-Villarreal L, Daniels S, Shaw SH, Cotton D, Galvin M, Geskes J, Bauer P, Sierra-Hernandez A, Buckler A, Tugores A (2000) High prevalence of the very rare Wilson disease gene mutation Leu708Pro in the Island of Gran Canaria (Canary Islands, Spain): a genetic and clinical study. Hepatology 32:1329–1336. https://doi.org/10.1053/jhep.2000.20152
Gomes A, Dedoussis GV (2016) Geographic distribution of ATP7B mutations in Wilson disease. Ann Hum Biol 43:1–8. https://doi.org/10.3109/03014460.2015.1051492
Guttmann S, Bernick F, Naorniakowska M, Michgehl U, Groba SR, Socha P, Zibert A, Schmidt HH (2018) Functional characterization of Novel ATP7B variants for diagnosis of Wilson disease. Front Pediatr 6:106. https://doi.org/10.3389/fped.2018.00106
Hahn SH, Lee SY, Jang YJ, Kim SN, Shin HC, Park SY, Han HS, Yu ES, Yoo HW, Lee JS, Chung CS, Lee SY, Lee DH (2002) Pilot study of mass screening for Wilson's disease in Korea. Mol Genet Metab 76:133–136
Hua R, Hua F, Jiao Y, Pan Y, Yang X, Peng S, Niu J (2016) Mutational analysis of ATP7B in Chinese Wilson disease patients. Am J Transl Res 8:2851–2861
Hughes BG, Harrison PM, Hekimi S (2017) Estimating the occurrence of primary ubiquinone deficiency by analysis of large-scale sequencing data. Sci Rep 7:17744. https://doi.org/10.1038/s41598-017-17564-y
Kim EK, Yoo OJ, Song KY, Yoo HW, Choi SY, Cho SW, Hahn SH (1998) Identification of three novel mutations and a high frequency of the Arg778Leu mutation in Korean patients with Wilson disease. Hum Mutat 11:275–278. https://doi.org/10.1002/(SICI)1098-1004(1998)11:4%3c275:AID-HUMU4%3e3.0.CO;2-L
Kroll CA, Ferber MJ, Dawson BD, Jacobson RM, Mensink KA, Lorey F, Sherwin J, Cunningham G, Rinaldo P, Matern D, Hahn SH (2006) Retrospective determination of ceruloplasmin in newborn screening blood spots of patients with Wilson disease. Mol Genet Metab 89:134–138. https://doi.org/10.1016/j.ymgme.2006.03.008
Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, O'Donnell-Luria AH, Ware JS, Hill AJ, Cummings BB, Tukiainen T, Birnbaum DP, Kosmicki JA, Duncan LE, Estrada K, Zhao F, Zou J, Pierce-Hoffman E, Berghout J, Cooper DN, Deflaux N, DePristo M, Do R, Flannick J, Fromer M, Gauthier L, Goldstein J, Gupta N, Howrigan D, Kiezun A, Kurki MI, Moonshine AL, Natarajan P, Orozco L, Peloso GM, Poplin R, Rivas MA, Ruano-Rubio V, Rose SA, Ruderfer DM, Shakir K, Stenson PD, Stevens C, Thomas BP, Tiao G, Tusie-Luna MT, Weisburd B, Won HH, Yu D, Altshuler DM, Ardissino D, Boehnke M, Danesh J, Donnelly S, Elosua R, Florez JC, Gabriel SB, Getz G, Glatt SJ, Hultman CM, Kathiresan S, Laakso M, McCarroll S, McCarthy MI, McGovern D, McPherson R, Neale BM, Palotie A, Purcell SM, Saleheen D, Scharf JM, Sklar P, Sullivan PF, Tuomilehto J, Tsuang MT, Watkins HC, Wilson JG, Daly MJ, MacArthur DG, Exome Aggregation C (2016) Analysis of protein-coding genetic variation in 60,706 humans. Nature 536:285–291. https://doi.org/10.1038/nature19057
Lepori MB, Lovicu M, Dessi V, Zappu A, Incollu S, Zancan L, Giacchino R, Iorio R, Vajro P, Maggiore G, Marcellini M, Barbera C, Pellecchia MT, Simonetti R, Kostic V, Farci AM, Solinas A, De Virgiliis S, Cao A, Loudianos G (2007) Twenty-four novel mutations in Wilson disease patients of predominantly Italian origin. Genet Test 11:328–332. https://doi.org/10.1089/gte.2007.0015
Loudianos G, Dessi V, Lovicu M, Angius A, Altuntas B, Giacchino R, Marazzi M, Marcellini M, Sartorelli MR, Sturniolo GC, Kocak N, Yuce A, Akar N, Pirastu M, Cao A (1999) Mutation analysis in patients of Mediterranean descent with Wilson disease: identification of 19 novel mutations. J Med Genet 36:833–836
Loudianos G, Dessi V, Lovicu M, Angius A, Nurchi A, Sturniolo GC, Marcellini M, Zancan L, Bragetti P, Akar N, Yagci R, Vegnente A, Cao A, Pirastu M (1998) Further delineation of the molecular pathology of Wilson disease in the Mediterranean population. Hum Mutat 12:89–94. https://doi.org/10.1002/(SICI)1098-1004(1998)12:2%3c89:AID-HUMU3%3e3.0.CO;2-G
Loudianos G, Incollu S, Mameli E, Lepori MB (2016) Wilson's disease in an adult asymptomatic patient: a potential role for modifying factors of copper metabolism. Ann Gastroenterol 29:96–98
Margarit E, Bach V, Gomez D, Bruguera M, Jara P, Queralt R, Ballesta F (2005) Mutation analysis of Wilson disease in the Spanish population—identification of a prevalent substitution and eight novel mutations in the ATP7B gene. Clin Genet 68:61–68. https://doi.org/10.1111/j.1399-0004.2005.00439.x
Medici V, Weiss KH (2017) Genetic and environmental modifiers of Wilson disease. Handb Clin Neurol 142:35–41. https://doi.org/10.1016/B978-0-444-63625-6.00004-5
Merle U, Schaefer M, Ferenci P, Stremmel W (2007) Clinical presentation, diagnosis and long-term outcome of Wilson's disease: a cohort study. Gut 56:115–120. https://doi.org/10.1136/gut.2005.087262
Moller LB, Horn N, Jeppesen TD, Vissing J, Wibrand F, Jennum P, Ott P (2011) Clinical presentation and mutations in Danish patients with Wilson disease. Eur J Hum Genet 19:935–941. https://doi.org/10.1038/ejhg.2011.80
Mukherjee S, Dutta S, Majumdar S, Biswas T, Jaiswal P, Sengupta M, Bhattacharya A, Gangopadhyay PK, Bavdekar A, Das SK, Ray K (2014) Genetic defects in Indian Wilson disease patients and genotype–phenotype correlation. Parkins Relat Disord 20:75–81. https://doi.org/10.1016/j.parkreldis.2013.09.021
Ohura T, Abukawa D, Shiraishi H, Yamaguchi A, Arashima S, Hiyamuta S, Tada K, Iinuma K (1999) Pilot study of screening for Wilson disease using dried blood spots obtained from children seen at outpatient clinics. J Inherit Metab Dis 22:74–80
Ohya K, Abo W, Tamaki H, Sugawara C, Endo T, Nomachi S, Fukushi M, Kinebuchi M, Matsuura A (2002) Presymptomatic diagnosis of Wilson disease associated with a novel mutation of the ATP7B gene. Eur J Pediatr 161:124–126
Okada T, Shiono Y, Hayashi H, Satoh H, Sawada T, Suzuki A, Takeda Y, Yano M, Michitaka K, Onji M, Mabuchi H (2000) Mutational analysis of ATP7B and genotype-phenotype correlation in Japanese with Wilson's disease. Hum Mutat 15:454–462. https://doi.org/10.1002/(SICI)1098-1004(200005)15:5%3c454:AID-HUMU7%3e3.0.CO;2-J
Owada M, Suzuki K, Fukushi M, Yamauchi K, Kitagawa T (2002) Mass screening for Wilson's disease by measuring urinary holoceruloplasmin. J Pediatr 140:614–616. https://doi.org/10.1067/mpd.2002.122731
Park RH, McCabe P, Fell GS, Russell RI (1991) Wilson's disease in Scotland. Gut 32:1541–1545
Poujois A, Woimant F, Samson S, Chaine P, Girardot-Tinant N, Tuppin P (2018) Characteristics and prevalence of Wilson's disease: a 2013 observational population-based study in France. Clin Res Hepatol Gastroenterol 42:57–63. https://doi.org/10.1016/j.clinre.2017.05.011
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, Committee ALQA (2015) 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 17:405–424. https://doi.org/10.1038/gim.2015.30
Ruderfer DM, Hamamsy T, Lek M, Karczewski KJ, Kavanagh D, Samocha KE, Exome Aggregation C, Daly MJ, MacArthur DG, Fromer M, Purcell SM (2016) Patterns of genic intolerance of rare copy number variation in 59,898 human exomes. Nat Genet 48:1107–1111. https://doi.org/10.1038/ng.3638
Sandahl TD, Laursen TL, Munk DE, Vilstrup H, Weiss KH, Ott P (2020) The prevalence of Wilson's disease: an update. Hepatology 71:722–732. https://doi.org/10.1002/hep.30911
Sandahl TD, Ott P (2019) Epidemiology of Wilson disease. In: Weiss KH, Schilsky M (eds) Wilson disease: pathogenesis, molecular mechanisms, diagnosis, treatment and monitoring, 1st edn. Academic Press, New York, pp 85–94
Santhosh S, Shaji RV, Eapen CE, Jayanthi V, Malathi S, Chandy M, Stanley M, Selvi S, Kurian G, Chandy GM (2006) ATP7B mutations in families in a predominantly Southern Indian cohort of Wilson's disease patients. Indian J Gastroenterol 25:277–282
Scheinberg IH, Sternlieb I (1984) Wilson's disease. Saunders, Philadelphia
Shah AB, Chernov I, Zhang HT, Ross BM, Das K, Lutsenko S, Parano E, Pavone L, Evgrafov O, Ivanova-Smolenskaya IA, Anneren G, Westermark K, Urrutia FH, Penchaszadeh GK, Sternlieb I, Scheinberg IH, Gilliam TC, Petrukhin K (1997) Identification and analysis of mutations in the Wilson disease gene (ATP7B): population frequencies, genotype-phenotype correlation, and functional analyses. Am J Hum Genet 61:317–328. https://doi.org/10.1086/514864
Stattermayer AF, Entenmann A, Gschwantler M, Zoller H, Hofer H, Ferenci P (2019) The dilemma to diagnose Wilson disease by genetic testing alone. Eur J Clin Invest 49:e13147. https://doi.org/10.1111/eci.13147
Tang N, Sandahl TD, Ott P, Kepp KP (2019) Computing the pathogenicity of Wilson's disease ATP7B mutations: implications for disease prevalence. J Chem Inf Model 59:5230–5243. https://doi.org/10.1021/acs.jcim.9b00852
Vrabelova S, Letocha O, Borsky M, Kozak L (2005) Mutation analysis of the ATP7B gene and genotype/phenotype correlation in 227 patients with Wilson disease. Mol Genet Metab 86:277–285. https://doi.org/10.1016/j.ymgme.2005.05.004
Wallace DF, Subramaniam VN (2016) The global prevalence of HFE and non-HFE hemochromatosis estimated from analysis of next-generation sequencing data. Genet Med 18:618–626. https://doi.org/10.1038/gim.2015.140
Whiffin N, Minikel E, Walsh R, O'Donnell-Luria AH, Karczewski K, Ing AY, Barton PJR, Funke B, Cook SA, MacArthur D, Ware JS (2017) Using high-resolution variant frequencies to empower clinical genome interpretation. Genet Med 19:1151–1158. https://doi.org/10.1038/gim.2017.26
Wildeman M, van Ophuizen E, den Dunnen JT, Taschner PE (2008) Improving sequence variant descriptions in mutation databases and literature using the Mutalyzer sequence variation nomenclature checker. Hum Mutat 29:6–13. https://doi.org/10.1002/humu.20654
Yuan ZF, Wu W, Yu YL, Shen J, Mao SS, Gao F, Xia ZZ (2015) Novel mutations of the ATP7B gene in Han Chinese families with pre-symptomatic Wilson's disease. World J Pediatr 11:255–260. https://doi.org/10.1007/s12519-015-0031-5
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We would like to acknowledge Diane Wilson Cox and the curators of the Wilson Disease Mutation Database, University of Alberta for the use of data in this study.
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Wallace, D.F., Dooley, J.S. ATP7B variant penetrance explains differences between genetic and clinical prevalence estimates for Wilson disease. Hum Genet 139, 1065–1075 (2020). https://doi.org/10.1007/s00439-020-02161-3
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DOI: https://doi.org/10.1007/s00439-020-02161-3