{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T06:42:10Z","timestamp":1784011330235,"version":"3.55.0"},"reference-count":48,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2022,12,15]],"date-time":"2022-12-15T00:00:00Z","timestamp":1671062400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,12,15]],"date-time":"2022-12-15T00:00:00Z","timestamp":1671062400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/L501529\/1"],"award-info":[{"award-number":["MR\/L501529\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/R024804\/1"],"award-info":[{"award-number":["MR\/R024804\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000269","name":"Economic and Social Research Council","doi-asserted-by":"crossref","award":["ES\/L008238\/1"],"award-info":[{"award-number":["ES\/L008238\/1"]}],"id":[{"id":"10.13039\/501100000269","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100012176","name":"Maudsley Charity","doi-asserted-by":"publisher","award":["980"],"award-info":[{"award-number":["980"]}],"id":[{"id":"10.13039\/100012176","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000380","name":"Guy's and St Thomas' Charity","doi-asserted-by":"publisher","award":["TR130505"],"award-info":[{"award-number":["TR130505"]}],"id":[{"id":"10.13039\/501100000380","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007601","name":"Horizon 2020","doi-asserted-by":"publisher","award":["H2020-PHC-2014-two-stage"],"award-info":[{"award-number":["H2020-PHC-2014-two-stage"]}],"id":[{"id":"10.13039\/501100007601","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007601","name":"Horizon 2020","doi-asserted-by":"publisher","award":["633413"],"award-info":[{"award-number":["633413"]}],"id":[{"id":"10.13039\/501100007601","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100011776","name":"MND Scotland","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100011776","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009362","name":"South London and Maudsley NHS Foundation Trust","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009362","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000406","name":"Motor Neurone Disease Association","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000406","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000272","name":"National Institute for Health and Care Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000272","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100017026","name":"Spastic Paraplegia Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100017026","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000833","name":"Rosetrees Trust","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000833","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Darby Rimmer MND Foundation"},{"DOI":"10.13039\/501100002283","name":"Alzheimer\u2019s Research UK","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002283","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Genome Med"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Genetic penetrance is the probability of a phenotype when harbouring a particular pathogenic variant. Accurate penetrance estimates are important across biomedical fields including genetic counselling, disease research, and gene therapy. However, existing approaches for penetrance estimation require, for instance, large family pedigrees or availability of large databases of people affected and not affected by a disease.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We present a method for penetrance estimation in autosomal dominant phenotypes. It examines the distribution of a variant among people affected (cases) and unaffected (controls) by a phenotype within population-scale data and can be operated using cases only by considering family disease history. It is validated through simulation studies and candidate variant-disease case studies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Our method yields penetrance estimates which align with those obtained via existing approaches in the Parkinson\u2019s disease\n                      <jats:italic>LRRK2<\/jats:italic>\n                      gene and pulmonary arterial hypertension\n                      <jats:italic>BMPR2<\/jats:italic>\n                      gene case studies. In the amyotrophic lateral sclerosis case studies, examining penetrance for variants in the\n                      <jats:italic>SOD1<\/jats:italic>\n                      and\n                      <jats:italic>C9orf72<\/jats:italic>\n                      genes, we make novel penetrance estimates which correspond closely to understanding of the disease.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The present approach broadens the spectrum of traits for which reliable penetrance estimates can be obtained. It has substantial utility for facilitating the characterisation of disease risks associated with rare variants with an autosomal dominant inheritance pattern. The yielded estimates avoid any kinship-specific effects and can circumvent ascertainment biases common when sampling rare variants among control populations.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13073-022-01142-7","type":"journal-article","created":{"date-parts":[[2022,12,15]],"date-time":"2022-12-15T06:04:16Z","timestamp":1671084256000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Calculating variant penetrance from family history of disease and average family size in population-scale data"],"prefix":"10.1186","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4297-6418","authenticated-orcid":false,"given":"Thomas P.","family":"Spargo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0951-8589","authenticated-orcid":false,"given":"Sarah","family":"Opie-Martin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4072-5255","authenticated-orcid":false,"given":"Harry","family":"Bowles","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8249-8476","authenticated-orcid":false,"given":"Cathryn M.","family":"Lewis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5280-5017","authenticated-orcid":false,"given":"Alfredo","family":"Iacoangeli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4924-7712","authenticated-orcid":false,"given":"Ammar","family":"Al-Chalabi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,12,15]]},"reference":[{"issue":"4","key":"1142_CR1","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1111\/j.1399-0004.2004.00241.x","volume":"65","author":"DR Langbehn","year":"2004","unstructured":"Langbehn DR, Brinkman RR, Falush D, Paulsen JS, Hayden MR. A new model for prediction of the age of onset and penetrance for Huntington\u2019s disease based on CAG length. Clin Genet. 2004;65(4):267\u201377. https:\/\/doi.org\/10.1111\/j.1399-0004.2004.00241.x.","journal-title":"Clin Genet"},{"issue":"11","key":"1142_CR2","doi-asserted-by":"publisher","first-page":"2144","DOI":"10.1002\/mds.23807","volume":"26","author":"S Goldwurm","year":"2011","unstructured":"Goldwurm S, Tunesi S, Tesei S, et al. Kin-cohort analysis of LRRK2-G2019S penetrance in Parkinson\u2019s disease. Mov Disord. 2011;26(11):2144\u20135. https:\/\/doi.org\/10.1002\/mds.23807.","journal-title":"Mov Disord"},{"issue":"10","key":"1142_CR3","doi-asserted-by":"publisher","first-page":"1035","DOI":"10.1001\/jama.2014.1717","volume":"311","author":"FE Dewey","year":"2014","unstructured":"Dewey FE, Grove ME, Pan C, et al. Clinical Interpretation and Implications of Whole-Genome Sequencing. JAMA. 2014;311(10):1035\u201345. https:\/\/doi.org\/10.1001\/jama.2014.1717.","journal-title":"JAMA"},{"issue":"2","key":"1142_CR4","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1038\/gim.2016.190","volume":"19","author":"SS Kalia","year":"2017","unstructured":"Kalia SS, Adelman K, Bale SJ, et al. Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics. Genet Med. 2017;19(2):249\u201355. https:\/\/doi.org\/10.1038\/gim.2016.190.","journal-title":"Genet Med."},{"issue":"1","key":"1142_CR5","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1186\/s12920-019-0561-0","volume":"12","author":"M Saelaert","year":"2019","unstructured":"Saelaert M, Mertes H, Moerenhout T, De Baere E, Devisch I. Criteria for reporting incidental findings in clinical exome sequencing \u2013 a focus group study on professional practices and perspectives in Belgian genetic centres. BMC Med Genomics. 2019;12(1):123. https:\/\/doi.org\/10.1186\/s12920-019-0561-0.","journal-title":"BMC Med Genomics"},{"issue":"12","key":"1142_CR6","doi-asserted-by":"publisher","first-page":"2765","DOI":"10.1038\/s41436-019-0560-8","volume":"21","author":"O Senol-Cosar","year":"2019","unstructured":"Senol-Cosar O, Schmidt RJ, Qian E, et al. Considerations for clinical curation, classification, and reporting of low-penetrance and low effect size variants associated with disease risk. Genet Med. 2019;21(12):2765\u201373. https:\/\/doi.org\/10.1038\/s41436-019-0560-8.","journal-title":"Genet Med"},{"issue":"3","key":"1142_CR7","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1590\/S1415-47572012005000051","volume":"35","author":"PA Otto","year":"2012","unstructured":"Otto PA, Horimoto ARVR. Penetrance rate estimation in autosomal dominant conditions. Genet Mol Biol. 2012;35(3):583\u20138. https:\/\/doi.org\/10.1590\/S1415-47572012005000051.","journal-title":"Genet Mol Biol"},{"issue":"322","key":"1142_CR8","doi-asserted-by":"publisher","first-page":"322ra9","DOI":"10.1126\/scitranslmed.aad5169","volume":"8","author":"EV Minikel","year":"2016","unstructured":"Minikel EV, Vallabh SM, Lek M, et al. Quantifying prion disease penetrance using large population control cohorts. Sci Transl Med. 2016;8(322):322ra9. https:\/\/doi.org\/10.1126\/scitranslmed.aad5169.","journal-title":"Sci Transl Med."},{"issue":"2","key":"1142_CR9","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1016\/j.ajhg.2018.12.015","volume":"104","author":"CF Wright","year":"2019","unstructured":"Wright CF, West B, Tuke M, et al. Assessing the Pathogenicity, Penetrance, and Expressivity of Putative Disease-Causing Variants in a Population Setting. Am J Hum Genet. 2019;104(2):275\u201386. https:\/\/doi.org\/10.1016\/j.ajhg.2018.12.015.","journal-title":"Am J Hum Genet"},{"issue":"5","key":"1142_CR10","doi-asserted-by":"publisher","first-page":"478","DOI":"10.1136\/jnnp-2013-305546","volume":"85","author":"A Chi\u00f2","year":"2014","unstructured":"Chi\u00f2 A, Battistini S, Calvo A, et al. Genetic counselling in ALS: facts, uncertainties and clinical suggestions. J Neurol Neurosurg Psychiatry. 2014;85(5):478. https:\/\/doi.org\/10.1136\/jnnp-2013-305546.","journal-title":"J Neurol Neurosurg Psychiatry"},{"key":"1142_CR11","doi-asserted-by":"publisher","first-page":"105156","DOI":"10.1016\/j.nbd.2020.105156","volume":"147","author":"A Shatunov","year":"2021","unstructured":"Shatunov A, Al-Chalabi A. The genetic architecture of ALS. Neurobiol Dis. 2021;147:105156. https:\/\/doi.org\/10.1016\/j.nbd.2020.105156.","journal-title":"Neurobiol Dis"},{"key":"1142_CR12","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1186\/s40478-019-0724-4","volume":"7","author":"A Iacoangeli","year":"2019","unstructured":"Iacoangeli A, Al Khleifat A, Jones AR, et al. C9orf72 intermediate expansions of 24\u201330 repeats are associated with ALS. Acta Neuropathol Commun. 2019;7:115. https:\/\/doi.org\/10.1186\/s40478-019-0724-4.","journal-title":"Acta Neuropathol Commun"},{"key":"1142_CR13","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1080\/21678421.2018.1562553","volume":"20","author":"A Iacoangeli","year":"2019","unstructured":"Iacoangeli A, Al Khleifat A, Sproviero W, et al. ALSgeneScanner: a pipeline for the analysis and interpretation of DNA sequencing data of ALS patients. Amyotroph Lateral Scler Frontotemporal Degener. 2019;20:207\u201315. https:\/\/doi.org\/10.1080\/21678421.2018.1562553.","journal-title":"Amyotroph Lateral Scler Frontotemporal Degener"},{"issue":"9","key":"1142_CR14","doi-asserted-by":"publisher","first-page":"1345","DOI":"10.1002\/humu.22157","volume":"33","author":"O Abel","year":"2012","unstructured":"Abel O, Powell JF, Andersen PM, Al-Chalabi A. ALSoD: A user-friendly online bioinformatics tool for amyotrophic lateral sclerosis genetics. Hum Mutat. 2012;33(9):1345\u201351. https:\/\/doi.org\/10.1002\/humu.22157.","journal-title":"Hum Mutat"},{"issue":"1","key":"1142_CR15","doi-asserted-by":"publisher","first-page":"6901","DOI":"10.1038\/s41467-022-34620-y","volume":"13","author":"S Opie-Martin","year":"2022","unstructured":"Opie-Martin S, Iacoangeli A, Topp SD, et al. The SOD1-mediated ALS phenotype shows a decoupling between age of symptom onset and disease duration. Nat Commun. 2022;13(1):6901. https:\/\/doi.org\/10.1038\/s41467-022-34620-y.","journal-title":"Nat Commun"},{"issue":"4","key":"1142_CR16","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1159\/000330167","volume":"71","author":"A Al-Chalabi","year":"2011","unstructured":"Al-Chalabi A, Lewis CM. Modelling the Effects of Penetrance and Family Size on Rates of Sporadic and Familial Disease. Hum Hered. 2011;71(4):281\u20138. https:\/\/doi.org\/10.1159\/000330167.","journal-title":"Hum Hered"},{"issue":"2","key":"1142_CR17","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1016\/S2213-2600(15)00544-5","volume":"4","author":"JDW Evans","year":"2016","unstructured":"Evans JDW, Girerd B, Montani D, et al. BMPR2 mutations and survival in pulmonary arterial hypertension: an individual participant data meta-analysis. Lancet Respir Med. 2016;4(2):129\u201337. https:\/\/doi.org\/10.1016\/S2213-2600(15)00544-5.","journal-title":"Lancet Respir Med"},{"key":"1142_CR18","doi-asserted-by":"publisher","DOI":"10.1017\/CBO9781139506779","volume-title":"Decision Making in Health and Medicine: Integrating Evidence and Values","author":"MGM Hunink","year":"2014","unstructured":"Hunink MGM, Weinstein MC, Wittenberg E, et al. Decision Making in Health and Medicine: Integrating Evidence and Values. 2nd ed. Cambridge: Cambridge University Press; 2014.","edition":"2"},{"key":"1142_CR19","unstructured":"Spargo TP, Opie-Martin S, Bowles H, Lewis CM, Iacoangeli A, Al-Chalabi A. ADPenetrance. 2022. GitHub. Available from: https:\/\/github.com\/ThomasPSpargo\/adpenetrance."},{"key":"1142_CR20","unstructured":"Spargo TP, Opie-Martin S, Bowles H, Lewis CM, Iacoangeli A, Al-Chalabi A. ADPenetrance: penetrance estimation for autosomal dominant traits. 2022. Available from: https:\/\/adpenetrance.rosalind.kcl.ac.uk\/."},{"key":"1142_CR21","unstructured":"Chang W, Cheng J, Allaire J, et al. shiny: Web Application Framework for R. 2022. R package version 1.7.3. Available from: https:\/\/CRAN.R-project.org\/package=shiny."},{"key":"1142_CR22","unstructured":"Fertility rate, total (births per woman) [Internet]. 2020. Available from: https:\/\/databank.worldbank.org\/reports.aspx?source=2&series=SP.DYN.TFRT.IN. Accessed 12 Jan 2021."},{"issue":"15","key":"1142_CR23","doi-asserted-by":"publisher","first-page":"2587","DOI":"10.1002\/mds.23361","volume":"25","author":"MY Shino","year":"2010","unstructured":"Shino MY, McGuire V, Van Den Eeden SK, et al. Familial aggregation of Parkinson\u2019s disease in a multiethnic community-based case-control study. Mov Disord. 2010;25(15):2587\u201394. https:\/\/doi.org\/10.1002\/mds.23361.","journal-title":"Mov Disord"},{"issue":"9","key":"1142_CR24","doi-asserted-by":"publisher","first-page":"1876","DOI":"10.1212\/WNL.52.9.1876","volume":"52","author":"A Elbaz","year":"1999","unstructured":"Elbaz A, Grigoletto F, Baldereschi M, et al. Familial aggregation of Parkinson\u2019s disease. Neurology. 1999;52(9):1876. https:\/\/doi.org\/10.1212\/WNL.52.9.1876.","journal-title":"Neurology"},{"key":"1142_CR25","unstructured":"Parkinson\u2019s UK. The Incidence and Prevalence of Parkinson\u2019s in the UK: Results from the Clinical Practice Research Datalink Reference Report. 2017. Available from: https:\/\/www.parkinsons.org.uk\/professionals\/resources\/incidence-and-prevalence-parkinsons-uk-report."},{"issue":"7","key":"1142_CR26","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1016\/S1474-4422(08)70117-0","volume":"7","author":"DG Healy","year":"2008","unstructured":"Healy DG, Falchi M, O\u2019Sullivan SS, et al. Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson\u2019s disease: a case-control study. Lancet Neurol. 2008;7(7):583\u201390. https:\/\/doi.org\/10.1016\/S1474-4422(08)70117-0.","journal-title":"Lancet Neurol"},{"issue":"7809","key":"1142_CR27","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1038\/s41586-020-2308-7","volume":"581","author":"KJ Karczewski","year":"2020","unstructured":"Karczewski KJ, Francioli LC, Tiao G, et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature. 2020;581(7809):434\u201343. https:\/\/doi.org\/10.1038\/s41586-020-2308-7.","journal-title":"Nature"},{"issue":"8","key":"1142_CR28","doi-asserted-by":"publisher","first-page":"707","DOI":"10.1164\/rccm.201207-1266ED","volume":"186","author":"T Thenappan","year":"2012","unstructured":"Thenappan T, Ryan JJ, Archer SL. Evolving epidemiology of pulmonary arterial hypertension. Am J Respir Crit Care Med. 2012;186(8):707\u20139. https:\/\/doi.org\/10.1164\/rccm.201207-1266ED.","journal-title":"Am J Respir Crit Care Med"},{"issue":"5","key":"1142_CR29","doi-asserted-by":"publisher","first-page":"L992","DOI":"10.1152\/ajplung.00098.2020","volume":"318","author":"PA Corris","year":"2020","unstructured":"Corris PA, Seeger W. Call it by the correct name\u2014pulmonary hypertension not pulmonary arterial hypertension: growing recognition of the global health impact for a well-recognized condition and the role of the Pulmonary Vascular Research Institute. Am J Physiol Lung Cell Mol. 2020;318(5):L992\u20134. https:\/\/doi.org\/10.1152\/ajplung.00098.2020.","journal-title":"Am J Physiol Lung Cell Mol"},{"issue":"2","key":"1142_CR30","doi-asserted-by":"publisher","first-page":"212","DOI":"10.1002\/humu.9398","volume":"27","author":"MA Aldred","year":"2006","unstructured":"Aldred MA, Vijayakrishnan J, James V, et al. BMPR2 gene rearrangements account for a significant proportion of mutations in familial and idiopathic pulmonary arterial hypertension. Hum Mutat. 2006;27(2):212\u20133. https:\/\/doi.org\/10.1002\/humu.9398.","journal-title":"Hum Mutat"},{"issue":"6","key":"1142_CR31","doi-asserted-by":"publisher","first-page":"623","DOI":"10.1136\/jnnp.2010.224501","volume":"82","author":"S Byrne","year":"2011","unstructured":"Byrne S, Walsh C, Lynch C, et al. Rate of familial amyotrophic lateral sclerosis: a systematic review and meta-analysis. J Neurol Neurosurg Psychiatry. 2011;82(6):623\u20137. https:\/\/doi.org\/10.1136\/jnnp.2010.224501.","journal-title":"J Neurol Neurosurg Psychiatry"},{"issue":"5","key":"1142_CR32","doi-asserted-by":"publisher","first-page":"699","DOI":"10.1002\/ana.23969","volume":"74","author":"S Byrne","year":"2013","unstructured":"Byrne S, Heverin M, Elamin M, et al. Aggregation of neurologic and neuropsychiatric disease in amyotrophic lateral sclerosis kindreds: A population-based case\u2013control cohort study of familial and sporadic amyotrophic lateral sclerosis. Ann Neurol. 2013;74(5):699\u2013708. https:\/\/doi.org\/10.1002\/ana.23969.","journal-title":"Ann Neurol"},{"issue":"6","key":"1142_CR33","doi-asserted-by":"publisher","first-page":"745","DOI":"10.1111\/j.1468-1331.2009.02586.x","volume":"16","author":"A Alonso","year":"2009","unstructured":"Alonso A, Logroscino G, Jick SS, Hern\u00e1n MA. Incidence and lifetime risk of motor neuron disease in the United Kingdom: a population-based study. Eur J Neurol. 2009;16(6):745\u201351. https:\/\/doi.org\/10.1111\/j.1468-1331.2009.02586.x.","journal-title":"Eur J Neurol"},{"key":"1142_CR34","doi-asserted-by":"publisher","first-page":"1.e","DOI":"10.1016\/j.neurobiolaging.2019.04.012","volume":"84","author":"C Marogianni","year":"2019","unstructured":"Marogianni C, Rikos D, Provatas A, et al. The role of C9orf72 in neurodegenerative disorders: a systematic review, an updated meta-analysis, and the creation of an online database. Neurobiol Aging. 2019;84:1.e-e10. https:\/\/doi.org\/10.1016\/j.neurobiolaging.2019.04.012.","journal-title":"Neurobiol Aging"},{"key":"1142_CR35","doi-asserted-by":"publisher","first-page":"540","DOI":"10.1136\/jnnp-2016-315018","volume":"88","author":"Z-Y Zou","year":"2017","unstructured":"Zou Z-Y, Zhou Z-R, Che C-H, Liu C-Y, He R-L, Huang H-P. Genetic epidemiology of amyotrophic lateral sclerosis: a systematic review and meta-analysis. J Neurol Neurosurg Psychiatry. 2017;88:540\u20139. https:\/\/doi.org\/10.1136\/jnnp-2016-315018.","journal-title":"J Neurol Neurosurg Psychiatry"},{"issue":"9","key":"1142_CR36","doi-asserted-by":"publisher","first-page":"892","DOI":"10.1164\/rccm.201205-0886OC","volume":"186","author":"EK Larkin","year":"2012","unstructured":"Larkin EK, Newman JH, Austin ED, et al. Longitudinal Analysis Casts Doubt on the Presence of Genetic Anticipation in Heritable Pulmonary Arterial Hypertension. Am J Respir Crit Care Med. 2012;186(9):892\u20136. https:\/\/doi.org\/10.1164\/rccm.201205-0886OC.","journal-title":"Am J Respir Crit Care Med"},{"issue":"1","key":"1142_CR37","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1007\/s11910-996-0008-9","volume":"6","author":"PM Andersen","year":"2006","unstructured":"Andersen PM. Amyotrophic lateral sclerosis associated with mutations in the CuZn superoxide dismutase gene. Curr Neurol Neurosci Rep. 2006;6(1):37\u201346. https:\/\/doi.org\/10.1007\/s11910-996-0008-9.","journal-title":"Curr Neurol Neurosci Rep"},{"issue":"2","key":"1142_CR38","doi-asserted-by":"publisher","first-page":"210","DOI":"10.1002\/ana.410410212","volume":"41","author":"ME Cudkowicz","year":"1997","unstructured":"Cudkowicz ME, McKenna-Yasek D, Sapp PE, et al. Epidemiology of mutations in superoxide dismutase in amyotrophic lateral sclerosis. Ann Neurol. 1997;41(2):210\u201321. https:\/\/doi.org\/10.1002\/ana.410410212.","journal-title":"Ann Neurol"},{"issue":"17","key":"1142_CR39","doi-asserted-by":"publisher","first-page":"3776","DOI":"10.1093\/hmg\/dds199","volume":"21","author":"M van Blitterswijk","year":"2012","unstructured":"van Blitterswijk M, van Es MA, Hennekam EAM, et al. Evidence for an oligogenic basis of amyotrophic lateral sclerosis. Hum Mol Genet. 2012;21(17):3776\u201384. https:\/\/doi.org\/10.1093\/hmg\/dds199.","journal-title":"Hum Mol Genet"},{"issue":"3","key":"1142_CR40","doi-asserted-by":"publisher","first-page":"345","DOI":"10.1016\/j.ajhg.2013.01.011","volume":"92","author":"J Beck","year":"2013","unstructured":"Beck J, Poulter M, Hensman D, et al. Large C9orf72 hexanucleotide repeat expansions are seen in multiple neurodegenerative syndromes and are more frequent than expected in the UK population. Am J Hum Genet. 2013;92(3):345\u201353. https:\/\/doi.org\/10.1016\/j.ajhg.2013.01.011.","journal-title":"Am J Hum Genet"},{"issue":"1","key":"1142_CR41","doi-asserted-by":"publisher","first-page":"2116","DOI":"10.1038\/s41598-017-02364-1","volume":"7","author":"NA Murphy","year":"2017","unstructured":"Murphy NA, Arthur KC, Tienari PJ, Houlden H, Chio A, Traynor BJ. Age-related penetrance of the C9orf72 repeat expansion. Sci Rep. 2017;7(1):2116. https:\/\/doi.org\/10.1038\/s41598-017-02364-1.","journal-title":"Sci Rep"},{"issue":"18","key":"1142_CR42","doi-asserted-by":"publisher","first-page":"1736","DOI":"10.1212\/WNL.0000000000002638","volume":"86","author":"ITS Coyle-Gilchrist","year":"2016","unstructured":"Coyle-Gilchrist ITS, Dick KM, Patterson K, et al. Prevalence, characteristics, and survival of frontotemporal lobar degeneration syndromes. Neurology. 2016;86(18):1736. https:\/\/doi.org\/10.1212\/WNL.0000000000002638.","journal-title":"Neurology"},{"issue":"12","key":"1142_CR43","doi-asserted-by":"publisher","first-page":"1042","DOI":"10.1136\/jnnp-2017-315995","volume":"88","author":"MR Turner","year":"2017","unstructured":"Turner MR, Al-Chalabi A, Chio A, et al. Genetic screening in sporadic ALS and FTD. J Neurol Neurosurg Psychiatry. 2017;88(12):1042\u20134. https:\/\/doi.org\/10.1136\/jnnp-2017-315995.","journal-title":"J Neurol Neurosurg Psychiatry"},{"issue":"4","key":"1142_CR44","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1016\/s1474-4422(12)70043-1","volume":"11","author":"E Majounie","year":"2012","unstructured":"Majounie E, Renton AE, Mok K, et al. Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study. Lancet Neurol. 2012;11(4):323\u201330. https:\/\/doi.org\/10.1016\/s1474-4422(12)70043-1.","journal-title":"Lancet Neurol"},{"issue":"7","key":"1142_CR45","doi-asserted-by":"publisher","first-page":"e635","DOI":"10.1212\/WNL.0000000000005996","volume":"91","author":"A Chi\u00f2","year":"2018","unstructured":"Chi\u00f2 A, Mazzini L, Alfonso S, et al. The multistep hypothesis of ALS revisited. Neurology. 2018;91(7):e635. https:\/\/doi.org\/10.1212\/WNL.0000000000005996.","journal-title":"Neurology"},{"issue":"10","key":"1142_CR46","doi-asserted-by":"publisher","first-page":"991","DOI":"10.1212\/wnl.0000000000003686","volume":"88","author":"A Vajda","year":"2017","unstructured":"Vajda A, McLaughlin RL, Heverin M, et al. Genetic testing in ALS: A survey of current practices. Neurol. 2017;88(10):991\u20139. https:\/\/doi.org\/10.1212\/wnl.0000000000003686.","journal-title":"Neurol"},{"key":"1142_CR47","doi-asserted-by":"publisher","unstructured":"King\u2019s College London. King's Computational Research, Engineering and Technology Environment (CREATE) 2022 [October 12 2022]. Available from: https:\/\/doi.org\/10.18742\/rnvf-m076.","DOI":"10.18742\/rnvf-m076"},{"key":"1142_CR48","volume-title":"Measurements and their uncertainties: a practical guide to modern error analysis","author":"I Hughes","year":"2010","unstructured":"Hughes I, Hase T. Measurements and their uncertainties: a practical guide to modern error analysis. Oxford: Oxford University Press; 2010."}],"container-title":["Genome Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13073-022-01142-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13073-022-01142-7\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13073-022-01142-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,15]],"date-time":"2022-12-15T06:14:26Z","timestamp":1671084866000},"score":1,"resource":{"primary":{"URL":"https:\/\/genomemedicine.biomedcentral.com\/articles\/10.1186\/s13073-022-01142-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,15]]},"references-count":48,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,12]]}},"alternative-id":["1142"],"URL":"https:\/\/doi.org\/10.1186\/s13073-022-01142-7","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2021.03.16.21253691","asserted-by":"object"}]},"ISSN":["1756-994X"],"issn-type":[{"value":"1756-994X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,15]]},"assertion":[{"value":"13 June 2022","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 November 2022","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 December 2022","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"CML sits on the SAB for Myriad Neuroscience. AAC reports consultancies or advisory boards for Amylyx, Apellis, Biogen Idec, Brainstorm, Cytokinetics, GSK, Lilly, Mitsubishi Tanabe Pharma, Novartis, OrionPharma, Quralis, and Wave Pharmaceuticals.The remaining authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"141"}}