{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,10]],"date-time":"2026-01-10T08:19:10Z","timestamp":1768033150860,"version":"3.49.0"},"reference-count":30,"publisher":"BMJ","issue":"6","content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Med Genet"],"accepted":{"date-parts":[[2020,5,16]]},"published-print":{"date-parts":[[2021,6]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy\u2019s disease, is an X-linked motor neuron disorder caused by an expanded CAG repeat in the gene coding for the androgen receptor (AR). The range and significance of reduced penetrance alleles in SBMA has not been fully determined to date. We presently sought to determine the range of reduced penetrance alleles in SBMA.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Through systematic literature review and meta-analysis, we collected and analysed data from 2576 patients with SBMA and compared the distributions of the CAG repeat number (CAG)<jats:sub>n<\/jats:sub> in the AR gene between patients and 112\u2009248 control alleles of the general population.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Our analysis revealed an unexpectedly high frequency of expanded SBMA-associated alleles, with (CAG)<jats:sub>n<\/jats:sub> \u226535 present in 107\/100,000 and (CAG)<jats:sub>n<\/jats:sub> \u226538 present in 27\/100,000 of the general population. Consequently, we suggest an updated model describing the distribution of expanded alleles in the general population. We argue against the established cut-off principle for the penetrance of SBMA and suggest that penetrance gradually increases from 35 to approximately 46 (CAG)<jats:sub>n<\/jats:sub>, above which it reaches a plateau approaching maximum value.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>Asymptomatic men of the general population with no\/unknown SBMA family history are free of risk when carrying (CAG)<jats:sub>n<\/jats:sub> \u226434, are at intermediate but increasing risk for developing SBMA when carrying (CAG)<jats:sub>n<\/jats:sub> \u224835\u201346 and have close to 100% risk of developing the disease when carrying (CAG)<jats:sub>n<\/jats:sub> \u226547. The above observations should be helpful and clinically useful when providing genetic counselling to individuals and families bearing SBMA-associated alleles.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jmedgenet-2020-106963","type":"journal-article","created":{"date-parts":[[2020,6,22]],"date-time":"2020-06-22T17:25:24Z","timestamp":1592846724000},"page":"385-391","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":10,"title":["Wide range of reduced penetrance alleles in spinal and bulbar muscular atrophy: a model-based approach"],"prefix":"10.1136","volume":"58","author":[{"given":"Achilleas","family":"Laskaratos","sequence":"first","affiliation":[{"name":"Neurogenetics Unit, 1st Department of Neurology, National and Kapodistrian University of Athens, Eginition University Hospital, Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marianthi","family":"Breza","sequence":"additional","affiliation":[{"name":"Neurogenetics Unit, 1st Department of Neurology, National and Kapodistrian University of Athens, Eginition University Hospital, Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Georgia","family":"Karadima","sequence":"additional","affiliation":[{"name":"Neurogenetics Unit, 1st Department of Neurology, National and Kapodistrian University of Athens, Eginition University Hospital, Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8980-8377","authenticated-orcid":false,"given":"Georgios","family":"Koutsis","sequence":"additional","affiliation":[{"name":"Neurogenetics Unit, 1st Department of Neurology, National and Kapodistrian University of Athens, Eginition University Hospital, Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"239","published-online":{"date-parts":[[2020,6,22]]},"reference":[{"key":"2025101710324843000_58.6.385.1","unstructured":"La Spada A . Spinal and bulbar muscular atrophy. GeneReviews\\textregistered[Internet]. Seattle: University of Washington, 2017."},{"key":"2025101710324843000_58.6.385.2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.ejhg.5200656"},{"key":"2025101710324843000_58.6.385.3","doi-asserted-by":"publisher","DOI":"10.1038\/352077a0"},{"key":"2025101710324843000_58.6.385.4","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awh381"},{"key":"2025101710324843000_58.6.385.5","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1007\/s00415-018-8968-7","article-title":"Kennedy's disease (spinal and bulbar muscular atrophy): a clinically oriented review of a rare disease","volume":"266","author":"Breza","year":"2019","journal-title":"J Neurol"},{"key":"2025101710324843000_58.6.385.6","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0122279"},{"key":"2025101710324843000_58.6.385.7","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1016\/j.jns.2015.10.021","article-title":"Spinobulbar muscular atrophy (Kennedy's disease): a rare diagnosis in the Greek population","volume":"359","author":"Koutsis","year":"2015","journal-title":"J Neurol Sci"},{"key":"2025101710324843000_58.6.385.8","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000000507"},{"key":"2025101710324843000_58.6.385.9","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awl096"},{"key":"2025101710324843000_58.6.385.10","doi-asserted-by":"crossref","unstructured":"Rosenbohm A , Hirsch S , Volk AE , Grehl T , Grosskreutz J , Hanisch F , Herrmann A , Kollewe K , Kress W , Meyer T , Petri S , Prudlo J , Wessig C , M\u00fcller HP , Dreyhaupt J , Weishaupt J , Kubisch C , Kassubek J , Weydt P , Ludolph AC . The metabolic and endocrine characteristics in spinal and bulbar muscular atrophy. J. Neurol 2018:1\u201311.","DOI":"10.1007\/s00415-018-8790-2"},{"key":"2025101710324843000_58.6.385.11","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1016\/j.ajhg.2017.09.013","article-title":"Profiling of Short-Tandem-Repeat disease alleles in 12,632 human whole genomes","volume":"101","author":"Tang","year":"2017","journal-title":"Am J Hum Genet"},{"key":"2025101710324843000_58.6.385.12","first-page":"137","article-title":"Molecular diagnosis of spinal and bulbar muscular atrophy in Slovakia","volume":"117","author":"Zelinkova","year":"2016","journal-title":"Bratisl Lek Listy"},{"key":"2025101710324843000_58.6.385.13","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1023\/A:1014580219761","article-title":"Epidemiological survey of X-linked bulbar and spinal muscular atrophy, or Kennedy","volume":"17","author":"Guidetti","year":"2001","journal-title":"Eur J Epidemiol"},{"key":"2025101710324843000_58.6.385.14","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1111\/ene.13850","article-title":"Insights into the genetic epidemiology of spinal and bulbar muscular atrophy: prevalence estimation and multiple founder haplotypes in the Veneto Italian region","volume":"26","author":"Bertolin","year":"2019","journal-title":"Eur J Neurol"},{"key":"2025101710324843000_58.6.385.15","doi-asserted-by":"crossref","first-page":"55","DOI":"10.17116\/jnevro201911902155","article-title":"Clinical and molecular-genetic characteristics of X-linked spinal-bulbar amyotrophy (Kennedy's disease) in the Sakha Republic (Yakutia)","volume":"119","author":"Maksimova","year":"2019","journal-title":"Zhurnal nevrologii i psikhiatrii imeni SS Korsakova"},{"key":"2025101710324843000_58.6.385.16","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1001\/jamaneurol.2019.0423","article-title":"Prevalence of carriers of intermediate and pathological polyglutamine disease-associated alleles among large population-based cohorts","volume":"76","author":"Gardiner","year":"2019","journal-title":"JAMA Neurol"},{"key":"2025101710324843000_58.6.385.17","doi-asserted-by":"crossref","unstructured":"Yapijakis C , Laskaratos A , Angelopoulou A , Voumvourakis C . Genetic counseling for adult-onset spinal and bulbar muscular atrophy (Kennedy syndrome): multiple cases of prenatal testing in a family. 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