{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T06:41:18Z","timestamp":1793947278986,"version":"4.8.0"},"reference-count":28,"publisher":"BMJ","issue":"10","content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Med Genet"],"accepted":{"date-parts":[[2013,5,28]]},"published-print":{"date-parts":[[2013,10]]},"abstract":"<jats:sec>\n                  <jats:title>Introduction<\/jats:title>\n                  <jats:p>New mutations for Huntington disease (HD) occur due to CAG repeat instability of intermediate alleles (IA). IAs have between 27 and 35 CAG repeats, a range just below the disease threshold of 36 repeats. While they usually do not confer the HD phenotype, IAs are prone to paternal germline CAG repeat instability. Consequently, they may expand into the HD range upon transmission to the next generation, producing a new mutation. Quantified risk estimates for IA repeat instability are extremely limited but needed to inform clinical practice.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Using small-pool PCR of sperm DNA from Caucasian men, we examined the frequency and magnitude of CAG repeat instability across the entire range of intermediate CAG sizes. The CAG size-specific risk estimates generated are based on the largest sample size ever examined, including 30 IAs and 18\u2005198 sperm.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Our findings demonstrate a significant risk of new mutations. While all intermediate CAG sizes demonstrated repeat expansion into the HD range, alleles with 34 and 35 CAG repeats were associated with the highest risk of a new mutation (2.4% and 21.0%, respectively). IAs with \u226533 CAG repeats showed a dramatic increase in the frequency of instability and a switch towards a preponderance of repeat expansions over contractions.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>These data provide novel insights into the origins of new mutations for HD. The CAG size-specific risk estimates inform clinical practice and provide accurate risk information for persons who receive an IA predictive test result.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jmedgenet-2013-101796","type":"journal-article","created":{"date-parts":[[2013,7,29]],"date-time":"2013-07-29T22:09:23Z","timestamp":1375135763000},"page":"696-703","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":87,"title":["CAG size-specific risk estimates for intermediate allele repeat instability in Huntington disease"],"prefix":"10.1136","volume":"50","author":[{"given":"Alicia","family":"Semaka","sequence":"first","affiliation":[{"name":"Department of Medical Genetics, Centre for Molecular Medicine & Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris","family":"Kay","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Centre for Molecular Medicine & Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Crystal","family":"Doty","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Centre for Molecular Medicine & Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer A","family":"Collins","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Centre for Molecular Medicine & Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilia K","family":"Bijlsma","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Centre for Human and Clinical Genetics, Leiden University Medical Centre (LUMC), Leiden, South Holland, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fiona","family":"Richards","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, The Children's Hospital at Westmead, Westmead, New South Wales, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Y Paul","family":"Goldberg","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Centre for Molecular Medicine & Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada"},{"name":"Xenon Pharmaceuticals Inc., Burnaby, British Columbia, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael R","family":"Hayden","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Centre for Molecular Medicine & Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2013,7,29]]},"reference":[{"key":"2025101711462152000_50.10.696.1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(93)90585-E"},{"key":"2025101711462152000_50.10.696.2","doi-asserted-by":"publisher","DOI":"10.1038\/ng1093-174"},{"key":"2025101711462152000_50.10.696.3","doi-asserted-by":"publisher","DOI":"10.1111\/j.1399-0004.2006.00668.x"},{"key":"2025101711462152000_50.10.696.4","doi-asserted-by":"publisher","DOI":"10.1111\/j.1399-0004.2010.01388.x"},{"key":"2025101711462152000_50.10.696.5","doi-asserted-by":"crossref","unstructured":"Semaka A Kay C Doty C Collins JA Tam N Hayden MR . 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