{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T07:30:36Z","timestamp":1790753436458,"version":"4.1.0"},"reference-count":36,"publisher":"BMJ","issue":"4","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J Med Genet"],"published-print":{"date-parts":[[2009,4]]},"abstract":"<jats:sec>\n                  <jats:title>Background:<\/jats:title>\n                  <jats:p>Autosomal recessive primary microcephaly (MCPH) is a model disease to study human neurogenesis. In affected individuals the brain grows at a reduced rate during fetal life resulting in a small but structurally normal brain and mental retardation. The condition is genetically heterogeneous with mutations in <jats:italic>ASPM<\/jats:italic> being most commonly reported.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods and results:<\/jats:title>\n                  <jats:p>We have examined this further by studying three cohorts of microcephalic children to extend both the phenotype and the mutation spectrum. Firstly, in 99 consecutively ascertained consanguineous families with a strict diagnosis of MCPH, 41 (41%) were homozygous at the MCPH5 locus and all but two families had mutations. Thus, 39% of consanguineous MCPH families had homozygous <jats:italic>ASPM<\/jats:italic> mutations. Secondly, in 27 non-consanguineous, predominantly Caucasian families with a strict diagnosis of MCPH, 11 (40%) had <jats:italic>ASPM<\/jats:italic> mutations. Thirdly, in 45 families with a less restricted phenotype including microcephaly and mental retardation, but regardless of other neurological features, only 3 (7%) had an <jats:italic>ASPM<\/jats:italic> mutation. This report contains 27 novel mutations and almost doubles the number of MCPH associated <jats:italic>ASPM<\/jats:italic> mutations known to 57. All but one of the mutations lead to the use of a premature termination codon, 23 were nonsense mutations, 28 deletions or insertions, 5 splicing, and 1 was a translocation. Seventeen of the 57 mutations were recurrent. There were no definitive missense mutations found nor was there any mutation\/phenotype correlation. <jats:italic>ASPM<\/jats:italic> mutations were found in all ethnic groups studied.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion:<\/jats:title>\n                  <jats:p>This study confirms that mutations in <jats:italic>ASPM<\/jats:italic> are the most common cause of MCPH, that <jats:italic>ASPM<\/jats:italic> mutations are restricted to individuals with an MCPH phenotype, and that <jats:italic>ASPM<\/jats:italic> testing in primary microcephaly is clinically useful.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jmg.2008.062380","type":"journal-article","created":{"date-parts":[[2008,11,21]],"date-time":"2008-11-21T20:26:08Z","timestamp":1227299168000},"page":"249-253","source":"Crossref","is-referenced-by-count":97,"title":["The molecular landscape of <i>ASPM<\/i> mutations in primary microcephaly"],"prefix":"10.1136","volume":"46","author":[{"given":"A K","family":"Nicholas","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E A","family":"Swanson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J J","family":"Cox","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G","family":"Karbani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S","family":"Malik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K","family":"Springell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D","family":"Hampshire","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M","family":"Ahmed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J","family":"Bond","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D","family":"Di Benedetto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M","family":"Fichera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C","family":"Romano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W B","family":"Dobyns","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C G","family":"Woods","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2008,11,21]]},"reference":[{"key":"2025100511061670000_46.4.249.1","doi-asserted-by":"crossref","unstructured":"Darwin C . The descent of man and selection in relation to sex. Princeton: Princeton University Press, 1981.","DOI":"10.5962\/bhl.title.70891"},{"key":"2025100511061670000_46.4.249.2","doi-asserted-by":"publisher","DOI":"10.1097\/00019052-200104000-00003"},{"key":"2025100511061670000_46.4.249.3","doi-asserted-by":"publisher","DOI":"10.1038\/ng995"},{"key":"2025100511061670000_46.4.249.4","doi-asserted-by":"publisher","DOI":"10.1086\/429930"},{"key":"2025100511061670000_46.4.249.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2006.06.006"},{"key":"2025100511061670000_46.4.249.6","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.39.10.718"},{"key":"2025100511061670000_46.4.249.7","first-page":"115","article-title":"Recurrence risks in severe undiagnosed mental deficiency.","volume":"18","author":"Bundey","year":"1974","journal-title":"J Ment Defic Res"},{"key":"2025100511061670000_46.4.249.8","unstructured":"Bundey S . Genetics and neurology , 2nd ed. London: Churchill Livingstone, 1992."},{"key":"2025100511061670000_46.4.249.9","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.1320270311"},{"key":"2025100511061670000_46.4.249.10","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.20.20.7813-7825.2000"},{"key":"2025100511061670000_46.4.249.11","doi-asserted-by":"publisher","DOI":"10.1086\/341283"},{"key":"2025100511061670000_46.4.249.12","doi-asserted-by":"publisher","DOI":"10.1038\/ng1539"},{"key":"2025100511061670000_46.4.249.13","doi-asserted-by":"crossref","first-page":"457","DOI":"10.4161\/cc.5.4.2481","article-title":"Microcephalin encodes a centrosomal protein.","volume":"5","author":"Zhong","year":"2006","journal-title":"Cell Cycle"},{"key":"2025100511061670000_46.4.249.14","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddi220"},{"key":"2025100511061670000_46.4.249.15","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2005.11.074"},{"key":"2025100511061670000_46.4.249.16","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0604066103"},{"key":"2025100511061670000_46.4.249.17","doi-asserted-by":"crossref","first-page":"2339","DOI":"10.4161\/cc.5.20.3358","article-title":"Microcephalin: a causal link between impaired damage response signalling and microcephaly.","volume":"5","author":"O\u00e2\u0080\u0099Driscoll","year":"2006","journal-title":"Cell Cycle"},{"key":"2025100511061670000_46.4.249.18","doi-asserted-by":"crossref","first-page":"322","DOI":"10.4161\/cc.5.3.2412","article-title":"Misregulated chromosome condensation in MCPH1 primary microcephaly is mediated by condensin II.","volume":"5","author":"Trimborn","year":"2006","journal-title":"Cell Cycle"},{"key":"2025100511061670000_46.4.249.19","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.020248"},{"key":"2025100511061670000_46.4.249.20","doi-asserted-by":"publisher","DOI":"10.1111\/j.1399-0004.2004.00304.x"},{"key":"2025100511061670000_46.4.249.21","doi-asserted-by":"publisher","DOI":"10.1007\/s10048-006-0042-4"},{"key":"2025100511061670000_46.4.249.22","first-page":"175","article-title":"Microcephaly: general considerations and aids to nosology.","volume":"10","author":"Opitz","year":"1990","journal-title":"J Craniofac Genet Dev Biol"},{"key":"2025100511061670000_46.4.249.23","doi-asserted-by":"publisher","DOI":"10.1136\/adc.61.9.927-a"},{"key":"2025100511061670000_46.4.249.24","doi-asserted-by":"publisher","DOI":"10.1016\/j.spen.2007.07.003"},{"key":"2025100511061670000_46.4.249.25","first-page":"506","article-title":"Nonspecific mental retardation in British Columbia as ascertained through a registry.","volume":"87","author":"Herbst","year":"1983","journal-title":"Am J Ment Defic"},{"key":"2025100511061670000_46.4.249.26","doi-asserted-by":"publisher","DOI":"10.1177\/088307380201700205"},{"key":"2025100511061670000_46.4.249.27","unstructured":"Menkes JH . Textbook of child neurology. Philadelphia: Lea and Febiger, 1974:148\u00e2\u0080\u009350."},{"key":"2025100511061670000_46.4.249.28","doi-asserted-by":"crossref","unstructured":"Aicardi J . Diseases of the nervous system in childhood , 2nd ed. London: Mac Keith Press, 1998.","DOI":"10.1097\/00005072-199812000-00014"},{"key":"2025100511061670000_46.4.249.29","first-page":"637","article-title":"A clinical and genetical study of microcephaly.","volume":"57","author":"Book","year":"1953","journal-title":"Am J Mental Defic"},{"key":"2025100511061670000_46.4.249.30","doi-asserted-by":"publisher","DOI":"10.1086\/503875"},{"key":"2025100511061670000_46.4.249.31","doi-asserted-by":"crossref","first-page":"1348","DOI":"10.1016\/S0002-9297(07)62966-8","article-title":"Pitfalls in homozygosity mapping.","volume":"67","author":"Miano","year":"2000","journal-title":"Am J Hum Genet"},{"key":"2025100511061670000_46.4.249.32","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-005-0104-y"},{"key":"2025100511061670000_46.4.249.33","doi-asserted-by":"publisher","DOI":"10.1038\/sj.ejhg.5201169"},{"key":"2025100511061670000_46.4.249.34","doi-asserted-by":"publisher","DOI":"10.1080\/01677060701508594"},{"key":"2025100511061670000_46.4.249.35","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2004.027706"},{"key":"2025100511061670000_46.4.249.36","doi-asserted-by":"publisher","DOI":"10.1126\/science.1151174"}],"container-title":["Journal of Medical Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jmg.2008.062380","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,5]],"date-time":"2025-10-05T18:06:26Z","timestamp":1759687586000},"score":1,"resource":{"primary":{"URL":"https:\/\/jmg.bmj.com\/lookup\/doi\/10.1136\/jmg.2008.062380"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2008,11,21]]},"references-count":36,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2009,4,8]]},"published-print":{"date-parts":[[2009,4]]}},"alternative-id":["10.1136\/jmg.2008.062380"],"URL":"https:\/\/doi.org\/10.1136\/jmg.2008.062380","relation":{},"ISSN":["0022-2593","1468-6244"],"issn-type":[{"value":"0022-2593","type":"print"},{"value":"1468-6244","type":"electronic"}],"subject":[],"published":{"date-parts":[[2008,11,21]]}}}