{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T19:57:26Z","timestamp":1789070246516,"version":"build-2803163510"},"reference-count":29,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2020,12,26]],"date-time":"2020-12-26T00:00:00Z","timestamp":1608940800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Reid Foundation and the Macquarie Foundation, and National Health and Medical Research Council Postgraduate Scholarship","award":["APP1133266"],"award-info":[{"award-number":["APP1133266"]}]},{"DOI":"10.13039\/100014555","name":"Murdoch Children\u2019s Research Institute","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100014555","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Campbell Edwards Trust"},{"name":"Genet Foundation and the Murdoch Children\u2019s Research Institute Translation Research Fund"},{"name":"Vincent Chiodo Foundation"},{"name":"Senior Clinical Investigator Fellowship from the Research Foundation - Flanders"},{"name":"Melbourne Children\u2019s Clinician Scientist Fellowship"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,1,16]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Polymicrogyria is a malformation of cortical development characterized by overfolding and abnormal lamination of the cerebral cortex. Manifestations include epilepsy, speech disturbance and motor and cognitive disability. Causes include acquired prenatal insults and inherited and de novo genetic variants. The proportion of patients with polymicrogyria and a causative germline or mosaic variant is not known. The aim of this study was to identify the monogenic causes of polymicrogyria in a heterogeneous cohort of patients reflective of specialized referral services. Patients with polymicrogyria were recruited from two clinical centres in Australia and Belgium. Patients with evidence of congenital cytomegalovirus infection or causative chromosomal copy number variants were excluded. One hundred and twenty-three patients were tested using deep sequencing gene panels including known and candidate genes for malformations of cortical development. Causative and potentially causative variants were identified and correlated with phenotypic features. Pathogenic or likely pathogenic variants were identified in 25\/123 (20.3%) patients. A candidate variant was identified for an additional patient but could not be confirmed as de novo, and therefore it was classified as being of uncertain significance with high clinical relevance. Of the 22 dominant variants identified, 5 were mosaic with allele fractions less than 0.33 and the lowest allele fraction 0.09. The most common causative genes were TUBA1A and PIK3R2. The other eleven causative genes were PIK3CA, NEDD4L, COL4A1, COL4A2, GPSM2, GRIN2B, WDR62, TUBB3, TUBB2B, ACTG1 and FH. A genetic cause was more likely to be identified in the presence of an abnormal head size or additional brain malformations suggestive of a tubulinopathy, such as dysmorphic basal ganglia. A gene panel test provides greater sequencing depth and sensitivity for mosaic variants than whole exome or genome sequencing but is limited to the genes included, potentially missing variants in newly discovered genes. The diagnostic yield of 20.3% indicates that polymicrogyria may be associated with genes not yet known to be associated with brain malformations, brain-specific somatic mutations or non-genetic causes.<\/jats:p>","DOI":"10.1093\/braincomms\/fcaa221","type":"journal-article","created":{"date-parts":[[2020,12,26]],"date-time":"2020-12-26T13:59:40Z","timestamp":1608991180000},"source":"Crossref","is-referenced-by-count":36,"title":["Genetic heterogeneity of polymicrogyria: study of 123 patients using deep sequencing"],"prefix":"10.1093","volume":"3","author":[{"given":"Chloe A","family":"Stutterd","sequence":"first","affiliation":[{"name":"Murdoch Children\u2019s Research Institute, Melbourne, 3052, Australia"},{"name":"University of Melbourne Department of Paediatrics, Melbourne, 3052, Australia"},{"name":"Royal Children's Hospital, Melbourne, 3052, Australia"},{"name":"Victorian Clinical Genetics Service, Melbourne, 3052, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefanie","family":"Brock","sequence":"additional","affiliation":[{"name":"Neurogenetics Research group, Vrije Universiteit Brussel, Belgium"},{"name":"Department of Pathology, UZ Brussel, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katrien","family":"Stouffs","sequence":"additional","affiliation":[{"name":"Neurogenetics Research group, Vrije Universiteit Brussel, Belgium"},{"name":"Centre for Medical Genetics, UZ Brussel, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miriam","family":"Fanjul-Fernandez","sequence":"additional","affiliation":[{"name":"Murdoch Children\u2019s Research Institute, Melbourne, 3052, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul J","family":"Lockhart","sequence":"additional","affiliation":[{"name":"Murdoch Children\u2019s Research Institute, Melbourne, 3052, Australia"},{"name":"University of Melbourne Department of Paediatrics, Melbourne, 3052, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George","family":"McGillivray","sequence":"additional","affiliation":[{"name":"Victorian Clinical Genetics Service, Melbourne, 3052, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"Mandelstam","sequence":"additional","affiliation":[{"name":"Murdoch Children\u2019s Research Institute, Melbourne, 3052, Australia"},{"name":"University of Melbourne Department of Paediatrics, Melbourne, 3052, Australia"},{"name":"Royal Children's Hospital, Melbourne, 3052, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kate","family":"Pope","sequence":"additional","affiliation":[{"name":"Murdoch Children\u2019s Research Institute, Melbourne, 3052, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin B","family":"Delatycki","sequence":"additional","affiliation":[{"name":"Murdoch Children\u2019s Research Institute, Melbourne, 3052, Australia"},{"name":"University of Melbourne Department of Paediatrics, Melbourne, 3052, Australia"},{"name":"Victorian Clinical Genetics Service, Melbourne, 3052, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Jansen","sequence":"additional","affiliation":[{"name":"Neurogenetics Research group, Vrije Universiteit Brussel, Belgium"},{"name":"Pediatric Neurology Unit, UZ Brussel, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0362-5607","authenticated-orcid":false,"given":"Richard J","family":"Leventer","sequence":"additional","affiliation":[{"name":"Murdoch Children\u2019s Research Institute, Melbourne, 3052, Australia"},{"name":"University of Melbourne Department of Paediatrics, Melbourne, 3052, Australia"},{"name":"Royal Children's Hospital, Melbourne, 3052, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,12,26]]},"reference":[{"key":"2021021203373096700_fcaa221-B1","doi-asserted-by":"crossref","first-page":"1676","DOI":"10.1093\/brain\/awu082","article-title":"The wide spectrum of tubulinopathies: what are the key features for the diagnosis?","volume":"137","author":"Bahi-Buisson","year":"2014","journal-title":"Brain"},{"key":"2021021203373096700_fcaa221-B2","doi-asserted-by":"crossref","first-page":"1348","DOI":"10.1093\/brain\/aws019","article-title":"A developmental and genetic classification for malformations of cortical development: update 2012","volume":"135","author":"Barkovich","year":"2012","journal-title":"Brain"},{"key":"2021021203373096700_fcaa221-B3","doi-asserted-by":"crossref","first-page":"3367","DOI":"10.1093\/brain\/awz272","article-title":"A novel lethal recognizable polymicrogyric syndrome caused by ATP1A2 homozygous truncating variants","volume":"142","author":"Chatron","year":"2019","journal-title":"Brain"},{"key":"2021021203373096700_fcaa221-B4","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1136\/jcp.12.5.427","article-title":"Microgyria and cytomegalic inclusion disease in infancy","volume":"12","author":"Crome","year":"1959","journal-title":"J Clin Pathol"},{"key":"2021021203373096700_fcaa221-B5","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1002\/ajmg.a.30862","article-title":"Schizencephaly: heterogeneous etiologies in a population of 4 million California births","volume":"137A","author":"Curry","year":"2005","journal-title":"Am J Med Genet A"},{"key":"2021021203373096700_fcaa221-B6","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1086\/425985","article-title":"Mutations in the AHI1 gene, encoding jouberin, cause Joubert syndrome with cortical polymicrogyria","volume":"75","author":"Dixon-Salazar","year":"2004","journal-title":"Am J Hum 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copy number gains","volume":"35","author":"Vanmarsenille","year":"2014","journal-title":"Hum Mutat"}],"container-title":["Brain 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