{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T03:56:40Z","timestamp":1790740600183,"version":"4.1.0"},"reference-count":26,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2022,2,25]],"date-time":"2022-02-25T00:00:00Z","timestamp":1645747200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["KU 911\/21-2 and KU 911\/22-1"],"award-info":[{"award-number":["KU 911\/21-2 and KU 911\/22-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Here, we report a consanguineous family harboring a novel homozygous frame-shift mutation in ASPM leading to a truncation of the ASPM protein after amino acid position 1830. The phenotype of the patients was associated with microcephaly, epilepsy, and behavioral and cognitive deficits. Despite the obvious genetic similarity, the affected patients show a considerable phenotypic heterogeneity regarding the degree of mental retardation, presence of epilepsy and MRI findings. Interestingly, the degree of mental retardation and the presence of epilepsy correlates well with the severity of abnormalities detected in brain MRI. On the other hand, we detected no evidence for substantial nonsense-mediated ASPM transcript decay in blood samples. This indicates that other factors than ASPM expression levels are relevant for the variability of structural changes in brain morphology seen in patients with primary hereditary microcephaly caused by ASPM mutations.<\/jats:p>","DOI":"10.3390\/genes13030429","type":"journal-article","created":{"date-parts":[[2022,2,27]],"date-time":"2022-02-27T20:46:17Z","timestamp":1645994777000},"page":"429","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Large Phenotypic Variation of Individuals from a Family with a Novel ASPM Mutation Associated with Microcephaly, Epilepsy, and Behavioral and Cognitive Deficits"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9430-5037","authenticated-orcid":false,"given":"Randi","family":"von Wrede","sequence":"first","affiliation":[{"name":"Department of Epileptology, University Hospital Bonn, 53127 Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Schidlowski","sequence":"additional","affiliation":[{"name":"Department of Epileptology, University Hospital Bonn, 53127 Bonn, Germany"},{"name":"German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3856-9094","authenticated-orcid":false,"given":"Hans-J\u00fcrgen","family":"Huppertz","sequence":"additional","affiliation":[{"name":"Swiss Epilepsy Clinic, Klinik Lengg AG, 8008 Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6180-7671","authenticated-orcid":false,"given":"Theodor","family":"R\u00fcber","sequence":"additional","affiliation":[{"name":"Department of Epileptology, University Hospital Bonn, 53127 Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anja","family":"Ivo","sequence":"additional","affiliation":[{"name":"Department of Epileptology, University Hospital Bonn, 53127 Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias","family":"Baumgartner","sequence":"additional","affiliation":[{"name":"Department of Epileptology, University Hospital Bonn, 53127 Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kerstin","family":"Hallmann","sequence":"additional","affiliation":[{"name":"Department of Experimental Epileptology and Cognition Research, University Hospital Bonn, 53127 Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6379-849X","authenticated-orcid":false,"given":"G\u00e1bor","family":"Zsurka","sequence":"additional","affiliation":[{"name":"Department of Epileptology, University Hospital Bonn, 53127 Bonn, Germany"},{"name":"Department of Experimental Epileptology and Cognition Research, University Hospital Bonn, 53127 Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6608-6244","authenticated-orcid":false,"given":"Christoph","family":"Helmstaedter","sequence":"additional","affiliation":[{"name":"Department of Epileptology, University Hospital Bonn, 53127 Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3177-8582","authenticated-orcid":false,"given":"Rainer","family":"Surges","sequence":"additional","affiliation":[{"name":"Department of Epileptology, University Hospital Bonn, 53127 Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1113-3493","authenticated-orcid":false,"given":"Wolfram S.","family":"Kunz","sequence":"additional","affiliation":[{"name":"Department of Epileptology, University Hospital Bonn, 53127 Bonn, Germany"},{"name":"Department of Experimental Epileptology and Cognition Research, University Hospital Bonn, 53127 Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,2,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1080\/14737159.2017.1335598","article-title":"The role of genetic testing in epilepsy diagnosis and management","volume":"17","author":"Weber","year":"2017","journal-title":"Expert Rev. Mol. Diagn."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1080\/14737159.2019.1573144","article-title":"From next-generation sequencing to targeted treatment of non-acquired epilepsies","volume":"19","author":"Hammer","year":"2019","journal-title":"Expert Rev. Mol. Diagn."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1055\/s-0037-1601448","article-title":"Autosomal Recessive Primary Microcephaly (MCPH): An Update","volume":"48","author":"Zaqout","year":"2017","journal-title":"Neuropediatrics"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1086\/429930","article-title":"Autosomal recessive primary microcephaly (MCPH): A review of clinical, molecular, and evolutionary findings","volume":"76","author":"Woods","year":"2005","journal-title":"Am. J. Hum. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1002\/humu.23381","article-title":"Autosomal recessive primary microcephaly due to ASPM mutations: An update","volume":"39","author":"Drunat","year":"2018","journal-title":"Hum. Mutat."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"962","DOI":"10.1212\/WNL.0b013e3181b8799a","article-title":"Expanding the clinical and neuroradiologic phenotype of primary microcephaly due to ASPM mutations","volume":"73","author":"Passemard","year":"2009","journal-title":"Neurology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2133","DOI":"10.1002\/ajmg.a.37724","article-title":"Molecular and phenotypic spectrum of ASPM-related primary microcephaly: Identification of eight novel mutations","volume":"170","author":"Ismail","year":"2016","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_8","unstructured":"Raven, J., and Court, J.H. (1989). Manual for Raven\u2019s Progressive Matrices and Vocabulary Scales. Research Supplement No. 4: Additional National and American Norms, and Summaries of Normative, Reliability, and Validity Studies, Oxford Psychologists Press."},{"key":"ref_9","unstructured":"Kaufman, A.S., and Kaufman, N.L. (2004). Kaufman Assessment Battery for Children, American Guidance Service. [2nd ed.]."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1950","DOI":"10.1111\/epi.13216","article-title":"Global assessment of the severity of epilepsy (GASE) scale in children: Validity, reliability, responsiveness","volume":"56","author":"Chan","year":"2015","journal-title":"Epilepsia"},{"key":"ref_11","unstructured":"Funke, U.-N., Sch\u00fcwer, U., Themann, P., and Gerdes, N. (2018). Selbst\u00e4ndigkeits- Index f\u00fcr die Neurologische und Geriatrische Rehabilitation SINGER: Manual zur Stufenzuordnung. 2., Vollst\u00e4ndig \u00dcberarbeitete und Erweitertete Auflage, S. Roderer Verlag."},{"key":"ref_12","first-page":"203","article-title":"Analyzing the modified Rankin Scale using concepts of the international classification of functioning, disability and health","volume":"52","author":"Berzina","year":"2016","journal-title":"Eur. J. Phys. Rehabil. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.ajhg.2013.12.003","article-title":"Mutations in POGLUT1, encoding protein O-glucosyltransferase 1, cause autosomal-dominant Dowling-Degos disease","volume":"94","author":"Basmanav","year":"2014","journal-title":"Am. J. Hum. Genet."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1038\/s41586-020-2308-7","article-title":"The mutational constraint spectrum quantified from variation in 141,456 humans","volume":"581","author":"Karczewski","year":"2020","journal-title":"Nature"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2216","DOI":"10.1016\/j.neuroimage.2009.10.066","article-title":"Intra- and interscanner variability of automated voxel-based volumetry based on a 3D probabilistic atlas of human cerebral structures","volume":"49","author":"Huppertz","year":"2010","journal-title":"Neuroimage"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1506","DOI":"10.1002\/mds.26715","article-title":"Differentiation of neurodegenerative parkinsonian syndromes by volumetric magnetic resonance imaging analysis and support vector machine classification","volume":"31","author":"Huppertz","year":"2016","journal-title":"Mov. Disord."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1006\/nimg.1998.0395","article-title":"Cortical surface-based analysis. I. Segmentation and surface reconstruction","volume":"9","author":"Dale","year":"1999","journal-title":"Neuroimage"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1186\/s13073-021-00835-9","article-title":"CADD-Splice\u2014Improving genome-wide variant effect prediction using deep learning-derived splice scores","volume":"13","author":"Rentzsch","year":"2021","journal-title":"Genome Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1038\/s41586-018-0035-0","article-title":"Aspm knockout ferret reveals an evolutionary mechanism governing cerebral cortical size","volume":"556","author":"Johnson","year":"2018","journal-title":"Nature"},{"key":"ref_21","unstructured":"(2021, December 21). Ensembl Genome Browser. Available online: https:\/\/www.ensembl.org\/Homo_sapiens\/Transcript\/ProteinSummary?db=core;g=ENSG00000066279;r=1:197084121-197146694;t=ENST00000367409."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1038\/ng995","article-title":"ASPM is a major determinant of cerebral cortical size","volume":"32","author":"Bond","year":"2002","journal-title":"Nat Genet."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1720","DOI":"10.1126\/science.1116815","article-title":"Ongoing adaptive evolution of ASPM, a brain size determinant in Homo sapiens","volume":"309","author":"Gilbert","year":"2005","journal-title":"Science"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2155","DOI":"10.1093\/hmg\/ddi220","article-title":"The microcephaly ASPM gene is expressed in proliferating tissues and encodes for a mitotic spindle protein","volume":"14","author":"Kouprina","year":"2005","journal-title":"Hum. Mol. Genet."},{"key":"ref_25","unstructured":"(2021, December 21). OMIM. Available online: https:\/\/www.omim.org\/entry\/605481?search=ASPM&highlight=aspm."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Rahit, K.M., and Tarailo-Graovac, M. (2020). Genetic modifiers and rare Mendelian disease. Genes, 11.","DOI":"10.3390\/genes11030239"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/13\/3\/429\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:27:54Z","timestamp":1760135274000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/13\/3\/429"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,25]]},"references-count":26,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2022,3]]}},"alternative-id":["genes13030429"],"URL":"https:\/\/doi.org\/10.3390\/genes13030429","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,2,25]]}}}