{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T21:07:28Z","timestamp":1790370448634,"version":"4.1.0"},"reference-count":72,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2022,6,30]],"date-time":"2022-06-30T00:00:00Z","timestamp":1656547200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100002347","name":"Bundesministerium f\u00fcr Bildung und Forschung","doi-asserted-by":"crossref","award":["EGYGERF-2018-124"],"award-info":[{"award-number":["EGYGERF-2018-124"]}],"id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Tuscany Region Call for Health 2018"},{"DOI":"10.13039\/501100015694","name":"Fondazione Cassa di Risparmio di Firenze","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100015694","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100017473","name":"Australian Genomics Health Alliance","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100017473","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"US National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"crossref","award":["R01NS098004"],"award-info":[{"award-number":["R01NS098004"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"crossref","award":["R01NS050375"],"award-info":[{"award-number":["R01NS050375"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"crossref"}]},{"name":"European Reference Network for rare and complex epilepsies"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,9,14]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Reelin, a large extracellular protein, plays several critical roles in brain development and function. It is encoded by RELN, first identified as the gene disrupted in the reeler mouse, a classic neurological mutant exhibiting ataxia, tremors and a \u2018reeling\u2019 gait. In humans, biallelic variants in RELN have been associated with a recessive lissencephaly variant with cerebellar hypoplasia, which matches well with the homozygous mouse mutant that has abnormal cortical structure, small hippocampi and severe cerebellar hypoplasia. Despite the large size of the gene, only 11 individuals with RELN-related lissencephaly with cerebellar hypoplasia from six families have previously been reported. Heterozygous carriers in these families were briefly reported as unaffected, although putative loss-of-function variants are practically absent in the population (probability of loss of function intolerance\u2009=\u20091). Here we present data on seven individuals from four families with biallelic and 13 individuals from seven families with monoallelic (heterozygous) variants of RELN and frontotemporal or temporal-predominant lissencephaly variant. Some individuals with monoallelic variants have moderate frontotemporal lissencephaly, but with normal cerebellar structure and intellectual disability with severe behavioural dysfunction. However, one adult had abnormal MRI with normal intelligence and neurological profile. Thorough literature analysis supports a causal role for monoallelic RELN variants in four seemingly distinct phenotypes including frontotemporal lissencephaly, epilepsy, autism and probably schizophrenia. Notably, we observed a significantly higher proportion of loss-of-function variants in the biallelic compared to the monoallelic cohort, where the variant spectrum included missense and splice-site variants. We assessed the impact of two canonical splice-site variants observed as biallelic or monoallelic variants in individuals with moderately affected or normal cerebellum and demonstrated exon skipping causing in-frame loss of 46 or 52 amino acids in the central RELN domain. Previously reported functional studies demonstrated severe reduction in overall RELN secretion caused by heterozygous missense variants p.Cys539Arg and p.Arg3207Cys associated with lissencephaly suggesting a dominant-negative effect. We conclude that biallelic variants resulting in complete absence of RELN expression are associated with a consistent and severe phenotype that includes cerebellar hypoplasia. However, reduced expression of RELN remains sufficient to maintain nearly normal cerebellar structure. Monoallelic variants are associated with incomplete penetrance and variable expressivity even within the same family and may have dominant-negative effects. Reduced RELN secretion in heterozygous individuals affects only cortical structure whereas the cerebellum remains intact. Our data expand the spectrum of RELN-related neurodevelopmental disorders ranging from lethal brain malformations to adult phenotypes with normal brain imaging.<\/jats:p>","DOI":"10.1093\/brain\/awac164","type":"journal-article","created":{"date-parts":[[2022,5,10]],"date-time":"2022-05-10T19:18:50Z","timestamp":1652210330000},"page":"3274-3287","source":"Crossref","is-referenced-by-count":24,"title":["Monoallelic and biallelic mutations in<i>RELN<\/i>underlie a graded series of neurodevelopmental disorders"],"prefix":"10.1093","volume":"145","author":[{"given":"Nataliya","family":"Di Donato","sequence":"first","affiliation":[{"name":"Institute for Clinical Genetics, University Hospital, TU Dresden , 01307 Dresden , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7272-7079","authenticated-orcid":false,"given":"Renzo","family":"Guerrini","sequence":"additional","affiliation":[{"name":"Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Meyer Children\u2019s Hospital, University of Florence , 50139 Florence , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr","given":"Charles J","family":"Billington","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Genetics and Metabolism, University of Minnesota , Minneapolis, MN 55454 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A James","family":"Barkovich","sequence":"additional","affiliation":[{"name":"Departments of Radiology and Biomedical Imaging, Neurology, Pediatrics, and Neurosurgery, University of California, San Francisco , San Francisco, CA 94143 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philine","family":"Dinkel","sequence":"additional","affiliation":[{"name":"Institute for Clinical Genetics, University Hospital, TU Dresden , 01307 Dresden , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Freri","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neuroscience, Fondazione IRCCS Istituto Neurologico Carlo Besta , 20133 Milan , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Heide","sequence":"additional","affiliation":[{"name":"Max Planck Institute of Molecular Cell Biology and Genetics , 01307 Dresden , Germany"},{"name":"German Primate Center, Leibniz Institute for Primate Research , 37077 Goettingen , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elliot S","family":"Gershon","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, The University of Chicago , Chicago, IL 60637 , USA"},{"name":"Department of Psychiatry and Behavioral Neuroscience, The University of Chicago , Chicago, IL 60637 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tracy S","family":"Gertler","sequence":"additional","affiliation":[{"name":"Division of Neurology, Department of Pediatrics, Ann and Robert H. Lurie Children\u2019s Hospital of Chicago , Chicago, IL 60611 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert J","family":"Hopkin","sequence":"additional","affiliation":[{"name":"Cincinnati Children\u2019s Hospital Medical Center and University of Cincinnati College of Medicine, Department of Pediatrics, Division of Human Genetics , Cincinnati, OH 45229 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suma","family":"Jacob","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, University of Minnesota , Minneapolis, MN 55454 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah K","family":"Keedy","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Behavioral Neuroscience, The University of Chicago , Chicago, IL 60637 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniz","family":"Kooshavar","sequence":"additional","affiliation":[{"name":"Bruce Lefory Centre, Murdoch Children\u2019s Research Institute and University of Melbourne Department of Pediatrics , Melbourne 3052 , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul J","family":"Lockhart","sequence":"additional","affiliation":[{"name":"Bruce Lefory Centre, Murdoch Children\u2019s Research Institute and University of Melbourne Department of Pediatrics , Melbourne 3052 , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dietmar R","family":"Lohmann","sequence":"additional","affiliation":[{"name":"Institut fur Humangenetik, Universitatsklinikum Essen , 45147 Essen , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4853-1874","authenticated-orcid":false,"given":"Iman G","family":"Mahmoud","sequence":"additional","affiliation":[{"name":"Pediatric Neurology Department, Cairo University Children\u2019s Hospital , Cairo , Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Parrini","sequence":"additional","affiliation":[{"name":"Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Meyer Children\u2019s Hospital, University of Florence , 50139 Florence , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evelin","family":"Schrock","sequence":"additional","affiliation":[{"name":"Institute for Clinical Genetics, University Hospital, TU Dresden , 01307 Dresden , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Severi","sequence":"additional","affiliation":[{"name":"Medical Genetics Unit, S. Orsola-Malpighi Hospital , 40138 Bologna , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew E","family":"Timms","sequence":"additional","affiliation":[{"name":"Center for Developmental Biology and Regenerative Medicine, Seattle Children\u2019s Research Institute , Seattle, WA 98101 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard I","family":"Webster","sequence":"additional","affiliation":[{"name":"T. Y. Nelson Department of Neurology and Neurosurgery, The Children's Hospital at Westmead , Sydney 2145 , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary J H","family":"Willis","sequence":"additional","affiliation":[{"name":"Uniformed Services University School of Medicine and Naval Medical Center, Department of Pediatrics , San Diego, CA 92134 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maha S","family":"Zaki","sequence":"additional","affiliation":[{"name":"Pediatric Neurology Department, Cairo University Children\u2019s Hospital , Cairo , Egypt"},{"name":"Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre , Cairo Governorate 12622 , Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph G","family":"Gleeson","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Howard Hughes Medical Institute, University of California, San Diego , La Jolla, CA 92093 , USA"}],"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":"Department of Neurology, Royal Children\u2019s Hospital, Murdoch Children\u2019s Research Institute and University of Melbourne Department of Pediatrics , Melbourne 3052 , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7681-2844","authenticated-orcid":false,"given":"William B","family":"Dobyns","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Genetics and Metabolism, University of Minnesota , Minneapolis, MN 55454 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,6,30]]},"reference":[{"key":"2023030706013593000_","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1002\/(SICI)1521-1878(199803)20:3<235::AID-BIES7>3.0.CO;2-Q","article-title":"Reeler: New tales on an old mutant mouse","volume":"20","author":"D'Arcangelo","year":"1998","journal-title":"Bioessays"},{"key":"2023030706013593000_","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1038\/374719a0","article-title":"A protein related to extracellular matrix proteins deleted in the mouse mutant reeler","volume":"374","author":"D'Arcangelo","year":"1995","journal-title":"Nature"},{"key":"2023030706013593000_","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1007\/BF02996215","article-title":"Two new mutations, trembler and reeler, with neurological actions in the house mouse (Mus musculus l)","volume":"50","author":"Falconer","year":"1951","journal-title":"J Genet"},{"key":"2023030706013593000_","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1038\/79246","article-title":"Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations","volume":"26","author":"Hong","year":"2000","journal-title":"Nat Genet"},{"key":"2023030706013593000_","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1038\/84886","article-title":"Correction: Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations","volume":"27","author":"Hong","year":"2001","journal-title":"Nat Genet"},{"key":"2023030706013593000_","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1002\/ajmg.b.30392","article-title":"The role of RELN in lissencephaly and neuropsychiatric disease","volume":"144B","author":"Chang","year":"2007","journal-title":"Am J Med Genet B Neuropsychiatr Genet"},{"key":"2023030706013593000_","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1002\/ajmg.a.31667","article-title":"Identification of a novel recessive RELN mutation using a homozygous balanced reciprocal translocation","volume":"143A","author":"Zaki","year":"2007","journal-title":"Am J Med Genet A"},{"key":"2023030706013593000_","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1111\/cge.12779","article-title":"RELN and VLDLR mutations underlie two distinguishable clinico-radiological phenotypes","volume":"90","author":"Valence","year":"2016","journal-title":"Clin Genet"},{"key":"2023030706013593000_","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1038\/ejhg.2015.192","article-title":"Mosaic parental germline mutations causing recurrent forms of malformations of cortical development","volume":"24","author":"Zillhardt","year":"2016","journal-title":"Eur J Hum 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Causing abnormal development of the cerebral cortex and hippocampus","volume":"37","author":"Ha","year":"2017","journal-title":"J Neurosci"},{"key":"2023030706013593000_","author":"Riva"},{"key":"2023030706013593000_","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1038\/sj.mp.4001310","article-title":"Analysis of reelin as a candidate gene for autism","volume":"8","author":"Bonora","year":"2003","journal-title":"Mol Psychiatry"},{"key":"2023030706013593000_","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1038\/nature13772","article-title":"Synaptic, transcriptional and chromatin genes disrupted in autism","volume":"515","author":"De Rubeis","year":"2014","journal-title":"Nature"},{"key":"2023030706013593000_","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1038\/nature13908","article-title":"The contribution of de novo coding mutations to autism spectrum 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networks","volume":"506","author":"Fromer","year":"2014","journal-title":"Nature"},{"key":"2023030706013593000_","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1038\/mp.2016.88","article-title":"High-resolution copy number variation analysis of schizophrenia in Japan","volume":"22","author":"Kushima","year":"2017","journal-title":"Mol sychiatry"},{"key":"2023030706013593000_","doi-asserted-by":"crossref","first-page":"13046","DOI":"10.1038\/s41598-018-31390-w","article-title":"Genetic and animal model analyses reveal the pathogenic role of a novel deletion of RELN in schizophrenia","volume":"8","author":"Sobue","year":"2018","journal-title":"Sci Rep"},{"key":"2023030706013593000_","doi-asserted-by":"crossref","first-page":"24327","DOI":"10.1038\/srep24327","article-title":"Identification of RELN variation p.Thr3192Ser in a Chinese family with schizophrenia","volume":"6","author":"Zhou","year":"2016","journal-title":"Sci 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