{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T13:42:15Z","timestamp":1792762935334,"version":"4.5.0"},"reference-count":32,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2021,9,3]],"date-time":"2021-09-03T00:00:00Z","timestamp":1630627200000},"content-version":"vor","delay-in-days":245,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,7,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>WIPI2 is a member of the human WIPI protein family (seven-bladed b-propeller proteins binding phosphatidylinositols, PROPPINs), which play a pivotal role in autophagy and has been implicated in the pathogenesis of several neurological conditions. The homozygous WIPI2 variant c.745G&amp;gt;A; p.(Val249Met) (NM_015610.4) has recently been associated with a neurodevelopmental disorder in a single family. Using exome sequencing and Sanger segregation analysis, here, two novel homozygous WIPI2 variants [c.551T&amp;gt;G; p.(Val184Gly) and c.724C&amp;gt;T; p.(Arg242Trp) (NM_015610.4)] were identified in four individuals of two consanguineous families. Additionally, follow-up clinical data were sought from the previously reported family. Three non-ambulant affected siblings of the first family harbouring the p.(Val184Gly) missense variant presented with microcephaly, profound global developmental delay\/intellectual disability, refractory infantile\/childhood-onset epilepsy, progressive tetraplegia with joint contractures and dyskinesia. In contrast, the proband of the second family carrying the p.(Arg242Trp) missense variant, similar to the initially reported WIPI2 cases, presented with a milder phenotype, encompassing moderate intellectual disability, speech and visual impairment, autistic features, and an ataxic gait. Brain MR imaging in five patients showed prominent white matter involvement with a global reduction in volume, posterior corpus callosum hypoplasia, abnormal dentate nuclei and hypoplasia of the inferior cerebellar vermis. To investigate the functional impact of these novel WIPI2 variants, we overexpressed both in WIPI2-knockout HEK293A cells. In comparison to wildtype, expression of the Val166Gly WIPI2b mutant resulted in a deficient rescue of LC3 lipidation whereas Arg224Trp mutant increased LC3 lipidation, in line with the previously reported Val231Met variant. These findings support a dysregulation of the early steps of the autophagy pathway. Collectively, our findings provide evidence that biallelic WIPI2 variants cause a neurodevelopmental disorder of variable severity and disease course. Our report expands the clinical spectrum and establishes WIPI2-related disorder as a congenital disorders of autophagy.<\/jats:p>","DOI":"10.1093\/braincomms\/fcab183","type":"journal-article","created":{"date-parts":[[2021,9,3]],"date-time":"2021-09-03T17:21:22Z","timestamp":1630689682000},"source":"Crossref","is-referenced-by-count":24,"title":["Homozygous missense <i>WIPI2<\/i> variants cause a congenital disorder of autophagy with neurodevelopmental impairments of variable clinical severity and disease course"],"prefix":"10.1093","volume":"3","author":[{"given":"Reza","family":"Maroofian","sequence":"first","affiliation":[{"name":"Department of Neuromuscular Diseases, University College London, Queen Square, Institute of Neurology, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Gubas","sequence":"additional","affiliation":[{"name":"Goethe University Medical School, University Hospital, 60590 Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1640-4010","authenticated-orcid":false,"given":"Rauan","family":"Kaiyrzhanov","sequence":"additional","affiliation":[{"name":"Department of Neuromuscular Diseases, University College London, Queen Square, Institute of Neurology, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcello","family":"Scala","sequence":"additional","affiliation":[{"name":"Department of Neuromuscular Diseases, University College London, Queen Square, Institute of Neurology, London, UK"},{"name":"Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy"},{"name":"Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto Giannina Gaslini, Via Gerolamo Gaslini, Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khalid","family":"Hundallah","sequence":"additional","affiliation":[{"name":"Division of Neurology, Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4730-5322","authenticated-orcid":false,"given":"Mariasavina","family":"Severino","sequence":"additional","affiliation":[{"name":"Neuroradiology Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed S","family":"Abdel-Hamid","sequence":"additional","affiliation":[{"name":"Medical Molecular Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5664-7987","authenticated-orcid":false,"given":"Jill A","family":"Rosenfeld","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA"},{"name":"Baylor Genetics Laboratories, Houston, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0026-4714","authenticated-orcid":false,"given":"Darius","family":"Ebrahimi-Fakhari","sequence":"additional","affiliation":[{"name":"Department of Neurology, The F.M. Kirby Neurobiology Center, Boston Children\u2019s Hospital, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zahir","family":"Ali","sequence":"additional","affiliation":[{"name":"Laboratory for Genome Engineering, Division of Biological Sciences, 4700 King Abdullah University of Science and Technology, Thuwal 23955-6900, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fazal","family":"Rahim","sequence":"additional","affiliation":[{"name":"Department of Physiology, Bacha Khan Medical College, Mardan, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2866-7777","authenticated-orcid":false,"given":"Henry","family":"Houlden","sequence":"additional","affiliation":[{"name":"Department of Neuromuscular Diseases, University College London, Queen Square, Institute of Neurology, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharon A","family":"Tooze","sequence":"additional","affiliation":[{"name":"The Francis Crick Institute, Molecular Cell Biology of Autophagy, NW1 1AT London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norah S","family":"Alsaleh","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics and Metabolic Medicine, Department of Pediatrics, Prince Sultan Military Medical City, 11159 Riyadh, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maha S","family":"Zaki","sequence":"additional","affiliation":[{"name":"Human Genetics and Genome Research Division, Clinical Genetics Department, National Research Centre, 12311 Cairo, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,9,3]]},"reference":[{"issue":"1","key":"2021090909581890400_fcab183-B1","first-page":"190","article-title":"WIPI2B links 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