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Pathogenic variants in <jats:italic>DPM1<\/jats:italic> and <jats:italic>DPM2<\/jats:italic> are associated with muscle\u2013eye\u2013brain (MEB) disease, whereas <jats:italic>DPM3<\/jats:italic> variants have mostly been reported in patients with isolated muscle disease\u2014dystroglycanopathy. Thus far, only one affected individual with compound heterozygous <jats:italic>DPM3<\/jats:italic> variants presenting with myopathy, mild intellectual disability, seizures, and nonspecific white matter abnormalities (WMA) around the lateral ventricles has been described. Here we present five affected individuals from four unrelated families with global developmental delay\/intellectual disability ranging from mild to severe, microcephaly, seizures, WMA, muscle weakness and variable cardiomyopathy. Exome sequencing of the probands revealed an ultra\u2010rare homozygous pathogenic missense <jats:italic>DPM3<\/jats:italic> variant NM_018973.4:c.221A&gt;G, p.(Tyr74Cys) which segregated with the phenotype in all families. Haplotype analysis indicated that the variant arose independently in three families. Functional analysis did not reveal any alteration in the <jats:italic>N<\/jats:italic>\u2010glycosylation pathway caused by the variant; however, this does not exclude its pathogenicity in the function of the DPM complex and related cellular pathways. This report provides supporting evidence that, besides <jats:italic>DPM1<\/jats:italic> and <jats:italic>DPM2<\/jats:italic>, defects in <jats:italic>DPM3<\/jats:italic> can also lead to a muscle and brain phenotype.<\/jats:p>","DOI":"10.1111\/cge.14208","type":"journal-article","created":{"date-parts":[[2022,8,6]],"date-time":"2022-08-06T11:59:35Z","timestamp":1659787175000},"page":"530-536","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["A recurrent homozygous missense <scp><i>DPM3<\/i><\/scp> variant leads to muscle and brain disease"],"prefix":"10.1111","volume":"102","author":[{"given":"Sara","family":"Nagy","sequence":"first","affiliation":[{"name":"MRC Centre for Neuromuscular Diseases UCL Queen Square Institute of Neurology  London UK"},{"name":"Department of Neurology University Hospital Basel, University of Basel  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tracy","family":"Lau","sequence":"additional","affiliation":[{"name":"MRC Centre for Neuromuscular Diseases UCL Queen Square Institute of Neurology  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3484-3423","authenticated-orcid":false,"given":"Shahryar","family":"Alavi","sequence":"additional","affiliation":[{"name":"Division of Genetics, Department of Cellular and Molecular Biology and Microbiology, Faculty of Science and Technology University of Isfahan  Isfahan Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ehsan Ghayoor","family":"Karimiani","sequence":"additional","affiliation":[{"name":"Molecular and Clinical Sciences Institute, St. George's, University of London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jalal","family":"Vallian","sequence":"additional","affiliation":[{"name":"Division of Genetics, Department of Cellular and Molecular Biology and Microbiology, Faculty of Science and Technology University of Isfahan  Isfahan Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bobby G.","family":"Ng","sequence":"additional","affiliation":[{"name":"Human Genetics Program Sanford Burnham Prebys Medical Discovery Institute  La Jolla California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samaneh","family":"Noroozi Asl","sequence":"additional","affiliation":[{"name":"Pediatrics Endocrinology Department Mashhad University of Medical Sciences  Mashhad Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javad","family":"Akhondian","sequence":"additional","affiliation":[{"name":"Pediatric Neurology Department Ghaem hospital, Mashhad University of Medical Sciences  Mashhad Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amir","family":"Bahreini","sequence":"additional","affiliation":[{"name":"Karyogen Medical Genetics Laboratory Alzahra University  Isfahan Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Omid","family":"Yaghini","sequence":"additional","affiliation":[{"name":"Child Growth and Development Research Center Research Institute for Primordial Prevention of Non\u2010Communicable Disease, Isfahan University of Medical Sciences  Isfahan Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prech","family":"Uapinyoying","sequence":"additional","affiliation":[{"name":"Neuromuscular and Neurogenetic Disorders of Childhood Section National Institute of Neurological Disorders and Stroke, National Institutes of Health  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carsten","family":"Bonnemann","sequence":"additional","affiliation":[{"name":"Neuromuscular and Neurogenetic Disorders of Childhood Section National Institute of Neurological Disorders and Stroke, National Institutes of Health  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hudson H.","family":"Freeze","sequence":"additional","affiliation":[{"name":"Human Genetics Program Sanford Burnham Prebys Medical Discovery Institute  La Jolla California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vajira H. W.","family":"Dissanayake","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Genetics &amp; Biomedical Informatics, Faculty of Medicine University of Colombo  Colombo Sri Lanka"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0994-6954","authenticated-orcid":false,"given":"Nirmala D.","family":"Sirisena","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Genetics &amp; Biomedical Informatics, Faculty of Medicine University of Colombo  Colombo Sri Lanka"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miriam","family":"Schmidts","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Adolescent Medicine University Hospital Freiburg, Freiburg University Faculty of Medicine  Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henry","family":"Houlden","sequence":"additional","affiliation":[{"name":"MRC Centre for Neuromuscular Diseases UCL Queen Square Institute of Neurology  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2732-4043","authenticated-orcid":false,"given":"Andres","family":"Moreno\u2010De\u2010Luca","sequence":"additional","affiliation":[{"name":"Autism &amp; Developmental Medicine Institute, Genomic Medicine Institute, Department of Radiology Diagnostic Medicine Institute  Danville Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reza","family":"Maroofian","sequence":"additional","affiliation":[{"name":"MRC Centre for Neuromuscular Diseases UCL Queen Square Institute of Neurology  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,8,19]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/jimd.12095"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2009.06.006"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nmd.2017.07.006"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nmd.2019.05.004"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13395-018-0170-1"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.13634"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-20584-4"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btv362"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.R112.429274"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-neuro-071714-034019"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M511311200"}],"container-title":["Clinical Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cge.14208","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/cge.14208","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cge.14208","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,22]],"date-time":"2023-08-22T06:10:23Z","timestamp":1692684623000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/cge.14208"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,19]]},"references-count":12,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2022,12]]}},"alternative-id":["10.1111\/cge.14208"],"URL":"https:\/\/doi.org\/10.1111\/cge.14208","archive":["Portico"],"relation":{},"ISSN":["0009-9163","1399-0004"],"issn-type":[{"value":"0009-9163","type":"print"},{"value":"1399-0004","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,19]]},"assertion":[{"value":"2022-04-08","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-08-02","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-08-19","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}