{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T03:40:56Z","timestamp":1759722056485,"version":"build-2065373602"},"reference-count":11,"publisher":"BMJ","issue":"8","license":[{"start":{"date-parts":[[2022,12,29]],"date-time":"2022-12-29T00:00:00Z","timestamp":1672272000000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["WT093205","WT104033AIA"],"award-info":[{"award-number":["WT093205","WT104033AIA"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["G0601943","MR\/S005021\/1"],"award-info":[{"award-number":["G0601943","MR\/S005021\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008164","name":"Muscular Dystrophy UK","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100008164","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000833","name":"Rosetree Trust","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100000833","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100000346","name":"Ataxia UK","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000346","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005202","name":"Muscular Dystrophy Association","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100005202","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100013790","name":"Brain Research UK","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100013790","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100013128","name":"Multiple System Atrophy Trust","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100013128","id-type":"DOI","asserted-by":"publisher"}]},{"name":"SPARKS GOSH Charity"},{"name":"International Centre for Genomic Medicine","award":["MR\/S005021\/1"],"award-info":[{"award-number":["MR\/S005021\/1"]}]},{"name":"London Hospitals Biomedical Research Centre"}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Med Genet"],"accepted":{"date-parts":[[2022,12,12]]},"published-print":{"date-parts":[[2023,8]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>MAPK-activated protein kinase 5 (MAPKAPK5) is an essential enzyme for diverse cellular processes. Dysregulation of the pathways regulated by MAPKAPK enzymes can lead to the development of variable diseases. Recently, homozygous loss-of-function variants in <jats:italic>MAPKAPK5<\/jats:italic> were reported in four patients from three families presenting with a recognisable neurodevelopmental disorder, so-called \u2018neurocardiofaciodigital\u2019 syndrome.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Objective and methods<\/jats:title>\n                  <jats:p>In order to improve characterisation of the clinical features associated with biallelic <jats:italic>MAPKAPK5<\/jats:italic> variants, we employed a genotype-first approach combined with reverse deep-phenotyping of three affected individuals.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>In the present study, we identified biallelic loss-of-function and missense <jats:italic>MAPKAPK5<\/jats:italic> variants in three unrelated individuals from consanguineous families. All affected individuals exhibited a syndromic neurodevelopmental disorder characterised by severe global developmental delay, intellectual disability, characteristic facial morphology, brachycephaly, digital anomalies, hair and nail defects and neuroradiological findings, including cerebellar hypoplasia and hypomyelination, as well as variable vision and hearing impairment. Additional features include failure to thrive, hypotonia, microcephaly and genitourinary anomalies without any reported congenital heart disease.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>In this study, we consolidate the causality of loss of MAPKAPK5 function and further delineate the molecular and phenotypic spectrum associated with this new ultra-rare neurodevelopmental syndrome.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jmg-2022-108566","type":"journal-article","created":{"date-parts":[[2022,12,29]],"date-time":"2022-12-29T13:25:39Z","timestamp":1672320339000},"page":"791-796","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["Consolidating the association of biallelic <i>MAPKAPK5<\/i> pathogenic variants with a distinct syndromic neurodevelopmental disorder"],"prefix":"10.1136","volume":"60","author":[{"given":"Reza","family":"Maroofian","sequence":"first","affiliation":[{"name":"Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, London, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4900-9877","authenticated-orcid":false,"given":"Stephanie","family":"Efthymiou","sequence":"additional","affiliation":[{"name":"Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, London, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohnish","family":"Suri","sequence":"additional","affiliation":[{"name":"Clinical Genetics Service, Nottingham University Hospitals NHS Trust, Nottingham, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fatima","family":"Rahman","sequence":"additional","affiliation":[{"name":"Department of Developmental - Behavioral Pediatrics, University of Child Health Sciences & The Children\u2019s Hospital, Lahore, Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7840-0002","authenticated-orcid":false,"given":"Maha S","family":"Zaki","sequence":"additional","affiliation":[{"name":"Clinical Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shazia","family":"Maqbool","sequence":"additional","affiliation":[{"name":"Department of Developmental - Behavioral Pediatrics, University of Child Health Sciences & The Children\u2019s Hospital, Lahore, Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Najwa","family":"Anwa","sequence":"additional","affiliation":[{"name":"Department of Developmental - Behavioral Pediatrics, University of Child Health Sciences & The Children\u2019s Hospital, Lahore, Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Victor L","family":"Ruiz-P\u00e9rez","sequence":"additional","affiliation":[{"name":"Instituto de Investigaciones Biom\u00e9dicas \"Alberto Sols\", Consejo Superior de Investigaciones Cient\u00edficas (CSIC), Universidad Aut\u00f3noma de Madrid (UAM), and CIBER de Enfermedades Raras (CIBERER), Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shira","family":"Yanovsky-Dagan","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Orly","family":"Elpeleg","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel"},{"name":"Department of Genetics, Hadassah Medical Center, Jerusalem, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sniya","family":"Sudhakar","sequence":"additional","affiliation":[{"name":"Department of Radiology, Great Ormond Street Hospital for Children, London, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kshitij","family":"Mankad","sequence":"additional","affiliation":[{"name":"Department of Radiology, Great Ormond Street Hospital for Children, London, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3595-7075","authenticated-orcid":false,"given":"Tamar","family":"Harel","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel"},{"name":"Department of Genetics, Hadassah Medical Center, Jerusalem, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Henry","family":"Houlden","sequence":"additional","affiliation":[{"name":"Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, London, 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