{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T04:32:36Z","timestamp":1791088356482,"version":"4.1.0"},"reference-count":41,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2022,7,24]],"date-time":"2022-07-24T00:00:00Z","timestamp":1658620800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000861","name":"Burroughs Wellcome Fund","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000861","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000011","name":"Howard Hughes Medical Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000011","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R01NS035129"],"award-info":[{"award-number":["R01NS035129"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Ann Clin Transl Neurol"],"published-print":{"date-parts":[[2022,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>This study delineates the clinical and molecular spectrum of <jats:italic>ANKLE2<\/jats:italic>\u2010related microcephaly (MIC), as well as highlights shared pathological mechanisms between <jats:italic>ANKLE2<\/jats:italic> and the Zika virus.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We identified 12 individuals with MIC and variants in <jats:italic>ANKLE2<\/jats:italic> with a broad range of features. Probands underwent thorough phenotypic evaluations, developmental assessments, and anthropometric measurements. Brain imaging studies were systematically reviewed for developmental abnormalities. We functionally interrogated a subset of identified <jats:italic>ANKLE2<\/jats:italic> variants in <jats:italic>Drosophila melanogaster<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>All individuals had MIC (<jats:italic>z<\/jats:italic>\u2010score\u2009\u2264\u2009\u22123), including nine with congenital MIC. We identified a broad range of brain abnormalities including simplified cortical gyral pattern, full or partial callosal agenesis, increased extra\u2010axial spaces, hypomyelination, cerebellar vermis hypoplasia, and enlarged cisterna magna. All probands had developmental delays in at least one domain, with speech and language delays being the most common. Six probands had skin findings characteristic of <jats:italic>ANKLE2<\/jats:italic> including hyper\u2010 and hypopigmented macules. Only one individual had scalp rugae. Functional characterization in Drosophila recapitulated the human MIC phenotype. Of the four variants tested, p.Val229Gly, p.Arg236*, and p.Arg536Cys acted as partial\u2010loss\u2010of\u2010function variants, whereas the c.1421\u20101G&gt;C splicing variant demonstrated a strong loss\u2010of\u2010function effect.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Deleterious variants in the <jats:italic>ANKLE2<\/jats:italic> gene cause a unique MIC syndrome characterized by congenital or postnatal MIC, a broad range of structural brain abnormalities, and skin pigmentary changes. Thorough functional characterization has identified shared pathogenic mechanisms between <jats:italic>ANKLE2\u2010<\/jats:italic>related MIC and congenital Zika virus infection. This study further highlights the importance of a thorough diagnostic evaluation including molecular diagnostic testing in individuals with MIC.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acn3.51629","type":"journal-article","created":{"date-parts":[[2022,7,24]],"date-time":"2022-07-24T10:40:08Z","timestamp":1658659208000},"page":"1276-1288","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["<scp><i>ANKLE2<\/i><\/scp>\u2010related microcephaly: A variable microcephaly syndrome resembling Zika infection"],"prefix":"10.1002","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5249-3255","authenticated-orcid":false,"given":"Ajay X.","family":"Thomas","sequence":"first","affiliation":[{"name":"Division Neurology and Developmental Neuroscience, Department of Pediatrics Baylor College of Medicine  Houston Texas USA"},{"name":"Jan and Dan Duncan Neurological Research Institute Texas Children's Hospital  Houston 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