{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T07:49:37Z","timestamp":1753861777672,"version":"3.41.2"},"reference-count":36,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2024,6,10]],"date-time":"2024-06-10T00:00:00Z","timestamp":1717977600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2024,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Pathogenic variants in <jats:italic>FLNA<\/jats:italic> cause a diversity of X\u2010linked developmental disorders associated with either preserved or diminished levels of filamin A protein and are conceptualized dichotomously as relating to underlying gain\u2010 or loss\u2010of\u2010function pathogenic mechanisms. Hemizygosity for germline deletions or truncating variants in <jats:italic>FLNA<\/jats:italic> is generally considered to result in embryonic lethality. Structurally, filamin A is composed of an N\u2010terminal actin\u2010binding region, followed by 24 immunoglobulin\u2010like repeat units. The repeat domains are separated into distinct segments by two regions of low\u2010complexity known as hinge\u20101 and hinge\u20102. Hinge\u20101 is proposed to confer flexibility to the otherwise rigid protein and is a target for cleavage by calpain with the resultant filamin fragments mediating crucial cellular signaling processes. Here, three families with pathogenic variants in <jats:italic>FLNA<\/jats:italic> that impair the function of hinge\u20101 in males are described, leading to distinct clinical phenotypes. One large in\u2010frame deletion that includes the hinge leads to frontometaphyseal dysplasia in affected males and females, while two germline truncating variants located within the exon encoding hinge 1 result in phenotypes in males that are explained by exon skipping and under\u2010expression of a transcript that deletes hinge\u20101 from the resultant protein. These three variants affecting hinge\u20101 indicate that this domain does not mediate cellular functions that, when deficientresult in embryonic lethality in males and that germline truncating variants in this region of <jats:italic>FLNA<\/jats:italic> can result in viable phenotypes in males.<\/jats:p>","DOI":"10.1002\/ajmg.a.63779","type":"journal-article","created":{"date-parts":[[2024,6,10]],"date-time":"2024-06-10T07:40:48Z","timestamp":1718005248000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Pathogenic <scp><i>FLNA<\/i><\/scp> variants affecting the hinge region of filamin A are associated with male survival"],"prefix":"10.1002","volume":"194","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2990-0232","authenticated-orcid":false,"given":"Emma M.","family":"Wade","sequence":"first","affiliation":[{"name":"Department of Women's and Children's Health, Dunedin School of Medicine Otago University  Dunedin New Zealand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tim","family":"Morgan","sequence":"additional","affiliation":[{"name":"Department of Women's and Children's Health, Dunedin School of Medicine Otago University  Dunedin New Zealand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gregory","family":"Gimenez","sequence":"additional","affiliation":[{"name":"Department of Pathology, Dunedin School of Medicine Otago University  Dunedin New Zealand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zandra A.","family":"Jenkins","sequence":"additional","affiliation":[{"name":"Department of Women's and Children's Health, Dunedin School of Medicine Otago University  Dunedin New Zealand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hannah","family":"Titheradge","sequence":"additional","affiliation":[{"name":"Birmingham Women's and Children's NHS Foundation Trust  Birmingham UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marie","family":"O'Donnell","sequence":"additional","affiliation":[{"name":"Birmingham Women's and Children's NHS Foundation Trust  Birmingham UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Skidmore","sequence":"additional","affiliation":[{"name":"IWK Hospital, Dalhousie University  Halifax Nova Scotia Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohnish","family":"Suri","sequence":"additional","affiliation":[{"name":"Clinical Genetics Service City Hospital  Nottingham UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5181-7809","authenticated-orcid":false,"given":"Stephen P.","family":"Robertson","sequence":"additional","affiliation":[{"name":"Department of Women's and Children's Health, Dunedin School of Medicine Otago University  Dunedin New Zealand"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2024,6,10]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkaa434"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceb.2020.08.007"},{"issue":"6","key":"e_1_2_10_4_1","first-page":"1229","article-title":"Methylation of HpaII and HhaI sites near the polymorphic CAG repeat in the human androgen\u2010receptor gene correlates with X chromosome inactivation","volume":"51","author":"Allen R. 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