{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T06:26:37Z","timestamp":1788848797322,"version":"build-2803163510"},"reference-count":27,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2025,9,22]],"date-time":"2025-09-22T00:00:00Z","timestamp":1758499200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","award":["RF_2021_12373524"],"award-info":[{"award-number":["RF_2021_12373524"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2026,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    The\n                    <jats:italic>ADNP<\/jats:italic>\n                    syndrome, also known as Helsmoortel\u2010Van der Aa syndrome (HVDAS), is an autosomal dominant neurodevelopmental disorder caused by heterozygous truncating variants abolishing the homeobox and\/or HP1 domains of ADNP. Rare missense changes in the\n                    <jats:italic>ADNP<\/jats:italic>\n                    gene are usually variants of uncertain significance or reclassified as (likely) benign because they are inherited from an unaffected parent, and a causative role was documented for only three of them. We report a 24\u2010year\u2010old Italian woman presenting with intellectual disability, visual and severe speech impairment, microcephaly, truncal obesity, and hirsutism. Behavioral disturbance was significant and included fragmented sleep, self\u2010 and hetero\u2010aggression, outbursts of anger, and verbal and physical violence crises. Additional unusual findings were hyperandrogenism and secondary amenorrhea. Next\u2010generation sequencing showed the novel\n                    <jats:italic>de novo<\/jats:italic>\n                    missense variant c.2405C&gt;T, p.(Ser802Phe) affecting the DNA\u2010binding homeodomain of\n                    <jats:italic>ADNP<\/jats:italic>\n                    .\n                    <jats:italic>In silico<\/jats:italic>\n                    analysis revealed this variant is located in a genomic region highly intolerant to missense changes, and several tools predicted a deleterious effect on protein function. Counterintuitively to the known molecular pathogenesis for\n                    <jats:italic>ADNP<\/jats:italic>\n                    syndrome, calculation of the binding free energy and dissociation constant of the p.(Ser802Phe) missense substitution suggested a stronger ADNP\u2010DNA interaction, thus opening the path to the hypothesis of a gain\u2010of\u2010function effect. This clinical report expands genotype\u2013phenotype variability and correlations in\n                    <jats:italic>ADNP<\/jats:italic>\n                    syndrome.\n                  <\/jats:p>","DOI":"10.1002\/ajmg.a.64264","type":"journal-article","created":{"date-parts":[[2025,9,22]],"date-time":"2025-09-22T09:15:38Z","timestamp":1758532538000},"page":"468-474","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["The\n                    <i>De Novo<\/i>\n                    p.(\n                    <scp>Ser802Phe<\/scp>\n                    ) Variant Causes Helsmoortel\u2010Van der Aa\/\n                    <scp>\n                      <i>ADNP<\/i>\n                    <\/scp>\n                    Syndrome in a 24\u2010Year\u2010Old Woman and Is Predicted to Perturb\n                    <scp>ADNP<\/scp>\n                    \u2010\n                    <scp>DNA<\/scp>\n                    Affinity"],"prefix":"10.1002","volume":"200","author":[{"given":"Mario","family":"Benvenuto","sequence":"first","affiliation":[{"name":"UOC Genetica Medica, Fondazione IRCCS Casa Sollievo della Sofferenza  San Giovanni Rotondo Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marilena Carmela Di","family":"Giacomo","sequence":"additional","affiliation":[{"name":"Servizio di Genetica Medica e Laboratorio di Citogenetica, SIC Anatomia Patologica, Ospedale \u201cSan Carlo\u201d  Potenza Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ada","family":"Piepoli","sequence":"additional","affiliation":[{"name":"UOC Genetica Medica, Fondazione IRCCS Casa Sollievo della Sofferenza  San Giovanni Rotondo Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimo","family":"Carella","sequence":"additional","affiliation":[{"name":"UOC Genetica Medica, Fondazione IRCCS Casa Sollievo della Sofferenza  San Giovanni Rotondo 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