{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T17:26:23Z","timestamp":1788542783547,"version":"build-2803163510"},"reference-count":20,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2025,4,30]],"date-time":"2025-04-30T00:00:00Z","timestamp":1745971200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["PJT\u2010178315"],"award-info":[{"award-number":["PJT\u2010178315"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100014370","name":"Simons Foundation Autism Research Initiative","doi-asserted-by":"publisher","award":["887172"],"award-info":[{"award-number":["887172"]}],"id":[{"id":"10.13039\/100014370","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Genetics"],"published-print":{"date-parts":[[2025,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Despite the massive adoption of sequencing technologies, disease\u2010specific diagnosis remains challenging, particularly for genes with highly homologous pseudogenes like\n                    <jats:italic>HNRNPK<\/jats:italic>\n                    . Pathogenic\n                    <jats:italic>HNRNPK<\/jats:italic>\n                    variants cause Au\u2010Kline syndrome (AKS), a neurodevelopmental disorder with malformations and distinctive facial features. We validated a novel\n                    <jats:italic>de novo HNRNPK<\/jats:italic>\n                    intronic variant (c.1192\u20103 C&gt;A, p.Leu398ValfsTer21) in a patient previously misdiagnosed with Kabuki Syndrome (KS). By combining sequencing, in\u00a0vitro splicing assays, molecular modelling, and protein function analysis, we characterised the molecular defect. A unique DNA methylation (DNAm) signature was recently identified in AKS, with missense variants showing an intermediate DNAm pattern, suggesting an epi\u2010genotype\u2013phenotype correlation linked to milder clinical features. The DNAm signature is a valuable tool for variant interpretation, especially in unclear AKS cases. We demonstrate that two independent approaches\u2014functional characterisation and DNAm evaluation\u2014confirmed a partial loss of HNRNPK function and validated an AKS diagnosis with a mild phenotype. Our findings highlight that a multidisciplinary approach integrating genomic and epigenomic analyses with functional studies and clinical assessment significantly improves rare disease diagnosis.\n                  <\/jats:p>","DOI":"10.1111\/cge.14763","type":"journal-article","created":{"date-parts":[[2025,4,30]],"date-time":"2025-04-30T05:42:57Z","timestamp":1745991777000},"page":"576-581","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["A Novel Intronic Variant in the\n                    <scp>KH3<\/scp>\n                    Domain of\n                    <scp>HNRNPK<\/scp>\n                    Leads to a Mild Form of Au\u2010Kline Syndrome"],"prefix":"10.1111","volume":"108","author":[{"given":"Maura","family":"Mingoia","sequence":"first","affiliation":[{"name":"Institute of Genetic and Biomedical Research, CNR  Cagliari Monserrato Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Meloni","sequence":"additional","affiliation":[{"name":"Institute of Genetic and Biomedical Research, CNR  Cagliari Monserrato Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Sedda","sequence":"additional","affiliation":[{"name":"Antonio Cao Children's Hospital ASL  Cagliari Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanaa","family":"Choufani","sequence":"additional","affiliation":[{"name":"Program in Genetics and Genome Biology, The Hospital for Sick Children  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isadora","family":"Asunis","sequence":"additional","affiliation":[{"name":"Institute of Genetic and Biomedical Research, CNR  Cagliari Monserrato 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for Computational Medicine, The Hospital for Sick Children  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleonora","family":"di Venere","sequence":"additional","affiliation":[{"name":"Laboratory of Regulatory and Functional Genomics Fondazione IRCCS Casa Sollievo Della Sofferenza, San Giovanni Rotondo  Foggia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriella Maria","family":"Squeo","sequence":"additional","affiliation":[{"name":"Laboratory of Regulatory and Functional Genomics Fondazione IRCCS Casa Sollievo Della Sofferenza, San Giovanni Rotondo  Foggia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincenzo","family":"Rallo","sequence":"additional","affiliation":[{"name":"Institute of Genetic and Biomedical Research, CNR  Cagliari Monserrato Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Giuseppina","family":"Marini","sequence":"additional","affiliation":[{"name":"Institute of Genetic and Biomedical Research, CNR  Cagliari Monserrato Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Moi","sequence":"additional","affiliation":[{"name":"Institute of Genetic and Biomedical Research, CNR  Cagliari Monserrato Italy"},{"name":"Antonio Cao Children's Hospital ASL  Cagliari Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salvatore","family":"Savasta","sequence":"additional","affiliation":[{"name":"Antonio Cao Children's Hospital ASL  Cagliari Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosanna","family":"Weksberg","sequence":"additional","affiliation":[{"name":"Program in Genetics and Genome Biology, The Hospital for Sick Children  Toronto Ontario 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