{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T04:27:39Z","timestamp":1786595259264,"version":"build-2736575974"},"reference-count":30,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T00:00:00Z","timestamp":1786492800000},"content-version":"vor","delay-in-days":223,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100005235","name":"Institute for Advanced Study","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005235","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005713","name":"Technische Universit\u00e4t M\u00fcnchen","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005713","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002347","name":"Bundesministerium f\u00fcr Bildung und Forschung","doi-asserted-by":"publisher","award":["01GM2302"],"award-info":[{"award-number":["01GM2302"]}],"id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003042","name":"Else Kr\u00f6ner-Fresenius-Stiftung","doi-asserted-by":"publisher","award":["2022_EKSE.185"],"award-info":[{"award-number":["2022_EKSE.185"]}],"id":[{"id":"10.13039\/501100003042","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Human Mutation"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:p>\n                    Patients with suspected monogenic disorders often remain undiagnosed after exome sequencing. We report a family with two sisters affected by a complex spastic paraplegia. Initial exome sequencing had identified monoallelic pathogenic nonsense variants in\n                    <jats:italic>AP4S1<\/jats:italic>\n                    and\n                    <jats:italic>AP4B1<\/jats:italic>\n                    , subunits of the adaptor protein complex 4 (AP\u20104), suggesting digenic inheritance. As digenic inheritance has not been established for AP\u20104\u2013associated disorders, we applied a multiomics approach including genome sequencing, RNA sequencing and proteomics to clarify the genetic cause. By RNA sequencing a predicted synonymous variant (NM_006594.5:c.969G &gt; A), compound heterozygous to the nonsense variant in\n                    <jats:italic>AP4B1<\/jats:italic>\n                    and previously considered as benign, was re\u2010prioritized as aberrant splicing was demonstrated. Proteomics showed reduced abundance of AP\u20104 components AP4B1 and AP4M1 and an upregulation of the cargo protein ATG9A, confirming AP\u20104 deficiency. Although the\n                    <jats:italic>AP4S1<\/jats:italic>\n                    variant resulted in nonsense\u2010mediated decay, the identification of biallelic causative variants in\n                    <jats:italic>AP4B1<\/jats:italic>\n                    established the diagnosis of monogenic \u201cSpastic paraplegia 47, autosomal recessive\u201d while the initial hypothesis of digenic inheritance was refuted. This study illustrates the value of multiomics approaches in the diagnostic workflow of rare diseases and the potential for pathogenicity of synonymous variants.\n                  <\/jats:p>","DOI":"10.1155\/humu\/8645235","type":"journal-article","created":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T03:41:23Z","timestamp":1786592483000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Splice effect of a synonymous variant in\n                    <i>AP4B1<\/i>\n                    : multiomics approach establishes the diagnosis in two sisters with spastic 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