{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T11:49:40Z","timestamp":1782301780001,"version":"3.54.5"},"reference-count":41,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T00:00:00Z","timestamp":1782259200000},"content-version":"vor","delay-in-days":174,"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"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genetics Research"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      The\n                      <jats:italic>CCDC22<\/jats:italic>\n                      gene is a key regulator of endosomal trafficking and NF\u2010\u03baB signaling, and its dysfunction is implicated in a spectrum of X\u2010linked neurodevelopmental disorders, including Ritscher\u2013Schinzel syndrome 2, intellectual disability, and epilepsy. Despite the identification of\n                      <jats:italic>CCDC22<\/jats:italic>\n                      variants having increased, a comprehensive biological characterization, including its spatiotemporal expression and functional molecular networks, remains to be systematically delineated. Furthermore, the rarity of\n                      <jats:italic>CCDC22<\/jats:italic>\n                      variants created a significant challenge in distinguishing their pathogenicity. This study aimed to explore the integration of biological context\u2010informed and clinical genetic analysis workflows and to perform an exploratory evaluation of prediction algorithms to better optimize the genetic diagnosis process for\n                      <jats:italic>CCDC22<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Multilevel biological analysis was performed to evaluate the spatiotemporal expression patterns of\n                      <jats:italic>CCDC22<\/jats:italic>\n                      across developmental stages. A protein\u2013protein interaction network was constructed to identify key functional modules and pathway enrichments. Additionally, an expert\u2010classified dataset of\n                      <jats:italic>CCDC22<\/jats:italic>\n                      missense variants was utilized to conduct an exploratory performance evaluation of twenty prediction algorithms, specifically assessing the effect of filtering out variants observed as population hemizygotes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Result<\/jats:title>\n                    <jats:p>\n                      <jats:italic>CCDC22<\/jats:italic>\n                      exhibits distinct spatiotemporal expression dynamics and chromatin accessibility patterns closely associated with neurodevelopmental processes. PPI and functional enrichment analyses highlighted its core involvement in endocytic recycling and vesicle transport. In the exploratory missense variant evaluation, meta\u2010predictors, notably ClinPred and MetaRNN, demonstrated the highest predictive potential within this limited cohort. After filtering out variants observed as hemizygotes in the gnomAD database, most of the algorithms\u2019 performance improved in distinguishing the pathogenicity of variants and genetic diagnosis. ClinPred, M\u2010CAP, MetaRNN, and SIFT achieved the highest balanced accuracy (84.6%, 80.8%, 78.7%, and 76.1%, respectively). ClinPred, M\u2010CAP, and MetaRNN achieved the highest AUC value (&gt; 0.9).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      This study delineates the spatiotemporal and functional molecular network of\n                      <jats:italic>CCDC22<\/jats:italic>\n                      in neurodevelopment. A combination of population\u2010based strategy and prediction enhanced the performance of most algorithms. ClinPred and MetaRNN showed higher predictive potential. This study may provide insights into the evaluation of variants in\n                      <jats:italic>CCDC22<\/jats:italic>\n                      \u2010related diseases.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1155\/genr\/8137770","type":"journal-article","created":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T11:09:55Z","timestamp":1782299395000},"source":"Crossref","is-referenced-by-count":0,"title":["Biological Context\u2013Informed and Population\u2010Stratified Strategies Improve Genetic Diagnosis of\n                    <i>CCDC22<\/i>\n                    \u2010Related Disorder"],"prefix":"10.1155","volume":"2026","author":[{"given":"Pei-Qi","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-6848-2021","authenticated-orcid":false,"given":"Peng-Yu","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-6657-289X","authenticated-orcid":false,"given":"Si-Qi","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Ding","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-9254-711X","authenticated-orcid":false,"given":"Wen-Hui","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-8327-4390","authenticated-orcid":false,"given":"Yao","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7957-7886","authenticated-orcid":false,"given":"Hua","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7184-1267","authenticated-orcid":false,"given":"Sheng","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8859-6042","authenticated-orcid":false,"given":"Heng","family":"Meng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6062-9527","authenticated-orcid":false,"given":"Jing","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,24]]},"reference":[{"key":"e_1_2_12_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41431-022-01162-2"},{"key":"e_1_2_12_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-34264-y"},{"key":"e_1_2_12_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2022.10.013"},{"key":"e_1_2_12_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2018.08.005"},{"key":"e_1_2_12_5_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkaa288"},{"key":"e_1_2_12_6_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddu733"},{"key":"e_1_2_12_7_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkx390"},{"key":"e_1_2_12_8_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.adg7492"},{"key":"e_1_2_12_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3703"},{"key":"e_1_2_12_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-19669-x"},{"key":"e_1_2_12_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-018-0329-z"},{"key":"e_1_2_12_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2009.86"},{"key":"e_1_2_12_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2015.123"},{"key":"e_1_2_12_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth0410-248"},{"key":"e_1_2_12_15_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkr407"},{"key":"e_1_2_12_16_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0046688"},{"key":"e_1_2_12_17_2","doi-asserted-by":"crossref","unstructured":"LiC. 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