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Currently, seven causative genes have been identified for WS, but clinical genetic testing results show that 38.9% of WS patients remain molecularly unexplained. In this study, we performed multi-data integration analysis through protein-protein interaction and phenotype-similarity to comprehensively decipher the potential causative factors of undiagnosed WS. In addition, we explored the association between genotypes and phenotypes in WS with the manually collected 443 cases from published literature.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>We predicted two possible WS pathogenic genes (<jats:italic>KIT<\/jats:italic>, <jats:italic>CHD7<\/jats:italic>) through multi-data integration analysis, which were further supported by gene expression profiles in single cells and phenotypes in gene knockout mouse. We also predicted twenty, seven, and five potential WS pathogenic variations in gene <jats:italic>PAX3<\/jats:italic>, <jats:italic>MITF<\/jats:italic>, and <jats:italic>SO<\/jats:italic>X10, respectively. Genotype-phenotype association analysis showed that white forelock and telecanthus were dominantly present in patients with <jats:italic>PAX3<\/jats:italic> variants; skin freckles and premature graying of hair were more frequently observed in cases with <jats:italic>MITF<\/jats:italic> variants; while aganglionic megacolon and constipation occurred more often in those with <jats:italic>SOX10<\/jats:italic> variants. Patients with variations of <jats:italic>PAX3<\/jats:italic> and <jats:italic>MITF<\/jats:italic> were more likely to have synophrys and broad nasal root. Iris pigmentary abnormality was more common in patients with variations of <jats:italic>PAX3<\/jats:italic> and <jats:italic>SOX10<\/jats:italic>. Moreover, we found that patients with variants of <jats:italic>SOX10<\/jats:italic> had a higher risk of suffering from auditory system diseases and nervous system diseases, which were closely associated with the high expression abundance of <jats:italic>SOX10<\/jats:italic> in ear tissues and brain tissues.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>Our study provides new insights into the potential causative factors of WS and an alternative way to explore clinically undiagnosed cases, which will promote clinical diagnosis and genetic counseling. However, the two potential disease-causing genes (<jats:italic>KIT<\/jats:italic>, <jats:italic>CHD7<\/jats:italic>) and 32 potential pathogenic variants (<jats:italic>PAX3<\/jats:italic>: 20, <jats:italic>MITF<\/jats:italic>: 7, <jats:italic>SOX10<\/jats:italic>: 5) predicted by multi-data integration in this study are all computational predictions and need to be further verified through experiments in follow-up research.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s13023-024-03220-y","type":"journal-article","created":{"date-parts":[[2024,6,6]],"date-time":"2024-06-06T11:05:25Z","timestamp":1717671925000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Deciphering potential causative factors for undiagnosed Waardenburg syndrome through multi-data integration"],"prefix":"10.1186","volume":"19","author":[{"given":"Fengying","family":"Sun","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minmin","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong","family":"Ji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5592-2836","authenticated-orcid":false,"given":"Tieliu","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,6,6]]},"reference":[{"issue":"9","key":"3220_CR1","doi-asserted-by":"publisher","first-page":"656","DOI":"10.1046\/j.1365-4362.1999.00750.x","volume":"38","author":"AL Dourmishev","year":"1999","unstructured":"Dourmishev AL, Dourmishev LA, Schwartz RA, Janniger CK. 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