{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T07:16:34Z","timestamp":1769757394327,"version":"3.49.0"},"reference-count":31,"publisher":"Wiley","issue":"11-12","license":[{"start":{"date-parts":[[2024,6,17]],"date-time":"2024-06-17T00:00:00Z","timestamp":1718582400000},"content-version":"vor","delay-in-days":16,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32300488"],"award-info":[{"award-number":["32300488"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005047","name":"Natural Science Foundation of Liaoning Province","doi-asserted-by":"publisher","award":["2022\u2010MS\u2010208"],"award-info":[{"award-number":["2022\u2010MS\u2010208"]}],"id":[{"id":"10.13039\/501100005047","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Laboratory Analysis"],"published-print":{"date-parts":[[2024,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Introduction<\/jats:title><jats:p>Piebaldism is a rare autosomal dominant disorder characterized by congenital white forelock and depigmented patches, which is most commonly caused by deleterious variants in the <jats:italic>KIT<\/jats:italic> gene.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Four <jats:italic>KIT<\/jats:italic> variants were identified in a piebaldism case series by whole\u2010exome sequencing. Functional experiments, including in\u00a0vitro minigene reporter assay and enzyme\u2010linked immunosorbent assay, were carried out to elucidate the pathogenicity of the variants. The genotype\u2013phenotype correlation was summarized through extensive literature reviewing.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>All the four cases had severe piebaldism presented with typical white forelock and diffuse depigmentation on the ventral trunk and limbs. Four germline variants at the tyrosine kinase (TK) domains of the <jats:italic>KIT<\/jats:italic> gene were identified: two novel variants c.1990+1G&gt;A (p.Pro627_Gly664delinsArg) and c.2716T&gt;C (p.Cys906Arg), and two known variants c.1879+1G&gt;A (p.Gly592_Pro627delinsAla) and c.1747G&gt;A (p.Glu583Lys). Both splicing variants caused exon skipping and inframe deletions in the TK1 domain. The missense variants resided at the TK1 and TK2 domains respectively impairing PI3K\/AKT and MAPK\/ERK signaling pathways, the downstream of KIT. All severe cases were associated with variants in the TK domains, eliciting a major dominant\u2010negative mechanism of the disease.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our data expand the mutation spectrum of <jats:italic>KIT<\/jats:italic>, emphasized by a dominant\u2010negative effect of variants in the critical TK domains in severe cases. We also share the experience of prenatal diagnosis and informed reproductive choices for the affected families.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcla.25073","type":"journal-article","created":{"date-parts":[[2024,6,18]],"date-time":"2024-06-18T05:44:28Z","timestamp":1718689468000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Novel Germline <i>KIT<\/i> Variants in Families With Severe Piebaldism: Case Series and Literature Review"],"prefix":"10.1002","volume":"38","author":[{"given":"Yuanyuan","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Clinical Genetics Shengjing Hospital of China Medical University  Shenyang China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haiming","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Shengjing Hospital of China Medical University  Shenyang China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Shengjing Hospital of China Medical University  Shenyang China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yunjing","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Developmental Pediatrics Shengjing Hospital of China Medical University  Shenyang China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chuang","family":"Qiu","sequence":"additional","affiliation":[{"name":"Department of Orthopedics Shengjing Hospital of China Medical University  Shenyang China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8653-0907","authenticated-orcid":false,"given":"Xiaoliang","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Shengjing Hospital of China Medical University  Shenyang China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2024,6,17]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1346-8138.2012.01583.x"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.4103\/2229-5178.96722"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.61576"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jdcr.2019.01.021"},{"issue":"1","key":"e_1_2_11_6_1","first-page":"58","article-title":"Novel Mutations and Deletions of the KIT (Steel Factor Receptor) Gene in Human Piebaldism","volume":"56","author":"Ezoe K.","year":"1995","journal-title":"American Journal of Human Genetics"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2007.05.055"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1711449114"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00395-007-0690-z"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1034\/j.1600-0749.2003.00055.x"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2133.1995.tb16951.x"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2022.1040747"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.20345"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/mgg3.1198"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI115772"},{"issue":"5","key":"e_1_2_11_16_1","first-page":"1058","article-title":"Mutations of the KIT (Mast\/Stem Cell Growth Factor Receptor) Proto\u2010Oncogene Account for a Continuous Range of Phenotypes in Human Piebaldism","volume":"51","author":"Spritz R. 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