{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T16:40:59Z","timestamp":1776271259922,"version":"3.50.1"},"reference-count":37,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,6,20]],"date-time":"2025-06-20T00:00:00Z","timestamp":1750377600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pediatr."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Non-syndromic congenital nail disorder type 4 (OMIM: 206800) is a rare autosomal recessive condition characterized by severe hypoplasia or complete absence of fingernails and toenails. This disorder results from variants in the <jats:italic>RSPO4<\/jats:italic> gene (OMIM: 610573) located on chromosome 20p13.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>This study aimed to assess the potential pathogenicity of a novel <jats:italic>RSPO4<\/jats:italic> variant identified in a Chinese patient and to explore the phenotypic and molecular genetic characteristics of Non-syndromic congenital nail disorder type 4.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Whole-exome sequencing was performed in the proband to identify candidate variants. Sanger sequencing validated the variant and determined its origin. In silico prediction tools were used to evaluate the variant's functional impact. Pathogenicity classification followed the American College of Medical Genetics and Genomics guidelines. A systematic literature review was conducted to collate previously reported cases.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A novel frameshift variant in the <jats:italic>RSPO4<\/jats:italic> gene\u2014c.268dupA\/p.Cys91fs*6\u2014was identified and classified as likely pathogenic based on the American College of Medical Genetics and Genomics guidelines. The clinical presentation of the patient was consistent with the diagnostic criteria for Non-syndromic congenital nail disorder type 4. Literature review confirmed that Non-syndromic congenital nail disorder type 4 primarily manifests as generalized nail dysplasia without associated hair, dental, or skeletal abnormalities.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This study expands the known genetic spectrum of Non-syndromic congenital nail disorder type 4 and enhances the understanding of phenotypic characteristics associated with <jats:italic>RSPO4<\/jats:italic> variants. The findings have potential implications for improving variant-based screening, genetic diagnostics, and molecular insights into <jats:italic>RSPO4<\/jats:italic>-related disorders.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fped.2025.1592954","type":"journal-article","created":{"date-parts":[[2025,6,20]],"date-time":"2025-06-20T05:23:12Z","timestamp":1750396992000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["A novel variation in RSPO4 causing nonsyndromic congenital nail disorder-4 in a Chinese patient"],"prefix":"10.3389","volume":"13","author":[{"given":"Qiang","family":"Zhang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qi","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xunzhao","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sujie","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jingsi","family":"Luo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,6,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"195","DOI":"10.15537\/smj.2020.2.24884","article-title":"Anonychia congenita in different generations of a single Saudi family","volume":"41","author":"Nooh","year":"2020","journal-title":"Saudi Med J"},{"key":"B2","doi-asserted-by":"publisher","first-page":"791","DOI":"10.1038\/sj.jid.5701088","article-title":"RSPO4 Is the major gene in autosomal-recessive anonychia and mutations cluster in the furin-like cysteine-rich domains of the wnt signaling ligand R-spondin 4","volume":"128","author":"Br\u00fcchle","year":"2008","journal-title":"J Invest Dermatol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"1245","DOI":"10.1038\/ng1883","article-title":"The gene encoding R-spondin 4 (RSPO4), a secreted protein implicated in wnt signaling, is mutated in inherited anonychia","volume":"38","author":"Blaydon","year":"2006","journal-title":"Nat Genet"},{"key":"B4","doi-asserted-by":"publisher","first-page":"1105","DOI":"10.1086\/509789","article-title":"Mutations in the gene encoding the wnt-signaling component R-spondin 4 (RSPO4) cause autosomal recessive anonychia","volume":"79","author":"Bergmann","year":"2006","journal-title":"Am J Hum Genet"},{"key":"B5","doi-asserted-by":"publisher","first-page":"351","DOI":"10.1001\/archderm.95.4.351","article-title":"Koilonychia. 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