{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T18:19:29Z","timestamp":1790705969597,"version":"4.1.0"},"reference-count":29,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2013,12,5]],"date-time":"2013-12-05T00:00:00Z","timestamp":1386201600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2014,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:label\/>\n                    <jats:p>\n                      Shah\u2010Waardenburg syndrome or Waardenburg syndrome type 4 (WS4) is a neurocristopathy characterized by the association of deafness, depigmentation and Hirschsprung disease. Three disease\u2010causing genes have been identified so far for WS4:\n                      <jats:italic>EDNRB<\/jats:italic>\n                      ,\n                      <jats:italic>EDN3<\/jats:italic>\n                      , and\n                      <jats:italic>SOX10<\/jats:italic>\n                      .\n                      <jats:italic>SOX10<\/jats:italic>\n                      mutations, found in 45\u201355% of WS4 patients, are inherited in autosomal dominant way. In addition, mutations in\n                      <jats:italic>SOX10<\/jats:italic>\n                      are also responsible for an extended syndrome involving peripheral and central neurological phenotypes, referred to as PCWH (peripheral demyelinating neuropathy, central dysmyelinating leucodystrophy, Waardenburg syndrome, Hirschsprung disease). Such mutations are mostly private, and a high intra\u2010 and inter\u2010familial variability exists. In this report, we present a patient with WS4 and a second with PCWH due to\n                      <jats:italic>SOX10<\/jats:italic>\n                      mutations supporting again the genetic and phenotypic heterogeneity of these syndromes. Interestingly, the WS4 family carries an insertion of 19 nucleotides in exon 5 of\n                      <jats:italic>SOX10<\/jats:italic>\n                      , which results in distinct phenotypes along three different generations: hypopigmentation in the maternal grandmother, hearing loss in the mother, and WS4 in the proband. Since mosaicism cannot explain the three different related\u2010WS features observed in this family, we propose as the most plausible explanation the existence of additional molecular events, acting in an additive or multiplicative fashion, in genes or regulatory regions unidentified so far. On the other hand, the PCWH case was due to a de novo deletion in exon 5 of the gene. Efforts should be devoted to unravel the mechanisms underlying the intrafamilial phenotypic variability observed in the families affected, and to identify new genes responsible for the still unsolved WS4 cases. \u00a9 2013 Wiley Periodicals, Inc.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ajmg.a.36302","type":"journal-article","created":{"date-parts":[[2013,12,5]],"date-time":"2013-12-05T15:31:10Z","timestamp":1386257470000},"page":"542-547","source":"Crossref","is-referenced-by-count":23,"title":["Waardenburg syndrome type 4: Report of two new cases caused by\n                    <i>SOX<\/i>\n                    <i>10<\/i>\n                    mutations in Spain"],"prefix":"10.1002","volume":"164","author":[{"given":"Raquel M.","family":"Fern\u00e1ndez","sequence":"first","affiliation":[{"name":"Department of Genetics, Reproduction and Fetal Medicine, Institute of Biomedicine of Seville (IBIS) University Hospital Virgen del Roc\u00edo\/CSIC\/University of Seville Seville Spain"},{"name":"Centre for Biomedical Network Research on Rare Diseases (CIBERER) Seville Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raquel","family":"N\u00fa\u00f1ez\u2010Ramos","sequence":"additional","affiliation":[{"name":"Department of Pediatrics University Hospital 12 de Octubre Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00aa Valle","family":"Enguix\u2010Riego","sequence":"additional","affiliation":[{"name":"Department of Genetics, Reproduction and Fetal Medicine, Institute of Biomedicine of Seville (IBIS) University Hospital Virgen del Roc\u00edo\/CSIC\/University of Seville Seville Spain"},{"name":"Centre for Biomedical Network Research on Rare Diseases (CIBERER) Seville Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco Jos\u00e9","family":"Rom\u00e1n\u2010Rodr\u00edguez","sequence":"additional","affiliation":[{"name":"Department of Genetics, Reproduction and Fetal Medicine, Institute of Biomedicine of Seville (IBIS) University Hospital Virgen del Roc\u00edo\/CSIC\/University of Seville Seville Spain"},{"name":"Centre for Biomedical Network Research on Rare Diseases (CIBERER) Seville Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enrique","family":"Gal\u00e1n\u2010G\u00f3mez","sequence":"additional","affiliation":[{"name":"Unit of Genetics University Hospital of Badajoz Badajoz Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilio","family":"Blesa\u2010S\u00e1nchez","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Department of Pediatrics University Hospital of Badajoz Badajoz Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guillermo","family":"Anti\u00f1olo","sequence":"additional","affiliation":[{"name":"Department of Genetics, Reproduction and Fetal Medicine, Institute of Biomedicine of Seville (IBIS) University Hospital Virgen del Roc\u00edo\/CSIC\/University of Seville Seville Spain"},{"name":"Centre for Biomedical Network Research on Rare Diseases (CIBERER) Seville Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ram\u00f3n","family":"N\u00fa\u00f1ez\u2010N\u00fa\u00f1ez","sequence":"additional","affiliation":[{"name":"Service of Paediatric Surgery University Hospital of Badajoz Badajoz Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salud","family":"Borrego","sequence":"additional","affiliation":[{"name":"Department of Genetics, Reproduction and Fetal Medicine, Institute of Biomedicine of Seville (IBIS) University Hospital Virgen del Roc\u00edo\/CSIC\/University of Seville Seville Spain"},{"name":"Centre for Biomedical Network Research on Rare Diseases (CIBERER) Seville 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