{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T18:30:38Z","timestamp":1791052238599,"version":"4.1.0"},"reference-count":26,"publisher":"BMJ","issue":"3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["BMJ Open"],"accepted":{"date-parts":[[2013,2,15]]},"published-print":{"date-parts":[[2013]]},"abstract":"<jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>\n                      Till date, mutations in the genes\n                      <jats:italic>PAX3<\/jats:italic>\n                      and\n                      <jats:italic>MITF<\/jats:italic>\n                      have been described in Waardenburg syndrome (WS), which is clinically characterised by congenital hearing loss and pigmentation anomalies. Our study intended to determine the frequency of mutations and deletions in these genes, to assess the clinical phenotype in detail and to identify rational priorities for molecular genetic diagnostics procedures.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Design<\/jats:title>\n                    <jats:p>Prospective analysis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Patients<\/jats:title>\n                    <jats:p>\n                      19 Caucasian patients with typical features of WS underwent stepwise investigation of\n                      <jats:italic>PAX3<\/jats:italic>\n                      and\n                      <jats:italic>MITF<\/jats:italic>\n                      . When point mutations and small insertions\/deletions were excluded by direct sequencing, copy number analysis by multiplex ligation-dependent probe amplification was performed to detect larger deletions and duplications. Clinical data and photographs were collected to facilitate genotype\u2013phenotype analyses.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Setting<\/jats:title>\n                    <jats:p>All analyses were performed in a large German laboratory specialised in genetic diagnostics.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      15 novel and 4 previously published heterozygous mutations in\n                      <jats:italic>PAX3<\/jats:italic>\n                      and\n                      <jats:italic>MITF<\/jats:italic>\n                      were identified. Of these, six were large deletions or duplications that were only detectable by copy number analysis. All patients with\n                      <jats:italic>PAX3<\/jats:italic>\n                      mutations had typical phenotype of WS with dystopia canthorum (WS1), whereas patients with\n                      <jats:italic>MITF<\/jats:italic>\n                      gene mutations presented without dystopia canthorum (WS2). In addition, one patient with bilateral hearing loss and blue eyes with iris stroma dysplasia had a de novo missense mutation (p.Arg217Ile) in\n                      <jats:italic>MITF<\/jats:italic>\n                      .\n                      <jats:italic>MITF<\/jats:italic>\n                      3-bp deletions at amino acid position 217 have previously been described in patients with Tietz syndrome (TS), a clinical entity with hearing loss and generalised hypopigmentation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      On the basis of these findings, we conclude that sequencing and copy number analysis of both\n                      <jats:italic>PAX3<\/jats:italic>\n                      and\n                      <jats:italic>MITF<\/jats:italic>\n                      have to be recommended in the routine molecular diagnostic setting for patients, WS1 and WS2. Furthermore, our genotype\u2013phenotype analyses indicate that WS2 and TS correspond to a clinical spectrum that is influenced by\n                      <jats:italic>MITF<\/jats:italic>\n                      mutation type and position.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/bmjopen-2012-001917","type":"journal-article","created":{"date-parts":[[2013,3,19]],"date-time":"2013-03-19T20:29:03Z","timestamp":1363724943000},"page":"e001917","source":"Crossref","is-referenced-by-count":38,"title":["Spectrum of novel mutations found in Waardenburg syndrome types 1 and 2: implications for molecular genetic diagnostics"],"prefix":"10.1136","volume":"3","author":[{"given":"Gabriele","family":"Wildhardt","sequence":"first","affiliation":[{"name":"bio.logis Center for Human Genetics, Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Birgit","family":"Zirn","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Pediatric Neurology, University Medicine, G\u00f6ttingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luitgard M","family":"Graul-Neumann","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Charit\u00e9 Campus Virchow, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juliane","family":"Wechtenbruch","sequence":"additional","affiliation":[{"name":"ENT-Department, Ludwig-Maximilians-University, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Suckf\u00fcll","sequence":"additional","affiliation":[{"name":"ENT-Department, Martha-Maria Hospital, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annegret","family":"Buske","sequence":"additional","affiliation":[{"name":"Medical Center Lichtenrade, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Axel","family":"Bohring","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Westfalian Wilhelms-University, Muenster, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Kubisch","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University of Ulm, Ulm, Germany"},{"name":"Institute of Human Genetics, University of Cologne, Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefanie","family":"Vogt","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Biomedical Center, Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gertrud","family":"Strobl-Wildemann","sequence":"additional","affiliation":[{"name":"Human Genetics Ulm, Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Greally","sequence":"additional","affiliation":[{"name":"National Centre for Medical Genetics, Our Lady's Children's Hospital, Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oliver","family":"Bartsch","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Steinberger","sequence":"additional","affiliation":[{"name":"bio.logis Center for Human Genetics, Frankfurt am Main, Germany"},{"name":"Institute of Human Genetics, Justus-Liebig University, Gie\u00dfen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2013,3,18]]},"reference":[{"key":"2025121600512919000_3.3.e001917.1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.34.8.656"},{"key":"2025121600512919000_3.3.e001917.2","first-page":"455","article-title":"Mutations in the paired domain of the human PAX3 gene cause Klein-Waardenburg syndrome (WS-III) as well as Waardenburg syndrome type I (WS-I)","volume":"52","author":"Hoth","year":"1993","journal-title":"Am J Hum Genet"},{"key":"2025121600512919000_3.3.e001917.3","first-page":"449","article-title":"Correlation between Waardenburg syndrome phenotype and genotype in a population of individuals with identified PAX3 mutations","volume":"102","author":"DeStafano","year":"1998","journal-title":"Hum Genet"},{"key":"2025121600512919000_3.3.e001917.4","unstructured":"Milunsky JM . 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