{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T14:31:46Z","timestamp":1783693906332,"version":"3.55.0"},"reference-count":44,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2017,8,21]],"date-time":"2017-08-21T00:00:00Z","timestamp":1503273600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molec Gen &amp; Gen Med"],"published-print":{"date-parts":[[2017,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Microphthalmia and anophthalmia (<jats:styled-content style=\"fixed-case\">MA<\/jats:styled-content>) are congenital eye abnormalities that show an extremely high clinical and genetic complexity. In this study, we evaluated the implementation of whole exome sequencing (<jats:styled-content style=\"fixed-case\">WES<\/jats:styled-content>) for the genetic analysis of <jats:styled-content style=\"fixed-case\">MA<\/jats:styled-content> patients. This approach was used to investigate three unrelated families in which previous single\u2010gene analyses failed to identify the molecular cause.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A total of 47 genes previously associated with nonsyndromic <jats:styled-content style=\"fixed-case\">MA<\/jats:styled-content> were included in our panel. <jats:styled-content style=\"fixed-case\">WES<\/jats:styled-content> was performed in one affected patient from each family using the AmpliSeq<jats:styled-content style=\"fixed-case\"><jats:sup>TM<\/jats:sup><\/jats:styled-content> Exome technology and the Ion Proton<jats:styled-content style=\"fixed-case\"><jats:sup>TM<\/jats:sup><\/jats:styled-content> platform.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A novel heterozygous <jats:italic><jats:styled-content style=\"fixed-case\">OTX<\/jats:styled-content>2<\/jats:italic> missense mutation was identified in a patient showing bilateral anophthalmia who inherited the variant from a parent who was a carrier, but showed no sign of the condition. We also describe a new <jats:italic><jats:styled-content style=\"fixed-case\">PAX<\/jats:styled-content>6<\/jats:italic> missense variant in an autosomal\u2010dominant pedigree affected by mild bilateral microphthalmia showing high intrafamiliar variability, with germline mosaicism determined to be the most plausible molecular cause of the disease. Finally, a heterozygous missense mutation in <jats:italic><jats:styled-content style=\"fixed-case\">RBP<\/jats:styled-content>4<\/jats:italic> was found to be responsible in an isolated case of bilateral complex microphthalmia.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This study highlights that panel\u2010based <jats:styled-content style=\"fixed-case\">WES<\/jats:styled-content> is a reliable and effective strategy for the genetic diagnosis of <jats:styled-content style=\"fixed-case\">MA<\/jats:styled-content>. Furthermore, using this technique, the mutational spectrum of these diseases was broadened, with novel variants identified in each of the <jats:italic><jats:styled-content style=\"fixed-case\">OTX<\/jats:styled-content>2<\/jats:italic>,<jats:italic> <jats:styled-content style=\"fixed-case\">PAX<\/jats:styled-content>6<\/jats:italic>, and <jats:italic><jats:styled-content style=\"fixed-case\">RBP<\/jats:styled-content>4<\/jats:italic> genes. Moreover, we report new cases of reduced penetrance, mosaicism, and variable phenotypic expressivity associated with <jats:styled-content style=\"fixed-case\">MA<\/jats:styled-content>, further demonstrating the heterogeneity of such disorders.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.329","type":"journal-article","created":{"date-parts":[[2017,8,22]],"date-time":"2017-08-22T02:26:45Z","timestamp":1503368805000},"page":"709-719","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Panel\u2010based whole exome sequencing identifies novel mutations in microphthalmia and anophthalmia patients showing complex Mendelian inheritance patterns"],"prefix":"10.1002","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4294-6999","authenticated-orcid":false,"given":"Marina","family":"Riera","sequence":"first","affiliation":[{"name":"Departament de Gen\u00e8tica Institut de Microcirurgia Ocular (IMO) Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Wert","sequence":"additional","affiliation":[{"name":"Departament d'Oftalmologia Pedi\u00e0trica, Estrabisme i Neuroftalmologia Institut de Microcirurgia Ocular (IMO) Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabel","family":"Nieto","sequence":"additional","affiliation":[{"name":"Departament de C\u00f2rnia, Cataracta i Cirurgia Refractiva Institut de Microcirurgia Ocular (IMO) Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esther","family":"Pomares","sequence":"additional","affiliation":[{"name":"Departament de Gen\u00e8tica Institut de Microcirurgia Ocular (IMO) Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2017,8,21]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0166-2236(98)01387-3"},{"key":"e_1_2_7_3_1","first-page":"2524","article-title":"Missense mutations in the PAX6 gene in aniridia","volume":"39","author":"Azuma N.","year":"1998","journal-title":"Invest. 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