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Despite recent sequencing strategies, in our cohort a significant proportion of individuals with Usher type 2 have just one heterozygous disease-causing mutation in <jats:italic>USH2A<\/jats:italic>, or no convincing disease-causing mutations across nine Usher genes. The purpose of this study was to improve the molecular diagnosis in these families by screening <jats:italic>USH2A<\/jats:italic> for duplications, heterozygous deletions and a common pathogenic deep intronic variant <jats:italic>USH2A<\/jats:italic>: c.7595-2144A&gt;G.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>Forty-nine Usher type 2 or atypical Usher families who had missing mutations (mono-allelic <jats:italic>USH2A<\/jats:italic> or no mutations following Sanger sequencing of nine Usher genes) were screened for duplications\/deletions using the <jats:italic>USH2A<\/jats:italic> SALSA MLPA reagent kit (MRC-Holland). Identification of <jats:italic>USH2A<\/jats:italic>: c.7595-2144A&gt;G was achieved by Sanger sequencing. Mutations were confirmed by a combination of reverse transcription PCR using RNA extracted from nasal epithelial cells or fibroblasts, and by array comparative genomic hybridisation with sequencing across the genomic breakpoints.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>Eight mutations were identified in 23 Usher type 2 families (35%) with one previously identified heterozygous disease-causing mutation in <jats:italic>USH2A<\/jats:italic>. These consisted of five heterozygous deletions, one duplication, and two heterozygous instances of the pathogenic variant <jats:italic>USH2A<\/jats:italic>: c.7595-2144A&gt;G. No variants were found in the 15 Usher type 2 families with no previously identified disease-causing mutations. In 11 atypical families, none of whom had any previously identified convincing disease-causing mutations, the mutation <jats:italic>USH2A<\/jats:italic>: c.7595-2144A&gt;G was identified in a heterozygous state in one family. All five deletions and the heterozygous duplication we report here are novel. This is the first time that a duplication in <jats:italic>USH2A<\/jats:italic> has been reported as a cause of Usher syndrome.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>We found that 8 of 23 (35%) of \u2018missing\u2019 mutations in Usher type 2 probands with only a single heterozygous <jats:italic>USH2A<\/jats:italic> mutation detected with Sanger sequencing could be attributed to deletions, duplications or a pathogenic deep intronic variant. Future mutation detection strategies and genetic counselling will need to take into account the prevalence of these types of mutations in order to provide a more comprehensive diagnostic service.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/1750-1172-8-122","type":"journal-article","created":{"date-parts":[[2013,8,8]],"date-time":"2013-08-08T06:14:25Z","timestamp":1375942465000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":43,"title":["Screening for duplications, deletions and a common intronic mutation detects 35% of second mutations in patients with USH2A monoallelic mutations on Sanger sequencing"],"prefix":"10.1186","volume":"8","author":[{"given":"Heather B","family":"Steele-Stallard","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Polona","family":"Le Quesne Stabej","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Lenassi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda M","family":"Luxon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mireille","family":"Claustres","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne-Francoise","family":"Roux","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew R","family":"Webster","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Bitner-Glindzicz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2013,8,8]]},"reference":[{"key":"620_CR1","doi-asserted-by":"publisher","first-page":"417217","DOI":"10.1155\/2011\/417217","volume":"2011","author":"JM Mill\u00e1n","year":"2011","unstructured":"Mill\u00e1n JM, Aller E, Jaijo T, Blanco-Kelly F, Gimenez-Pardo A, Ayuso C: An update on the genetics of usher syndrome. 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