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While six genes have been implicated in this hereditary condition (<jats:italic>MFRP, PRSS56, MYRF, TMEM98, CRB1,VMD2\/BEST1<\/jats:italic>), the relative contribution of these to nanophthalmos or to less severe high hyperopia (\u2265\u2009+\u20095.50 spherical equivalent) has not been fully elucidated. We collected probands and families (n\u2009=\u200956) with high hyperopia or nanophthalmos (\u2264\u200921.0\u00a0mm axial length). Of 53 families that passed quality control, plausible genetic diagnoses were identified in 10\/53 (18.8%) by high-throughput panel or pooled exome sequencing. These include 1 <jats:italic>TMEM98<\/jats:italic> family (1.9%), 5 <jats:italic>MFRP<\/jats:italic> families (9.4%), and 4 <jats:italic>PRSS56<\/jats:italic> families (7.5%), with 4 additional families having single allelic hits in <jats:italic>MFRP<\/jats:italic> or <jats:italic>PRSS56<\/jats:italic> (7.5%). A novel deleterious <jats:italic>TMEM98<\/jats:italic> variant (NM_015544.3, c.602G&gt;C, p.(Arg201Pro)) segregated with disease in 4 affected members of a family. Multiple novel missense and frameshift variants in <jats:italic>MFRP<\/jats:italic> and <jats:italic>PRSS56<\/jats:italic> were identified. <jats:italic>PRSS56<\/jats:italic> families were more likely to have choroidal folds than other solved families, while <jats:italic>MFRP<\/jats:italic> families were more likely to have retinal degeneration. Together, this study defines the prevalence of nanophthalmos gene variants in high hyperopia and nanophthalmos and indicates that a large fraction of cases remain outside of single gene coding sequences.<\/jats:p>","DOI":"10.1038\/s41598-020-76725-8","type":"journal-article","created":{"date-parts":[[2020,11,17]],"date-time":"2020-11-17T11:02:56Z","timestamp":1605610976000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":37,"title":["Novel TMEM98, MFRP, PRSS56 variants in a large United States high hyperopia and nanophthalmos cohort"],"prefix":"10.1038","volume":"10","author":[{"given":"Lev","family":"Prasov","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Guan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ehsan","family":"Ullah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven M.","family":"Archer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernadete M.","family":"Ayres","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cagri G.","family":"Besirli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurel","family":"Wiinikka-Buesser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grant M.","family":"Comer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monte A.","family":"Del Monte","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan G.","family":"Elner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah J.","family":"Garnai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laryssa A.","family":"Huryn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kayla","family":"Johnson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shivani S.","family":"Kamat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip","family":"Lieu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shahzad I.","family":"Mian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine A.","family":"Rygiel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jasmine Y.","family":"Serpen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hemant S.","family":"Pawar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian P.","family":"Brooks","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sayoko E.","family":"Moroi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia E.","family":"Richards","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert B.","family":"Hufnagel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,11,17]]},"reference":[{"key":"76725_CR1","doi-asserted-by":"publisher","first-page":"802","DOI":"10.1001\/jamaophthalmol.2016.1284","volume":"134","author":"R Varma","year":"2016","unstructured":"Varma, R. et al. 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