Novel TMEM98, MFRP, PRSS56 variants in a large United States high hyperopia and nanophthalmos cohort.

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  • Additional Information
    • Source:
      Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE
    • Publication Information:
      Original Publication: London : Nature Publishing Group, copyright 2011-
    • Subject Terms:
      Eye Diseases, Hereditary/*genetics ; Frameshift Mutation/*genetics ; Hyperopia/*genetics ; Membrane Proteins/*genetics ; Microphthalmos/*genetics ; Mutation, Missense/*genetics ; Serine Proteases/*genetics; Alleles ; Cohort Studies ; Eye/metabolism ; Female ; Humans ; Male ; Pedigree ; United States
    • Abstract:
      Nanophthalmos is a rare condition defined by a small, structurally normal eye with resultant high hyperopia. While six genes have been implicated in this hereditary condition (MFRP, PRSS56, MYRF, TMEM98, CRB1,VMD2/BEST1), the relative contribution of these to nanophthalmos or to less severe high hyperopia (≥ + 5.50 spherical equivalent) has not been fully elucidated. We collected probands and families (n = 56) with high hyperopia or nanophthalmos (≤ 21.0 mm 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 TMEM98 family (1.9%), 5 MFRP families (9.4%), and 4 PRSS56 families (7.5%), with 4 additional families having single allelic hits in MFRP or PRSS56 (7.5%). A novel deleterious TMEM98 variant (NM_015544.3, c.602G>C, p.(Arg201Pro)) segregated with disease in 4 affected members of a family. Multiple novel missense and frameshift variants in MFRP and PRSS56 were identified. PRSS56 families were more likely to have choroidal folds than other solved families, while MFRP 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.
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    • Grant Information:
      R01 EY011671 United States EY NEI NIH HHS; T32 HG000040 United States HG NHGRI NIH HHS; R56 EY011671 United States EY NEI NIH HHS; K12-EY022299 United States EY NEI NIH HHS; EY011671 United States EY NEI NIH HHS; K12 EY022299 United States EY NEI NIH HHS
    • Accession Number:
      0 (MFRP protein, human)
      0 (Membrane Proteins)
      0 (TMEM98 protein, human)
      EC 3.4.- (PRSS56 protein, human)
      EC 3.4.- (Serine Proteases)
    • Subject Terms:
      Hyperopia, High
    • Publication Date:
      Date Created: 20201118 Date Completed: 20210114 Latest Revision: 20220815
    • Publication Date:
      20231215
    • Accession Number:
      PMC7672112
    • Accession Number:
      10.1038/s41598-020-76725-8
    • Accession Number:
      33203948