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John H Fingert, Benjamin Roos, Michael Choi; Identification of novel TMEM98 mutations in two large nanophthalmia pedigrees. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):2534. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
To investigate the clinical features and the genetic basis of nanophthalmia in two large autosomal dominant nanophthalmia pedigrees.
14 members of two unrelated pedigrees (one Caucasian pedigree from the United States and one pedigree from the Mariana Islands) had complete eye examinations and axial eye length measurements. DNA samples were collected from all available family members and were studied with linkage analysis, whole exome sequencing, and candidate gene (i.e. TMEM98) sequencing to identify the nanophthalmia-causing gene in each pedigree.
Nine members of the pedigree from the United States and 7 members of the pedigree from the Mariana Islands were diagnosed with nanophthalmia that is transmitted as an autosomal dominant trait. The nanophthalmia patients were found to have abnormally short axial eye lengths, which ranged from 15.87-18.35mm. Linkage analysis of the nanophthalmia pedigree from the United States identified 9 large regions of the genome (greater than 10 Mbp) that were co-inherited with disease in this family. Genes within these “linked regions” were examined for disease-causing mutations using exome sequencing and a His196Pro mutation was discovered in the TMEM98 gene, a recently reported nanophthalmia gene. Sanger sequencing subsequently showed that all other members of this pedigree with nanophthalmia also carry the His196Pro TMEM98 mutation. Testing the Mariana Islands pedigree for TMEM98 mutations identified a 34 bp heterozygous deletion that spans the 3' end of exon 4 in all affected family members. Neither TMEM98 mutation was detected in public exome sequence databases.
A recent report identified a single TMEM98 missense mutation in one nanophthalmia pedigree. Our report of two additional TMEM98 mutations confirms the important role of the gene in the pathogenesis of autosomal dominant nanophthalmia.
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