Autosomal dominant nanophthalmos and high hyperopia associated with a C-terminal frameshift variant in MYRF

Abstract

Purpose: Nanophthalmos is a rare subtype of microphthalmia associated with high hyperopia and an increased risk of angle-closure glaucoma. We investigated the genetic cause of nanophthalmos and high hyperopia in an autosomal dominant kindred.

Methods: A proband with short axial length, high hyperopia, and dextrocardia was subjected to exome sequencing. Human and rodent gene expression data sets were used to investigate the expression of relevant genes.

Results: We identified a segregating heterozygous frameshift variant at the 3' end of the penultimate exon of MYRF. Using Myc-MYRF chromatin immunoprecipitation data from rat oligodendrocytes, MYRF was found to bind immediately upstream of the transcriptional start site of Tmem98, a gene that itself has been implicated in autosomal dominant nanophthalmos. MYRF and TMEM98 were found to be expressed in the human retina, with a similar pattern of expression across several dissected human eye tissues.

Conclusions: C-terminal variants in MYRF, which are expected to escape nonsense-mediated decay, represent a rare cause of autosomal dominant nanophthalmos with or without dextrocardia or congenital diaphragmatic hernia.

Figure 1

Autosomal dominant nanophthalmos and high hyperopia associated with a heterozygous frameshift variant in MYRF. A: Nanophthalmos pedigree showing affected (filled) and unaffected (unfilled) members. Asterisks indicate individuals in which the c.3361delC variant was confirmed with capillary sequencing. B: Chest X-ray of the proband’s son (IV:2) showing a right congenital diaphragmatic hernia. C: Capillary sequencing trace of the MYRF c.3361delC variant in the proband (III:2), showing the reference and frameshifted variant sequences above and below the trace, respectively. D: Expanded cDNA and translated protein sequences from the MYRF reference sequence (NM_001127392.3), and the c.3361delC variant. Sequence encoded by the penultimate exon (exon 26) is highlighted in blue, with the frameshifted protein sequence highlighted in red. The c.3361 nucleotide is marked with an asterisk. E: MYRF locus schematic, showing the location of the variant described here (black symbol) and its proximity to variants described previously (gray [14] or white [15] symbols). F: MYRF protein schematic, showing the location of individual domains, and relative positions of reported disease-associated variants associated with nanophthalmos or high hyperopia (squares), or syndromic presentations (colored circles). Symbols (^) indicate nanophthalmos or high hyperopia variants associated with syndromic features. CC, coiled-coil domain; TM, transmembrane domain; red asterisk indicates the autolytic cleavage site.

Figure 2

Coordinated expression of MYRF and TMEM98 in human and rodent tissues. A: Myc-MYRF chromatin immunoprecipitation binding peak (highlighted in red) at the Tmem98 locus in rat oligodendrocytes. Intervals constrained across 35 mammalian species are highlighted in green. B: Mean expression of MYRF and TMEM98 in human tissue as measured with gene expression array [21]. C: Expression of MYRF and TMEM98 transcripts in dissected human cadaveric eye tissue, represented as reads per kilobase per million mapped reads (RPKM). Bars represent mean with standard error of the mean (SEM; n=5–7 biologic replicates per tissue). S, sclera; CS, corneal stroma; CE, corneal epithelium; TM, trabecular meshwork; DM, Descemet’s membrane; ON, optic nerve; ONH, optic nerve head; PI, peripheral iris; CB, ciliary body.