Elucidating the genotypic spectrum of nanophthalmos and high hyperopia

Abstract

Purpose : Nanophthalmos is characterized by a small, structurally normal eye, and can be complicated by angle closure glaucoma, retinal and/or choroidal detachments, strabismus, amblyopia, and retinoschisis. It constitutes the extreme of high hyperopia, which has an estimated heritability of 70-90%. Six genes (MFRP, MYRF, TMEM98, PRSS56, VMD2/BEST1, and CRB1) have been implicated in nanophthalmos, but the relative contribution of these genes has not been fully explored. Our purpose was to conduct a systematic study of the genetic causes of nanophthalmos and high hyperopia in a large cohort of familial and sporadic cases.

Methods : Probands and families (n=51) meeting the definition of high hyperopia (>+5.50 spherical equivalent) or nanophthalmos (<21 mm axial length) underwent pooled exome sequencing or panel-based next-generation sequencing (NGS) using a 730 eye development and disease gene panel (xGene Lockdown probes, IDT). For large families, linkage exclusion analysis was performed in MERLIN, using Illumina QC Array genotyping data. Variants were aligned, filtered, and annotated and prioritized using the GEMINI framework. Variant segregation within families was confirmed by Sanger sequencing. Missense variants were modeled using SWISS-Model and visualized in PyMol.

Results : Proband DNA from 51 families underwent NGS panel sequencing, with 4 families undergoing parallel pooled exome sequencing. Likely pathogenic variants in known nanophthalmos genes were identified in 9/51 (18%) of cases, including 3/4 of families that underwent exome sequencing. For familial cases, all variants segregated perfectly with the disease phenotype. A novel TMEM98 variant (NM_001033504, c.602G>C, p.R201P) found to segregate with disease in one family was predicted to be deleterious and was absent in gnomAD. A recurrent novel variant in MFRP (c.1022T>C p.L341P) found in multiple unrelated families was predicted to affect protein folding and found at a very low frequency in the European population (5x10^-5 in gnomAD).

Conclusions : We identified likely genetic causes for nanophthalmos and high hyperopia in 18% of cases in one of the largest examined cohorts to date. A higher rate of familial cases than sporadic cases were explained by variants in known genes. These results suggest missing heritability for high hyperopia that could be explained by rare or common variants in genes yet to be identified.

This is a 2020 ARVO Annual Meeting abstract.