Detection of Clinically Relevant Genetic Variants in Chinese Patients With Nanophthalmos by Trio-Based Whole-Genome Sequencing Study

Purpose: Nanophthalmos is a rare genetic disorder commonly characterized by a short axial length (AL) and severe hyperopia. Mutations that have been identified through Mendelian genetic analysis can only explain a fraction of nanophthalmic cases. We investigate the clinically relevant genetic variants in nanophthalmos by whole-genome sequencing (WGS), including de novo mutations (DNMs) and inherited mutations.

Methods: Clinically relevant genetic variants of 11 trios (11 nanophthalmic probands and their unaffected parents) from the Zhongshan Ophthalmic Center, China, were analyzed by WGS. We further screened three trios and 10 sporadic cases to identify the MYRF mutations.

Results: In two of 11 trios, without evidence of the presence of deleterious inherited autosomal variants, two DNMs of MYRF (c.789delC, p.S264fs and c.789dupC, p.S264fs) were identified in the probands. These loss-of-function DNMs were predicted to result in premature stop codons and protein structure damage in both probands. In addition, deleterious inherited genetic variants in PRSS56 and MFRP were found in eight probands of the other nine trios. Expanded screening found an additional MYRF DNM (c.1433G>C, p.R478P) in one trio and a stop-gain MYRF mutation (c.2956C>T, p.R986X) in one sporadic case, suggesting the recurrence of MYRF mutations in nanophthalmic patients.

Conclusions: This is the first trio-based WGS study for nanophthalmos, revealing the potential role of DNMs in MYRF and rare inherited genetic variants in PRSS56 and MFRP. The underlying mechanism of MYRF in the development of nanophthalmos needs to be further investigated.