Detection of clinically relevant genetic variants in nanophthalmos by whole genome sequencing

Abstract

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

Methods : The clinically relevant genetic variants of 11 trios (11 nanophthalmos probands and their unaffected parents) from Zhongshan Ophthalmic Center, China were analyzed through WGS.

Results : In 2 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, respectively, which were validated by Sanger sequencing (Fig.1). These loss-of-function DNMs were predicted to result in premature stop codons and protein structure damage in both probands. None of the DNMs were found in the following publicly population databases, including Genome Aggregation Database (gnomAD), Exome Sequencing Project 6500 (ESP6500siv2), and 1000 Genomes Project dataset (1000g). Furthermore, the gene co-expression and genetic interaction networks analyses demonstrated that MYRF had correlations with validated pathogenic genes of nanophthalmos (TMEM98), microphthalmia, anophthalmia and coloboma (PITX3 and BMP4), angle-closure glaucoma (GLIS3), and AL (RSPO1). In addition, deleterious inherited genetic variants in PRSS56 and MFRP were found in 8 probands of the other 9 trios (Fig.2). Among them, p.Gln356fs in PRSS56 and p.Asn167fs in MFRP have been reported in nanophthalmos cases.

Conclusions : This is the first trio-based WGS study for nanophthalmos, which reveals the potential role of DNMs and rare inherited genetic variants. In addition to inherited autosomal mutations in PRSS56 and MFRP, we report two novel frameshift DNMs in MYRF that suggest probably a mechanism, unknown so far, responsible for the development of nanophthalmos.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.

 

Fig.1 Two de novo mutations (DNMs) of MYRF were found. A. The DNM (MYRF: c.789delC, p.S264fs) in trio No.8. B. The DNM (MYRF: c.789dupC, p.S264fs) in trio No.10. Both of them were confirmed by Sanger sequencing.

 

Fig.2 Pedigrees of families with nanophthalmos-relevant inherited autosomal variants.