Clinical features of patients with mutations in genes for nanophthalmos

Abstract

Background/AimsTo distinguish the clinical feature of nanophthalmos (NNO) caused by mutations in protease serine 56 (PRSS56), membrane-type frizzled-related protein (MFRP), myelin regulatory factor (MYRF) and transmembrane protein 98 (TMEM98) and to evaluate the association between angle-closure glaucoma (ACG) and NNO.MethodsVariants in those four genes were identified through exome sequencing/whole genome sequencing data, and bioinformatic analysis was conducted to identify pathogenic/likely pathogenic (P/LP) variants. This observational study comprehensively summarised ophthalmological data of 67 patients with NNO from 63 families. Ocular parameters from 68 eyes without surgical treatment were subjected to further analysis.ResultsTotally, 67 patients from 63 families harboured 57 P/LP variants in the four genes, including 30 inPRSS56(47.6%), 23 inMFRP(36.5%), 5 inTMEM98(7.9%) and 5 inMYRF(7.9%). ACG was present in 79.1% of patients. An analysis of ocular parameters from 68 eyes revealed that shorter axial length (AL), lower vitreous-to-AL ratios and severe foveal hypoplasia were associated with variants inPRSS56andMFRP. Uveal effusion was more common in patients withPRSS56variants, while retinitis pigmentosa was frequently observed in patients withMFRPvariants. Patients withMYRFvariants exhibited the thinnest retinal nerve fibre layer thickness. Patients withTMEM98variants had an earlier average onset age of glaucoma.ConclusionVariants inPRSS56andMFRPare the most common genetic cause of NNO. ACG is a severe complication frequently observed in these patients. Earlier onset of ACG is observed in patients with dominant NNO, while foveal hypoplasia is more common in patients with recessive disease. Recognising these features is helpful in clinical care and genetic counselling.