# Variable Ophthalmologic Phenotypes Associated with Biallelic Loss-of-Function Variants in POMGNT1

## TL;DR

This paper reports on a family with retinal disease caused by POMGNT1 gene mutations, showing that the condition can vary in severity and affect only the eyes.

## Contribution

The study highlights the isolated and variable ocular phenotype caused by POMGNT1 mutations, expanding the known clinical spectrum of this genetic disorder.

## Key findings

- Three siblings with biallelic POMGNT1 variants exhibited isolated retinal disease without muscular or neuronal involvement.
- The retinal phenotype varied in onset, presentation, and severity among the affected siblings.
- POMGNT1 defects disrupt retinal basal membrane organization, leading to rod-cone dystrophy.

## Abstract

O-mannosylation is a post-translational modification required for the proper function of various proteins and critical for development and growth. POMGNT1 encodes the enzyme O-linked-mannose β-1,2-N-acetylglucosaminyltransferase 1, which catalyzes the second step in the synthesis of α-dystroglycan O-mannosyl glycans. Among POMGNT1-related α-dystroglycanopathies, muscle–eye–brain (MEB) disease presents with congenital muscular dystrophy, structural brain abnormalities, and retinal dystrophy. Defects in protein O-mannosylation due to biallelic loss-of-function POMGNT1 mutations produce disturbances in assembling and organizing the basal membrane in the neuroretinal system, involving both the central and peripheral nervous systems. In the retina, POMGNT1 is expressed in photoreceptors and is localized near the photoreceptor cilium basal body, a structure critical for protein transport. Recent studies have reported an isolated degenerative ocular phenotype without any involvement of muscular or neuronal tissues. Here, we report on a family with three siblings affected by an apparently isolated clinically variable retinal disease and sharing biallelic inactivating POMGNT1 variants. Notably, the rod-cone dystrophy phenotype in the three siblings varied significantly in onset, presentation, and severity. These findings provide further evidence of the clinical variability associated with defective POMGNT1 function.