Glaucoma gene mutations and their association with angle dysgenesis

Abstract

AbstractAngle dysgenesis is associated with developmental immaturity of the outflow pathways regulated by genes, which can only be ascertained with the help of histopathological studies. Mutations in some of the commonly associated genes with glaucoma, namely CYP1B1,FOXC1 PITX2, and TEK have been shown to be associated with developmental abnormalities in the outflow pathways in experimental studies. The severity of angle dysgenesis has been correlated on histopathology with certain CYP1B1 gene mutations in patients with Primary congenital glaucoma (PCG). Though MYOC mutations are known to be associated with Juvenile onset open angle glaucoma (JOAG) and even with PCG, no studies have shown the involvement of MYOC mutations in causing angle dysgenesis. There is only one histopathological report of a JOAG patient with MYOC Tyr453His mutation, where no apparent changes of the Trabecular meshwork(TM) or Sclemm's canal were noted though intense MYOC immune‐reactivity was observed at the TM. Histopathological studies for angle dysgenesis in human glaucomatous eyes are difficult to perform and are inherently associated with tissue handling artefacts. While grossly identifiable features of Ange dysgenesis on ASOCT (ADoA) have been described before, many subtle changes may also be present on ASOCT scans which are challenging to detect or precisely quantify by human observers.We studied the ASOCT scans of patients with open angle glaucoma diagnosed between 10 to 40 years of age, who had undergone Whole Exome Sequencing (WES) followed by a bioinformatics analysis and were found to harbour a mutation (that was pathogenic) in a known glaucoma gens. We used Deep learning (DL) models to detect ADoA.We detected MYOC mutations in 15 patients, 10 had CYP1B1, 2 had FOXC1 and 2 had LTBP2 mutation. Among these patients, angle dysgenesis on ASOCT was observed as predicted by the DL models, among all patients with known gene mutations. Overall, our DL Model was predictive of angle dysgenesis in 81% scans among MYOC positive patients, 89% CYP1B1 patients, 85% FOXC1 and 96% among those with LTBP2 mutation on an average.Our findings demonstrated that different gene mutations affect different parts of the proximal outflow pathways. While CYP1B1 and LTBP2 was found to affect primarily the SC morphology, the MYOC and FOXC1 were found to be associated with morphological variations in the TM, since the SC in the latter was normally developed.