Prevalence of MYOC mutations in a cohort of juvenile open-angle glaucoma (JOAG) patients from Sub-Saharan Africa.

Abstract

Purpose: Determine the prevalence and the role of myocilin (MYOC) gene mutations in a sub-Saharan population of juvenile open-angle glaucoma (JOAG) patients DESIGN: Prospective case-control PARTICIPANTS: 45 JOAG patients and 41 normal control subjects from the ophthalmology clinics of the University College Hospital Ibadan, Nigeria.

Methods: DNA was tested for MYOC coding sequence mutations using Sanger sequencing. Identified mutations were evaluated for pathogenicity by 1) ClinGen scoring 2) assessing prevalence in large public databases of patients with African ancestry (gnomAD and 1000 Genomes); and 3) Mutation analysis algorithms (PolyPhen, SIFT, Blosum62, MutationTaster, CADD, and AlphaMissense). The prevalence of variants was compared between JOAG patients and normal controls from Ibadan using a mutation burden analysis using SKAT-O.

Main outcome measures: Sanger DNA sequencing data indicating the presence or absence of glaucoma-causing mutations in the MYOC gene.

Results: A total of 10 instances of 4 MYOC variants were detected. A p.Pro370Leu variant, which has been previously categorized by the ClinGen as Pathogenic, was detected in three (6.7%) of 45 JOAG probands. A p.Arg470Cys MYOC variant, previously categorized a Variant of Unknown Significance, was identified in one (2.2%) of 45 JOAG probands. A p.Glu352Lys variant, previously categorized as Benign, was detected in 2 (4.4%) of JOAG probands. Both the p.Pro370Leu and p.Arg470Cys variants were absent from control subjects and large public databases, while p.Glu352Lys was present at a frequency >1%, which is inconsistent with pathogenicity. Finally, synonymous missense variant, p.Glu396Glu, was also detected. Five of six mutation analysis algorithms supported the pathogenicity of the p.Pro370Leu and p.Arg470Cys variants, while slightly fewer (4 of 6) suggested that p.Glu352Lys is pathogenic.

Conclusions: MYOC mutations are the most common known cause of JOAG in populations of European ancestry. Our case-control study estimated the prevalence of pathogenic MYOC mutations to be 8.9% in an African population from Nigeria. MYOC mutations are the most common known cause of JOAG in sub-Saharan Africa, however, they account for a minority of cases.