Prevalence of Myocilin Mutations in a Cohort of Patients with Juvenile Open-Angle Glaucoma from sub-Saharan Africa.

Abstract

Purpose: Determine the prevalence and the role of myocilin (MYOC) gene mutations in a sub-Saharan population of patients with juvenile open-angle glaucoma (JOAG).

Design: Prospective case-control.

Participants: Forty-five patients with JOAG 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 using ClinGen scoring; assessing prevalence in large public databases of patients with African ancestry (gnomAD and 1000 Genomes); and mutation analysis algorithms: PolyPhen, Sorting Intolerant from Tolerant (SIFT), BLOSUM62, MutationTaster, Combined Annotation Dependent Depletion (CADD), and AlphaMissense. The prevalence of variants was compared between patients with JOAG and normal controls from Ibadan using a mutation burden analysis using Sequence Kernel Association Test (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 3 (6.7%) of 45 JOAG probands. A p.Arg470Cys MYOC variant, previously categorized a variant of unknown significance, was identified in 1 (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, whereas p.Glu352Lys was present at a frequency > 1%, which is inconsistent with pathogenicity. Finally, synonymous missense variant, p.Glu396Glu, was also detected. A total of 5 of 6 mutation analysis algorithms supported the pathogenicity of the p.Pro370Leu and p.Arg470Cys variants, whereas slightly fewer (4 of 6) suggested that p.Glu352Lys is pathogenic.

Conclusions: Myocilin 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. Myocilin mutations are the most common known cause of JOAG in sub-Saharan Africa; however, they account for a minority of cases.

Financial disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.