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

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

designProspective case-control.

participantsForty-five patients with JOAG and 41 normal control subjects from the ophthalmology clinics of the University College Hospital Ibadan, Nigeria.

methodsDNA 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 measuresSanger DNA sequencing data indicating the presence or absence of glaucoma-causing mutations in the MYOC gene.

resultsA 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.

conclusionsMyocilin 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.