Olawoye Olusola, Young Brian P, Nyunt Angela W, Fafowora Oluwatoyin F, Ajani Magdalene, Sarimiye Tarela, Creemer Brendan A, Roos Ben R, Coleman Anne L, Gorin Michael B, Hauser Michael A, Scheetz Todd E, Ashaye Adeyinka, Fingert John H
Department of Ophthalmology, College of Medicine, University of Ibadan, Ibadan, Nigeria.
Carver College of Medicine, University of Iowa, Iowa City, Iowa.
Ophthalmol Glaucoma. 2025 Apr 23. doi: 10.1016/j.ogla.2025.04.010.
Determine the prevalence and the role of myocilin (MYOC) gene mutations in a sub-Saharan population of patients with juvenile open-angle glaucoma (JOAG).
Prospective case-control.
Forty-five patients with JOAG and 41 normal control subjects from the ophthalmology clinics of the University College Hospital Ibadan, Nigeria.
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).
Sanger DNA sequencing data indicating the presence or absence of glaucoma-causing mutations in the MYOC gene.
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.
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.
确定撒哈拉以南地区青少年开角型青光眼（JOAG）患者中肌纤蛋白（MYOC）基因突变的患病率及其作用。
前瞻性病例对照研究。
来自尼日利亚伊巴丹大学学院医院眼科门诊的45例JOAG患者和41名正常对照者。
使用桑格测序法检测DNA的MYOC编码序列突变。使用临床基因组学（ClinGen）评分评估鉴定出的突变的致病性；评估在非洲血统患者的大型公共数据库（gnomAD和千人基因组计划）中的患病率；以及突变分析算法：多酚类（PolyPhen）、从耐受中筛选不耐受（SIFT）、布隆矩阵（BLOSUM62）、突变预测器（MutationTaster）、联合注释依赖损耗（CADD）和AlphaMissense。使用序列核关联检验（SKAT-O）的突变负担分析比较伊巴丹JOAG患者和正常对照者之间变异的患病率。
桑格DNA测序数据表明MYOC基因中是否存在导致青光眼的突变。
共检测到4种MYOC变异的10个实例。在45例JOAG先证者中有3例（6.7%）检测到p.Pro370Leu变异，该变异先前被ClinGen分类为致病性变异。在45例JOAG先证者中有1例（2.2%）鉴定出p.Arg470Cys MYOC变异，该变异先前被分类为意义未明的变异。在JOAG先证者中有2例（4.4%）检测到p.Glu352Lys变异，该变异先前被分类为良性变异。对照者和大型公共数据库中均未发现p.Pro370Leu和p.Arg470Cys变异，而p.Glu352Lys的出现频率>1%，这与致病性不一致。最后，还检测到同义错义变异p.Glu396Glu。6种突变分析算法中有5种支持p.Pro370Leu和p.Arg470Cys变异的致病性，而支持p.Glu352Lys致病性的算法略少（6种中的4种）。
在欧洲血统人群中，肌纤蛋白突变是JOAG最常见的已知病因。我们的病例对照研究估计，在尼日利亚的非洲人群中，致病性MYOC突变的患病率为8.9%。肌纤蛋白突变是撒哈拉以南非洲地区JOAG最常见的已知病因；然而，它们占病例的少数。
在本文末尾的脚注和披露中可能会发现专有或商业披露。
