Neurogenetics Laboratory, Department of Biochemistry and Molecular Genetics, American University of Beirut Medical Center, Beirut, Lebanon.
Department of Ophthalmology, American University of Beirut Medical Center, Beirut, Lebanon.
Ophthalmic Genet. 2023 Jun;44(3):234-245. doi: 10.1080/13816810.2023.2189949. Epub 2023 Mar 30.
Mutations were previously identified in the CYP1B1 gene in six out of 18 Lebanese families (33%) with primary congenital glaucoma (PCG). The purpose of this study is to determine the frequency and type of pathogenic mutations in other genes and compare to other populations using whole-exome sequencing and perform genotype-phenotype correlations.
Twelve PCG patients previously negative for CYP1B1/MYOC mutations were subjected to whole-exome sequencing. Targeted screening for glaucoma-associated genes was performed. Candidate variants were verified by Sanger sequencing and evaluated in family members for segregation analysis and in 100 normal controls. Clinical correlations were established as to severity of disease presentation, course, and visual outcomes.
Six mutations in known PCG-causing genes were identified in five patients: homozygous mutations in CYP1B1 (p.R368G), LTBP2 (p.E1013G), and TEK (p.T693I), and heterozygous mutations in FOXC1 (p.Q92*), TEK (c.3201-1 G>A), ANGPT1 (p.K186N), and CYP1B1 (p.R368G). Two patients, negative for CYP1B1 in the previous study, were revealed positive in the current study, due to different sets of primers and PCR conditions. Potentially damaging variants were noted in several candidate genes. Except for FOXC1 mutations, all genetic variants described here are novel. Intra-ocular pressure and final optic nerve cup-to-disc ratio were highest in the patient with three mutations in LTBP2/TEK/ANGPT1 genes.
This study provides new data on the spectrum of mutations of PCG in Lebanon. This highlights the genetic heterogeneity of the Lebanese population, noted for high rates of consanguinity in 50% in this cohort. This study emphasizes the importance of whole-exome sequencing in elucidating new candidate genes for PCG in the Lebanese.
先前在 18 个黎巴嫩原发性先天性青光眼（PCG）家族中的 6 个家族（33%）中鉴定出 CYP1B1 基因中的突变。本研究的目的是确定其他基因中致病性突变的频率和类型，并与其他人群进行比较，方法是进行全外显子组测序，并进行基因型-表型相关性分析。
对先前 CYP1B1/MYOC 突变阴性的 12 名 PCG 患者进行全外显子组测序。对青光眼相关基因进行靶向筛查。通过 Sanger 测序验证候选变异，并在家族成员中进行遗传分析，在 100 名正常对照中进行验证。建立了与疾病表现严重程度、病程和视觉结局相关的临床相关性。
在 5 名患者中发现了已知导致 PCG 的 6 个基因中的突变：CYP1B1（p.R368G）、LTBP2（p.E1013G）和 TEK（p.T693I）的纯合突变，FOXC1（p.Q92*）、TEK（c.3201-1 G>A）、ANGPT1（p.K186N）和 CYP1B1（p.R368G）的杂合突变。在先前的研究中 CYP1B1 阴性的 2 名患者，由于引物和 PCR 条件不同，在当前研究中被发现呈阳性。在几个候选基因中发现了潜在的有害变异。除 FOXC1 突变外，此处描述的所有遗传变异均为新发现。LTBP2/TEK/ANGPT1 基因中存在 3 种突变的患者的眼内压和最终视神经杯盘比最高。
本研究提供了黎巴嫩 PCG 突变谱的新数据。这突出了黎巴嫩人群的遗传异质性，在本队列中，50%的人群有近亲结婚的情况。本研究强调了全外显子组测序在阐明黎巴嫩 PCG 的新候选基因方面的重要性。
