Department of Ophthalmology, Faculty of Medical and Health Sciences, New Zealand National Eye Centre, University of Auckland, Auckland, New Zealand.
Clin Exp Ophthalmol. 2012 May-Jun;40(4):e208-17. doi: 10.1111/j.1442-9071.2011.02714.x. Epub 2011 Dec 6.
Despite increasing knowledge of the genetic pathophysiology of glaucoma, mutations in known genes account for less than 15% of disease. Gene screening predominantly remains a research tool rather than an essential part of the clinical work-up. We aimed to determine the mutational spectrum and frequency in the genes implicated in glaucoma, in a range of glaucoma and 'glaucoma suspect' (GS) participants, with a positive family history.
Observational large case series. One hundred fifteen patients recruited from public hospital and private clinics had diagnoses of GS, ocular hypertension, pseudoexfoliative glaucoma (PXG) or primary open-angle glaucoma (POAG), and at least one affected family member. In a university laboratory, DNA samples were screened for mutations in all coding exons of MYOC and CYP1B1, and OPTN (exons 4, 5 and 16). WDR36 (exons 1, 4, 5, 8, 11, 13 and 17) was screened in those with CYP1B1 changes. LOXL1 risk variants were screened in PXG pedigrees. Cascade screening of family members was undertaken.
Seven out of one hundred fifteen (6.1%) individuals had at least one pathogenic or hypomorphic CYP1B1 allele associated with GS, POAG (5) and PXG phenotypes, including two novel sequence variations (p.Ser6Gly, p.Val243Leu). No pathogenic MYOC change was detected. Five individuals (4.3%) carried an OPTN sequence variation. Three of the seven with CYP1B1 changes had polygenic changes.
Mutational analysis of known glaucoma genes in a mixed glaucoma population replicates the reported frequency of pathogenic CYP1B1 changes. Heterozygous CYP1B1 changes occurred at a greater frequency than other genes. Glaucoma pathogenesis in the clinic setting is genetically heterogeneous and may be polygenic.
尽管人们对青光眼的遗传病理生理学有了更多的了解，但已知基因的突变仅占疾病的 15%以下。基因筛查主要仍是一种研究工具，而不是临床评估的必要组成部分。我们旨在确定一系列青光眼和“青光眼疑似患者”（GS）患者中涉及的基因的突变谱和频率，这些患者具有阳性家族史。
观察性大型病例系列。从公立医院和私人诊所招募了 115 名患者，他们被诊断为 GS、眼压升高、假性剥脱性青光眼（PXG）或原发性开角型青光眼（POAG），并且至少有一位受影响的家族成员。在大学实验室中，对所有 MYOC 和 CYP1B1 以及 OPTN（外显子 4、5 和 16）的编码外显子的 DNA 样本进行了突变筛选。对 CYP1B1 改变的患者进行 WDR36（外显子 1、4、5、8、11、13 和 17）的筛选。对 PXG 家系进行 LOXL1 风险变体筛查。对家庭成员进行级联筛查。
在 115 名患者中，有 7 名（6.1%）至少有一个与 GS、POAG（5）和 PXG 表型相关的致病性或低功能 CYP1B1 等位基因，包括两种新的序列变异（p.Ser6Gly，p.Val243Leu）。未发现致病性 MYOC 变化。有 5 名患者（4.3%）携带 OPTN 序列变异。在 7 名 CYP1B1 改变的患者中有 3 名存在多基因改变。
在混合青光眼人群中对已知青光眼基因进行突变分析，重复了报道的致病性 CYP1B1 改变的频率。杂合性 CYP1B1 改变的频率高于其他基因。临床环境中的青光眼发病机制是遗传异质性的，可能是多基因的。
