Genetic testing for retinal dystrophies and dysfunctions: benefits, dilemmas and solutions
Genetic testing for retinal dystrophies and dysfunctions: benefits, dilemmas and solutions
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DOI：
10.1111/j.1442-9071.2007.01534.x
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发表时间：
2007-07-01
影响因子：
4
通讯作者：
Cremers, Frans P. M.
中科院分区：
文献类型：
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作者：
Koenekoop, Robert K.;Lopez, Irma;Cremers, Frans P. M.
人类视网膜营养不良具有无与伦比的遗传和临床多样性，目前与超过185个遗传基因座相关。基因分型是一项至关重要的工作，因为研究光感受器拯救的人类基因特异性临床试验正在进行中。检测在分子水平上确认诊断，并允许对未来可能的临床演变进行更精确的预测。由于治疗是基因特异性的，“机会之窗”是时间敏感的;准确，快速和具有成本效益的基因检测将发挥越来越重要的作用。黄金标准是测序，但充满了过高的成本，时间，人力问题和寻找非致病性变体。因此，没有一个中心提供对所有132个已知基因的检测。最近出现了几种新的微阵列技术，可提供快速，成本效益和准确的基因分型。Asper Ophthalopathy的新疾病芯片（Stargardt营养不良，Leber先天性黑蒙[LCA]，Usher综合征和视网膜色素变性）提供了一个极好的第一次通过机会。所有已知的突变都放在芯片上，在4小时内筛选出患者的DNA。识别率（识别至少一种疾病相关突变）目前接近70%（Stargardt），接近60-70%（LCA），接近45%（Usher综合征亚型1）。这可能与基因型-表型相关性相结合，从临床表现中提示致病基因（例如，保留的动脉旁视网膜色素上皮细胞提示CRB 1基因参与LCA）。由于50%的视网膜营养不良基因仍在等待发现，这些技术将随着额外的新突变的添加而显着改善。然后，基因检测将成为补充眼科评估的标准做法。
Human retinal dystrophies have unparalleled genetic and clinical diversity and are currently linked to more than 185 genetic loci. Genotyping is a crucial exercise, as human gene-specific clinical trials to study photoreceptor rescue are on their way. Testing confirms the diagnosis at the molecular level and allows for a more precise prognosis of the possible future clinical evolution. As treatments are gene-specific and the 'window of opportunity' is time-sensitive; accurate, rapid and cost-effective genetic testing will play an ever-increasing crucial role. The gold standard is sequencing but is fraught with excessive costs, time, manpower issues and finding non-pathogenic variants. Therefore, no centre offers testing of all currently 132 known genes. Several new micro-array technologies have emerged recently, that offer rapid, cost-effective and accurate genotyping. The new disease chips from Asper Ophthalmics (for Stargardt dystrophy, Leber congenital amaurosis [LCA], Usher syndromes and retinitis pigmentosa) offer an excellent first pass opportunity. All known mutations are placed on the chip and in 4 h a patient's DNA is screened. Identification rates (identifying at least one disease-associated mutation) are currently similar to 70% (Stargardt), similar to 60-70% (LCA) and similar to 45% (Usher syndrome subtype 1). This may be combined with genotype-phenotype correlations that suggest the causal gene from the clinical appearance (e.g. preserved para-arteriolar retinal pigment epithelium suggests the involvement of the CRB1 gene in LCA). As similar to 50% of the retinal dystrophy genes still await discovery, these technologies will improve dramatically as additional novel mutations are added. Genetic testing will then become standard practice to complement the ophthalmic evaluation.