Siemiatkowska Anna M, Collin Rob W J, den Hollander Anneke I, Cremers Frans P M
Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands Department of Ophthalmology, Radboud University Medical Center, Nijmegen, The Netherlands.
Cold Spring Harb Perspect Med. 2014 Jun 17;4(8):a017137. doi: 10.1101/cshperspect.a017137.
In view of their high degree of genetic heterogeneity, inherited retinal diseases (IRDs) pose a significant challenge for identifying novel genetic causes. Thus far, more than 200 genes have been found to be mutated in IRDs, which together contain causal variants in >80% of the cases. Accurate genetic diagnostics is particularly important for isolated cases, in which X-linked and de novo autosomal dominant variants are not uncommon. In addition, new gene- or mutation-specific therapies are emerging, underlining the importance of identifying causative mutations in each individual. Sanger sequencing of selected genes followed by cost-effective targeted next-generation sequencing (NGS) can identify defects in known IRD-associated genes in the majority of the cases. Exome NGS in combination with genetic linkage or homozygosity mapping studies can aid the identification of the remaining causal genes. As these are thought to be mutated in <1% of the cases, validation through functional modeling in, for example, zebrafish and/or replication through the genotyping of large patient cohorts is required. In the near future, whole genome NGS in combination with transcriptome NGS may reveal mutations that are currently hidden in the noncoding regions of the human genome.
鉴于其高度的遗传异质性，遗传性视网膜疾病（IRDs）对确定新的遗传病因构成了重大挑战。到目前为止，已发现200多个基因在IRDs中发生突变，这些基因总共包含超过80%病例的致病变异。准确的基因诊断对于散发病例尤为重要，在这些病例中，X连锁和新发常染色体显性变异并不罕见。此外，新的基因或突变特异性疗法不断涌现，凸显了在每个个体中确定致病突变的重要性。对选定基因进行桑格测序，随后进行经济高效的靶向新一代测序（NGS），在大多数情况下可以识别已知IRD相关基因中的缺陷。外显子组NGS与遗传连锁或纯合性定位研究相结合，有助于识别其余的致病基因。由于这些基因被认为在不到1%的病例中发生突变，因此需要通过例如斑马鱼的功能建模进行验证和/或通过大型患者队列的基因分型进行重复验证。在不久的将来，全基因组NGS与转录组NGS相结合可能会揭示目前隐藏在人类基因组非编码区域的突变。
