Van Cauwenbergh Caroline, Coppieters Frauke, Roels Dimitri, De Jaegere Sarah, Flipts Helena, De Zaeytijd Julie, Walraedt Sophie, Claes Charlotte, Fransen Erik, Van Camp Guy, Depasse Fanny, Casteels Ingele, de Ravel Thomy, Leroy Bart P, De Baere Elfride
Center for Medical Genetics Ghent, Ghent University and Ghent University Hospital, Ghent, Belgium.
Department of Ophthalmology, Ghent University and Ghent University Hospital, Ghent, Belgium.
PLoS One. 2017 Jan 11;12(1):e0170038. doi: 10.1371/journal.pone.0170038. eCollection 2017.
Autosomal dominant retinitis pigmentosa (adRP) is characterized by an extensive genetic heterogeneity, implicating 27 genes, which account for 50 to 70% of cases. Here 86 Belgian probands with possible adRP underwent genetic testing to unravel the molecular basis and to assess the contribution of the genes underlying their condition.
Mutation detection methods evolved over the past ten years, including mutation specific methods (APEX chip analysis), linkage analysis, gene panel analysis (Sanger sequencing, targeted next-generation sequencing or whole exome sequencing), high-resolution copy number screening (customized microarray-based comparative genomic hybridization). Identified variants were classified following American College of Medical Genetics and Genomics (ACMG) recommendations.
Molecular genetic screening revealed mutations in 48/86 cases (56%). In total, 17 novel pathogenic mutations were identified: four missense mutations in RHO, five frameshift mutations in RP1, six mutations in genes encoding spliceosome components (SNRNP200, PRPF8, and PRPF31), one frameshift mutation in PRPH2, and one frameshift mutation in TOPORS. The proportion of RHO mutations in our cohort (14%) is higher than reported in a French adRP population (10.3%), but lower than reported elsewhere (16.5-30%). The prevalence of RP1 mutations (10.5%) is comparable to other populations (3.5%-10%). The mutation frequency in genes encoding splicing factors is unexpectedly high (altogether 19.8%), with PRPF31 the second most prevalent mutated gene (10.5%). PRPH2 mutations were found in 4.7% of the Belgian cohort. Two families (2.3%) have the recurrent NR2E3 mutation p.(Gly56Arg). The prevalence of the recurrent PROM1 mutation p.(Arg373Cys) was higher than anticipated (3.5%).
Overall, we identified mutations in 48 of 86 Belgian adRP cases (56%), with the highest prevalence in RHO (14%), RP1 (10.5%) and PRPF31 (10.5%). Finally, we expanded the molecular spectrum of PRPH2, PRPF8, RHO, RP1, SNRNP200, and TOPORS-associated adRP by the identification of 17 novel mutations.
常染色体显性遗传性视网膜色素变性（adRP）具有广泛的遗传异质性，涉及27个基因，这些基因占病例的50%至70%。在此，86名可能患有adRP的比利时先证者接受了基因检测，以揭示其分子基础并评估其病情相关基因的贡献。
过去十年中，突变检测方法不断发展，包括突变特异性方法（APEX芯片分析）、连锁分析、基因panel分析（桑格测序、靶向新一代测序或全外显子测序）、高分辨率拷贝数筛选（定制的基于微阵列的比较基因组杂交）。根据美国医学遗传学与基因组学学会（ACMG）的建议对鉴定出的变异进行分类。
分子遗传学筛查显示，86例中有48例（56%）存在突变。总共鉴定出17个新的致病突变：RHO中有4个错义突变，RP1中有5个移码突变，编码剪接体成分的基因（SNRNP200、PRPF8和PRPF31）中有6个突变，PRPH2中有1个移码突变，TOPORS中有1个移码突变。我们队列中RHO突变的比例（14%）高于法国adRP人群的报道（10.3%），但低于其他地方的报道（16.5%-30%）。RP1突变的患病率（10.5%）与其他人群相当（3.5%-10%）。编码剪接因子的基因中的突变频率出乎意料地高（总计19.8%），PRPF31是第二常见的突变基因（10.5%）。在比利时队列中，4.7%的患者发现了PRPH2突变。两个家族（2.3%）具有复发性NR2E3突变p.(Gly56Arg)。复发性PROM1突变p.(Arg373Cys)的患病率高于预期（3.5%）。
总体而言，我们在86例比利时adRP病例中的48例（56%）中鉴定出了突变，其中RHO（14%）、RP1（10.5%）和PRPF31（10.5%）的患病率最高。最后，我们通过鉴定17个新突变，扩展了PRPH2、PRPF8、RHO、RP1、SNRNP200和TOPORS相关adRP的分子谱。
