国人Stargardt病患者ABCA4基因突变分析与表型特征

Characteristics of ABCA4 genotype in Chinese patients with Stargardt disease

目的通过对眼底黄色斑点症患者ABCA4基因突变分析,分析国人Stargardt病(STGDI)患者中ABCA4基因突变特点及其表型特征。设计回顾性病例系列。研究对象北京同仁医院可疑Stargardt病患者119例,其中17例家族史明确,102例为散发。方法利用PCR扩增DNA直接测序方法检测患者ABCA4基因50个编码外显子及外显子与内含子交界区,并记录患者的表型特征。主要指标ABCA4基因测序结果、家族史、眼底像、相干光断层扫描(OCT)、眼底自发荧光(AF)、视网膜电图(ERG)、视力。结果 119例STGDI患者中110例(92.4%)检测到2个及以上ABCA4基因致病突变,9例(7.6%)检测到1个致病突变。本研究共检出136种突变,其中新发现突变16种。基因突变中55.1%(75/136)为错义突变,15.4%(21/136)为缺失或插入,17.6%(24/136)为剪接位点突变,11.8%(16/136)为无义突变。最常见突变为无义突变p.Y808X,其等位基因频率最高为17次(7.1%)。STGDI患者平均发病年龄(12.85±9.01)岁,平均最佳矫正视力(0.11±0.12)。结论本研究结果拓展了ABCA4基因突变谱。中国人STGDI患者发病年龄早、视力损伤重,且ABCA4基因特点与其他种族明显不同。

Objective To report the results of mutation analysis of the A BCA 4 gene in a cohort of patients with Stargardt disease （STGDI） and describe their associated phenotype. Design Retrospective case series. Participants 119 suspected STGDI probands including 17 patients with family history and 102 sporadic cases were recruited. Methods All the exons including intron-exon boundary of the ABCA4 gene, were amplified by PCR and the products were analyzed by direct sequencing in all the patients. The clinical features of STGDI patients were recorded. Main Outcome Measures Mutations of ABCA4 gene, family history, fundus photography, optical co- herence tomography （OCT）, fundus autofluorescence （AF）, electroretinogram （ERG） and visual acuity. Results 119 ABCA4 pathogenic mutations were found in 110 patients （110/119, 92.4%）. Of the 136 intragenic mutations, 16 were detected for the first time in this study. The mutations contained 55.1% （75/136） of missense mutations, 15.4% （21/136） of deletions or insertions, 17.6% （24/136） of splice site mutations, and 11.8% （16/136） of nonsense mutations. The most frequent mutation in this cohort was c.2424C〉G p.Y808X, i- dentified 17 times （7.1%）. The median age of onset was 12.85±9.01 years and the median BCVA upon review was 0.11±0.12. Conclusion The mutations found in this study broaden the spectrum of ABCA4 gene mutations, and Chinese patients appeared to have early onset age and severe visual defects. The mutation spectrum of the ABCA4 gene in Chinese patients is quite different from that for other populations. （Ophthalmol CHN, 2016, 25： 219-224）