视网膜色素变性和视锥-视杆细胞营养不良患者的基因型及临床表型分析

Genotype and clinical phenotype analysis in patients with retinitis pigmentosa and cone rod dystrophy

目的 观察视网膜色素变性（RP）和视锥-视杆细胞营养不良（CORD）患者基因突变及临床表型。 方法 临床检查确诊的37例RP患者和6例CORD患者以及95名家庭成员纳入研究。详细收集患者病史、家族史；患者以及家庭成员均行最佳矫正视力、裂隙灯显微镜、间接检眼镜、彩色眼底照相、光相干断层扫描、全视野视网膜电图、荧光素眼底血管造影检查。采集患者及其家庭成员外周静脉血，提取全基因组DNA。应用目标区域捕获结合二代测序技术对目前已知的232个视网膜疾病致病基因进行相关基因筛查，确定候选致病基因突变位点；聚合酶链反应和直接测序法进行验证，并在家庭成员中进行共分离，确定致病性突变位点。分析RP、CORD患者的基因型与临床表型的关系。 结果 37例RP患者中，13例来自6个家系，其中常染色体显性遗传RP 10例（4个家系），常染色体隐性遗传RP 3例（2个家系）；24例为散发RP。6例CORD患者来自4个家系，均为常染色体隐性遗传。43例患者中，21例患者检测出致病性基因突变，检测阳性率48.8%。21例患者中，RP患者15例，检测出USH2A、RP1、MYO7A、C8orf37、RPGR、SNRNP200、CRX、PRPF31、C2orf71、IMPDH1等10个致病性基因突变；典型RP 10例，无色素性RP 2例，Usher综合征2型 3例。CORD患者6例，均检测到致病性基因突变。其中，ABCA4、RIMS1基因突变各2例，CLN3基因突变1例，CRB1和RPGR双基因突变1例。 结论 RP和CORD具有基因型多样化，临床表型相似性；早期RP和CORD诊断需结合临床表型和基因检测分析才能最终确定。

To observe the gene mutation and clinical phenotype of patients with retinitis pigmentosa （RP） and cone rod dystrophy （CORD）. Methods Thirty-seven patients with RP and 6 patients with CORD and 95 family members were enrolled in the study. The patient’s medical history and family history were collected. All the patients and family members received complete ophthalmic examinations to determine the phenotype, including best corrected visual acuity, slit lamp microscope, indirect ophthalmoscopy, color fundus photography, optical coherence tomography, full-field electroretinogram, and fluorescein fundus angiography. DNA was abstracted from patients and family members. Using target region capture sequencing combined with next-generation sequencing to screen the 232 candidate pathogenic mutations. Polymerase chain reaction and direct sequencing were used to confirm the pathogenic pathogenic mutations and Co-segregation is performed among members in the family to determine pathogenic mutation sites. The relationship between genotype and clinical phenotype of RP and CORD was analyzed. Results Of the 37 patients with RP, 13 were from 6 families, including 4 families with autosomal dominant inheritance, 2 families with autosomal recessive inheritance, and 3 in 6 families were detected pathogenic gene mutations. 24 cases were scattered RP. Six patients with CORD were from four families, all of which were autosomal recessive. Of the 43 patients, 21 patients were detected the pathogenic gene mutation, and the positive rate was 48.8%. Among them, 15 patients with RP were detected 10 pathogenic gene mutations including USH2A, RP1, MYO7A, C8orf37, RPGR, SNRNP200, CRX, PRPF31, C2orf71, IMPDH1, and the clinical phenotype included 10 typical RP, 2 cases of RPSP, 3 cases of Usher syndrome type 2 and 6 cases of CORD patients were all detected pathogenic gene mutations, including 2 cases of ABCA4, 2 mutations of RIMS1 gene, 1 case of CLN3 gene mutation, and 1 case of CRB1 and RPGR double gene mutation. Conclusions RP and CORD are clinically diverse in genotype and clinically phenotypically similar. For patients with early RP and CORD, clinical phenotype combined with genetic analysis is required to determine the diagnosis of RP and CORD.