视网膜格子样变性并颗粒状角膜营养不良一家系临床观察和基因突变检测

Clinical observation and gene mutation detection in a pedigree of retinal lattice degeneration combined with granular corneal dystrophy

目的 观察一个视网膜格子样变性并颗粒状角膜营养不良（GCD）2型家系的临床表现和基因突变位点。 方法 1个视网膜格子样变性并GCD 2型家系三代10名成员纳入研究。其中，患者6例、健康成员4名。患者中男、女各3例；均为双眼。所有受试者均行视力、裂隙灯显微镜、三面镜、眼底彩色照相、光相干断层扫描、角膜内皮计数检查。采集所有受试者以及与其共同生活、无相关遗传性疾病的配偶外周静脉血2 ml，提取基因组DNA，二代测序法检测转化生长因子β诱导（TGFBI）基因突变位点；并对受试者以及配偶进行Sanger验证。 结果 6例患者12只眼中，视力数指/20 cm～1.0。角膜中央可见浅基质层雪花样混浊3例6只眼；少量点状浅基质层颗粒样混浊3例6只眼。角膜内皮细胞计数均正常。视网膜格子样变性3例6只眼，其中孔源性视网膜脱离3例4只眼；视网膜轻度变薄、未见明显格子样变性2例4只眼。眼球旋转震颤、眼底检查未见明显异常1例2只眼。基因检测结果显示，先证者和4例患者的TGFBI基因第4外显子均存在c.371G＞A错义突变，该突变位点所对应的氨基酸改变为TGFBI基因所编码蛋白的第124号氨基酸由精氨酸变异为组氨酸（p.R124H）。携带该位点的患者均有不同程度临床表型。 结论 TGFBI基因突变位点c.371G＞A（p.R124H）是该家系GCD的致病基因；携带该位点的患者均有不同临床表型。

Objective To investigate the clinical manifestations and gene mutation of a pedigree with retinal lattice degeneration and granular corneal dystrophy （GCD） type 2. Methods Ten members in 3 generations of a pedigree with retinal lattice degeneration and GCD2 were included in the study, including 6 patients （3 males and 3 females） and 4 healthy family members. All members underwent visual acuity, slit lamp microscope, three-mirror lens, fundus color photography, optical coherence tomography, and corneal endothelial cells counting. Genomic DNA was extracted from peripheral venous blood （2 ml） from all the subjects and their spouses, who had no related inherited diseases. The next generation sequencing method was used to detect the mutation sites of transforming growth factor β （TGFBI）, and all results underwent Sanger verification. Results Among the 12 eyes of 6 patients, the visual acuity was FC/20 cm-1.0. In the superficial central corneal stroma, snowflake-like deposits were observed in three cases （6 eyes）, and a small amount of granular deposits were observed in three cases （6 eyes）. Corneal endothelial cell counts were normal. Retinal lattice degeneration were observed in 3 cases, 6 eyes （including 3 cases of rhegmatogenous retinal detachment in 4 eyes）; retinal thinning without obvious lattice degeneration in 4 eyes of 2 patients. Nystagmus in 1 patient and fundus examination showed no significant abnormalities. DNA sequencing results showed that the proband and 4 patients had missense mutation of TGFBI gene in exon 4 c.371G〉 A, the mutation site corresponding to the amino acid change encoded by TGFBI gene No. 124 Amino acids, from arginine to histidine （p.R124H）. Patients with this mutation have varying degrees of clinical phenotype. Conclusions The mutation of c.701G〉 A （p.R124H） in TGFBI gene is the causative gene of GCD in this pedigree. The patients with this mutation have different clinical phenotypes.