后节小眼畸形-视网膜劈裂-视网膜玻璃膜疣综合征一家系临床表型和基因型分析

Genetic analysis of a family with posterior segment microphthalmia-retinoschisis and drusen syndrome

目的分析后节小眼畸形-视网膜劈裂-视网膜玻璃膜疣综合征一家系的临床表型和基因型。方法采用家系调查研究方法,收集2021年7月于深圳市眼科医院就诊的来自中国惠州地区汉族后节小眼畸形综合征一家系共2代4人的临床资料,对各家系成员进行详细的眼科检查,包括最佳矫正视力、眼压、裂隙灯显微镜、彩色眼底照相、光学相干断层扫描(OCT)、眼前节OCT、荧光素眼底血管造影(FFA)和视野检查。采集该家系成员外周静脉血,进行全外显子组测序和数据分析,应用ACMG指南对新发现的变异位点进行致病性分析。结果先证者女,14岁,自幼高度远视,视力右眼+9.75 DS-0.75 DC×150°=0.9,左眼+11.75 DS-1.25 DC×30°=0.7。角膜横径分别为12.1和12.2 mm,前房深度分别为2.56和2.92 mm,晶状体厚度分别为3.92和3.94 mm,眼轴长度分别为17.47和17.01 mm。彩色眼底照相显示中周部视网膜弥漫性分布边界不清的黄白色玻璃膜疣样病灶;OCT显示视网膜内核层劈裂,视网膜色素上皮下多个均质土堆状隆起和高反射致密点;FFA显示双眼中周部视网膜弥漫性斑点状透见荧光;视野检查显示双眼视觉灵敏度总体降低。先证者胞弟8岁,体征与其相似。父母近亲结婚,表型正常。全外显子测序结果显示,先证者及其胞弟膜型卷曲相关蛋白(MFRP)基因第5、10外显子上分别有c.1150_1151insC(p.His384Profs*8)和c.498_499insC(p.Asn167Glnfs*34)2个复合杂合变异,先证者父亲携带c.498_499insC,母亲携带c.1150_1151insC。两者均为移码变异,均可导致基因功能的改变。该家系确定的2个变异位点在ESP数据库、千人数据库(Phase3)、ExAC数据库中未见报道,为新发变异,变异与疾病共分离。根据ACMG指南,以上2个位点的变异均被判断为致病变异。根据临床表型和基因型结果,该家系符合常染色体隐性遗传方式,诊断为后节小眼畸形-视网膜劈裂-视网膜玻璃膜疣综合征。结论MFRP基因c.1150_1151insC和c.498_499insC为该后节小眼畸形-视网膜劈裂-视网膜玻璃膜疣综合征家系的致病变异位点,该复合杂合变异为首次报道。

Objective To analyze the clinical phenotypes and genotypes of a family with posterior segment microphthalmia-retinoschisis and drusen syndrome.Methods A pedigree investigation study was conducted.A family with four members across two generations treated at Shenzhen Eye Hospital in July 2021 was enrolled.Detailed ophthalmic examinations,including best corrected visual acuity(BCVA),intraocular pressure,slit-lamp microscopy,color fundus photography,optical coherence tomography(OCT),anterior segment OCT,fundus fluorescein angiography(FFA),and visual field tests were performed in the four members.Peripheral venous blood samples were collected from members for whole exome sequencing and data analysis.The pathogenicity of novel variant sites was assessed according to the ACMG guidelines.This study adhered to the Declaration of Helsinki.The study protocol was approved by the Ethics Committee of Shenzhen Eye Hospital(No.22KYPJ018).Written informed consent was obtained from each subject or the guardian.Results The proband is a 14-year-old female with high hyperopia since childhood,BCVA of+9.75 DS-0.75 DC×150°=0.9 and+11.75 DS-1.25 DC×30°=0.7,corneal transverse diameters of 12.1 and 12.2 mm,anterior chamber depths of 2.56 and 2.92 mm,lens thicknesses of 3.92 and 3.94 mm,and axial lengths of 17.47 and 17.01 mm in the right and left eyes,respectively.Fundus photography revealed diffuse yellow-white drusen-like lesions with unclear borders in the mid-peripheral retina,while OCT showed retinoschisis in the inner nuclear layer and homogeneous mound-like elevations with hyperreflective dense spots under the retinal pigment epithelium.FFA demonstrated diffuse punctate transilllumination of the mid-peripheral retina in both eyes,and visual field tests revealed a general decrease in visual acuity.The proband's 8-year-old brother exhibited similar signs to the proband.The consanguineously married parents were phenotypically normal.Whole exome sequencing identified compound heterozygous mutations in the membrane frizzled-related protein(MFRP)gene in the proband and her brother,c.1150_1151insC(p.His384Profs*8)in exon 5 and c.498_499insC(p.Asn167Glnfs*34)in exon 10.The father carried the c.498_499insC mutation,while the mother carried the c.1150_1151insC mutation.Both were frameshift mutations predicted to alter gene function.These novel mutations had not been reported in the ESP,1000 Genomes(Phase 3),or ExAC databases,indicating they are novel variants.The variants co-segregated with the disease and both were classified as pathogenic according to ACMG guidelines.Based on the clinical and genetic findings,the family was diagnosed with posterior segment microphthalmia-retinoschisis and drusen syndrome,inherited in an autosomal recessive manner.Conclusions The MFRP gene mutations c.1150_1151insC and c.498_499insC are the pathogenic variants for the posterior segment microphthalmia-retinoschisis and drusen syndrome in this family,and these compound heterozygous mutations are reported for the first time.