CDHR1和C2orf71基因新变异相关的视锥视杆细胞营养不良

Cone-rod dystrophy associated with novel variations on CDHR1 and C2orf71 gene

目的观察并分析视锥视杆细胞营养不良(CORD)患者基因突变和临床表型。方法家系调查研究。2021年2月于宁夏回族自治区人民医院宁夏眼科医院就诊的2个CORD家系中的2例患者及其家系成员6名纳入研究。患者分别来自2个无血缘关系家系,均为先证者。采集病史并行最佳矫正视力(BCVA)、色觉、裂隙灯显微镜、间接检眼镜、眼底彩色照相、光相干断层扫描(OCT)、自身荧光(AF)、荧光素眼底血管造影(FFA)、视网膜电图(ERG)检查。采集患者及其父母外周静脉血,提取全基因组DNA,行Trio全基因组外显子测序,对可疑致病突变位点进行Sanger验证及家系共分离检测。根据遗传规律,分析家族史,确立其遗传类型。参照美国医学遗传学和基因组学学会(ACMG)指南和4个在线工具对突变位点致病性进行分析。结果2个家系均为常染色体隐性遗传CORD。家系1先证者,女,49岁。双眼视力下降伴畏光9年,夜盲4年。右眼、左眼BCVA分别为0.03、0.06。ERG检查,双眼暗适应0.01 b波和暗适应3.0 a、b波振幅轻度降低,明适应3.0 a、b波振幅重度降低。家系2先证者,男,30岁。双眼视力下降4年;否认夜盲史。右眼、左眼BCVA分别为0.3、0.2。ERG检查,双眼暗适应0.01 b波和暗适应3.0 a、b波振幅轻度降低,明适应3.0 a、b波振幅重度降低。双眼视盘颜色淡红,黄斑区萎缩,中心凹反光消失,周边视网膜点状色素沉着。2例患者眼底主要改变为黄斑区萎缩。基因检测结果显示,家系1先证者携带CDHR1基因c.439-2A>G(M1)、c.676delT(p.F226fs)(M2)复合杂合突变;其父亲、母亲分别携带M2、M1杂合突变。家系2先证者携带C2orf71基因c.2665dupC(p.L889fs)(M3)、c.878T>C(p.L293P)(M4)复合杂合突变;其父亲、母亲分别携带M4、M3杂合突变。根据ACMG指南和在线工具分析结果,提示4个突变均为新的致病性变异。结论CDHR1基因M1、M2和C2orf71基因M3、M4是CORD新的致病性突变位点;患者均表现为视力下降伴有黄斑区萎缩的临床表型。

Objective To observe and analyze the gene mutation and clinical phenotype of patients with cone and rod dystrophy(CORD).Methods A pedigree investigarion.Two CORD pedigrees including 2 patients and 6 family members were enrolled in Ningxia Eye Hospital of People'Hospital of Ningxia Hui Automous Region for this study.The patients were from 2 unrelated families,all of whom were probands.Take medical history with best-corrected visual acuity(BCVA),color vision,slit lamp microscopy,indirect ophthalmoscopy,fundus color photography,optical coherence tomography(OCT),autofluorescence(AF),fluorescein fundus angiography(FFA),electroretinogram(ERG).The peripheral venous blood of patients and their parents was collected,whole genome DNA was extracted,Trio whole genome exome sequencing was performed,Sanger verification and pedigree co-segregation were performed for suspected pathogenic mutation sites.According to the law of inheritance,family history was analyzed to establish its genetic type.Mutational loci pathogenicity was analyzed according to the American College of Medical Genetics(ACMG)guidelines and 4 online tools.Results Two CORD families showed autosomal recessive inheritance.The proband of pedigree 1 was female,49 years old.Binocular vision loss with photophobia lasted for 9 years and night blindness for 4 years.The BCVA of right eye and left eye were 0.03 and 0.06,respectively.The results of ERG showed that the amplitudes of dark adaptation 0.01 b-wave and dark adaptation 3.0 a-wave and b-wave in both eyes were slightly decreased,and the amplitudes of light adaptation 3.0 a-wave and b-wave were severely decreased.The proband of pedigree 2 was male,30 years old.Vision loss in both eyes for 4 years.Denying a history of night blindness.The BCVA of right eye and left eye were 0.3 and 0.2,respectively.The results of ERG showed that the amplitudes of dark adaptation 0.01 b-wave and dark adaptation 3.0 a-wave and b-wave in both eyes were slightly decreased,and the amplitudes of light adaptation 3.0 a-wave and b-wave were severely decreased.The color of optic disc in both eyes was light red,the macular area was atrophic,the foveal reflection disappeared,and the peripheral retina was punctate pigmentation.The main fundus changes in 2 patients were macular atrophy.The proband of pedigree 1 carried compound heterozygous variations c.439-2A>G(M1)and c.676delT(p.F226fs)(M2)on CDHR1 gene.Her father and mother carried M2 and M1 heterozygous mutations,respectively.The proband of pedigree 2 carried compound heterozygous variations c.2665dupC(p.L889fs)(M3)and c.878T>C(p.L293P)(M4)on C2orf71 gene.His father and mother carried M4 and M3 heterozygous mutations,respectively.According to ACMG guidelines and on line tools,4 variations were considered as pathogenic level.Conclusions M1 and M2 of CDHR1 gene and M3 and M4 of C2orf71 gene are new pathogenic mutations of CORD.All patients presented with the clinical phenotype of decreased visual acuity and macular atrophy.