筛查一个家族性渗出性玻璃体视网膜病变(FEVR)致病基因变异的突变位点。

2019年7月收集常染色体显性遗传FEVR家系三代6例的临床资料。采集家系中2例FEVR患者和2位眼正常者的外周血样本。利用二代高通量基因测序技术及Sanger测序对4位受检者的20 000个基因进行测序分析，比较分析眼科疾病相关基因，明确该家系致病基因的突变位点。

本家系的先证者，女性，15岁，右眼最佳矫正视力为0.6，左眼最佳矫正视力为0.5。眼底检查结果显示视网膜周边部血管分支多，呈"柳枝"样形态，荧光素眼底造影可见无血管区。患儿四肢修长，身材高大，全身患有二尖瓣和三尖瓣关闭不全，疑似Loeys-Dietz综合征。先证者父亲右眼最佳矫正视力为0.2，左眼最佳矫正视力为0.5，曾行双眼激光治疗，眼底显示有FEVR改变。其余家族成员中，先证者祖父母可见晶状体混浊，眼底检查未见异常；先证者母亲和姑母，视力良好，眼前节及眼底检查均未见异常。家系中4位受检者周围血的遗传基因检测结果显示，先证者及其父亲2例FEVR患者携带基因/转录本FZD4/NM_012193.3核苷酸杂合变异c.1498delA，氨基酸变异p.Thr500fs，该变异导致第500位氨基酸由苏氨酸突变为亮氨酸，可致后续蛋白翻译发生提前终止，产生截断蛋白。根据美国医学遗传学与基因组学学会遗传变异分类标准与指南，该变异被评定为疑似致病性变异，2位眼正常人未检测出该基因变异。4位受检者中发现先证者及其母亲携带基因/转录本转化生长因子β2(TGFβ2)/NM_001135599.3核苷酸杂合变异c.673G>A，氨基酸变异p.Glu225Lys，该变异点为临床意义不明变异，可能与Loeys-Dietz综合征相关。

FZD4基因核苷酸变异c.1498delA(p.Thr500fs)属于基因位点变异，该变异可以解释此FEVR家系的致病原因。FZD4和TGFβ2基因突变可以共存于一个个体。

The aim of this study was to investigate a novel pathogenic mutation of FZD4 gene in a Chinese family with familial exudative vitreoretinopathy (FEVR).

Clinical data of 6 cases with autosomal dominant FEVR representing 3 generations of a single family was collected. DNA was extracted from peripheral blood sample taken from 2 FEVR patients and 2 healthy participants. Direct sequencing of 20 000 genes was performed with next-generation sequencing and Sanger sequencing was used to identify the pathogenic gene locus in the FEVR family.

The proband was a 15-year-old female with low vision in both eyes; her best corrected visual acuity (BCVA) were 0.6 (right eye) and 0.5 (left eye). After fundus examination, it showed that there were many vascular branches around the retina, like "willow" shape. After fluorescein fundus angiography, it showed ischemic region. The child had longer limbs, mitral and tricuspid insufficiency, and was suspected of loeys Dietz syndrome. In the family, the BCVA of the proband′s father after laser treatment were 0.2 (right eye) and 0.5 (left eye) with FEVR changes. The proband′s grandparents had cataract, and no abnormality in fundus examination; the proband′s mother and aunt had good visions, and no abnormality in the anterior segments and fundus of her both eyes. After genetic detection of peripheral blood from 4 detector, we found a novel FZD4 pathogenic mutation locus c. 1498delA (p.Thr500fs) mutation (heterozygous frame-shift mutation), which resulted in leucine substitute for threonine in the 500 locus and affected protein′s structure and function. No mutations in FZD4 gene was found in 2 normal participants. Among of 4 tested members, the proband and her mother, were found to carry genes associated with loeys Dietz syndrome, namely TGFβ2/ NM_001135599.3 nucleotide heterozygous variation c. 673G>A, amino acid mutation p. Glu225Lys.

c. 1498delA (p.Thr500fs) was first identified a novel heterozygous frame-shift mutation in the FZD4 gene. It may be the disease-causing mutation in this FEVR family. FZD4 and TGFβ2 genes mutations could exist in one individual.