Retinoblastoma (RB) is the most common primary intraocular malignant tumor in infants and the prototype of human hereditary tumors. Its occurrence and development are closely related to the pathogenic variant of tumor suppressor RB1 gene. We aim to analyze the characteristics of RB1 gene pathogenic variant and clinical phenotype in retinoblastoma patients and their relatives. Children with RB were recruited from August 2007 to November 2017. QT-PCR, probing, and gene sequencing were used to analyze the sequence of RB1 gene in RB children, their parents, or grandparents with a clear history of illness. The SPSS20.0 software was used to analyze the correlation between polymorphisms of RB1 gene and the incidence and prognosis of the enrolled children and relatives. 40 RB children (20 males and 20 females) were recruited, unilateral RB accounted for 52.5% (21/40), bilateral RB accounted for 42.5% (17/40), and trilateral RB accounted for 5.0% (2/40). 6 patients had a clear family history (15.0%, 6/40). It had been verified that 19 probands (47.5%) have RB1 gene pathogenic variants (11 frameshift and 8 missense pathogenic variants), of which germline inheritance accounted for 47.4% (9/19) and nongermline heredity accounted for 52.6% (10/19). Pathogenic variants of 10 nucleic acid sites without reported were found, among which c.2455C>G (p.L819V) was confirmed to have heterozygous pathogenic variants in both a bilateral RB patient and his mother with unilateral RB. Family genetic high-risk factors, bilateral/trilateral RB, >12-month-onset RB have a higher proportion of RB1 gene pathogenic variant than children with no family history, unilateral RB, and ≤12-month (, 0.001,0.034). The proportion of pedigree inheritance of infantile retinoblastoma with bilateral disease is high. There was a certain proportion of RB1 gene pathogenic variant in 3-5-year-old children with bilateral RB, even if they had no family genetic history. Therefore, the detection of RB1 gene pathogenic variant should not only focus on infants but also on the phenotype of RB1 gene pathogenic variant in children over 3 years old with bilateral eye disease.

中文翻译：

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5岁以下视网膜母细胞瘤家族RB1基因致病变异与临床特征与预后的相关性

视网膜母细胞瘤（RB）是婴儿最常见的原发性眼内恶性肿瘤，是人类遗传性肿瘤的原型。其发生发展与抑癌基因RB1基因的致病变异密切相关。我们旨在分析视网膜母细胞瘤患者及其亲属中RB1基因致病变异的特征和临床表型。招募 2007 年 8 月至 2017 年 11 月患有 RB 的儿童。使用 QT-PCR、探测和基因测序分析有明确病史的 RB 儿童、其父母或祖父母的RB1基因序列。采用SPSS20.0软件分析RB1基因多态性之间的相关性基因与入组儿童及亲属的发病率及预后有关。入组 RB 儿童 40 名（男 20 名，女 20 名），单侧 RB 占 52.5%（21/40），双侧 RB 占 42.5%（17/40），三侧 RB 占 5.0%（2/40）。6例患者有明确的家族史（15.0%，6/40）。已证实有 19 名先证者（47.5%）有RB1基因致病变异（11个移码和8个错义致病变异），其中种系遗传占47.4%（9/19），非种系遗传占52.6%（10/19）。发现10个未报道的核酸位点的致病变异，其中c.2455C>G（p.L819V）在双侧RB患者及其母亲单侧RB中均被证实存在杂合致病变异。家族遗传高危因素、双侧/三侧RB、>12个月起病RB的RB1基因致病变异的比例高于无家族史、单侧RB、≤12个月的儿童。, 0.001,0.034)。婴儿型视网膜母细胞瘤双侧病变的谱系遗传比例较高。3~5岁双侧RB患儿即使无家族遗传史，也存在一定比例的RB1基因致病变异。因此， RB1基因致病变异的检测不仅要关注婴儿，还应关注3岁以上双侧眼病患儿RB1基因致病变异的表型。