Spectrum of RB1 Mutations in Argentine Patients: 20-years Experience in the Molecular Diagnosis of Retinoblastoma
Spectrum of RB1 Mutations in Argentine Patients: 20-years Experience in the Molecular Diagnosis of Retinoblastoma
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DOI：
10.3109/13816810.2012.755553
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发表时间：
2013-12-01
影响因子：
1.2
通讯作者：
Szijan, Irene
中科院分区：
文献类型：
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作者：
Ottaviani, Daniela;Parma, Diana;Szijan, Irene
背景：视网膜母细胞瘤是一种由RB1肿瘤抑制基因突变引起的儿童期遗传性癌症。早期诊断对于生存和眼睛保护至关重要，因此RB1突变的识别对于遗传性视网膜母细胞瘤的明确诊断和亲属的风险评估至关重要。方法：我们对144个家庭进行了20年的研究，对方法进行了改变，以提高突变的检测。多态性分离分析、MLPA、FISH和细胞遗传学分析用于检测“危险单倍型”和大缺失。通过异双工/DNA测序鉴定出小突变。结果：在11例家族性病例和26例散发病例中鉴定出危险单倍型，对发现无症状携带者、排除亲属风险和发现RB1重组具有重要意义。在6例双侧/家族性视网膜母细胞瘤和4例单侧视网膜母细胞瘤中发现10个大缺失（8个全基因缺失）。在29例（4例单侧视网膜母细胞瘤患者）中发现了小突变，其中大多数是无义/移码突变。基因型-表型相关性证实视网膜母细胞瘤的表现与突变的类型有关，但也可能出现一些例外，因此考虑进行遗传咨询是至关重要的。三个家庭包括患有视网膜母细胞瘤的远房表亲，携带不同的单倍型，这表明独立的突变事件。结论：本研究使我们能够获得阿根廷视网膜母细胞瘤患者的分子和遗传特征信息，并将其与表型相关联。
Background: Retinoblastoma is a hereditary cancer of childhood caused by mutations in the RB1 tumor suppressor gene. An early diagnosis is critical for survival and eye preservation, thus identification of RB1 mutations is important for unequivocal diagnosis of hereditary retinoblastoma and risk assessment in relatives.Methods: We studied 144 families for 20 years, performing methodological changes to improve detection of mutation. Segregation analysis of polymorphisms, MLPA, FISH and cytogenetic assays were used for detection of "at risk haplotypes" and large deletions. Small mutations were identified by heteroduplex/DNA sequencing.Results: At risk haplotypes were identified in 11 familial and 26 sporadic cases, being useful for detection of asymptomatic carriers, risk exclusion from relatives and uncovering RB1 recombinations. Ten large deletions (eight whole gene deletions) were identified in six bilateral/familial and four unilateral retinoblastoma cases. Small mutations were identified in 29 cases (four unilateral retinoblastoma patients), being the majority nonsense/frameshift mutations. Genotype-phenotype correlations confirm that the retinoblastoma presentation is related to the type of mutation, but some exceptions may occur and it is crucial to be considered for genetic counseling. Three families included second cousins with retinoblastoma carrying different haplotypes, which suggest independent mutation events.Conclusion: This study enabled us to obtain information about molecular and genetic features of patients with retinoblastoma in Argentina and correlate them to their phenotype.