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Frequency of low-level and high-level mosaicism in sporadic retinoblastoma: genotype-phenotype relationships.
Journal of Human Genetics ( IF 2.6 ) Pub Date : 2019-11-26 , DOI: 10.1038/s10038-019-0696-z Carlos Rodríguez-Martín 1 , Cristina Robledo 1 , Gema Gómez-Mariano 2 , Sara Monzón 3 , Ana Sastre 4 , Jose Abelairas 4 , Constantino Sábado 5 , Nieves Martín-Begué 6 , Joan Carles Ferreres 7 , Ana Fernández-Teijeiro 8 , Ricardo González-Campora 9 , María José Rios-Moreno 9 , Ángel Zaballos 10 , Isabel Cuesta 3 , Beatriz Martínez-Delgado 2, 11 , Manuel Posada 2, 11 , Javier Alonso 1, 11
Journal of Human Genetics ( IF 2.6 ) Pub Date : 2019-11-26 , DOI: 10.1038/s10038-019-0696-z Carlos Rodríguez-Martín 1 , Cristina Robledo 1 , Gema Gómez-Mariano 2 , Sara Monzón 3 , Ana Sastre 4 , Jose Abelairas 4 , Constantino Sábado 5 , Nieves Martín-Begué 6 , Joan Carles Ferreres 7 , Ana Fernández-Teijeiro 8 , Ricardo González-Campora 9 , María José Rios-Moreno 9 , Ángel Zaballos 10 , Isabel Cuesta 3 , Beatriz Martínez-Delgado 2, 11 , Manuel Posada 2, 11 , Javier Alonso 1, 11
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Somatic mutational mosaicism is a common feature of monogenic genetic disorders, particularly in diseases such as retinoblastoma, with high rates of de novo mutations. The detection and quantification of mosaicism is particularly relevant in these diseases, since it has important implications for genetic counseling, patient management, and probably also on disease onset and progression. In order to assess the rate of somatic mosaicism (high- and low-level mosaicism) in sporadic retinoblastoma patients, we analyzed a cohort of 153 patients with sporadic retinoblastoma using ultra deep next-generation sequencing. High-level mosaicism was detected in 14 out of 100 (14%) bilateral patients and in 11 out of 29 (38%) unilateral patients in whom conventional Sanger sequencing identified a pathogenic mutation in blood DNA. In addition, low-level mosaicism was detected in 3 out of 16 (19%) unilateral patients in whom conventional screening was negative in blood DNA. Our results also reveal that mosaicism was associated to delayed retinoblastoma onset particularly in unilateral patients. Finally we compared the level of mosaicism in different tissues to identify the best DNA source to identify mosaicism in retinoblastoma patients. In light of these results we recommended analyzing the mosaic status in all retinoblastoma patients using accurate techniques such as next-generation sequencing, even in those cases in which conventional Sanger sequencing identified a pathogenic mutation in blood DNA. Our results suggest that a significant proportion of those cases are truly mosaics that could have been overlooked. This information should be taking into consideration in the management and genetic counseling of retinoblastoma patients and families.
中文翻译：
散发性视网膜母细胞瘤的低水平和高水平镶嵌的频率：基因型-表型关系。
体细胞突变镶嵌症是单基因遗传疾病的普遍特征，尤其是在视网膜新生母细胞瘤等疾病中，从头突变率很高。镶嵌症的检测和定量在这些疾病中特别重要，因为它对遗传咨询，患者管理以及可能对疾病的发作和进展都具有重要意义。为了评估散发性视网膜母细胞瘤患者的体细胞镶嵌术（高水平和低水平镶嵌术）的发生率，我们使用超深度下一代测序方法分析了153例散发性视网膜母细胞瘤患者。在100名（14％）的双侧患者中有14名和29名（38％）的单侧患者中有11名被检测到高水平的镶嵌性，其中传统的Sanger测序确定了血液DNA的致病突变。此外，在常规筛查血液DNA阴性的16名单侧患者中，有16名（19％）单侧患者中有3名检测到低水平镶嵌症。我们的结果还表明，镶嵌症与视网膜母细胞瘤的发作有关，尤其是在单侧患者中。最后，我们比较了不同组织中镶嵌的水平，以鉴定出最佳的DNA来源，以鉴定成视网膜细胞瘤患者的镶嵌。根据这些结果，我们建议使用下一代测序等准确的技术分析所有视网膜母细胞瘤患者的镶嵌状态，即使在常规Sanger测序识别出血液DNA的致病突变的情况下也是如此。我们的结果表明，这些案例中有很大一部分是真正的马赛克，可以忽略不计。
更新日期：2019-11-27
中文翻译：
散发性视网膜母细胞瘤的低水平和高水平镶嵌的频率：基因型-表型关系。
体细胞突变镶嵌症是单基因遗传疾病的普遍特征，尤其是在视网膜新生母细胞瘤等疾病中，从头突变率很高。镶嵌症的检测和定量在这些疾病中特别重要，因为它对遗传咨询，患者管理以及可能对疾病的发作和进展都具有重要意义。为了评估散发性视网膜母细胞瘤患者的体细胞镶嵌术（高水平和低水平镶嵌术）的发生率，我们使用超深度下一代测序方法分析了153例散发性视网膜母细胞瘤患者。在100名（14％）的双侧患者中有14名和29名（38％）的单侧患者中有11名被检测到高水平的镶嵌性，其中传统的Sanger测序确定了血液DNA的致病突变。此外，在常规筛查血液DNA阴性的16名单侧患者中，有16名（19％）单侧患者中有3名检测到低水平镶嵌症。我们的结果还表明，镶嵌症与视网膜母细胞瘤的发作有关，尤其是在单侧患者中。最后，我们比较了不同组织中镶嵌的水平，以鉴定出最佳的DNA来源，以鉴定成视网膜细胞瘤患者的镶嵌。根据这些结果，我们建议使用下一代测序等准确的技术分析所有视网膜母细胞瘤患者的镶嵌状态，即使在常规Sanger测序识别出血液DNA的致病突变的情况下也是如此。我们的结果表明，这些案例中有很大一部分是真正的马赛克，可以忽略不计。
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