Genotype-phenotype correlations in hereditary familial retinoblastoma
Genotype-phenotype correlations in hereditary familial retinoblastoma
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DOI：
10.1002/humu.20443
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发表时间：
2007-03-01
期刊：
影响因子：
3.9
通讯作者：
Gauthier-Villars, Marion
中科院分区：
文献类型：
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作者：
Taylor, Melissa;Dehainault, Catherine;Gauthier-Villars, Marion
我们研究了50个有视网膜母细胞瘤(RB)家族史的无关家系(165个RB1突变携带者)，以描绘RB1胚系突变在家族性RB中的频谱，并确定基因-表型相关性以及可能的修饰因素。在居里研究所对患者进行了跟踪，并由眼科医生、儿科医生和遗传学家对他们进行了检查。所有家族性RB病例均经遗传咨询确诊。临床特征包括疾病状态、偏侧、确诊年龄、突变类型、随访和病眼比(DER)。为了排除马赛克病例，第一代低外显率(LP)RB携带者被排除在分析之外。完全外显性是无稽之谈和移码突变的规律(25个家系)，大重排(8个家系)观察到高外显性。启动子(两个家族)和错义(两个家族)突变表现为异质性表型，剪接异常(13个家族)表现为LE可变外显性，可通过框内/框外突变或功能域方面来解释。令人惊讶的是，两个携带LP g.45867G>；T/IVS6+1G>；T突变的家系提供的数据与之前报道的数据相矛盾，因为未受影响的携带者具有父系遗传的突变等位基因。此外，RNA分析表明，未受影响的携带者缺乏外显性可以通过野生型等位基因表达水平的增加来解释。这一观察结果促使我们定义了一类新的Lp等位基因“3”。我们相信，这是第一次对家族性RB进行大规模研究，在患者及其亲属的临床和基因分析中具有高度的同质性，从而允许可靠的家族内基因-表型相关性。我们的分析表明，在某些情况下，修饰因素的影响可能参与了mRNA水平的调节和/或pRb途径的调节。
We studied 50 unrelated pedigrees with a family history of retinoblastoma (Rb) (165 carriers of a RB1 mutation) to delineate the spectrum of RB1 germline mutations in familial Rb and to identify genotype-phenotype correlations as well as putative modifiers. Patients were followed at Institut Curie and they were examined by an ophthalmologist, a pediatrician, and a geneticist. All cases of familial Rb were determined via genetic counseling. Clinical features included disease status, laterality, age at diagnosis, mutation type, follow-up, and disease-eye ratio (DER). To eliminate mosaic cases, first- generation carriers displaying low, penetrance (LP) Rb were excluded from the analysis. Complete penetrance was the rule for nonsense and frameshift mutations (25 families) and high penetrance was observed for large rearrangements (eight families). Promoter (two families) and missense (two families) mutations displayed heterogeneous phenotypes and LE Variable penetrance was observed for splice abnormalities (13 families) and was explained by in/out of frame mutations or respect of functional domains. Surprisingly, two families with the LP g.45867G > T/IVS6+ 1G > T mutation presented data that conflicted with the data reported in previous publications, as unaffected carriers had paternally inherited mutant alleles. Moreover, RNA analyses suggested that the lack of penetrance in unaffected carriers could be explained by an increase in expression levels of the wild-type allele. This observation prompted us to define a new class "3" of LP alleles. We believe this is the first large-scale study of familial Rb with a high level of homogeneity in the clinical and genetic analysis of patients and their relatives, thereby allowing for reliable intrafamilial genotype-phenotype correlations. Our analysis suggests in some cases the influence of modifier factors probably involved in mRNA level regulation and/or pRB pathway regulation.