Bia B, Cowell J K
Haematology Oncology Unit, Institute of Child Health, London.
Oncogene. 1995 Sep 7;11(5):977-9.
The inheritance of a genetic susceptibility to the development of retinoblastoma generally follows an autosomal mode of inheritance with high penetrance. Rare families, however, show evidence of incomplete penetrance where individuals can transmit the mutant gene without being affected themselves. In these families formal proof of this dogma requires the identification of the predisposing mutation. In this study we have identified the mutations in cousins with bilateral (hereditary) disease. Using SSCP and DNA sequencing, different constitutional mutations were detected in the affected cousins in this pedigree. One cousin carries a C-->T mutation in exon 8 generating a stop codon directly which was also present in his affected mother whereas the other cousin carries an 8 base pair deletion in exon 20. Neither half of the family carried the same mutation as the other. The mother of the patient with the 8 bp deletion carried neither of the mutations. Thus, we have demonstrated that the retinoblastomas in this family have developed as a result of independent, sporadic genetic events which occurred coincidentally in the same extended family rather than being due to a common mutation which manifests as incompletely penetrant. These observations have important implications for genetic counselling in this type of family.
视网膜母细胞瘤发生遗传易感性的遗传通常遵循具有高外显率的常染色体遗传模式。然而，罕见的家族显示出不完全外显的证据，即个体可以传递突变基因而自身不受影响。在这些家族中，这一规律的正式证据需要确定易感突变。在本研究中，我们已确定了患有双侧（遗传性）疾病的堂兄弟姊妹中的突变。使用单链构象多态性（SSCP）和DNA测序，在这个家系中受影响的堂兄弟姊妹中检测到了不同的结构突变。一名堂兄弟姊妹在第8外显子中有一个C→T突变，直接产生一个终止密码子，其患病母亲也有该突变；而另一名堂兄弟姊妹在第20外显子中有一个8个碱基对的缺失。家族中没有任何一方携带与另一方相同的突变。患有8个碱基对缺失的患者的母亲不携带这两种突变中的任何一种。因此，我们证明了这个家族中的视网膜母细胞瘤是由独立的、散发性的遗传事件导致的，这些事件碰巧发生在同一个大家庭中，而不是由于一个表现为不完全外显的共同突变。这些观察结果对这类家族的遗传咨询具有重要意义。
