Giannelli F, Morris A H, Garrett C, Daker M, Thurston C, Smith C A
Paediatric Research Unit, United Medical School of Guy's, St Thomas' Hospital, London.
Ann Hum Genet. 1987 May;51(2):107-24. doi: 10.1111/j.1469-1809.1987.tb01052.x.
X-linked mental retardation with fragile X or Martin-Bell Syndrome (MBS) is a frequent cause of mental retardation. So far segregation analysis of MBS in pedigrees ascertained by different, incomplete criteria has produced results, difficult to interpret, which suggest genetic complexity (Sherman et al. 1985). Biochemical and cell biological studies have failed to provide an assay for genetic heterogeneity in MBS and linkage analysis is the only available method. Such analysis, however, is complicated by the incomplete penetrance of the disease in males and the variable penetrance and expression of the defect in heterozygous females. We have used a new approach to test the heterogeneity of recombination between MBS and the coagulation factor IX gene or the anonymous probe 52A in a group of nine families who have sought genetic counselling at Guy's Hospital. We find that both our families alone and our families plus apparently complete samples of pedigrees reported in the literature, separate into two groups: one tightly and one loosely linked to factor IX. In the combined family sample these represent respectively 0.3 and 0.7 of the total and show recombination fractions of 0.0-0.15 and 0.25-0.5. Furthermore, the families with non-penetrant carrier males show tighter linkage to factor IX than the others, thus confirming the suggestion of a systematic difference among MBS families in the recombination between the disease and the factor IX locus. By contrast, no significant differences were found in the recombination between 52A and factor IX in the two groups of MBS families or in these families versus those with Hunter syndrome examined in our laboratory. The causes of the linkage heterogeneity we describe are not known. At least two alternatives can be considered: The existence of two MBS loci or differences in the recombination between a single MBS locus and the factor IX gene. The association between incomplete penetrance and tight linkage to factor IX as well as the discontinuous variation in recombination fraction we have observed seem to favour the former alternative.
与脆性X相关的X连锁智力迟钝或马丁-贝尔综合征（MBS）是智力迟钝的常见原因。迄今为止，通过不同的、不完整的标准确定的家系中MBS的分离分析产生了难以解释的结果，这表明存在遗传复杂性（谢尔曼等人，1985年）。生化和细胞生物学研究未能提供MBS遗传异质性的检测方法，连锁分析是唯一可用的方法。然而，这种分析因疾病在男性中的不完全外显以及杂合子女性中缺陷的可变外显和表达而变得复杂。我们采用了一种新方法，在一组在盖伊医院寻求遗传咨询的九个家庭中，测试MBS与凝血因子IX基因或匿名探针52A之间重组的异质性。我们发现，单独的我们的家庭以及我们的家庭加上文献中报道的明显完整的家系样本，都分为两组：一组与因子IX紧密连锁，一组与因子IX松散连锁。在合并的家庭样本中，这些分别占总数的0.3和0.7，重组率分别为0.0 - 0.15和0.25 - 0.5。此外，具有非外显携带者男性特征的家庭与因子IX表现出比其他家庭更紧密的连锁，从而证实了MBS家庭在疾病与因子IX基因座之间的重组存在系统性差异的推测。相比之下，在两组MBS家庭中，或者在这些家庭与我们实验室检测的亨特综合征家庭之间，52A与因子IX之间的重组未发现显著差异。我们所描述的连锁异质性的原因尚不清楚。至少可以考虑两种可能性：存在两个MBS基因座，或者单个MBS基因座与因子IX基因之间重组存在差异。我们观察到的不完全外显与因子IX紧密连锁之间的关联以及重组率的不连续变化似乎支持前一种可能性。
