Bu X, Shohat M, Jaber L, Rotter J I
Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048.
Genet Epidemiol. 1993;10(1):3-15. doi: 10.1002/gepi.1370100102.
We have previously reported a large Israeli-Arab pedigree with sensorineural deafness possibly determined simultaneously by two loci--one mitochondrial, and one autosomal recessive. This was analyzed by extending classic segregation analysis methods to the many nuclear families derived from the maternal line pedigree. Here we expand this pedigree and extend our analysis by using the regressive models for segregation analysis on the entire pedigree. The corresponding REGD computer program was utilized and the marrying-in males' and paternal line members' affection statuses were assigned as unknown to accommodate the exclusive maternal transmission pattern. For the autosomal locus, a simple autosomal recessive (q = 0.52) model with a nearly complete penetrance (0.93) was found to be the best-fitting model. Equally importantly, we were also able to use the power of the regressive models to test the hypothesis of mitochondrial heteroplasmy as an alternative for the proposed autosomal locus. We found no evidence for the heteroplasmy hypothesis as an explanation for the incomplete maternal transmission of deafness in this pedigree. Thus, even if the mitochondrial mutation occurred in a heteroplasmic distribution in the family members, this could not explain the familial aggregation in this pedigree, and an autosomal recessive locus is still required. These results provide further support for the concept that the sensorineural deafness occurring in this large Israeli-Arab pedigree results from simultaneous involvement of two genes at two different loci, one mitochondrial and likely homoplasmic, and the other autosomal and recessive.
我们之前报道过一个大型以色列-阿拉伯家系，其中感音神经性耳聋可能由两个基因座同时决定——一个是线粒体基因座，另一个是常染色体隐性基因座。通过将经典的分离分析方法扩展到源自母系家系的众多核心家庭，对此进行了分析。在此，我们扩展了这个家系，并通过对整个家系使用回归模型进行分离分析来扩展我们的研究。使用了相应的REGD计算机程序，并将入赘男性和父系成员的患病状态设为未知，以适应独特的母系遗传模式。对于常染色体基因座，发现一个简单的常染色体隐性（q = 0.52）模型，其外显率近乎完全（0.93），是最合适的模型。同样重要的是，我们还能够利用回归模型的功效来检验线粒体异质性假说，作为所提出的常染色体基因座的一种替代解释。我们没有发现证据支持异质性假说可解释该家系中耳聋不完全母系遗传的现象。因此，即使线粒体突变在家庭成员中以异质分布形式出现，这也无法解释该家系中的家族聚集现象，仍然需要一个常染色体隐性基因座。这些结果进一步支持了这样一种观点，即这个大型以色列-阿拉伯家系中出现的感音神经性耳聋是由两个不同基因座上的两个基因同时作用导致的，一个是线粒体基因座且可能是同质性的，另一个是常染色体隐性基因座。
