Marazita M L, Spence M A, Melnick M
Am J Med Genet. 1984 Sep;19(1):9-18. doi: 10.1002/ajmg.1320190104.
The present study population consists of 2,532 families ascertained through non-syndromic cleft lip with or without cleft palate (CL +/- P) surgical probands born in Denmark between 1941 and 1971. Three samples were derived for analyses of the trait "clefted (CL +/- P) or not." Sample 1 consists of the 26 largest multigenerational families with four or more affected members. Both samples 2-MG and 2-N consist of nuclear families with at least two children and at least one proband among the children. Sample 2-MG contains 846 nuclear families derived from the kindreds with three or more generations. Sample 2-N contains a further 1,181 kindreds with only two generations, nuclear family information available. Four methods of analysis were used: 1) Pedigree analysis was performed on each of the multigenerational kindreds of Sample 1. Results were consistent with autosomal recessive inheritance in eight families and codominant inheritance in three families. These simple genetic hypotheses could not be distinguished in the remaining 15 families. 2) The goodness-of-fit of the multifactorial threshold (MF/T) model was tested in Samples 2-MG and 2-N. The MF/T model was rejected in both samples. 3) Classical segregation analysis was performed on Samples 2-MG and 2-N. Results were consistent with a possible recessive major gene for CL +/- P in Sample 2-MG, but not in Sample 2-N, and with significant admixture of sporadic cases in both samples. 4) Complex segregation analysis under the mixed model was performed on Samples 2-MG and 2-N. In Sample 2-MG, results were consistent with either the general mixed model or with an hypothesis of no major gene. In Sample 2-N, four hypotheses were equally likely: the mixed model with no polygenic component, the mixed model with the major gene component, the mixed model with no sib environmental correlation, and major gene alone. Three conclusions may be drawn: 1) The data provide no support for the MF/T model. 2) The data are consistent with the possibility of a major gene in a portion of the kindreds. 3) The data provide evidence for genetic heterogeneity for CL +/- P.
本研究人群包括2532个家庭，这些家庭是通过1941年至1971年在丹麦出生的非综合征性唇裂伴或不伴腭裂（CL+/-P）手术先证者确定的。为分析“是否患唇裂（CL+/-P）”这一性状，选取了三个样本。样本1由26个最大的多代家庭组成，每个家庭有四名或更多受影响成员。样本2-MG和样本2-N均由核心家庭组成，家庭中至少有两个孩子，且孩子中至少有一名先证者。样本2-MG包含846个来自三代或更多代亲属关系的核心家庭。样本2-N还包含另外1181个仅有两代的亲属关系，且可获取核心家庭信息。使用了四种分析方法：1）对样本1的每个多代亲属关系进行系谱分析。结果显示，八个家庭符合常染色体隐性遗传，三个家庭符合共显性遗传。在其余15个家庭中，无法区分这些简单的遗传假设。2）在样本2-MG和样本2-N中检验多因素阈值（MF/T）模型的拟合优度。两个样本均拒绝了MF/T模型。3）对样本2-MG和样本2-N进行经典分离分析。结果表明，样本2-MG中可能存在一个导致CL+/-P的隐性主基因，但样本2-N中不存在，且两个样本中散发病例均有显著混合。4）在混合模型下对样本2-MG和样本2-N进行复杂分离分析。在样本2-MG中，结果符合一般混合模型或无主基因假设。在样本2-N中，四种假设可能性相同：无多基因成分的混合模型、有主基因成分的混合模型、无同胞环境相关性的混合模型以及仅有主基因。可以得出三个结论：1）数据不支持MF/T模型。2）数据与部分亲属关系中存在主基因的可能性一致。3）数据为CL+/-P的遗传异质性提供了证据。
