Clementi M, Tenconi R, Forabosco P, Calzolari E, Milan M
Dipartimento di Pediatria, Università di Padova, Italy.
Hum Genet. 1997 Aug;100(2):204-9. doi: 10.1007/s004390050491.
Although several studies have demonstrated familial aggregation of nonsyndromic cleft palate (CP), the mode of inheritance still remains uncertain. We report the results of complex segregation analysis performed in families of 357 consecutive newborns affected with nonsyndromic CP (i.e., CP not a component feature of malformation syndrome, sequence or association), and registered in the North East Italy and Emilia Romagna congenital malformation registries in the period 1981-1993. This sample, based on a large number of consecutive births, in a well-defined geographical area, with quality control to detect associated anomalies and malformation syndromes, is independent of the number of affected subjects in the family and of CP severity, fitness, and survival. We have analyzed, using the mixed model, the whole sample of nonsyndromic CP, including isolated (i.e., without other anomalies) CP (CPI) and CP associated with at least one other anomaly (CPA), for which a diagnosis of malformation syndrome was not possible. When nonsyndromic CP (including CPA) are considered in the analysis, there is no heterogeneity between CPA and CPI nor between CP including hard palate (CPH) and CP of the soft palate only (CPS). POINTER and COMDS programs cannot discriminate between alternative genetic models; only the hypothesis of non-genetic transmission is rejected. The COMDS analysis two-locus model, which indicates that a modifier locus (or loci) operates in addition to a single major locus (SML), does not show evidence of better fit than SML, polygenic, and multifactorial models. When the severity parameter (defined as CPH and CPS) is added, CPI and CPA show heterogeneity. Eventually, when the analysis is limited to CPI and includes information on severity, a recessive SML, with low penetrance and determining CPH, provides a significant best fit. To have defined a genetic model for CPI and provided evidence for SML inheritance suggests that genetic linkage studies could be implemented. This conclusion is in agreement with previous studies which showed a significant association between alleles of transforming growth factor alpha and CP only in humans, and that single recessive genes may play a crucial role during palatogenesis in mice as well as in Brittany spaniels. Application of the candidate genes to human CPH families could reveal whether these genes are involved.
尽管多项研究已证实非综合征性腭裂（CP）存在家族聚集现象，但遗传模式仍不明确。我们报告了对357例连续出生的受非综合征性CP影响的新生儿家庭进行复杂分离分析的结果（即CP不是畸形综合征、序列或关联的组成特征），这些新生儿于1981年至1993年期间登记在意大利东北部和艾米利亚-罗马涅先天性畸形登记处。该样本基于大量连续出生的病例，来自明确界定的地理区域，具备检测相关异常和畸形综合征的质量控制，独立于家庭中受影响个体的数量以及CP的严重程度、健康状况和存活率。我们使用混合模型分析了非综合征性CP的整个样本，包括孤立性（即无其他异常）CP（CPI）和与至少一种其他异常相关的CP（CPA），对于后者无法做出畸形综合征的诊断。在分析中考虑非综合征性CP（包括CPA）时，CPA和CPI之间以及包括硬腭CP（CPH）和仅软腭CP（CPS）的CP之间均无异质性。POINTER和COMDS程序无法区分替代遗传模型；仅非遗传传递的假设被拒绝。COMDS分析的双基因座模型表明，除单个主要基因座（SML）外，还有一个修饰基因座（或多个修饰基因座）起作用，但与SML、多基因和多因素模型相比，并未显示出更好的拟合证据。当加入严重程度参数（定义为CPH和CPS）时，CPI和CPA显示出异质性。最终，当分析仅限于CPI并纳入严重程度信息时，一个低外显率且决定CPH的隐性SML提供了显著的最佳拟合。为CPI定义遗传模型并为SML遗传提供证据表明可以开展遗传连锁研究。这一结论与先前的研究一致，先前研究表明仅在人类中转化生长因子α等位基因与CP之间存在显著关联，并且单个隐性基因在小鼠以及不列塔尼猎犬的腭发育过程中可能起关键作用。将候选基因应用于人类CPH家庭可能会揭示这些基因是否参与其中。
