Liu Guoqing, Inglis Julie, Cardy Amanda, Shaw Duncan, Sahota Sukhy, Hennekam Raoul, Sharp Linda, Miedzybrodzka Zosia
Department of Medicine and Therapeutics, University of Aberdeen, Aberdeen, UK.
BMC Med Genet. 2008 Jun 6;9:50. doi: 10.1186/1471-2350-9-50.
Genetic factors make an important contribution to the aetiology of congenital talipes equinovarus (CTEV), the most common developmental disorder of the lower limb. WNT7A was suggested as a candidate gene for CTEV on the basis of a genome-wide scan for linkage in a large multi-case family. WNT7A is a plausible candidate gene for CTEV as it provides a signal for pattern formation during limb development, and mutation in WNT7A has been reported in a number of limb malformation syndromes.
We investigated the role of WNT7A using a family-based linkage approach in our large series of European multi-case CTEV families. Three microsatellite markers were used, of which one (D3S2385) is intragenic, and the other two (D3S2403, D3S1252) are 700 kb 5' to the start and 20 kb from the 3' end of the gene, respectively. Ninety-one CTEV families, comprising 476 individuals of whom 211 were affected, were genotyped. LOD scores using recessive and incomplete-dominant inheritance models, and non-parametric linkage scores, excluded linkage.
No significant evidence for linkage was observed using either parametric or non-parametric models. LOD scores for the parametric models remained strongly negative in the regions between the markers, and in the 0.5 cM intervals outside the marker map. No significant lod scores were obtained when the data were analysed allowing for heterogeneity.
Our evidence suggests that the WNT7A gene is unlikely to be a major contributor to the aetiology of familial CTEV.
遗传因素在先天性马蹄内翻足（CTEV）的病因学中起着重要作用，CTEV是下肢最常见的发育障碍。在一个大型多病例家族中进行全基因组连锁扫描后，WNT7A被认为是CTEV的候选基因。WNT7A是CTEV的一个合理候选基因，因为它在肢体发育过程中为模式形成提供信号，并且在一些肢体畸形综合征中已报道WNT7A存在突变。
我们在大量欧洲多病例CTEV家族中采用基于家系的连锁分析方法研究WNT7A的作用。使用了三个微卫星标记，其中一个（D3S2385）位于基因内，另外两个（D3S2403、D3S1252）分别位于基因起始端5'端700 kb处和基因3'端20 kb处。对91个CTEV家族进行了基因分型，这些家族包括476名个体，其中211名受影响。使用隐性和不完全显性遗传模型计算的LOD分数以及非参数连锁分数均排除了连锁关系。
无论是参数模型还是非参数模型，均未观察到显著的连锁证据。参数模型的LOD分数在标记之间的区域以及标记图谱外的0.5 cM区间内仍为强负值。在考虑异质性进行数据分析时，未获得显著的LOD分数。
我们的证据表明，WNT7A基因不太可能是家族性CTEV病因的主要贡献者。
