Genetic factors are major determinants of phenotypic variability in a mouse model of the DiGeorge/del22q11 syndromes

The del22q11 syndrome is associated with a highly variable phenotype despite the uniformity of the chromosomal deletion that causes the disease in most patients. Df1/+ mice, which model del22q11, present with reduced penetrance of cardiovascular defects similar to those seen in deleted patients but not with other del22q11-like findings. The reduced penetrance of cardiovascular defects is caused by the ability of mutant embryos to recover from a fourth pharyngeal arch artery growth abnormality that is fully penetrant in early embryos. Here we show that genetic background has a major effect on penetrance of cardiovascular defects by affecting this embryonic recovery process. This effect could not be explained by allelic variation at the haploid locus, and it is likely to be caused by genetic modifiers elsewhere in the genome. We also show that genetic factors control extension of the Df1/+ phenotype to include thymic and parathyroid anomalies, establishing the Df1 mouse as a model for the genetic analysis of three major features of human del22q11 syndrome. We found that in Df1/+ mice, as in human patients, expression of the heart and thymic phenotypes are essentially independent from each other, suggesting that they may be controlled by different genetic modifiers. These data provide a framework for our understanding of phenotypic variability in patients with del22q11 syndrome and the tools for its genetic dissection.

尽管大多数患者的致病染色体缺失均保持一致，但22q11缺失综合征（del22q11 syndrome）的表型却呈现高度异质性。作为该综合征的疾病模型，Df1/+小鼠（Df1/+）表现出与缺失患者相似的心血管缺陷外显率降低，但未出现其他22q11缺失综合征相关表型。心血管缺陷外显率降低的原因在于，突变胚胎可从早期胚胎中完全外显的第四咽弓动脉生长异常中恢复。本研究证实，遗传背景通过调控该胚胎恢复过程，对心血管缺陷的外显率具有显著影响。该效应无法通过单倍体位点的等位基因变异予以解释，其成因大概率为基因组其他区域的遗传修饰因子。本研究还发现，遗传因素可调控Df1/+小鼠表型的扩展，使其出现胸腺与甲状旁腺异常，从而确立Df1小鼠可作为分析人类22q11缺失综合征三大核心特征的遗传研究模型。研究观察到，与人类患者一致，Df1/+小鼠的心脏与胸腺表型表达基本相互独立，提示二者可能受不同的遗传修饰因子调控。本研究数据为解析22q11缺失综合征患者的表型异质性提供了理论框架，同时也为该疾病的遗传解析提供了研究工具。