Zhu Hao, Zhang Jiao, Rao Soumya, Durbin Matthew D, Li Ying, Lang Ruirui, Liu Jiqiang, Xiao Baichuan, Shan Hailin, Meng Ziqiu, Wang Jinmo, Tang Xiaokai, Shi Zhenni, Cox Liza L, Zhao Shouqin, Ware Stephanie M, Tan Tiong Y, de Silva Michelle, Gallacher Lyndon, Liu Ting, Mi Jie, Zeng Changqing, Zheng Hou-Feng, Zhang Qingguo, Antonarakis Stylianos E, Cox Timothy C, Zhang Yong-Biao
School of Engineering Medicine, Beihang University, Beijing 100191, China.
Plastic Surgery Hospital, Chinese Academy of Medical Sciences, Beijing 100144, China.
Genome Res. 2025 May 2;35(5):1065-1079. doi: 10.1101/gr.280047.124.
Pathogenic coding variants have been identified in thousands of genes, yet the mechanisms underlying the incomplete penetrance in individuals carrying these variants are poorly understood. In this study, in a cohort of 2009 craniofacial microsomia (CFM) patients of Chinese ancestry and 2625 Han Chinese controls, we identified multiple predicted pathogenic coding variants in in both CFM patients and healthy individuals. We found that the penetrance of CFM correlates with specific haplotype combinations containing likely pathogenic-coding variants and CFM-associated expression quantitative trait loci (eQTLs) of expression. Further investigations implicate specific eQTL combinations, such as rs1001322 or rs344131, in combination with other significant CFM-associated eQTLs, which we term combined eQTL phenotype modifiers (CePMods). We additionally show that rs344131, located within a regulatory enhancer region of , demonstrates allele-specific effects on enhancer activity and thus impacts expression levels of the associated allele harboring any rare coding variant. Our findings also suggest that CePMods may serve as pathogenic determinants, even in the absence of rare deleterious coding variants in This highlights the critical role of allelic expression in determining the penetrance and severity of craniofacial abnormalities, including microtia and facial asymmetry. Additionally, using quantitative phenotyping, we demonstrate that both microtia and facial asymmetry are present in two separate mouse models, the severity of which is dependent on gene dosage. Our study establishes as a likely pathogenic gene for CFM and demonstrates eQTLs as determinants of modified penetrance in the manifestation of the disease in individuals carrying likely pathogenic rare coding variants.
在数以千计的基因中已鉴定出致病性编码变体，但对于携带这些变体的个体中不完全外显的潜在机制却知之甚少。在本研究中，我们在一个由2009名具有中国血统的颅面短小畸形（CFM）患者和2625名汉族对照组成的队列中，在CFM患者和健康个体中均鉴定出多个预测的致病性编码变体。我们发现CFM的外显率与特定的单倍型组合相关，这些组合包含可能的致病性编码变体和CFM相关的表达定量性状位点（eQTL）。进一步的研究表明，特定的eQTL组合，如rs1001322或rs344131，与其他显著的CFM相关eQTL结合，我们将其称为联合eQTL表型修饰因子（CePMods）。我们还表明，位于一个调控增强子区域内的rs344131对增强子活性具有等位基因特异性效应，从而影响携带任何罕见编码变体的相关等位基因的表达水平。我们的研究结果还表明，即使在没有罕见有害编码变体的情况下，CePMods也可能作为致病决定因素。这突出了等位基因表达在决定颅面异常（包括小耳畸形和面部不对称）的外显率和严重程度方面的关键作用。此外，通过定量表型分析，我们证明在两个独立的小鼠模型中均存在小耳畸形和面部不对称，其严重程度取决于基因剂量。我们的研究确定 为CFM的一个可能致病基因，并证明eQTL是携带可能致病的罕见编码变体的个体中疾病表现的修饰外显率的决定因素。
