Zhang Yong-Biao, Hu Jintian, Zhang Jiao, Zhou Xu, Li Xin, Gu Chaohao, Liu Tun, Xie Yangchun, Liu Jiqiang, Gu Mingliang, Wang Panpan, Wu Tingting, Qian Jin, Wang Yue, Dong Xiaoqun, Yu Jun, Zhang Qingguo
Chinese Academy of Sciences and Key Laboratory of Genome Science and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China.
Department of Ear Reconstruction, Plastic Surgery Hospital, Chinese Academy of Medical Sciences, Beijing 100144, China.
Nat Commun. 2016 Feb 8;7:10605. doi: 10.1038/ncomms10605.
Craniofacial microsomia (CFM) is a rare congenital anomaly that involves immature derivatives from the first and second pharyngeal arches. The genetic pathogenesis of CFM is still unclear. Here we interrogate 0.9 million genetic variants in 939 CFM cases and 2,012 controls from China. After genotyping of an additional 443 cases and 1,669 controls, we identify 8 significantly associated loci with the most significant SNP rs13089920 (logistic regression P=2.15 × 10(-120)) and 5 suggestive loci. The above 13 associated loci, harboured by candidates of ROBO1, GATA3, GBX2, FGF3, NRP2, EDNRB, SHROOM3, SEMA7A, PLCD3, KLF12 and EPAS1, are found to be enriched for genes involved in neural crest cell (NCC) development and vasculogenesis. We then perform whole-genome sequencing on 21 samples from the case cohort, and identify several novel loss-of-function mutations within the associated loci. Our results provide new insights into genetic background of craniofacial microsomia.
颅面短小畸形（CFM）是一种罕见的先天性异常，涉及第一和第二鳃弓的未成熟衍生物。CFM的遗传发病机制仍不清楚。在此，我们对来自中国的939例CFM病例和2012例对照中的90万个基因变异进行了研究。在对另外443例病例和1669例对照进行基因分型后，我们确定了8个显著相关位点，其中最显著的单核苷酸多态性（SNP）为rs13089920（逻辑回归P = 2.15×10^(-120)）以及5个提示性位点。上述13个相关位点由ROBO1、GATA3、GBX2、FGF3、NRP2、EDNRB、SHROOM3、SEMA7A、PLCD3、KLF12和EPAS1的候选基因所携带，发现这些位点在参与神经嵴细胞（NCC）发育和血管生成的基因中富集。然后，我们对病例队列中的21个样本进行了全基因组测序，并在相关位点内鉴定出几个新的功能丧失突变。我们的结果为颅面短小畸形的遗传背景提供了新的见解。
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