Identification of rare PTCH1 nonsense variant causing orofacial cleft in a Chinese family and an up-to-date genotype- phenotype analysis  

作　　者：Wenjie Zhong Huaxiang Zhao Wenbin Huang Mengqi Zhang Qian Zhang Yue Zhang Chong Chen Zulihumaer Nueraihemaiti Dilifeire Tuerhong Huizhe Huang Gulibaha Maimaitili Feng Chen Jiuxiang Lin 

机构地区：[1]Department of Orthodontics,Peking University School and Hospital of Stomatology,Beijing,100081,PR China [2]Central Laboratory,Peking University School and Hospital of Stomatology,Beijing,100081,PR China [3]Department of Stomatology,The Fifth Affiliated Hospital of Xinjiang Medical University,Urumqi,830000,PR China [4]Xinjiang Medical University,Urumqi,830000,PR China [5]Chongqing Medical University,Chongqing,400016,PR China [6]Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research [7]Department of Orthodontics,College of Stomatology,Xi’an Jiaotong University,Xi’an 710004,PR China

出　　处：《Genes & Diseases》2021年第5期689-697,共9页基因与疾病（英文）

基　　金：This study was supported by the National Natural Science Foundation of China(grant numbers:81870747,81860194,and 31771619);Beijing Municipal Natural Science Foundation(grant number:7182184).

摘　　要：The Patched 1(PTCH1)gene encodes a membrane receptor involved in the Hedge-hog(Hh)signaling pathway,an abnormal state of which may result in congenital defects or hu-man tumors.In this study,we conducted whole-exome sequencing on a three-generation Chinese family characterized with variable penetrance of orofacial clefts.A rare heterozygous variant in the PTCH1 gene(c.2833C>T p.R945X)was identified as a disease-associated mutation.Structural modeling revealed a truncation starting from the middle of the second extracellular domain of PTCH1 protein.This may damage its ligand recognition and sterol transportation abilities,thereby affecting the Hh signaling pathway.Biochemical assays indi-cated that the R945X protein had reduced stability compared to the wild-type in vitro.In addi-tion,we reviewed the locations and mutation types of PTCH1 variants in individuals with clefting phenotypes,and analyzed the associations between clefts and locations or types of variants within PTCH1.Our findings provide further evidence that PTCH1 variants result in or-ofacial clefts,and contributed to genetic counseling and clinical surveillance in this family.

关 键 词：Cleft lip with or without palate Clinical genetics Genotype-phenotype analysis PTCH1 Whole-exome sequencing 

分 类 号：R394[医药卫生—医学遗传学]