Zhang Shujie, Qin Haisong, Lv Weigang, Luo Shiyu, Wang Jin, Fu Chunyun, Ma Ruiyu, Shen Yiping, Chen Shaoke, Wu Lingqian
State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan 410078, China; Department of Genetic Metabolism, Children's Hospital, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi 530003, China.
Department of Genetic Metabolism, Children's Hospital, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi 530003, China.
Gene. 2016 Feb 15;577(2):187-92. doi: 10.1016/j.gene.2015.11.034. Epub 2015 Nov 25.
Familial adenomatous polyposis (FAP) is mainly caused by germline mutations in the adenomatous polyposis coli (APC) gene. This study aimed to detect pathogenic variants in five Chinese FAP families and review all previously reported pathogenic variants of APC gene in Chinese population.
Five non-consanguineous FAP families and 100 unrelated ethnicity-matched controls were included in the study. Sanger sequencing was performed to screen for APC coding and splicing variants. Chinese and English literature on APC germline mutations were reviewed to compile the mutation spectrum of APC gene in Chinese FAP patients.
One pathogenic variant was detected in each family for the five pedigrees we tested. Three variants (c.3183_3187delACAAA, c.2626C>T and c.1312+1G>A) were previously reported as pathogenic. The other two variants were novel: c.794_795insG/p.Val266SerfsTer11 and c.2142_2143insG/p.His715AlafsTer19. They are absent from public databases (1000 Genomes, dbSNP, ESP and ExAC) and 100 normal controls, and are classified as pathogenic based on the new ACMG/AMP variant classification guidelines. Literature review and current study revealed a total of 82 different pathogenic variants from 127 Chinese FAP families. Among these families, 83 families had frameshift variants (65.35%), 26 with nonsense variants (20.47%), six with splice site variants (4.72%), three with missense variants (2.36%) and nine with large deletion or duplication variants (7.09%). Apart from the two previously reported mutation hotspots c.3927_3931delAAAGA (20.47%) and c.3183_3187delACAAA (7.09%), c.847C>T/p.Arg283Ter variant occurred with a frequency of 3.15% (4 out of 127) in Chinese FAP patients.
We reported two novel pathogenic variants. The comprehensive compilation of variants and comparison revealed largely similar mutation spectrum between Chinese and Western patient populations. Some unique features noticed in Chinese patient population may help to better understand the pathogenesis of FAP.
家族性腺瘤性息肉病（FAP）主要由腺瘤性息肉病 coli（APC）基因的种系突变引起。本研究旨在检测五个中国FAP家系中的致病变异，并回顾中国人群中所有先前报道的APC基因致病变异。
本研究纳入了五个非近亲FAP家系和100名种族匹配的无关对照。采用Sanger测序法筛选APC编码和剪接变异。回顾中英文关于APC种系突变的文献，以汇编中国FAP患者中APC基因的突变谱。
在我们检测的五个家系中，每个家系都检测到一个致病变异。三个变异（c.3183_3187delACAAA、c.2626C>T和c.1312+1G>A）先前被报道为致病性变异。另外两个变异是新发现的：c.794_795insG/p.Val266SerfsTer11和c.2142_2143insG/p.His715AlafsTer19。它们在公共数据库（千人基因组、dbSNP、ESP和ExAC）和100名正常对照中均未出现，并根据新的ACMG/AMP变异分类指南被分类为致病性变异。文献回顾和当前研究共发现127个中国FAP家系中有82个不同的致病变异。在这些家系中，83个家系有移码变异（65.35%），26个家系有无义变异（20.47%），6个家系有剪接位点变异（4.72%），3个家系有错义变异（2.36%），9个家系有大片段缺失或重复变异（7.09%）。除了两个先前报道的突变热点c.3927_3931delAAAGA（20.47%）和c.3183_3187delACAAA（7.09%）外，c.847C>T/p.Arg283Ter变异在中国FAP患者中的发生率为3.15%（127例中有4例）。
我们报道了两个新的致病变异。变异的综合汇编和比较显示，中国和西方患者群体的突变谱基本相似。在中国患者群体中注意到的一些独特特征可能有助于更好地理解FAP的发病机制。
