TBX6 null variants and a common hypomorphic allele in congenital scoliosis.
TBX6 null variants and a common hypomorphic allele in congenital scoliosis.
复制标题
TBX6 无效变异和先天性脊柱侧凸中常见的低等位基因。
DOI：
10.1056/nejmoa1406829
复制
发表时间：
2015-01-22
期刊：
影响因子：
--
通讯作者：
Zhang F
中科院分区：
文献类型：
--
作者：
Wu N;Ming X;Xiao J;Wu Z;Chen X;Shinawi M;Shen Y;Yu G;Liu J;Xie H;Gucev ZS;Liu S;Yang N;Al-Kateb H;Chen J;Zhang J;Hauser N;Zhang T;Tasic V;Liu P;Su X;Pan X;Liu C;Wang L;Shen J;Shen J;Chen Y;Zhang T;Zhang J;Choy KW;Wang J;Wang Q;Li S;Zhou W;Guo J;Wang Y;Zhang C;Zhao H;An Y;Zhao Y;Wang J;Liu Z;Zuo Y;Tian Y;Weng X;Sutton VR;Wang H;Ming Y;Kulkarni S;Zhong TP;Giampietro PF;Dunwoodie SL;Cheung SW;Zhang X;Jin L;Lupski JR;Qiu G;Zhang F
先天性脊柱侧凸是一种常见的脊椎畸形。遗传易感性与先天性脊柱侧凸有关。我们评估了161例汉族散发性先天性脊柱侧凸患者，166例汉族对照，以及2个家系，其中家族成员有16p11.2缺失，采用比较基因组杂交，定量聚合酶链反应分析和DNA测序。我们进行了复制试验，使用一个额外的系列76例汉族先天性脊柱侧凸和一个多中心系列42人16p11.2缺失。我们在161例散发性先天性脊柱侧凸患者中共发现了17个杂合TBX 6无效突变（11%）;在166例对照组中未观察到任何TBX 6无效突变（P<3.8×10−6）。这些无效等位基因包括拷贝数变异（12例影响TBX 6的16p11.2缺失）和单核苷酸变异（1例无义突变和4例移码突变）。然而，16p11.2缺失携带者不一致的家族内表型表明杂合TBX 6无效突变不足以引起先天性脊柱侧凸。我们继续在所有17名TBX 6无效突变携带者中鉴定出一种常见的TBX 6单倍型作为第二风险等位基因（P<1.1×10−6）。涉及额外先天性脊柱侧凸患者的复制研究证实了这种复合遗传模型，这些患者携带影响TBX 6的缺失。体外功能分析表明，风险单倍型是一个亚型等位基因。半椎体是TBX 6相关先天性脊柱侧凸的特征。在我们分析的系列中，TBX 6的一个罕见无效突变和一个亚型等位基因的复合遗传占先天性脊柱侧凸病例的11%。
Congenital scoliosis is a common type of vertebral malformation. Genetic susceptibility has been implicated in congenital scoliosis. We evaluated 161 Han Chinese persons with sporadic congenital scoliosis, 166 Han Chinese controls, and 2 pedigrees, family members of which had a 16p11.2 deletion, using comparative genomic hybridization, quantitative polymerase-chain-reaction analysis, and DNA sequencing. We carried out tests of replication using an additional series of 76 Han Chinese persons with congenital scoliosis and a multi-center series of 42 persons with 16p11.2 deletions. We identified a total of 17 heterozygous TBX6 null mutations in the 161 persons with sporadic congenital scoliosis (11%); we did not observe any null mutations in TBX6 in 166 controls (P<3.8×10−6). These null alleles include copy-number variants (12 instances of a 16p11.2 deletion affecting TBX6) and single-nucleotide variants (1 nonsense and 4 frame-shift mutations). However, the discordant intrafamilial phenotypes of 16p11.2 deletion carriers suggest that heterozygous TBX6 null mutation is insufficient to cause congenital scoliosis. We went on to identify a common TBX6 haplotype as the second risk allele in all 17 carriers of TBX6 null mutations (P<1.1×10−6). Replication studies involving additional persons with congenital scoliosis who carried a deletion affecting TBX6 confirmed this compound inheritance model. In vitro functional assays suggested that the risk haplotype is a hypomorphic allele. Hemivertebrae are characteristic of TBX6-associated congenital scoliosis. Compound inheritance of a rare null mutation and a hypomorphic allele of TBX6 accounted for up to 11% of congenital scoliosis cases in the series that we analyzed.