Li Shan, You Yi, Gao Jinsong, Mao Bin, Cao Yixuan, Zhao Xiuli, Zhang Xue
Department of Medical Genetics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine, Peking Union Medical College, 5 Dong Dan San Tiao, Dong Cheng District, Beijing, 100005, China.
Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Beijing, 100730, China.
BMC Med Genet. 2018 Oct 3;19(1):179. doi: 10.1186/s12881-018-0692-8.
Distal arthrogryposis (DA) is a group of clinically and genetically heterogeneous disorders that involve multiple congenital limb contractures and comprise at least 10 clinical subtypes. Here, we describe our findings in two Chinese families: Family 1 with DA2B (MIM 601680) and Family 2 with mild DA.
To map the disease locus, two-point linkage analysis was performed with microsatellite markers closed to TPM2, TNNI2/TNNT3 and TNNC2. In Family 1, a positive LOD (logarithm of odds) score was only obtained at the microsatellite marker close to TPM2 and mutation screening was performed using direct sequencing of TPM2 in the proband. In Family 2, for the LOD score that did not favor linkage to any markers, whole-exome sequencing (WES) was performed on the proband. PCR-restriction fragment length polymorphism (RFLP) and bioinformatics analysis were then applied to identify the pathogenic mutations in two families. In order to correlate genotype with phenotype in DA, retrospective analyses of phenotypic features according to the TPM2 and PIEZO2 mutation spectrums were carried out.
A heterozygous missense mutation c.308A > G (p.Q103R) in TPM2 in Family 1, and a novel variation c.8153G > A (p.R2718Q) in PIEZO2 in Family 2 were identified. Each of the two novel variants was co-segregated with the DA manifestations in the corresponding family. Bioinformatics analysis from several tools supported the pathogenicity of the mutations. Furthermore, our study suggests that there is no relation between the types or locations of TPM2 mutations and the clinical characteristics, and that different inheritance modes and mutation types concerning PIEZO2 cause distinct clinical manifestations.
We report two novel mutations within TPM2 and PIEZO2 responsible for DA2B and mild DA in two Chinese families, respectively. Our study expands the spectrum of causal mutations in the TPM2 and PIEZO2 genes.
远端关节挛缩症（DA）是一组临床和遗传异质性疾病，涉及多个先天性肢体挛缩，至少包括10种临床亚型。在此，我们描述了在两个中国家系中的研究结果：家系1患有DA2B（MIM 601680），家系2患有轻度DA。
为了定位疾病基因座，使用靠近TPM2、TNNI2/TNNT3和TNNC2的微卫星标记进行两点连锁分析。在家系1中，仅在靠近TPM2的微卫星标记处获得了阳性对数优势（LOD）评分，并对先证者使用TPM2直接测序进行突变筛查。在家系2中，对于不支持与任何标记连锁的LOD评分，对先证者进行了全外显子组测序（WES）。然后应用聚合酶链反应-限制性片段长度多态性（PCR-RFLP）和生物信息学分析来鉴定两个家系中的致病突变。为了将DA的基因型与表型相关联，根据TPM2和PIEZO2突变谱对表型特征进行了回顾性分析。
在家系1中鉴定出TPM2基因的杂合错义突变c.308A>G（p.Q103R），在家系2中鉴定出PIEZO2基因的新变异c.8153G>A（p.R2718Q）。这两个新变异中的每一个都与相应家系中的DA表现共分离。来自几种工具的生物信息学分析支持了这些突变的致病性。此外，我们的研究表明TPM2突变的类型或位置与临床特征之间没有关系，并且PIEZO2的不同遗传模式和突变类型导致不同的临床表现。
我们报告了TPM2和PIEZO2基因内的两个新突变，分别导致两个中国家系中的DA2B和轻度DA。我们的研究扩展了TPM2和PIEZO2基因中致病突变的谱。
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