基于全国多中心大样本量标本库对TBX6及LHX1基因在MRKH综合征中的致病机制研究

MRKH综合征，国内称为先天性无子宫无阴道。患者青春期后无月经来潮、无法正常性生活及生育，身心影响巨大。其遗传病因学研究始终是国际妇产科界关注的热点，但因其发病率低，一直鲜有明确的结果报道。近年来，通过微阵列比较基因组杂交技术可反复发现这类患者中TBX6及LHX1基因的杂合缺失，但其具体致病机制仍不明确。在前期研究中，我们基于已建立的全国最大的MRKH综合征患者的资料库及标本库，利用多重荧光竞争性PCR和aCGH芯片筛查350例患者中合并TBX6及LHX1杂合缺失者。本研究将基于预实验，进一步筛查标本库中550例患者，并对筛查出的合并TBX6及LHX1杂合缺失者行全外显子组测序，分析TBX6和LHX1的SNV/Indel层面突变及TBX6和LHX1相关通路基因突变，系统阐明TBX6及LHX1基因在MRKH综合征发生中的具体致病机制，以期进行遗传筛查和围产保健，从源头降低该病发生率。

Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is a congenital malformation which causes the absence of a normal uterus and vagina and contributes to failure of menstrual periods after puberty, disability of normal sexual life and infertility. Despite of growing interests and research in this field, the etiology of MRKH is still unclear. Thus, the investigations of its pathogenesis are current hot issues. In the past 10 years, the search for genomic rearrangements by array Comparative Genomic Hybridization (a-CGH) in MRKH cases identified recurrent deletions at chromosomal regions 16p11.2 and 17q12 harboring potential causative genes (TBX6 and LHX1 respectively) for MRKH syndrome, which indicates the importance of identification of copy number variations of these two regions in MRKH cases. In the preliminary experiments, we have finished the screening of deletions of TBX6 and LHX1 in 350 MRKH cases using multiplex fluorescence competitive PCR and a-CGH technology based on the largest national multi-centered clinical and biological specimen bank of MRKH syndrome we have established in the past 5 years. Basing on the result, remaining cases in our bank will be screened and whole exome sequencing analysis will be carried out in patients screened out. Mutational analysis of Snv/indel-level in TBX6 and LHX1 and TBX6 and LHX1-associated pathway genes based on the whole exome sequencing data will be done to illuminate the responsible pathogenic mechanisms of TBX6 and LHX1 related to the occurrence and development of MRKH syndrome. Furthermore, we hope to carry out genetic screening and perinatal care to reduce the incidence of MRKH syndrome from the source.