Molecular Genetic Study Of Pathogenic Genes In Mayer-Rokitansky-K(u|")ster-Hauser Syndrome

Mayer-Rokitansky-Kiister-Hauser syndrome (MRKHS) is a rare congenital malformation of the female reproductive ducts resulting in incurable infertility and sexual dysfunction. The etiology and pathogenic mechanism of MRKHS remain poorly understood.The general aim of the study is to explore the whole genome pathogenic genes and variants in MRKH syndrome using comprehensive and multi-level innovative exploration studies, including the next generation sequencing technology, exome capture technology and GWAS. First, blood samples from a pair of monozygotic twins discordant for MRKH syndrome were collected. Their whole genome and whole exome were sequenced and compared to identify pathogenic variants. Second, all candidate loci of MRKH syndrome were summarized from previous studies and investigated to check if these variants are associated with MRKH syndrome (type I and II), and if any gene-gene epistatic interactions exist among these variants. In specfic, single-maker association, additive effects and multifactor interactions were also studied. Third, in order to prove the hypothesis that MRKH syndrome is a complex disease in which common variants increase the pathogenic risk, a genome-wide association study on MRKH syndrome to scan the susceptibility SNPs of MRKH syndrome was performed.Some major conclusions of the study can be drawn:Frist, the monozygotic twins were discordant for phenotype. One individual was a patient with MRKH syndrome, while the other was absolutely healthy. However, no difference of functional variants between the monozygotic twins was found. Second, multi-factor epistatic interactions could increase the MRKH syndrome risk. Therefore, MRKH syndrome is more likely to be viewed as a complex disease. Third, three stages of genome-wide association study showed that rs17627965 and rs7822839 in RBPMS were significantly associated with MRKH syndrome, increasing the MRKH syndrome risk. These findings provide new study direction and crucial clues for future study of the pathogenesis of MRKH syndrome.