Research On The Cause Of Molecular Genetics MRKH Syndrome

Mayer-Rokitansky-Kiister-Hauser (MRKH) syndrome is a congenital malformation characterized by a failure of the Miillerian ducts to develop, resulting in the absence of a normal uterus and vagina in the presence of a normal46, XX karyotype. Although most of the cases are sporadic, familial clustering has been described, indicating a genetic cause of the disease.The mode of inheritance and the pathogenic basis underlying MRKH syndrome, however, remain unknown. Traditional linkage analysis was difficult to be performed, for traits were seldom passed down in their family due to the patients’infertility. Many candidate genes, involved in embryonic development, organofaction, and sex differentiation, have been studied among sporadic patients, though no mutation has yet been identified. Several recurrent copy number variants (chromosomal microdeletions or microduplications) have been described in a minority of cases, but none of them was consistently found in a larger group of patients, and whether they are associated with MRKH syndrome is unclear.Here, we discovered a five-generation consanguineous Chinese Han family affected by MRKH syndrome with three confirmed individuals alive and one suspected dead.(1) We studied the pedigree and clinical characteristics, and explained this case by an autosomal dominant inheritance with imcomplete penetrance.(2) We examined copy number variants in the proband using genome-wide analysis of array-comparative genomic hybridization, and detected no copy number variants.(3) We then sequenced the whole exome of other two patients in the family for finding causative genes. By Sanger sequencing, we verified all five possible mutations-c.2711C>T (p. S904L) in BCL9L, c.9412C>G (p. P3138A) in APOB, c.290A>G (p. Q97R) in DQX1, c.4862C>T (p. A1621V) in MYO7B, and a A>G of3’UTR in KYNU. We also confirmed their cosegregation with the MRKH phenotype in the pedigree.Taken together, we first report a multi-generation MRKH familiy showing autosomal dominant inheritance with imcomplete penetrance, which contributes strong evidence for determinating the inheritance mode of MRKH syndrome. There are no copy number variants, while single base substitution mutations, especially missence mutations mav be the genetic bases of this family.