Genetics of disorders of sex development
Recent progress in molecular genetics has successfully identified multiple causative genes for DSD. Such advance is primarily based on the detection of pathologic mutations on coding sequences. However, genetic disorders can be caused by other mechanisms. Here, I will review such mechanisms that have been identified recently.
Aromatase excess syndrome (AEXS) as a model for genomic disorder: AEXS is a rare autosomal dominant disorder characterized by gynecomastia in which no causative mutation has been identified on the coding region of CYP19A1. Here, I will explain three genomic rearrangements leading to AEXS because of CYP19A1overexpression: i) a tandem duplication involving seven of 11 non-coding CYP19A1 exons 1 associated with tissue-specific promoters; ii) two types of deletions at the upstream region of CYP19A1 that have produced a chimeric mRNA between CYP19A1 coding exons and a promoter-associated DMXL2 exon 1; and iii) four types of inversions involving the upstream region of CYP19A1 that have yielded chimeric mRNAs between CYP19A1 coding exons and promoter-associated exon 1 of CGN1, MAPK6, TMOD3, and TLN2. This represents novel mechanisms leading to gain-of-function of CYP19A1.
SOX9-related DSD as a model for a regulatory region disorder: SOX9 is a causative gene for DSD and campomelic dysplasia. Recent studies have indicated that heterozygous deletions of the 5′ region of SOX9 can lead to 46,XY DSD with gonadal dysgenesis (I will introduce a hitherto unreported patient with this condition), and that heterozygous duplications involving similar regions can result in 46,XX DSD with variable degree of testis development. In addition, larger duplications involving the commonly duplicated segment in 46,XX DSD patients permit normal male sex development. These findings imply that the contrastive DSD phenotypes may be caused by loss or duplication of a testis-specific enhancer(s), or by alteration of a chromatin structure affecting SOX9 expression.
Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.
Funding: This work was supported, however funding details are unavailable.