Genetic analyses using chromosomal microarray and exome sequencing in fetuses and women with Müllerian duct anomalies

This study aims to explore the genetic anomalies (excluding aneuploidy) associated with Müllerian duct anomalies (MDA). This project is part of a large uterine transplantation (UTx) program, where women with MRKH (Mayer-Rokitansky-Küster-Hauser) syndrome are the primary candidates. The potential of the hereditary nature of MDA was evaluated to facilitate appropriate genetic counseling when applicable.

We used chromosome microarray analysis (CMA) and exome sequencing (ES) to identify genetic variations that may contribute to the phenotype of MDA. A comprehensive description of the genital and extra-genital phenotype was established for each individual in whom a potentially relevant genetic variant has been identified.

We analyzed data from 3 fetuses and 75 women with MDA. All individuals had CMA and 65 ES were analyzed. CMA identified 6 copy number variations (CNVs) of interest (diagnostic yield: 7.7%), notably the recurrent 17q12 deletion. In 13.8% of individuals, ES revealed likely pathogenic or pathogenic variants that fully explained the phenotype in affected individuals, variants of uncertain significance (VUS) of interest in the pathology, or variants unrelated to MDA but linked to other symptoms presented by the individuals.

The findings underscore the crucial role of genetics in understanding and managing MDA. With the emergence of UTx, assessing the risk of transmission and recurrence of genetic anomalies is essential. In addition, genetic analysis may enable early medical prevention for associated phenotypes. Genetic analysis is therefore becoming an essential component of the clinical assessment and counseling for women with MDA.