The genetics of Mullerian aplasia

Abstract

Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome consists of Mullerian aplasia with or without other anomalies, most commonly renal and skeletal. The genetic etiology of MRKH syndrome is unknown for most patients, but supportive evidence exists for heterozygous mutations in WNT4, LHX1, and HNF1B. Chromosomal microarray analyses have demonstrated chromosomal regions with copy number variants in multiple patients – deletions in17q12 and 16p11.2, and either deletions or duplications in 22q11.2. Genomic analyses of expression and methylation have also suggested potential molecular pathways. Positional cloning in MRKH patients with chromosomal rearrangements and exome sequencing are likely to result in new genes. Although some single gene defects and copy number variant regions have been identified, the molecular basis for the vast majority of MRKH remains unknown.

Keywords::

• development of uterus and vagina
• Mayer-Rokitansky-Kuster-Hauser syndrome
• molecular genetics
• MRKH
• Mullerian aplasia
• MURCS

Financial & competing interests disclosure

LCL was supported from NIH grant HD33004 for this work. The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Mullerian aplasia, also known as Mayer–Rokitansky–Kuster–Hauser (MRKH) syndrome, is a multiorgan congenital anomaly syndrome not only involving the uterus and vagina but also renal, skeletal, cardiac and auditory systems.

• Little is known about the genetic basis of MRKH, but it is important since affected women may conceive with surrogacy and they could be at risk for having an affected child with these anomalies.

• Heterozygous mutations in a few genes (WNT4, LHX1 and HNF1B) account for only a small proportion of affected patients.

• Chromosomal microarray analyses have helped determine certain chromosomes that could contain a causative gene – 17q12, 16p11.2 and 22q11.2.

• Genomic analyses of gene expression and methylation may be helpful in understanding the molecular pathways.

• It is likely that affected patients could have de novo heterozygous mutations in as of yet unknown genes.

• The use of two genetic methods is likely to improve the chances of identifying causative genes: positional cloning in MRKH patients with chromosomal rearrangements and exome sequencing.