A Danish family with two women born without a uterus has provided researchers with a unique opportunity to study associations that may explain the rare syndrome.

The Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is a congenital malformation affecting 1 in 5000 women; these women are born without a uterus. Women with the MRKH syndrome often have malformations of other organs – most frequently the kidneys, where malformations are seen in one third. The women have a normal chromosomal composition and develop normally.

Until recently, the causal pathway of the MRKH syndrome has been unknown, but genetic alterations have been considered to be the most important factor causing the syndrome.

The genetic mapping of the causal pathway of the MRKH syndrome has been difficult as the syndrome most often occurs as isolated cases without previous cases in the patient’s family. Thus, familial occurrence of the syndrome would be interesting to researchers searching for new genetic explanations.

It was possible to study familial occurrence in a rare family in Denmark with two women who both have the MRKH syndrome and only one kidney. In the family, two men also lack kidneys. The researchers at Aarhus and Aalborg university hospitals have made a comprehensive mapping of the genome in a total of eight family members. The researchers have looked for genetic variants in common for all four relatives who had the malformations in common. Among the family members with malformations, the researchers found the genetic variant GREB1L.

- Our study is the first to identify a variant in GREB1L in patients with MRKH syndrome and it is the most comprehensive genetic mapping of one single family with MRKH syndrome so far, says Morten Krogh Herlin, MD and PhD student at Department of Paediatrics and Adolescent Medicine at Aarhus University Hospital, who has been in charge of the study.

The study has been conducted in close collaboration with doctors and molecular biologists from Aalborg University Hospital.

In 2017, researchers from Aarhus University Hospital and Aarhus University identified the gene GREB1L, causing bilateral renal agenesis. Animal studies have confirmed that the gene is decisive for the formation of both kidneys and the female reproductive tract. GREB1L is now going to be studied in a larger number of patients with MRKH syndrome to create more knowledge of the gene and its importance.

- It is important to study and understand the genetic background of rare conditions such as the MRKH syndrome. First of all, to help the patients and their families in the best possible way with information and counselling, says Morten Krogh Herlin.

- But rare diseases and syndromes also provide a unique opportunity to identify and understand the importance of certain factors for the normal human biology and physiology – in this case the formation of the uterus and kidneys – which would otherwise be difficult to learn about.

In the future, patients may receive a uterus transplant, which has been successfully completed by Swedish doctors a few years ago. Knowledge of the genetics of each patient with the MRKH syndrome would then be useful in prenatal genetic testing to reduce the hereditary risk of the syndrome.

The study is published in Human Reproduction, a leading scientific journal in gynaecology and reproduction.

d the research result:

Study design: Case report, genetic investigation of family by whole-exome sequencing

Collaborators: Department of Clinical Genetics and Department of Molecular Diagnostics, Aalborg University Hospital

External financing: No external financing

Conflicts of interest: None

Read the scientific article:

Authors: Morten Krogh Herlin, Vang Quy Le, Allan Thomas Højland, Anja Ernst, Henrik Okkels, Astrid Christine Petersen, Michael Bjørn Petersen and Inge Søkilde Pedersen

Title: Whole-exome sequencing identifies a GREB1L variant in a three-generation family with Müllerian and renal agenesis: a novel candidate gene in Mayer–Rokitansky–Küster–Hauser (MRKH) syndrome. A case report

Scientific journal: Human Reproduction

Date: 19 August 2019 (epub ahead of print)

DOI: https://doi.org/10.1093/humrep/dez126


Further information:

Morten Krogh Herlin,

MD, PhD student

Department of Paediatrics and Adolescent Medicine

Aarhus University Hospital

Tel. + 45 6014 7605

Email: m.herlin@clin.au.dk