GREB1L variants in familial and sporadic hereditary urogenital adysplasia and Mayer‐Rokitansky‐Kuster‐Hauser syndrome

Abstract

We would like to thank the families for their participation to this study and the members of both the MAIA (http://www.maia-asso.org) and Syndrome de Rokitansky-MRKH (http://asso.orpha.net/MRKH) associations for their contribution. We are also indebted to the physicians involved in the French national PRAM network (Programme de Recherches sur les Aplasies Müllériennes), the GACUA and the GARD research programs. We thank the GIGA Genomics Platform for technical assistance with NGS data generation. This research was supported by funding from the CHU Liège (FIRS), the Walloon Region (WALGEMED project), the University of Liège and the Fond Léon Frédéricq. AJ is supported by the National Fund for Scientific Research, Belgium. Conflict of Interest statementThe authors declare that they have no conflict of interest. Ethics approvalThe GARD (genetic alterations in rare diseases) protocol was approved by the UBC Children's and Women's Research Ethics Board (Vancouver, Canada). The GACUA (Identification of genetic factors involved in uterine development by exome sequencing of individuals with hereditary or syndromic uterine and kidney malformation) protocol was approved by the ethics committee from the University Hospital and the University of Liège, Belgium. The PRAM project was approved by the local institutional review board (Comité de Protection des Personnes), and is registered with the French Ministry of Health. The procedures used in this study adhere to the tenets of the Declaration of Helsinki.

Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: a comprehensive update

“…The study reported a co-segregating missense variant in GREB1L (Table 1) [24], a gene identified in 2017 to cause bilateral renal agenesis in fetuses of which several female fetuses also had uterus agenesis [73,74]. Just recently, Jacquinet et al reported four additional multiplex families with either type II MRKH syndrome or uterovaginal aplasia (fetuses) associated with renal malformations (agenesis in particular) in which pathogenic GREB1L variants were identified from WES data [72]. GREB1L now seems to be the first gene to show a strong association with type II MRKH syndrome with kidney anomalies following autosomal dominant inheritance with incomplete penetrance.…”

“… Type I [ 55 , 56 ] c.665G > A; p.Arg222His c.722G > A; p.Arg241His c.974G > A; p.Arg325His c.1029C > A; p.Cys343* 18q11.1–2 GREB1L c.705G > T; p.Trp235Cys Additional GREB1L variants of unknown significance have been reported in unrelated MRKH syndrome patients [ 72 ]. Several GREB1L variants have been reported in female fetuses with BRA and uterus/uterovaginal agenesis [ 72 – 74 ]. Greb1l- null mice also have BRA and Müllerian aplasia [ 73 , 74 ].…”

“…Greb1l- null mice also have BRA and Müllerian aplasia [ 73 , 74 ]. Type II with renal malfor-mations (familial, autosomal dominant inheritance) [ 24 , 72 ] c.2227del; p.(Gln743Argfs*10) Abbrevations : BRA bilateral agenesis, CNV copy number variations, MA Müllerian aplasia, URA unilateral renal agenesis a MRKH type II also encompasses MURCS association; b Trancripts for the genes are: TBX6 , NM_004608.3; LHX1 , NM_005568.3; WNT9B , NM_003396.1; GREB1L , NM_001142966.2 …”

“…Additional GREB1L variants of unknown significance have been reported in unrelated MRKH syndrome patients [ 72 ].…”

“…Several GREB1L variants have been reported in female fetuses with BRA and uterus/uterovaginal agenesis [ 72 – 74 ].…”