Rare Variant Enrichment Analysis Supports GREB1L as a Contributory Driver Gene in the Etiology of Mayer-Rokitansky-Küster-Hauser Syndrome

Authors

Angad Jolly
Haowei Du
Christelle Borel
Na Chen
Sen Zhao
Christopher M Grochowski
Ruizhi Duan
Jawid M Fatih
Moez Dawood
Sejal Salvi
Shalini N Jhangiani
Donna M Muzny
André Koch
Konstantinos Rouskas
Stavros Glentis
Efthymios Deligeoroglou
Flora Bacopoulou
Carol A Wise
Jennifer E Dietrich
Ignatia B Van den Veyver
Antigone S Dimas
Sara Brucker
V Reid Sutton
Richard A Gibbs
Stylianos E Antonarakis
Nan Wu
Zeynep H Coban-Akdemir
Lan Zhu
Jennifer E Posey
James R Lupski

Publication Date

3-29-2023

Journal

Human Genetics and Genomics Advances

Abstract

Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is characterized by aplasia of the female reproductive tract; the syndrome can include renal anomalies, absence or dysgenesis, and skeletal anomalies. While functional models have elucidated several candidate genes, only WNT4 (MIM: 603490) variants have been definitively associated with a subtype of MRKH with hyperandrogenism (MIM: 158330). DNA from 148 clinically diagnosed MRKH probands across 144 unrelated families and available family members from North America, Europe, and South America were exome sequenced (ES) and by family-based genomics analyzed for rare likely deleterious variants. A replication cohort consisting of 442 Han Chinese individuals with MRKH was used to further reproduce GREB1L findings in diverse genetic backgrounds. Proband and OMIM phenotypes annotated using the Human Phenotype Ontology were analyzed to quantitatively delineate the phenotypic spectrum associated with GREB1L variant alleles found in our MRKH cohort and those previously published. This study reports 18 novel GREB1L variant alleles, 16 within a multiethnic MRKH cohort and two within a congenital scoliosis cohort. Cohort-wide analyses for a burden of rare variants within a single gene identified likely damaging variants in GREB1L (MIM: 617782), a known disease gene for renal hypoplasia and uterine abnormalities (MIM: 617805), in 16 of 590 MRKH probands. GREB1L variant alleles, including a CNV null allele, were found in 8 MRKH type 1 probands and 8 MRKH type II probands. This study used quantitative phenotypic analyses in a worldwide multiethnic cohort to identify and strengthen the association of GREB1L to isolated uterine agenesis (MRKH type I) and syndromic MRKH type II.

Keywords

rare variant gene enrichment, exonic deletion CNV, Alu-Alu mediated rearrangement, developmental genomics, genitourinary development, infertility, sex-limited trait, transcriptional regulation, human phenotype ontology

Comments

Supplementary Materials

PMID: 37124138