Rare variant enrichment analysis supports GREB1L as a contributory driver gene in the etiology of Mayer-Rokitansky-Küster-Hauser syndrome

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

doi:10.1016/j.xhgg.2023.100188

Rare variant enrichment analysis supports GREB1L as a contributory driver gene in the etiology of Mayer-Rokitansky-Küster-Hauser syndrome

HGG Adv. 2023 Mar 29;4(3):100188. doi: 10.1016/j.xhgg.2023.100188. eCollection 2023 Jul 13.

Authors

Angad Jolly¹, Haowei Du¹, Christelle Borel², Na Chen³, Sen Zhao^{4

5}, Christopher M Grochowski¹, Ruizhi Duan¹, Jawid M Fatih¹, Moez Dawood¹, Sejal Salvi⁶, Shalini N Jhangiani⁶, Donna M Muzny⁶, André Koch⁷, Konstantinos Rouskas^{8

9}, Stavros Glentis⁸, Efthymios Deligeoroglou¹⁰, Flora Bacopoulou¹⁰, Carol A Wise^{11

12}, Jennifer E Dietrich^{13

14

15}, Ignatia B Van den Veyver^{1

13

15}, Antigone S Dimas⁸, Sara Brucker⁷, V Reid Sutton^{1

15}, Richard A Gibbs^{1

6}, Stylianos E Antonarakis^{2

16

17}, Nan Wu^{1

4

5}, Zeynep H Coban-Akdemir¹, Lan Zhu³, Jennifer E Posey¹, James R Lupski^{1

6

14

15}

Affiliations

¹ Department of Molecular and Human Genetics, Baylor College of Medicine (BCM), Houston, TX, USA.
² University of Geneva Medical School, 1211 Geneva, Switzerland.
³ Department of Obstetrics and Gynaecology, Beijing 100730, China.
⁴ Department of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases and Key Laboratory of Big Data for Spinal Deformities, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China.
⁵ Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Chinese Academy of Medical Sciences, Beijing 100730, China.
⁶ Human Genome Sequencing Center, Baylor College of Medicine (BCM), Houston, TX, USA.
⁷ University of Tübingen, Department of Obstetrics and Gynecology, Tübingen, Germany.
⁸ Institute for Bioinnovation, Biomedical Sciences Research Center Al. Fleming, Vari, Athens 16672, Greece.
⁹ Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki, Greece.
¹⁰ Center for Adolescent Medicine and UNESCO Chair on Adolescent Health Care, First Department of Pediatrics, School of Medicine, National and Kapodistrian University of Athens, Aghia Sophia Children's Hospital, Athens 11527, Greece.
¹¹ Center for Pediatric Bone Biology and Translational Research, Scottish Rite for Children, Dallas, TX, USA.
¹² McDermott Center for Human Growth and Development, Department of Pediatrics and Department of Orthopaedic Surgery, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA.
¹³ Department of Obstetrics and Gynecology, Houston, TX, USA.
¹⁴ Department of Pediatrics, BCM, Houston, TX, USA.
¹⁵ Texas Children's Hospital, Houston, TX, USA.
¹⁶ Institute of Genetics and Genomics in Geneva, University of Geneva, 1205 Geneva, Switzerland.
¹⁷ Medigenome, the Swiss Institute of Genomic Medicine, 1207 Geneva, Switzerland.

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

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

46, XX Disorders of Sex Development* / genetics
Congenital Abnormalities
Female
Humans
Mullerian Ducts / abnormalities
Urogenital Abnormalities*
Uterus / abnormalities

Rare variant enrichment analysis supports GREB1L as a contributory driver gene in the etiology of Mayer-Rokitansky-Küster-Hauser syndrome

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