TY - JOUR
T1 - Rare variant enrichment analysis supports GREB1L as a contributory driver gene in the etiology of Mayer-Rokitansky-Küster-Hauser syndrome
AU - Jolly, Angad
AU - Du, Haowei
AU - Borel, Christelle
AU - Chen, Na
AU - Zhao, Sen
AU - Grochowski, Christopher M.
AU - Duan, Ruizhi
AU - Fatih, Jawid M.
AU - Dawood, Moez
AU - Salvi, Sejal
AU - Jhangiani, Shalini N.
AU - Muzny, Donna M.
AU - Koch, André
AU - Rouskas, Konstantinos
AU - Glentis, Stavros
AU - Deligeoroglou, Efthymios
AU - Bacopoulou, Flora
AU - Wise, Carol A.
AU - Dietrich, Jennifer E.
AU - Van den Veyver, Ignatia B.
AU - Dimas, Antigone S.
AU - Brucker, Sara
AU - Sutton, V. Reid
AU - Gibbs, Richard A.
AU - Antonarakis, Stylianos E.
AU - Wu, Nan
AU - Coban-Akdemir, Zeynep H.
AU - Zhu, Lan
AU - Posey, Jennifer E.
AU - Lupski, James R.
N1 - Publisher Copyright:
© 2023 The Author(s)
PY - 2023/7/13
Y1 - 2023/7/13
N2 - 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.
AB - 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.
KW - Alu-Alu mediated rearrangement
KW - developmental genomics
KW - exonic deletion CNV
KW - genitourinary development
KW - human phenotype ontology
KW - infertility
KW - rare variant gene enrichment
KW - sex-limited trait
KW - transcriptional regulation
UR - http://www.scopus.com/inward/record.url?scp=85153506617&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85153506617&partnerID=8YFLogxK
U2 - 10.1016/j.xhgg.2023.100188
DO - 10.1016/j.xhgg.2023.100188
M3 - Article
C2 - 37124138
AN - SCOPUS:85153506617
SN - 2666-2477
VL - 4
JO - Human Genetics and Genomics Advances
JF - Human Genetics and Genomics Advances
IS - 3
M1 - 100188
ER -