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

TitleRare variant enrichment analysis supports as a contributory driver gene in the etiology of Mayer-Rokitansky-Küster-Hauser syndrome.
Publication TypeJournal Article
Year of Publication2023
AuthorsJolly, A, Du, H, Borel, C, Chen, N, Zhao, S, Grochowski, CM, Duan, R, Fatih, JM, Dawood, M, Salvi, S, Jhangiani, SN, Muzny, DM, Koch, A, Rouskas, K, Glentis, S, Deligeoroglou, E, Bacopoulou, F, Wise, CA, Dietrich, JE, Van den Veyver, IB, Dimas, AS, Brucker, S, V Sutton, R, Gibbs, RA, Antonarakis, SE, Wu, N, Coban-Akdemir, ZH, Zhu, L, Posey, JE, Lupski, JR
JournalHGG Adv
Date Published2023 Jul 13
Keywords46, XX Disorders of Sex Development, Female, Humans, Urogenital Abnormalities, Uterus

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 (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 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 variant alleles found in our MRKH cohort and those previously published. This study reports 18 novel 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 (MIM: 617782), a known disease gene for renal hypoplasia and uterine abnormalities (MIM: 617805), in 16 of 590 MRKH probands. 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 to isolated uterine agenesis (MRKH type I) and syndromic MRKH type II.

Alternate JournalHGG Adv
PubMed ID37124138
PubMed Central IDPMC10130500
Grant ListR35 NS105078 / NS / NINDS NIH HHS / United States
UM1 HG006542 / HG / NHGRI NIH HHS / United States
K08 HG008986 / HG / NHGRI NIH HHS / United States
U01 HG011758 / HG / NHGRI NIH HHS / United States
/ HHMI / Howard Hughes Medical Institute / United States
P50 HD103555 / HD / NICHD NIH HHS / United States