HOXD10: A novel gene implicated in human Müllerian duct anomalies.

Background: Müllerian duct anomalies (MDAs) are developmental malformations of the female genital tract. Genetic factors linked to MDAs and recent advancements in whole-exome sequencing (WES) have provided innovative perspectives in this field.

Methods: In total, 97 patients with MDAs were recruited. A novel HOXD10 variant, screened using the in-house database of WES performed in the MDAs cohort, was identified, and its pathogenicity was further assessed using molecular dynamics simulation and functional assays. RNA sequencing was performed to determine the mechanisms underlying pathogenesis.

Results: The HOXD10 c.238A>C (p.S80R) variant was identified in a sporadic patient with complete septate uterus, septate cervix, and longitudinal vaginal septum. This variant was absent in all the 100 controls. The variant was assessed to be pathogenic using in silico algorithms. The HOXD10 S80R variant exhibited conformational alterations compared with the wild type (WT) protein. Both proteins were stable during molecular dynamics simulations. However, S80R exhibited a larger radius of gyration, fewer hydrogen bonds, and an expanded solvent-accessible surface area. RNA sequencing revealed that the inhibition of HOXD10 WT on IFIT1, IFIT2 and IFIT3 were abrogated by S80R variant and resulted in an abnormal cell state.

Conclusions: To the best of our knowledge, this is the first study to report a novel HOXD10 p.S80R variant and explore its implications in MDAs. Identification of this variant has shed new light on the molecular genetic etiology of MDAs.