The Polycomb Repressive Complex 1 (PRC1) represses gene expression through CBX2, which binds to H3K27me3 and promotes chromatin expression. Recently, CBX2 has been shown to function in testis-formation by directly repressing Wnt4's downstream target, Lef1, in Sertoli cells rather than positively controlling Sry expression, as previously thought. Here, we describe two new cases carrying missense mutations in CBX2. The first is a female with 46,XY complete gonadal dysgenesis and the second is a 46,XX individual with intellectual deficiency, facial dysmorphia, a small uterus with no ovaries. In an exome sequencing approach, the former patient was found to carry a CBX2, c.G404A mutation that is predicted to result in an p.R135Q amino acid change, whilst the latter patient carried a CBX2, c.G1339A mutation that is predicted to result in an p.G447R amino acid change. Both mutations are predicted to be damaging to the protein by multiple prediction tools. The p.R135Q mutation is absent from all public SNP databases and the p.G447R change has been reported in gnomAD at a minor allelic frequency of 6.6x10-5 in South Asian populations. Analysis of our exome data and public SNP databases also indicate that the smaller CBX2 isoform 2.2 is unlikely to be functional as healthy controls carry multiple loss-of-function mutations in this isoform. Mice lacking Cbx2 have been reported to have small ovaries associated with a spectrum of meiotic anomalies in germ cells and our data suggest that mutations in the human CBX2 gene could be a novel cause of ovarian insufficiency as well as 46,XY gonadal dysgenesis.
19 - 21 Sep 2019
European Society for Paediatric Endocrinology