Rare genetic variants suggest dysregulation of signaling pathways in low- and high-risk patients developing severe ovari
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GENETICS
Rare genetic variants suggest dysregulation of signaling pathways in low- and high-risk patients developing severe ovarian hyperstimulation syndrome L. Borgwardt 1 & K. W. Olsen 2 & M. Rossing 1 & R. Borup Helweg-Larsen 3 & M. Toftager 4 & A. Pinborg 5 & J. Bogstad 4 & K. Løssl 4 & A. Zedeler 4 & M. L. Grøndahl 2 Received: 11 June 2020 / Accepted: 7 September 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Purpose To investigate if rare gene variants in women with severe ovarian hyperstimulation syndrome (OHSS) provide clues to the mechanisms involved in the syndrome. Methods Among participants in a prospective randomized study (Toftager et al. 2016), six women with predicted low and six women with predicted high risk of OHSS developing severe OHSS (grades 4 and 5, Golan classification) were selected. In the same cohort, six plus six matched controls developing no signs of OHSS (Golan grade 0) were selected. Whole-exome sequencing was performed. Analysis using a predefined in silico OHSS gene panel, variant filtering, and pathway analyses was done. Results We found no convincing monogenetic association with the development of OHSS using the in silico gene panel. Pathway analysis of OHSS variant lists showed substantial overlap in highly enriched top pathways (p value range p < 0.0001 and p > 9.8E-17) between the low- and high-risk group developing severe OHSS, i.e., “the integrin-linked kinase (ILK) signaling pathway” and the “axonal guidance signaling pathway,” both being connected to vasoactive endothelial growth factor (VEGF) and endothelial function. Conclusion Rare variants in OHSS cases with two distinct risk profiles enrich the same signaling pathways linked to VEGF and endothelial function. Clarification of the mechanism as well as potentially defining genetic predisposition of the high vascular permeability is important for future targeted treatment and prevention of OHSS; the potential roles of ILK signaling and the axonal guidance signaling need to be validated by functional studies. Keywords Ovarian hyperstimulation syndrome . Pathway analyses . ILK signaling pathway . Axonal guidance signaling
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10815-020-01941-0) contains supplementary material, which is available to authorized users. * L. Borgwardt [email protected] 1
Centre for Genomic Medicine, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
2
Department of Obstetrics and Gynaecology, Fertility Clinic, Copenhagen University Hospital, Herlev, Denmark
3
Functional Genomics and Reproductive Health Group, Faculty of Health and Medical Sciences- Copenhagen University, Copenhagen, Denmark
4
Department of Obstetrics and Gynaecology, Fertility Clinic, Copenhagen University Hospital, Hvidovre, Denmark
5
Fertility Clinic, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
Introduction Ovarian hyperstimulation syndrome (OHSS) is a complication to assisted reproduc
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