The transcriptomic landscape of monosomy X (45,X) during early human fetal and placental development

Jenifer P. Suntharalingham; Valle Ignacio del; Federica Buonocore; Sinead M. McGlacken-Byrne; Tony Brooks; Olumide K. Ogunbiyi; Danielle Liptrot; Nathan Dunton; Gaganjit K. Madhan; Kate Metcalfe; Lydia Nel; Abigail R. Marshall; Miho Ishida; Neil J. Sebire; Gudrun E. Moore; Berta Crespo; Nita Solanky; Gerard S. Conway; John C. Achermann

doi:10.1530/ey.22.2.1

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ESPE Yearbook of Paediatric Endocrinology (2025) 22 2.1 | DOI: 10.1530/ey.22.2.1

ESPEYB25 2. Antenatal and Neonatal Endocrinology Sex Chromosome Aneuploidies (3 abstracts)

2.1. The transcriptomic landscape of monosomy X (45,X) during early human fetal and placental development

Jenifer P. Suntharalingham , Ignacio del Valle , Federica Buonocore , Sinead M. McGlacken-Byrne , Tony Brooks , Olumide K. Ogunbiyi , Danielle Liptrot , Nathan Dunton , Gaganjit K. Madhan , Kate Metcalfe , Lydia Nel , Abigail R. Marshall , Miho Ishida , Neil J. Sebire , Gudrun E. Moore , Berta Crespo , Nita Solanky , Gerard S. Conway & John C. Achermann

Commun Biol. 2025 Feb 16;8(1):249.doi: 10.1038/s42003-025-07699-4

Brief Summary: These investigators sought to understand why complete or partial loss of the second X chromosome not only explains the high incidence of fetal demise in monosomy X Turner Syndrome but also results in a panoply of clinical signs and symptoms beginning in prenatal life and extending throughout the lifespan. Previous genotype-phenotype studies have shed some light¹ but this study focused on bulk RNA-seq using human monosomy X fetal samples (placenta, liver, kidney, pancreas, skin and mixed group of brain, heart, lung and spleen) between 11 and 15 weeks post-conception compared to tissue- and age-matched 46,XX and 46, XY controls.

Major findings of this first multi-tissue, detailed transcriptome analysis include: 1) As expected for haploinsufficiency of the pseudoautosomal region (PAR) genes, lower expression was found in many, but not all, PAR1 and PAR2 genes and not entirely because of tissue-specific gene expression, suggesting possible compensatory mechanisms; 2) Some non-PAR genes escaping X-chromosome inactivation were also decreased, that are known to play a role in transcription, translation and histone methylation status - all important for fundamental developmental processes;3) Genes showing decreased expression in all tissues included some enrichment for connective tissue pathways linked to aneurysms and connective tissue disorders; 4) One gene upregulated in multiple tissues is a long non-coding RNA. These types of RNA are involved in gene and post-transcriptional regulation, chromatin modification, and several other fundamental cellular mechanisms; 5) The placenta-specific PAR1 gene CSF2RA (encoding a granulocyte-macrophage colony-stimulating factor receptor subunit) showed decreased expression (as were other transcripts in immune and inflammatory pathways), with immunohistochemistry for this gene showing non-specific placental inflammatory changes. This suggests that dysregulation of immune/inflammatory pathways may contribute to placental dysfunction – and if so, to early fetal demise.

The strength of this study lies in its original approach and in the wealth of testable hypotheses that it generated. It is further supported by the known rare variants in some of the same genes found in this study which have been implicated in phenotypes such as Kabuki Syndrome (horseshoe kidney, hearing loss), Marfan’s syndrome (associated with thoracic aortic aneurysms), dyslipidemia and hypertension.

Reference: 1. Tanoshima M et al. Karyotype and phenotype association in Turner syndrome with non-mosaic X chromosome structural rearrangements: Systematic review. CongenitAnom (Kyoto) ^.2025;65(1):e70002. doi: 10.1111/cga.70002.