{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T19:30:35Z","timestamp":1792524635195,"version":"4.5.0"},"reference-count":46,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T00:00:00Z","timestamp":1771804800000},"content-version":"vor","delay-in-days":53,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,2,23]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Down syndrome (DS), caused by trisomy of chromosome 21, is associated with a high prevalence of congenital non-autoimmune thyroid dysfunction, typically characterized by an elevated serum thyroid stimulating hormone (TSH) concentration. Early-life observational studies and fetal cordocentesis data, consistently reporting elevated TSH levels, suggest a developmental origin. However, the underlying pathophysiological mechanism remains unclear. This study aimed to investigate the molecular and developmental features underlying thyroid dysfunction in DS.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Thyroid tissue of fetuses with DS (n\u2009=\u20094) and fetuses without a genetic\/developmental abnormality (n\u2009=\u20095) were analyzed using histology, bulk RNA sequencing (RNA-seq), and DNA methylation (DNAm) profiling.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Histological analysis revealed underdevelopment of DS fetal thyroid tissue, with smaller follicles and greater heterogeneity. RNA-seq identified 1035 differentially expressed genes (DEGs) distributed across the genome. Notably, three thyroid-relevant genes, FOXE1, IYD, and DIO2, were significantly downregulated in DS tissue. Gene set enrichment analysis (GSEA) showed widespread disruption of cellular processes. DNAm analysis identified 266 differentially methylated regions (DMRs), several of which overlapped with loci previously implicated in DS. Integration of expression and DNAm data revealed 20 significant integrative methylation\u2013expression analysis associations, indicating cis-regulatory DNAm effects on gene expression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These findings suggest that congenital thyroid dysfunction in DS represents a DS-specific form of thyroid dysfunction, characterized by impaired thyroid development and altered expression and regulation of genes involved in thyroid function and general cellular processes. The genome-wide molecular changes observed likely result from gene dosage effects and systemic (epi)genomic disturbances caused by trisomy 21.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/hmg\/ddag005","type":"journal-article","created":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T08:34:45Z","timestamp":1771835685000},"source":"Crossref","is-referenced-by-count":1,"title":["Multi-omics investigation of thyroid development and dysfunction in down syndrome"],"prefix":"10.1093","volume":"35","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1174-7340","authenticated-orcid":false,"given":"Peter","family":"Lauffer","sequence":"first","affiliation":[{"name":"Department of Pediatric Endocrinology, Emma Children\u2019s Hospital, Amsterdam University Medical Center, University of Amsterdam , Meibergdreef 9, Amsterdam, AZ, 1105 ,","place":["Netherlands"]},{"name":"Amsterdam Gastroenterology Endocrinology Metabolism (AGEM) Research Institute, Amsterdam University Medical Center, University of Amsterdam , Meibergdreef 9, Amsterdam, AZ, 1105 ,","place":["Netherlands"]},{"name":"Department of Human Genetics, Amsterdam University Medical Center, University of Amsterdam , Meibergdreef 9, Amsterdam, AZ, 1105 ,","place":["Netherlands"]},{"name":"Amsterdam Reproduction & Development Institute, Amsterdam University Medical Center, University of Amsterdam , Meibergdreef 9, Amsterdam, AZ, 1105 ,","place":["Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0318-5541","authenticated-orcid":false,"given":"Nitash","family":"Zwaveling-Soonawala","sequence":"additional","affiliation":[{"name":"Department of Pediatric Endocrinology, Emma Children\u2019s Hospital, Amsterdam University Medical Center, University of Amsterdam , Meibergdreef 9, Amsterdam, AZ, 1105 ,","place":["Netherlands"]},{"name":"Amsterdam Gastroenterology Endocrinology Metabolism (AGEM) Research Institute, Amsterdam University Medical Center, 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