Overview
- Published in Nature, the study pinpoints increased HMGN1 dosage on chromosome 21 as a key contributor to congenital heart defects in Down syndrome, especially atrioventricular canal and valvuloseptal malformations.
- A multidisciplinary pipeline used mosaic trisomy 21 iPSC-derived cardiomyocytes, single-cell RNA sequencing, an AI model, and a CRISPRa screen of 66 chromosome 21 genes to nominate HMGN1.
- Trisomy 21 pushed atrioventricular canal cardiomyocytes toward a ventricular-like state, while deletion of one HMGN1 allele in trisomic human cells restored normal gene-expression programs.
- In a Down syndrome mouse model, reducing HMGN1 dosage lowered the incidence of valvuloseptal defects, demonstrating in vivo rescue of heart development.
- Investigators note the defects are likely multigenic with genes such as DYRK1 under evaluation, so any therapeutic approach to dampen HMGN1 remains at an early, preclinical stage.