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Monoallelic intragenic POU3F2 variants lead to neurodevelopmental delay and hyperphagic obesity, confirming the gene's candidacy in 6q16.1 deletions

Lookup NU author(s): Laura Devlin, Ruxandra Neatu, Professor John SayerORCiD


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© 2023 American Society of Human GeneticsWhile common obesity accounts for an increasing global health burden, its monogenic forms have taught us underlying mechanisms via more than 20 single-gene disorders. Among these, the most common mechanism is central nervous system dysregulation of food intake and satiety, often accompanied by neurodevelopmental delay (NDD) and autism spectrum disorder. In a family with syndromic obesity, we identified a monoallelic truncating variant in POU3F2 (alias BRN2) encoding a neural transcription factor, which has previously been suggested as a driver of obesity and NDD in individuals with the 6q16.1 deletion. In an international collaboration, we identified ultra-rare truncating and missense variants in another ten individuals sharing autism spectrum disorder, NDD, and adolescent-onset obesity. Affected individuals presented with low-to-normal birth weight and infantile feeding difficulties but developed insulin resistance and hyperphagia during childhood. Except for a variant leading to early truncation of the protein, identified variants showed adequate nuclear translocation but overall disturbed DNA-binding ability and promotor activation. In a cohort with common non-syndromic obesity, we independently observed a negative correlation of POU3F2 gene expression with BMI, suggesting a role beyond monogenic obesity. In summary, we propose deleterious intragenic variants of POU3F2 to cause transcriptional dysregulation associated with hyperphagic obesity of adolescent onset with variable NDD.

Publication metadata

Author(s): Schonauer R, Jin W, Findeisen C, Valenzuela I, Devlin LA, Murrell J, Bedoukian EC, Poschla L, Hantmann E, Riedhammer KM, Hoefele J, Platzer K, Biemann R, Campeau PM, Munch J, Heyne H, Hoffmann A, Ghosh A, Sun W, Dong H, Noe F, Wolfrum C, Woods E, Parker MJ, Neatu R, Le Guyader G, Bruel A-L, Perrin L, Spiewak H, Missotte I, Fourgeaud M, Michaud V, Lacombe D, Paolucci SA, Buchan JG, Glissmeyer M, Popp B, Bluher M, Sayer JA, Halbritter J

Publication type: Article

Publication status: Published

Journal: American Journal of Human Genetics

Year: 2023

Volume: 110

Issue: 6

Pages: 998-1007

Print publication date: 01/06/2023

Online publication date: 18/05/2023

Acceptance date: 28/04/2023

ISSN (print): 0002-9297

ISSN (electronic): 1537-6605

Publisher: Cell Press


DOI: 10.1016/j.ajhg.2023.04.010

PubMed id: 37207645


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