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

While 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. Copyright © 2023 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Citation

Ria Schönauer, Wenjun Jin, Christin Findeisen, Irene Valenzuela, Laura Alice Devlin, Jill Murrell, Emma C Bedoukian, Linda Pöschla, Elena Hantmann, Korbinian M Riedhammer, Julia Hoefele, Konrad Platzer, Ronald Biemann, Philipp M Campeau, Johannes Münch, Henrike Heyne, Anne Hoffmann, Adhideb Ghosh, Wenfei Sun, Hua Dong, Falko Noé, Christian Wolfrum, Emily Woods, Michael J Parker, Ruxandra Neatu, Gwenael Le Guyader, Ange-Line Bruel, Laurence Perrin, Helena Spiewak, Genomics England Research Consortium, Isabelle Missotte, Melanie Fourgeaud, Vincent Michaud, Didier Lacombe, Sarah A Paolucci, Jillian G Buchan, Margaret Glissmeyer, Bernt Popp, Matthias Blüher, John A Sayer, Jan Halbritter. Monoallelic intragenic POU3F2 variants lead to neurodevelopmental delay and hyperphagic obesity, confirming the gene's candidacy in 6q16.1 deletions. American journal of human genetics. 2023 Jun 01;110(6):998-1007

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PMID: 37207645

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