FBXO22 deficiency defines a pleiotropic syndrome of growth restriction and multi-system anomalies associated with a unique epigenetic signature

FBXO22 deficiency defines a pleiotropic syndrome of growth restriction and multi-system anomalies associated with a unique epigenetic signature

The American Journal of Human Genetics

10.1016/j.ajhg.2025.03.013

https://doi.org/10.1016/j.ajhg.2025.03.013

Navin B. Ramakrishna, Umar Bin Mohamad Sahari, Yoshikazu Johmura, Nur Ain Ali, Malak Alghamdi, Peter Bauer, Suliman Khan, Natalia Ordoñez, Mariana Ferreira, Jorge Pinto Basto, Fowzan S. Alkuraya, Eissa Ali Faqeih, Mari Mori, Naif A.M. Almontashiri, Aisha Al Shamsi, Gehad ElGhazali, Hala Abu Subieh, Mode Al Ojaimi, Ayman W. El-Hattab, Said Ahmed Said Al-Kindi, Nadia Alhashmi, Fahad Alhabshan, Abdulaziz Al Saman, Hala Tfayli, Mariam Arabi, Simone Khalifeh, Alan Taylor, Majid Alfadhel, Ruchi Jain, Shruti Sinha, Shruti Shenbagam, Revathy Ramachandran, Umut Altunoglu, Anju Jacob, Nandu Thalange, Mireille El Bejjani, Arnaud Perrin, Jay W. Shin, Almundher Al-Maawali, Azza Al-Shidhani, Amna Al-Futaisi, Fatma Rabea, Ikram Chekroun, Mohamed A. Almarri, Tomohiko Ohta, Makoto Nakanishi, Alawi Alsheikh-Ali, Fahad R. Ali, Aida M. Bertoli-Avella, Bruno Reversade, Ahmad Abou Tayoun

10 April 2025

Ramakrishna, N. B., Mohamad Sahari, U. B., Johmura, Y., Ali, N. A., Alghamdi, M., Bauer, P., Khan, S., Ordoñez, N., Ferreira, M., Pinto Basto, J., Alkuraya, F. S., Faqeih, E. A., Mori, M., Almontashiri, N. A. M., Al Shamsi, A., ElGhazali, G., Abu Subieh, H., Al Ojaimi, M., El-Hattab, A. W., … Abou Tayoun, A. (2025). FBXO22 deficiency defines a pleiotropic syndrome of growth restriction and multi-system anomalies associated with a unique epigenetic signature. The American Journal of Human Genetics, 112(5), 1233–1246. https://doi.org/10.1016/j.ajhg.2025.03.013

FBXO22 encodes an F-box protein, which acts as a substrate-recognition component of the SKP1-CUL1-F-box (SCF) E3 ubiquitin ligase complex. Despite its known roles in the post-translational ubiquitination and degradation of specific substrates, including histone demethylases, the impact of FBXO22 on human development remains unknown. Here, we characterize a pleiotropic syndrome with prominent prenatal onset growth restriction and notable neurodevelopmental delay across 16 cases from 14 families. Through exome and genome sequencing, we identify four distinct homozygous FBXO22 variants with loss-of-function effects segregating with the disease: three predicted to lead to premature translation termination due to frameshift effects and a single-amino-acid-deletion variant, which, we show, impacts protein stability in vitro. We confirm that affected primary fibroblasts with a frameshift mutation are bereft of endogenous FBXO22 and show increased levels of the known substrate histone H3K9 demethylase KDM4B. Accordingly, we delineate a unique epigenetic signature for this disease in peripheral blood via long-read sequencing. Altogether, we identify and demonstrate that FBXO22 deficiency leads to a pleiotropic syndrome in humans, encompassing growth restriction and neurodevelopmental delay, the pathogenesis of which may be explained by broad chromatin alterations.

Publisher Copyright

This research / project is supported by the Ministry of Health - National Medical Research Council - Open Fund - Young Individual Research Grant
Grant Reference no. : OFYIRG23jan-0036; MOH-001341

https://oar.a-star.edu.sg/communities-collections/articles/22476

0002-9297

Genome Institute of Singapore