Clinical and molecular characterization of patients with YWHAG-related epilepsy

Valentina Cetica, Tiziana Pisano, Gaetan Lesca, Dana Marafi, Laura Licchetta, Florence Riccardi, Davide Mei, Hon yin B. Chung, Allan Bayat, Meena Balasubramanian, Daniel H. Lowenstein, Milda Endzinienė, Maha Alotaibi, Nathalie Villeneuve, Julia Jacobs, Bertrand Isidor, Roberta Solazzi, Nicolette S. den Hollander, Dragan Marjanovic, Christelle Rougeot-JungJulien Jung, Marion Lesieur-Sebellin, Andrea Accogli, Vincenzo Salpietro, Nebal W. Saadi, Eleni Panagiotakaki, Thomas Foiadelli, Sylvia Redon, Meng Han Tsai, Francesca Bisulli, Trine B. Hammer, James R. Lupski, Elena Parrini, Renzo Guerrini*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review


Objective: YWHAG variant alleles have been associated with a rare disease trait whose clinical synopsis includes an early onset epileptic encephalopathy with predominantly myoclonic seizures, developmental delay/intellectual disability, and facial dysmorphisms. Through description of a large cohort, which doubles the number of reported patients, we further delineate the spectrum of YWHAG-related epilepsy. Methods: We included in this study 24 patients, 21 new and three previously described, with pathogenic/likely pathogenic variants in YWHAG. We extended the analysis of clinical, electroencephalographic, brain magnetic resonance imaging, and molecular genetic information to 24 previously published patients. Results: The phenotypic spectrum of YWHAG-related disorders ranges from mild developmental delay to developmental and epileptic encephalopathy (DEE). Epilepsy onset is in the first 2 years of life. Seizure freedom can be achieved in half of the patients (13/24, 54%). Intellectual disability (23/24, 96%), behavioral disorders (18/24, 75%), neurological signs (13/24, 54%), and dysmorphisms (6/24, 25%) are common. A genotype–phenotype correlation emerged, as DEE is more represented in patients with missense variants located in the ligand-binding domain than in those with truncating or missense variants in other domains (90% vs. 19%, p <.001). Significance: This study suggests that pathogenic YWHAG variants cause a wide range of clinical presentations with variable severity, ranging from mild developmental delay to DEE. In this allelic series, a genotype–phenotype correlation begins to emerge, potentially providing prognostic information for clinical management and genetic counseling.

Original languageEnglish
Publication statusE-pub ahead of print - 16. Mar 2024

Bibliographical note

Publisher Copyright:
© 2024 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.


  • epilepsy
  • genotype–phenotype correlation


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