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