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- Title
Clinical and molecular characterization of patients with YWHAG‐related epilepsy.
- Authors
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
- Abstract
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.
- Subjects
EPILEPSY; PEOPLE with epilepsy; DEVELOPMENTAL delay; MAGNETIC resonance imaging; MYOCLONUS; MISSENSE mutation
- Publication
Epilepsia (Series 4), 2024, Vol 65, Issue 5, p1439
- ISSN
0013-9580
- Publication type
Article
- DOI
10.1111/epi.17939