Article,
Clinical and molecular characterization of patients with YWHAG-related epilepsy
Contributors
Cetica V.
0000-0001-8549-4158
[1]
Pisano T.
0000-0001-8920-9078
[1]
Lesca G.
0000-0001-7691-9492
[2]
[3]
Marafi D.
0000-0003-2233-3423
[4]
[5]
Licchetta L.
0000-0001-7979-9895
[6]
Mei D.
0000-0001-6790-6251
[1]
Chung B.H.Y.
0000-0002-7044-5916
[9]
Bayat A.
0000-0003-4986-8006
[10]
[11]
[12]
Balasubramanian M.
0000-0003-1488-3695
[13]
[14]
Solazzi R.
0000-0001-6657-3328
[22]
Jung J.
0000-0002-9274-0086
[25]
Accogli A.
0000-0001-8724-6721
[27]
[28]
Salpietro V.
0000-0003-0132-7921
[29]
Bisulli F.
0000-0002-1109-7296
[6]
[38]
Hammer T.B.
0000-0001-8935-5761
[12]
Lupski J.R.
0000-0001-9907-9246
[5]
[39]
Guerrini R.
0000-0002-7272-7079
(Corresponding author)
[1]
[40]
Affiliations
- [1] University of Florence [NORA names: Italy; Europe, EU; OECD];
- [2] Université Lyon 1 [NORA names: France; Europe, EU; OECD];
- [3] Hospices Civils de Lyon [NORA names: France; Europe, EU; OECD];
- [4] Kuwait University [NORA names: Kuwait; Asia, Middle East];
- [5] Baylor College of Medicine [NORA names: United States; America, North; OECD];
(... more)
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.
