Clinical and molecular characterization of patients with YWHAG-related epilepsy

Epilepsia. 2024 May;65(5):1439-1450. doi: 10.1111/epi.17939. Epub 2024 Mar 16.

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.

Keywords: YWHAG; epilepsy; genotype–phenotype correlation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Child
  • Child, Preschool
  • Cohort Studies
  • Developmental Disabilities / genetics
  • Electroencephalography
  • Epilepsy* / diagnostic imaging
  • Epilepsy* / genetics
  • Epilepsy* / pathology
  • Female
  • Genetic Association Studies
  • Humans
  • Infant
  • Intellectual Disability / genetics
  • Magnetic Resonance Imaging
  • Male
  • Phenotype
  • Young Adult