YWHAG – Developmental and epileptic encephalopathy 56

Developmental and epileptic encephalopathy 56 (DEE-56) is an early-onset autosomal dominant epileptic encephalopathy characterized by febrile seizures, diverse seizure types, neurodevelopmental delay (HP:0012758), and mild intellectual disability (HP:0001256). Heterozygous pathogenic variants in YWHAG underlie DEE-56, supporting a dominant mechanism of pathogenicity ([MONDO:0033365])(https://monarchinitiative.org/MONDO:0033365).

In a recent cohort of 39 individuals from 21 families (12 novel cases, including two with recurrent distal 7q11.23 deletions, and 27 published cases), heterozygous YWHAG variants were associated with variable psychomotor delay, mild intellectual disability, early-onset seizures (predominantly febrile), and movement disorders such as ataxia and tremor. Valproic acid was reported as an effective antiseizure medication in several patients (PMID:39413657).

Initial evidence for de novo YWHAG variants in early-onset epilepsy came from exome sequencing of 42 subjects, where 7 rare non-synonymous variants in YWHAG were validated in probands and parents, with subsequent identification of 6 additional individuals bearing de novo YWHAG changes. This significant enrichment of de novo events established YWHAG as an EE gene (PMID:28777935).

The variant spectrum in DEE-56 is dominated by missense substitutions and an in-frame deletion. Recurrent alterations at codon 132 (p.Arg132Cys, p.Arg132His) and other ligand-binding residues highlight mutational hotspots. Representative pathogenic alleles include c.1A>G (p.Met1Val) and c.634_645del (p.Asn212_Ser215del), each leading to disruption of critical functional domains in 14-3-3γ (PMID:39413657).

Functional data remain limited. Structural modeling of a novel p.Leu173Ser variant indicates that substitution of a hydrophobic leucine within the internal core of 14-3-3γ by serine destabilizes the protein fold, suggesting impaired ligand interactions as a pathogenic mechanism (PMID:40152536). No disease-relevant cellular or animal models have yet been described.

Collectively, the abundance of case-level genetic observations—40 probands with diverse de novo heterozygous variants—and segregation in 21 families across independent cohorts meet ClinGen criteria for a Strong gene–disease association. While functional characterization is emerging, recognition of recurrent hotspots and genotype–phenotype correlations supports inclusion of YWHAG in diagnostic epilepsy panels.

Key Take-home: De novo heterozygous YWHAG variants cause DEE-56, and identification of recurrent mutational hotspots enhances genetic diagnosis and informs personalized management.

References

• PMID:39413657
• American journal of human genetics • 2017 • De Novo Mutations in YWHAG Cause Early-Onset Epilepsy PMID:28777935
• Molecular genetics & genomic medicine • 2025 • A Novel YWHAG Variant L173S Causes Developmental and Epileptic Encephalopathy by Disrupting the Hydrophobic Internal Protein Structure PMID:40152536

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