Research paper
The genetic landscape of developmental and epileptic encephalopathy with spike-and-wave activation in sleep
Review of DEE-SWAS genetic architecture. GRIN2A is the most common single-gene cause; CNKSR2 (X-linked scaffolding protein) produces severe epilepsy-aphasia phenotypes; ZEB2, 17q21.31 deletions, and other genes contribute smaller proportions. Approximately 18% genetic, 43% structural/metabolic, 39% unknown etiology on standard workup.
Freibauer AE, et al.
Markdown path
content/research/papers/2023-freibauer-dee-swas-genetic-landscape.mdFindings
Review of DEE-SWAS genetic architecture. GRIN2A is the most common single-gene cause; CNKSR2 (X-linked scaffolding protein) produces severe epilepsy-aphasia phenotypes; ZEB2, 17q21.31 deletions, and other genes contribute smaller proportions. Approximately 18% genetic, 43% structural/metabolic, 39% unknown etiology on standard workup.
Why it may matter for Levi
Quantifies the prior: only ~18% of DEE-SWAS is germline single-gene. Levi's three negative germline workups are therefore a weaker 'rule-out' than the raw negative result suggests and support extending to mosaic-sensitive tissue-based testing. GRIN2A coverage should be confirmed in prior reports.
Freibauer et al. (2023) — The genetic landscape of DEE-SWAS
Source
- European Journal of Paediatric Neurology, 2023.
- URL: https://www.sciencedirect.com/science/article/pii/S1059131123001759
Why this paper is in the corpus
Review of the known genetic architecture of DEE-SWAS (the ILAE-2022 umbrella term). Complements the Viswanathan 2024 etiology cohort already in the corpus by providing a curated review of the genes most commonly implicated, with GRIN2A, CNKSR2, ZEB2, and specific chromosomal deletions (17q21.31) highlighted as recurring.
Key findings
- Pathogenic variants in GRIN2A (encoding an NMDA receptor subunit) are the most common single-gene cause of DEE-SWAS.
- CNKSR2 (X-linked postsynaptic scaffolding protein) is associated with severe epilepsy-aphasia phenotypes.
- ZEB2, 17q21.31 deletions, and additional genes contribute smaller proportions of cases.
- Approximately 18% of DEE-SWAS cases are estimated to have an identifiable genetic cause; roughly 43% are structural/metabolic; ~39% remain of unknown etiology on standard workup.
Levi-relevant takeaways
- Consistent with Viswanathan 2024: GRIN2A is the single highest-yield gene to confirm coverage for in Levi's prior sequencing reports.
- Supports keeping a broad DEE-SWAS gene panel — not just the mTOR axis — on the priority list if the mosaic-sensitive tissue-based PROS panel is negative.
- Levi had three negative germline workups (Stanford trio exome, GeneDx trio WGS, GeneDx reanalysis). The 18% germline yield quoted by Freibauer anchors how much the germline-negative result actually rules out: a substantial majority of DEE-SWAS cases were never expected to have a germline single-gene answer even before those tests began. This supports the mosaic hypothesis and the call for tissue-based sequencing.
Citation note
Referenced as [9] in the 2026-04-21 user-supplied comprehensive DEE-SWAS / ESES / CSWS research report. Related to (and complements) Viswanathan 2024 at content/research/papers/2024-viswanathan-dee-swas-etiology-cohort.md.