Early onset or syndromic epilepsy

Gene: CELSR3

Green List (high evidence)

Comment on list classification: There is sufficient evidence available for the association of both monoallelic and biallelic variants in CELSR3 gene with epilepsy/ seizures (five families with each MOI). Hence, this gene can be promoted to green rating in the next GMS update.

Created: 13 Jan 2026, 12:31 p.m. | Last Modified: 13 Jan 2026, 12:31 p.m.

Panel Version: 8.93

PMID:34951123 (2022) reported trio-based whole-exome sequencing in a cohort of 462 cases with febrile seizures (FS)/ epilepsy with antecedent FS (EFS+), where five heterozygous missense variants in CELSR3 gene were identified in eight individuals from five unrelated families. All affected individuals were diagnosed with FS/EFS+, including six patients with FS and two patients with EFS+. All cases presented favorable outcomes without neurodevelopmental disorders.

PMID:38429302 (2024) reported the identification of biallelic variants in CELSR3 gene in 12 individuals from 11 unrelated families. Six of 12 patients presented with homozygous missense and five with compound heterozygous missense CELSR3 variants, while one individual carried a heterozygous missense variant and an in-frame-deletion in trans. Affected individuals presented with an overlapping phenotypic spectrum comprising central nervous system (CNS) anomalies (7/12), combined CNS anomalies and congenital anomalies of the kidneys and urinary tract (CAKUT) (3/12) and CAKUT only (2/12). Seizures were reported in six patients from five unrelated families.

There is also functional evidence available from zebrafish, where transient suppression of CELSR3 ortholog Celsr3 leads to anomalies in the developing CNS and urinary system.

This gene has not yet been associated with relevant phenotypes in OMIM (last accessed 13 January 2026) or ClinGen, but biallelic CELSR3 variants have been associated with 'limited' rating on the DD panel of Gene2Phenotype.
Sources: Literature

Created: 13 Jan 2026, 12:29 p.m.

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
neurodevelopmental disorder, MONDO:0700092; epilepsy, MONDO:0005027

Publications

• 34951123
• 38429302