Early onset or syndromic epilepsy

Gene: CRNKL1

Comment on phenotypes: OMIM phenotype added 30th Jan 2026.

Created: 30 Jan 2026, 11:36 a.m. | Last Modified: 30 Jan 2026, 11:36 a.m.

Panel Version: 8.103

Green List (high evidence)

Recurrent de novo variants in this gene have been reported to cause severe microcephaly and pontocerebellar hypoplasia with seizures. These variants are listed as positions 267 and possibly 301. The authors propose that the variants act in a gain-of-function or dominant-negative manner. the pLI scores in gnomADv4.1.0 would support this theory as there appears to be little constraint for LOF variants in this gene.

Created: 14 Jan 2026, 11:02 a.m. | Last Modified: 14 Jan 2026, 11:02 a.m.

Panel Version: 8.93

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
microcephaly; pontocerebellar hypoplasia; seizures

Publications

• 40857589

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments

Green List (high evidence)

Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS update.

Created: 9 Jul 2025, 3:33 p.m. | Last Modified: 9 Jul 2025, 3:33 p.m.

Panel Version: 8.9

There are 10 unrelated patents identified with de novo missense variants in the spliceosomal component CRNKL1, where nine of them harboured one of the two missense variants affecting the same amino acid residue, Arg 267 (p.Arg267Cys & p.Arg267His), while the tenth patient harboured a different variant (p.Arg301Gly). All affected individuals share a common and specific phenotype: profound pre- and post-natal microcephaly (8 of 10 patients), with pontocerebellar hypoplasia (9 patients), seizures (8 patients), and severe intellectual disability (8 patients).

Microinjection of mRNA encoding Crnkl1 variant into a zebrafish model caused a severe lack of brain development accompanied by a significant reduction in proliferating cells and widespread cellular stress, as indicated by p53 staining. RNA sequencing analysis of injected zebrafish embryos showed broad transcriptomic changes, with altered expression of neuronal and cell cycle genes.

This gene has not yet been associated with relevant phenotypes in OMIM or in Gene2Phenotype.
Sources: Literature

Created: 9 Jul 2025, 3:29 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
complex neurodevelopmental disorder, MONDO:0100038

Publications

• https://doi.org/10.1016/j.ajhg.2025.05.013