Early onset or syndromic epilepsy

Gene: WDR4

Comment on list classification: As reviewed by Luke Stuart, there are now 2 unrelated probands reported in literature with biallelic variants in WDR4 and early-onset seizures. Hence, this gene should be rated Amber, until more evidence emerges.

Created: 17 Aug 2026, 1:16 p.m. | Last Modified: 17 Aug 2026, 1:16 p.m.

Panel Version: 9.73

I don't know

PMID 26416026 (Shaheen et al., 2015): Two patients from presumed unrelated, but geographically linked, consanguineous Egyptian families were homozygous for WDR4 c.509G>T (p.Arg170Leu). Both presented with severe prenatal and postnatal growth restriction, severe microcephaly, profound developmental impairment, early-onset epilepsy (seizure onset at 10 months and 4 months), hypertonia/spasticity, optic atrophy, and distinctive facial dysmorphism. Functional studies demonstrated that the variant impairs WDR4 function, resulting in reduced tRNA m7G46 methylation.
Kim et al., 2020 (Case report, journal of Genetic Medicine, 10.5734/jgm.2020.17.2.97): Trio WES identified compound heterozygous WDR4 variants (c.540C>G (p.Ile180Met) and c.494G>A (p.Arg165Gln)) in a patient presenting with seizure, delayed development, and microcephaly at referral. Both variants were classified VUS- rare in Gnomad v4 (0 homozygotes) with equivocal REVEL scores favouring benignity.

Other reports of WDR4-related disease have not described epilepsy, reporting phenotypes consistent with Galloway-Mowat syndrome 6 (OMIM: 618347):

PMID 28617965 (Trimouille et al., 2018): Two sisters with compound heterozygous WDR4 variants (c.509G>A; p.Arg170Gln and c.911_927dup; p.Gln310GlyfsTer30) presented with severe microcephaly, growth retardation, and severe intellectual disability, without seizures or epilepsy.
PMID 29597095 (Chen et al., 2018): A patient with compound heterozygous WDR4 variants (c.491A>C; p.Asp164Ala and c.940dupC; p.Leu314ProfsTer16) had speech and language delay, without a history of seizures or epilepsy.
PMID 30079490 (Braun et al., 2018): Four siblings homozygous for WDR4 c.454-2A>C presented with microcephaly, developmental delay, and, in most cases, nephrotic syndrome consistent with Galloway-Mowat syndrome; none had seizures or epilepsy.

In summary, an epilepsy/seizure phenotype is described in two reports of WDR4-related disease, one comprising two patients from linked consanguineous families with one shared homozygous variant (Shaheen et al. 2015, PMID 26416026). An amber recommendation for early onset or syndromic epilepsy is recommended.
Sources: Literature

Created: 17 Aug 2026, 11:55 a.m. | Last Modified: 17 Aug 2026, 12:48 p.m.

Panel Version: 9.72

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Microcephaly, growth deficiency, seizures, and brain malformations, OMIM:618346; Galloway-Mowat syndrome 6, OMIM:618347

Publications

• 26416026
• 28617965
• 29597095
• 30079490