Malformations of cortical development

Gene: WDR91

Green List (high evidence)

Comment on list classification: There are now 3 unrelated individuals reported in literature with biallelic WDR91 variants and cortical malformations (1 case non-specific; 2 cases with findings such as CC agenesis, lissencephaly, cerebral hemisphere hypoplasia). Animal models support the role of WDR91 in neuronal development and function. Hence, this gene should be promoted to Green at the next update.

Created: 22 Apr 2026, 4:36 p.m. | Last Modified: 22 Apr 2026, 4:37 p.m.

Panel Version: 7.56

PMID: 32732226 Lefebvre et al., 2021
Homozygous variant WDR91 c.240C>G, p.(Tyr80*) detected in a male fetus with hygroma, macrocephaly, abnormal ears, cerebellar hypoplasia, and hydrocephaly. Concordant segregation among 4 affected fetus, 2 healthy sibs, and both parents.

PMID: 34791078 Kurul et al., 2022
Large study, trio exome seq of consanguineous families with neurogenetic diseases. FMAL006_01 - female patient with 'brain malformation' was homozygous for WDR91 c.1395+1G>A. No more details provided.

PMID: 38041506 Rosina et al., 2024
Case 75 - male, 3yrs 5mo, homozygous for WDR91 NM_014149.4:c.511+1A>G. Phenotype: severe developmental delay, microcephaly, severe microlissencephaly, agenesis of corpus callosum, epilepsy, spastic tetraparesis, laryngomalacia, bicuspid aortic valve, congenital hip dislocation, growth retardation, dysmorphisms.

PMID: 40550703 Marinakis et al., 2026
Consanguineous Syrian family. Proband (4mo female) presented with severe microcephaly, dysmorphic features, organomegaly, early onset psychomotor delay, hypotonia, sensorineural hearing impairment, and visual impairment. Brain MRI revealed bilateral cerebral hemisphere hypoplasia with incomplete sulcation, agenesis of the corpus callosum, suspected bilateral periventricular heterotopias. WES identified a homozygous splice site variant, WDR91 NM_014149.4: c.1395+1G>A (same as in PMID: 34791078, but NOT the same patient).

Functional: PMID: 34028500 Xing et al., 2021 - Mice lacking Wdr91 specifically in the central nervous system exhibited behavioral defects and marked neuronal loss in the cerebral and cerebellar cortices. At a cellular level, Wdr91 deficiency caused dysfunction of lysosomes, leading to accumulation of autophagic cargoes in mouse neurons.

WDR91 is not yet associated with a phenotype in OMIM, G2P, or ClinGen (accessed 22nd Apr 2026).
Sources: Literature

Created: 22 Apr 2026, 4:30 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Abnormal brain morphology, HP:0012443

Publications

• 32732226
• 34028500
• 34791078
• 38041506
• 40550703