Early onset or syndromic epilepsy

Gene: PGBD5

Green List (high evidence)

Comment on list classification: As reviewed by Karen Stals, there are ten patients from five unrelated families reported with biallelic PGBD5 variants and neurodevelopmental disorder. Epilepsy was reported in nine of these ten patients. There is also functional evidence available in support of the association. Hence, this gene can be promoted to green rating in the next GMS update.

Created: 28 Apr 2026, 11:06 a.m. | Last Modified: 28 Apr 2026, 11:27 a.m.

Panel Version: 8.195

PMID:41533792 (2026) reported the identification of genetic variants in PGBD5 gene using GeneMatcher in ten individuals from five unrelated consanguineous families. Exome sequencing was used to identify distinct homozygous PGBD5 variants segregating with the affected family members and this was confirmed by Sanger sequencing. These affected children shared conserved clinical phenotypes across neurodevelopmental and motor domains.

Neurodevelopmental features included intellectual disability and developmental delay (ID/DD; ten of ten), epilepsy (nine of nine), limited or no speech (nine of nine), autism spectrum disorder, or social delay (ASD; four of six). Prominent motor features included axial hypotonia (nine of nine), increased peripheral tone (seven of nine) or decreased peripheral tone (two of nine), increased tendon reflexes (five of nine), or decreased tendon reflexes (four of nine). Other observed neurological phenotypes include spasticity that mainly affected the lower limbs (five of nine), intermittent dystonia (three of ten), and ataxia (seven of ten).

There is also evidence available from Pgbd5-null mice, which were runted and had significantly smaller brains compared to wildtype. Mutant mice showed increased locomotor activity, reduced anxiety-like behavior, impaired motor coordination, increased susceptibility to seizures, and decreased cortical volume on brain MRI. Analysis of neurons derived from Pgbd5-null mouse brains showed reduced DNA breakage and repair in postmitotic neuronal precursors during cortical development compared to controls.

This gene has already been associated with relevant phenotype in OMIM (MIM #41533792, last accessed 28 April 2026), but not yet in Gene2Phenotype.

Created: 28 Apr 2026, 11:04 a.m. | Last Modified: 28 Apr 2026, 11:04 a.m.

Panel Version: 8.192

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Neurodevelopmental disorder with seizures, hypotonia, and variable spasticity, OMIM:621482; neurodevelopmental disorder with seizures, hypotonia, and variable spasticity, MONDO:0980968

Publications

• 41533792

Green List (high evidence)

Zapater et al. 2026 PMID:41533792 report 5 families with homozygous loss of function variants in PGBD5 co-segregating in two affected siblings in each family (variants identified via whole exome sequencing). Authors show that PGBD5 contributes to normal brain development in mice and humans.
Sources: Literature

Created: 22 Apr 2026, 10:43 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Seizures; global developmental delay; spasticity; hypotonia

Publications

• PMID: 41533792

Variants in this GENE are reported as part of current diagnostic practice