White matter disorders and cerebral calcification - narrow panel

Gene: EPB41L3

Green List (high evidence)

Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.

Created: 1 May 2025, 10:38 a.m. | Last Modified: 1 May 2025, 10:38 a.m.

Panel Version: 9.6

PMID: 39292993 – reports 6 individuals from 5 unrelated consanguineous families with homozygous LOF variants and a neurodevelopmental condition. Core features of the phenotype include mild to moderate ID, seizures (onset: 3-10 months) followed by hypotonia, neuroregression and delayed myelination. Two patients presented with developmental delay without any history of regression.

EPB41L3 knockdown in mouse oligodendroglia demonstrated significant reduction in mRNA expression of key myelin genes, reduced branching and increased apoptosis.

Created: 1 May 2025, 10:37 a.m. | Last Modified: 1 May 2025, 10:37 a.m.

Panel Version: 9.5

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Developmental disorder with seizures and myelination defects

Publications

• 39292993

Green List (high evidence)

Six individuals from five unrelated families with global developmental delay, intellectual disability, seizures, hypotonia, neuroregression and delayed myelination. Exome sequencing identified biallelic variants in EPB41L3 in all affected individuals: two nonsense [c.466C>T, p.(R156*); c.2776C>T, p.(R926*)] and three frameshift [c.666delT, p.(F222Lfs*46); c.2289dupC, p.(V764Rfs*19); c.948_949delTG, p.(A317Kfs*33)].
Sources: Literature

Created: 27 Apr 2025, 3:59 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
developmental delay; intellectual disability; seizures; hypotonia; neuroregression

Publications

• 39292993