Early onset or syndromic epilepsy

Gene: SP9

Green List (high evidence)

Comment on list classification: As there is sufficient evidence available (three unrelated cases) for the association of SP9 to epilepsy, this gene can be promoted to green rating in the next GMS update.

Created: 30 Jul 2026, 2:33 p.m. | Last Modified: 30 Jul 2026, 2:33 p.m.

Panel Version: 9.55

PMID:38288683 (2024) reported the identification of four different de novo heterozygous variants in SP9 as a cause of a novel form of interneuronopathy in five unrelated cases.

Individual 1 is a male fetus with moderate ventriculomegaly and multiple periventricular and deep gray matter cystic/ischemic lesions (choroid plexus and periventricular cysts, bilateral GE and caudate signal abnormalities with restricted diffusion) identified on late third‑trimester MRI, leading to termination of pregnancy at 35 weeks’ gestation. This individual was identified with c.1133A>C (p.Glu378Ala) variant in SP9 gene.

The age of other four individuals ranged from six months to six years and all had neurodevelopmental disorder of variable severity. A first clinical phenotype consisting of moderate intellectual disability (ID) associated with an ASD with or without epilepsy was present in individuals 2 and 5 who carried frameshift SP9 variants, p.c.1216del (p.His406ThrfsTer2) and c.1192_1207dup (p.Arg403Glnfs∗15), respectively. A second, more severe clinical phenotype consisting of epileptic encephalopathy was present in individuals 3 and 4, who both carried a missense variant c.1133A>G (p.Glu378Gly) involving the same glutamate residue in position 378 as individual 1.

In summary, (global) developmental delay and/or intellectual disability was reported in four patients, while epilepsy was reported in three.

This gene has been associated with relevant phenotype in Gene2Phenotype (with 'moderate' rating on the DD panel), but not yet reported in OMIM (last accessed 30 July 2026).
Sources: Literature

Created: 30 Jul 2026, 2:25 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
neurodevelopmental disorder, MONDO:0700092

Publications

• 38288683