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Synaptojanin-1 (Gene Symbol) is a dual-phosphatase highly expressed in the brain, where it regulates synaptic vesicle recycling and membrane homeostasis. Biallelic loss-of-function variants in SYNJ1 cause a developmental and epileptic encephalopathy (DEE) characterized by neonatal refractory seizures, severe global developmental delay, and progressive neurological decline.
Autosomal recessive inheritance is supported by 11 probands from five unrelated families: three consanguineous sib pairs harboring homozygous missense and truncating alleles (PMID:27435091), a child with intractable epilepsy carrying a homozygous nonsense variant (PMID:25316601), and a recent Afro-Caribbean female with a novel splice-site variant (PMID:36148638).
Segregation analysis demonstrates that all parents are heterozygous carriers and multiple affected siblings segregate the variants in each family (PMID:27435091; PMID:36148638).
The variant spectrum includes splice-site disruption (c.242-2A>G) and premature termination codons (p.Arg136Ter), as well as missense changes (p.Tyr888Cys) that selectively impair phosphatase activity (PMID:27435091).
Functional studies reveal that Synj1 knockout mice exhibit neonatal seizures and early lethality mirroring human DEE (PMID:25316601), and in vitro assays show that patient missense variants reduce dual-phosphatase function, which can be rescued by wild-type SYNJ1 expression.
No conflicting evidence has been reported. The consistent genotype-phenotype correlation and concordant functional data across models underpin a robust association.
SYNJ1-related DEE should be suspected in infants with early-onset refractory seizures and developmental delay. Genetic testing for biallelic SYNJ1 variants informs diagnosis, genetic counseling, and paves the way for targeted modulation of phosphoinositide pathways.
Gene–Disease AssociationStrong11 probands with biallelic SYNJ1 variants across five independent families, segregation in multiple sib pairs, and concordant functional data Genetic EvidenceStrongMultiple homozygous and truncating variants in 11 unrelated DEE cases under autosomal recessive inheritance; reached ClinGen genetic evidence cap Functional EvidenceModerateKnockout mouse models recapitulate seizures and early lethality; patient missense variants impair dual-phosphatase activity with rescue in vitro |