️ Episode 71: ELFN1 Deficiency Disorder — Mechanistic Basis and Phenotypic Spectrum of a Neurodevelopmental Disorder with Epilepsy

In this episode of Base by Base, we dive into the recent pre-proof study by Dore et al. (2025) in Genetics in Medicine, which defines a new autosomal recessive neurodevelopmental syndrome caused by biallelic variants in the synaptic adhesion molecule ELFN1. Through detailed clinical phenotyping of fourteen patients, molecular assays in human cells, and in vivo modeling in mice and zebrafish, the authors reveal how loss-of-function ELFN1 variants disrupt cell-surface trafficking, impair synaptic localization of group III metabotropic glutamate receptors, and give rise to developmental delay, epilepsy, and movement abnormalities.

Study Highlights:
Affected individuals uniformly present with moderate to severe developmental delay and intellectual disability accompanied by a broad range of seizure types and movement disorders; functional characterization shows that pathogenic ELFN1 variants fail to reach the neuronal surface, leading to loss of synaptic ELFN1 function; both Elfn1 knockout mice and zebrafish morphants exhibit hyperactivity, motor deficits, and spontaneous epileptiform brain activity, validating ELFN1 deficiency as the causal mechanism .

Conclusion:
This work establishes “ELFN1 Deficiency Disorder” as a distinct, rare monogenic condition and provides a mechanistic framework for future studies into its pathophysiology and the development of targeted therapeutic strategies.

Reference:
Dore R., Chang C.-T., Declève A., Brunori G., Ludlam W.G., Huang A., Movahedinia M., Damseh N.S., Anwar I., Vahidi Mehrjardi M.Y., Ny A., Khorrami M., Kheirollahi M., Frederiksen H., Eghbal F., Mirjalili M.R., Dehghani M., Karimiani E.G., Oreshkov S., Alves C., Striano P., Suri M., Martinez-Agosto J., Ansar M., Zahid M., Akram S., Ansar M., Nelson S.F., Undiagnosed Diseases Network, Antonarakis S.E., Houlden H., Copmans D., Martemyanov K.A., Maroofian R. ELFN1 Deficiency: the mechanistic basis and phenotypic spectrum of a neurodevelopmental disorder with epilepsy. Genetics in Medicine (2025). https://doi.org/10.1016/j.gim.2025.101506

Licença:
Este episódio é baseado em um artigo de acesso aberto publicado sob a licença Creative Commons Attribution 4.0 International (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/