71: ELFN1 Deficiency: Mechanisms and Clinical Spectrum

Dore R et al., Genetics in Medicine - This episode reviews a multi-center study that defines ELFN1 deficiency as a recessive neurodevelopmental disorder. The authors report new patients with biallelic ELFN1 variants, show that pathogenic variants impair ELFN1 surface trafficking and mGlu receptor binding, and present mouse and zebrafish models that reproduce hyperactivity and epileptiform activity. Key terms: ELFN1, synaptic adhesion, epilepsy, neurodevelopmental disorder, loss of function. Study Highlights:The study describes eight new patients from five unrelated families with homozygous ELFN1 variants and integrates clinical data from previously reported cases to define a consistent spectrum of developmental delay, epilepsy and movement disorders. Functional assays in HEK293 cells showed that multiple ELFN1 variants severely reduce plasma membrane trafficking and abolish interaction with group III metabotropic glutamate receptors. Structural modelling of an in-frame Val159 deletion predicts local disruption of the LRR domain consistent with trafficking and binding defects. Elfn1 knockout mice and zebrafish morphants display hyperactivity and epileptiform brain activity, supporting loss of function as the disease mechanism. Conclusion:Biallelic ELFN1 variants cause a loss-of-function recessive neurodevelopmental disorder—proposed as ELFN1 Deficiency Disorder—characterized by developmental delay, epilepsy and movement abnormalities, driven by impaired ELFN1 trafficking and disrupted mGlu receptor interactions. Music:Enjoy the music based on this article at the end of the episode. Article title:ELFN1 Deficiency: the mechanistic basis and phenotypic spectrum of a neurodevelopmental disorder with epilepsy First author:Dore R Journal:Genetics in Medicine DOI:10.1016/j.gim.2025.101506 Reference:Dore R, Chang CT, Declève A, Brunori G, Ludlam WG, Huang A, Movahedinia M, Damseh NS, Anwar I, Vahidi Mehrjardi MY, Ny A, Khorrami M, Kheirollahi M, Frederiksen H, Eghbal F, Mirjalili MR, Dehghani M, Karimiani EG, Oreshkov S, Alves C, Striano P, Suri M, Martinez-Agosto J, Ansar M, Zahid M, Akram S, Ansar M, Nelson SF, Undiagnosed Diseases Network, Antonarakis SE, Houlden H, Copmans D, Martemyanov KA, Maroofian R. ELFN1 Deficiency: the mechanistic basis and phenotypic spectrum of a neurodevelopmental disorder with epilepsy. Genetics in Medicine. 2025. doi: https://doi.org/10.1016/j.gim.2025.101506 License:© 2025 Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics. Support:Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/elfn1-deficiency-mechanisms-phenotype QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-07-10. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited the transcript sections describing ELFN1 function, variant impact on trafficking and mGlu binding, Val159del structural effects, cell-surface trafficking assays, mouse and zebrafish models, human clinical phenotype, and potential therapeutic directions.- transcript topics: ELFN1 function as trans-synaptic synaptic adhesion and mGlu receptor anchoring; Variants causing ELFN1 loss of function and trafficking defects; Val159del structural impact and loss of mGlu binding; Cell surface trafficking assays (biotinylation) and ectodomain pull-downs; Mouse Elfn1 knockout and haploinsufficiency hyperactivity; Zebrafish elfn1a/elfn1b mo...