De novo missense variants in EIF3I cause a novel neurodevelopmental disorder with midline brain defects and skeletal abnormalities

Targeted gene(s)/phenotype under study :

  • EIF3I (OMIM * 603911)

Abstract :

All stages of the eukaryotic canonical translation initiation on a 5’-capped mRNA are highly coordinated and require a set of eukaryotic initiation factors (eIFs), including eIF1, eIF1A, eIF2, eIF3, eIF4B, eIF4F, eIF5, and eIF5B. The largest and most complex initiation factor is eIF3, consisting of 12 subunits (a-m) in humans and essential during all stages of translation initiation. The i subunit, encoded by EIF3I, is the most conserved subunit and supports basic functions of the whole eIF3 complex. Aside from being a protein scaffold for the formation of initiation complexes, eIF3i drives the specialized translation of specific mRNAs. Furthermore, it is involved in the regulation of PI3K-Akt signaling cascade through a direct interaction with Akt1. Through whole exome sequencing, we identified de novo missense variants in EIF3I in several individuals presenting with a novel neurodevelopmental disorder characterized by intellectual disability, variable midline brain defects, and skeletal features. We have ongoing functional studies aiming to investigate the effects of EIF3I variants on the translation initiation and eIF3-driven specialized regulation, as well as their functional consequences on the modulation of Akt activity. These data most likely support the association between EIF3I variants and a novel neurodevelopmental disorder.

We look forward to including additional patients harboring missense EIF3I variants and displaying a similar phenotype in our collaborative research study.

Coordinating clinicians/researchers:  Marcello Scala,Valeria Capra

Institution :

University of Genoa, Department of Neurosciences,

Genoa, Italy; IRCCS Istituto Giannina Gaslini, Department of Neurology,

Genoa, Italy.

Contact :, 

Specific requirements beyond clinical data and genotype data sharing:

  • Re-analysis of DNA samples : N
  • Resampling of patients : N
  • Linked to a translational/basic research project? Y