EIF3F was first reported in relation to autosomal recessive syndromic intellectual disability in 2018 (Martin et al., PMID: 30409806). EIF3F encodes an essential subunit of eIF3, the largest eukaryotic translation initiation factor, which plays a role in cell proliferation and growth, cell cycle control, differentiation, and apoptosis. At least 31 patients from 24 families have been reported with biallelic EIF3F variants; 30 of these patients were homozygous for the same p.Phe232Val missense variant, and 1 patient was compound heterozygous for the p.Phe232Val missense variant and a frameshift variant (PMIDs: 30409806, 33736665). Haplotype analyses suggested that p.Phe232Val is a founder variant (PMID: 33736665). The p.Phe232Val variant has a frequency of 0.16% in non-Finnish Europeans, and no homozygotes are observed in gnomAD (v4.0.0). The mechanism of pathogenicity appears to be loss of function. Affected individuals present with global developmental delay, motor and speech delays, and intellectual disability; variable features include hearing loss, dysmorphic facial features, abnormal behaviors, hypo- or hypertonia, ophthalmological abnormalities, and epilepsy (PMIDs: 30409806, 33736665).
Induced pluripotent stem cells (iPSC) homozygous for the p.Phe232Val missense variant had ~27% lower EIF3F protein levels, and significantly reduced translation and proliferation rates compared to heterozygous and wild-type cells (PMID: 30409806).
In summary, there is definitive evidence supporting the relationship between EIF3F and autosomal recessive syndromic intellectual disability. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on December 6, 2023 (SOP Version 9).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. The GenCC does not independently verify the submitted information. Though the information is obtained from sources believed to be reliable, no warranty, expressed or implied, is made regarding accuracy, adequacy, completeness, reliability or usefulness of any information. This disclaimer applies to both isolated and aggregate uses of the information. The information is provided on an "as is" basis, collected through periodic submission and therefore may not represent the most up-to-date information from the submitters. If you have questions about the medical relevance of information contained on this website, please see a healthcare professional; if you have questions about specific gene-disease claims, please contact the relevant sources; and if you have questions about the representation of the data on this website, please contact gencc@thegencc.org.