Early onset or syndromic epilepsy

Gene: EIF3F

I don't know

Review and rating collated by Tracy Lester (Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust, 2019_02_06) on behalf of Wessex and West Midlands GLH for GMS Neurology specialist test group, for Clinical Indication R59 'Early onset or syndromic epilepsy'. Review contributors: John Taylor and Helen Lord. Suggested gene rating: Green.

Created: 6 Aug 2019, 8:38 p.m. | Last Modified: 6 Aug 2019, 8:38 p.m.

Panel Version: 1.189

Green List (high evidence)

AR MR67. Martin et al, 2018 - 9 patients with intellectual disorder from 7 nonconsang families of European ancestry - all hom for the same mutation in EIF3 6/9 had seizures. This variant is one of the most common protein altering variants in the gene and is present at an allele freq of 0.12% but never hom in Non-Finnish Europeans in gnomAD. Functional studies also done on this variant.

Created: 6 Aug 2019, 8:31 p.m. | Last Modified: 6 Aug 2019, 8:31 p.m.

Panel Version: 1.188

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Publications

• 30409806

Comment when marking as ready: Not associated with phenotype in OMIM or in Gen2Phen. A single variant (rs141976414, ENSP00000310040.4:p.Phe232Val) has been identified as a homozygote in 9 subjects with intellectual disability and other phenotypic features, 6/9 have seizures. rs141976414 has a frequency of 0.12% in non-Finnish Europeans, however, it is not found as a homozygote in gnomAD (http://gnomad.broadinstitute.org) Supportive functional studies were also provided (PMID 30409806).

Created: 19 Nov 2018, 10:20 a.m.

Green List (high evidence)

EIF3F was identified in a recent DDD publication (PMID: 30409806) as a cause of autosomal recessive intellectual disability.

All 9 individuals reported were homozygous for a missense variant (Phe232Val - rs141976414) which has a frequency of 0.12% in non-Finnish Europeans.

Features included intellectual disability (9/9), seizures (6/9), behavioral problems (3/9) and sensorineural hearing loss (3/9). Facial features were not specific.

Extensive functional studies were performed and support pathogenicity of the variant in the homozygous state (reduced protein levels, reduced translation rate in line with the role of EIF3F encoding a subunit for eukaryotic translation initiation factor 3, as well as reduced proliferation rates).

As a result this gene can be considered for inclusion in this panel as green (or amber).
Sources: Literature, Expert Review

Created: 18 Nov 2018, 10:15 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Intellectual disability; Seizures; Behavioral abnormality; Sensorineural hearing impairment

Publications

• 30409806