Introduction
Bi-allelic variants in the EIF3F gene have recently been
published as the cause for a syndromic neurodevelopmental disorder (NDD)
(OMIM #618295: intellectual developmental disorder, autosomal recessive
67). Variants were identified by a large exome-wide recessive burden
analysis of >4,500 families with no previous molecular
diagnosis (Martin et al., 2018). All nine affected individuals from
seven families carried the same homozygous EIF3F missense variant
c.694T>G/ p.(Phe232Val). Beside variable intellectual
disability (ID) in all individuals, epilepsy occurred in six, and
behavioral problems or sensorineural hearing loss in three individuals,
respectively (Martin et al., 2018). EIF3F encodes an essential
subunit of the largest eukaryotic translation initiation factor eIF3
which binds to a highly specific group of mRNAs involved in cell
proliferation and growth, including cell cycle control, differentiation
and apoptosis (Lee, Kranzusch, & Cate, 2015; Masutani, Sonenberg,
Yokoyama, & Imataka, 2007). In vitro studies of induced
pluripotent stem cells (iPSC), gene-edited to be homozygous for the
c.694T>G/ p.(Phe232Val) variant, demonstrated lower EIF3F
protein levels and reduced proliferation rates (Martin et al., 2018).
Furthermore, both heterozygous and homozygous variants reduced
translation rates in iPSC cells (Martin et al., 2018), suggesting aloss-of-function mechanism.
In the current study, we assembled a group of 21 previously unreported
individuals with homozygosity or compound heterozygosity for the variant
c.694T>G/ p.(Phe232Val). We further delineate theEIF3F -related phenotypic spectrum in this group and describe an
additional, so far unreported disease-causing variant. Thus, we confirmEIF3F -deficiency as a relatively prevalent cause for
autosomal-recessive NDD.