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.