INTRODUCTION
There are many genetic conditions that are linked to various aspects of
protein translation in humans, including Vanishing White Matter Disease
and Wolcott–Rallison syndrome. The main regulatory step of translation
is the initiation. To initiate protein translation in a mammalian cell,
a ternary complex consisting of one GTP, the initiator methionyl-tRNA,
and the translation initiation factor eIF2 is required. The core subunit
is called eIF2γ, and is encoded by EIF2S3 , located on the
X-chromosome. The first paper linking this gene to disease appeared in
2012, when a missense variant was linked to a clinical phenotype with
moderate-to-severe ID, microcephaly, short stature, and facial
dysmorphic features in three male patients of the same family (Borck et
al., 2012). Subsequently, a more severe phenotype with severe
developmental delay, hypertonus, epilepsy and short lifespan was
described to result from a truncating variant in EIF2S3 (Moortgat
et al., 2016). A genetic retrospective analysis of a clinical group of
patients described in 1998 as suffering from MEHMO syndrome (MIM#
300148) (Steinmuller et al., 1998), revealed that this group had
pathogenic variants in EIF2S3 . The first description includedM ental retardation, E pileptic seizures,H ypogonadism and -genitalism, M icrocephaly,O besity, and hence the acronym. Here, we describe an expanded
MEHMO phenotype in two brothers with attenuating variants inEIF2S3 .