Discussion
Our study confirms a relevant role of EIF3F in syndromic NDD. We
observed the same pathogenic homozygous missense variant
c.694T>G/ p.(Phe232Val) in all but one affected individual.
This variant represents the 7th most commonEIF3F missense variant in gnomAD (0.07%) with highest
frequencies in Ashkenazi Jewish (0.21%) and non-Finnish European
individuals (0.12%) (Karczewski et al., 2020). In line with its
pathogenicity, no individual in gnomAD was reported to be homozygous for
this variant, in contrast to five of the six more frequent variants. The
haplotype analyses performed in this study add the finding that the
variant most probably arose once on a single haplotype, indicating a
founder variant.
EIF3F was previously reported to be one of few genes
significantly enriched for bi-allelic genotypes in large cohorts of
individuals with NDD, due to the shared variant c.694T>G/
p.(Phe232Val) in all affected individuals (Martin et al., 2018). The
frequency of heterozygous carriers in gnomAD, especially in Non-Finnish
European and Askenazi Jewish individuals, is higher than for most other
autosomal recessive NDDs. For many of the other autosomal recessive
NDDs, only few or a handful of families have been reported (Anazi et
al., 2017; Reuter et al., 2017). In those diseases, predominantly
truncating variants are causative. Therefore, an identical, rather
frequent missense variant in EIF3F in almost all affected
individuals is an uncommon finding in NDDs, particularly in a cohort
with heterogeneous, ethnical and regional backgrounds. Particularly
common pathogenic variants have been observed in certain other genetic
diseases: e.g. p.Phe508del variant in CFTR in cystic fibrosis in
Europeans, population-specific variants in HFE in
hemochromatosis, and population-specific truncating variants inGJB2 in deafness. In this study, the EIF3F missense
variant was identified in affected individuals of a wide spectrum of
European/ West Asian origins including French, English, Irish, Scottish,
German, Bulgarian, Ukranian, Russian, Ashkenazi Jewish, and Iraqi.
Haplotype analyses support a single mutational event on a founder
haplotype, while the nascence of the missense variant cannot be
determined to a more localized region.
As only the identical missense variant in EIF3F has been
functionally characterized and shown to result in reduced protein
amount/ stability, decreased proliferation rate and reduced
translational rate, it remains speculative whether other missense
variants might have comparable effects. Other rare missense variants
might be functionally irrelevant or less harmful, as they might reach a
certain harmful threshold causing NDD as in case of
c.694T>G/ p.(Phe232Val) (Martin et al., 2018). In contrast,
the finding of the rather severe phenotype in the individual with
compound heterozygous variants in EIF3F suggests some
genotype-phenotype correlation and a possibly residual EIF3F function in
individuals homozygous for c.694T>G/ p.(Phe232Val). Of
note, the overall number of truncating alleles in individuals in gnomAD
v2.1.1 is extremely low (probability of being loss-of-functionintolerant = 0.97, observed over expected variants = 0.07). Regarding
lack of individuals with two truncating variants and of further affected
individuals who are compound heterozygous for truncating variants, one
might speculate that truncating variants on both alleles might not be
compatible with life.
In this study, all affected individuals had global developmental delay
of variable degree. Motor developmental delay was variable: one patient
did not learn to walk independently, while most individuals learned
walking late, and some individuals achieved motor milestones at a normal
age. Similarly, the degree of ID varied widely. This study adds the
finding of significant speech delay to the phenotype: the majority of
individuals spoke more than few words, while a quarter of affected
individuals had no speech development. Hearing loss and behavioral
difficulties were common findings, whereas epilepsy was less frequent
than initially reported (Martin et al., 2018). Other frequent, so far
unreported symptoms observed in this study are muscular hypotonia and/
or hypertonia, ophthalmologic findings and sleeping problems. Results of
a murine study might indicate some concordance with the human phenotype
and support loss-of-function as the underlying cause: partial
depletion of murine eIF3f amplified muscle atrophy compared to wild-type
mice and reduced the MTOR pathway activation (Docquier et al., 2019). In
regard to this study’s ophthalmologic findings, some of these (hyper-/
myopia) might not necessarily be related to EIF3F deficiency, as they
are common in the general population.
The observation of reduced pain sensitivity in this study supports an
association with this previously described, however rare symptom (Martin
et al., 2018), as did the finding of muscular atrophy/ muscular
hypoplasia in another individual. In concordance with the previous
study, brain imaging did not reveal specific findings and were therefore
not considered diagnostically indicative in EIF3F related NDD.
Thus, genome-wide sequencing approaches (genome or exome sequencing)
represent an essential component of the diagnostic work-up.
Developmental regression or neurodegeneration at various ages (2.5 to
~30 years) was observed in three of the 20 affected
individuals which might be relevant for prognosis. However, two of the
three individuals had additional diagnoses that are not necessarily
related to this syndromic disorder: encephalopathy in an individual with
vitamin B12 deficiency and psychosis in an individual with meningioma.
In another individual, an increased seizure frequency also led to the
diagnosis of meningioma. The cohort size and the relatively young ages
of the majority of individuals did not allow conclusions as to whether
those symptoms are part of the disease spectrum or might have an
independent cause.
Short stature, also occurring until adulthood, was commonly observed in
this study group. Microcephaly was less frequent than short stature and
of variable degree within this cohort, while longitudinal data indicated
that head growth had a more constant course along the centiles than
height.
Rare features that might be part of the EIF3F related NDD include
functional problems of the gastrointestinal tract, cleft lip and palate,
heart defect and nasal fistula. Of those, the latter two had not been
previously described. In agreement with the previous study, we did not
recognize an obvious distinctive facial appearance. While the previous
study had indicated tapered fingers and dysplastic toe nails (Martin et
al., 2018), we observed nasal findings (tubular nose, pointed nasal tip,
anteverted nares), posteriorly rotated ears as well as short and/ or
encased finger and toe nails as more frequent, recurrent features.
In summary, this study confirms the previously reported EIF3Fmissense variant as a relatively frequent cause of autosomal-recessive
NDD. Characteristic features include global developmental delay, delayed
speech development, behavioral difficulties, altered muscular tone,
hearing loss, ophthalmological symptoms, short stature, and minor
anomalies of the ears, nose, hands and feet.