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 common EIF3F missense variant in gnomAD (0.07%) with highest frequencies in Ashkenazi Jewish (0.21%) and non-Finnish European individuals (0.12%) [6]. 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 [9]. 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 [1, 11]. 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 in GJB2 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) [9]. 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-function intolerant = 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. In comparison to the initial report [9], hearing loss and behavioral difficulties were more common findings, and epilepsy less frequent in this study. 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 [3]. 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 [9], 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. In large collections of malignancies (COSMIC; accessed on 3rd of December 2020 at cancer.sanger.ac.uk), somatic EIF3F variants have been detected in 0.9% of 38,579 samples (n = 353) and did not include 130 meningioma samples, providing no further evidence for a role of EIF3F in tumorigenesis of meningioma [16].
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, undescended testes, 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 [9], 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 EIF3F missense 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.