Results
We identified the same homozygous missense variant c.694T>G/ p.(Phe232Val) in EIF3F (NM_003754) in 21 individuals from 16 families (Figure 1). All tested parents were heterozygous carriers of the variant (parents of pedigree 16 (P16) were not available for testing). Parental consanguinity was reported in one of 16 families. An additional affected individual (P3) was compound heterozygous for the maternally inherited missense variant c.694T>G/ p.(Phe232Val) and a paternally inherited variant c.861dup/ p.(Gln288AlafsTer14). The latter variant was absent in the Genome Aggregation Database (gnomAD) (Karczewski et al., 2020), and was predicted to result in a frameshift and subsequently either in mRNA decay or a truncated protein (length reduced by 20%, exon 6 of 8) with altered structure.
The female individual of family P2 had two molecular diagnoses. In addition to the homozygous EIF3F variant, she had a de novo frameshift variant in MECP2 , implicated in Rett syndrome (OMIM #312750). As symptoms in EIF3F -related NDD considerably overlap with those in Rett syndrome, we did not include this individual in the summary of clinical aspects (Table 1), but presented details in Supportive Table 1.
Among the reported individuals were 15 females (14 total when excluding the individual with Rett syndrome) and 7 males. Overall, history of pregnancies and deliveries were largely uneventful, although oligohydramnios was noted in one pregnancy (P9), and perinatal asphyxia suspected in another case (P14). The average age at the time of the last physical examination was 12.1 ± 9.6 years (mean +/- standard deviation), with a median of 8.5 years; four individuals had an age of >18 years.
All affected individuals had developmental delays. Considering motor milestones, 33% of ascertained individuals (4/12) exhibited delays in unassisted sitting (>10 months) and 70% of individuals (14/20) in independent walking (≥ 18 months, Supportive Table 1). The single individual with compound heterozygous EIF3F variants (P3) did not walk independently at the age of 5 years, but crawled. 24% of individuals (5/21) had not developed speech at the last examination including the compound heterozygous individual, while speech abilities varied widely between few words and simplified, but usable language in the remaining individuals.
Hearing loss was reported in 57% of affected individuals (12/21). More than half of the probands (12/21; 57%) were observed to have behavioral problems such as obsessive compulsory disorder, social problems, anxiety, autism, hyperactivity, attention deficit, aggressivity or pica. Muscular hypo- or hypertonia was also common and diagnosed in 48% of affected individuals (10/21). Notably, different ophthalmological findings were observed in up to 38% of affected individuals (8/21) and included hyper-/myopia (38%), strabismus (14%), nystagmus (5%) and coloboma (5%). Brain imaging revealed nonspecific findings in five of 13 examined affected individuals (38%). Five of 21 individuals (24%) had sleeping problems. Epilepsy was diagnosed in 15% of individuals (3/20).
Regression of cognitive abilities was observed in three of 21 individuals at an age of 2.5 years (P11.1), 21 years (P4.1) and in adulthood (P14). Two of these lost their speech abilities, while the third developed mood swings and demanded more attention. P14 had a combination of meningioma and psychosis, and an additional individual (P16) was operated on a meningioma.
Two individuals were noted to have reduced pain sensitivity. In one proband, muscle atrophy was noted, while in two of the ten individuals with altered muscular tone, a combination of truncal hypotonia and hypertonic extremities was diagnosed.
Short stature was observed in 40% of affected individuals at the last physical examination (Table 1, Supportive Table 1). Interestingly, four of the seven individuals with short stature at the last examination (with available data of body length at birth and at the last examination), had normal body length at birth. Microcephaly was common at the last physical examination (6/19; 32%), and microcephaly (4/10; 40%) or normocephaly (6/10; 60%) remained consistent between birth and the last measurement. Notably, the compound heterozygous individual of P3 was both short for age and microcephalic.
Five of the individuals (24%) had gastrointestinal problems which included gastro-esophageal reflux disease, difficulties to swallow, alternating constipation and diarrhea and neonatal feeding problems. Cleft lip and palate (P15), tetralogy of Fallot (P3) or combination (P5) of a groove of lip (considered a minor variant of cleft lip, Figure 2C,D) and a nasal fistula (Figure 2C) were observed in a single individual each. The compound heterozygous individual had gastrointestinal problems and a congenital heart defect.
More prevalent dysmorphic findings included a tubular and/ or narrow nose, a pointed nasal tip and anteverted nares. We also observed posteriorly rotated ears, short and/ or encased (= embedded by abundant skin) finger and toe nails (Figure 2, Table 1). Also, palpebral fissures were fairly even in all affected individuals (Figure 2). A unilateral single palmar crease was noted in four individuals. Dysmorphic features were generally subtle and non-specific and were not considered a recognizable facial gestalt.
Two individuals had initially received targeted diagnostics for short stature or failure to thrive including a gene panel for short stature and testing for Russel-Silver syndrome (OMIM #180860). The individual compound heterozygous for EIF3F variants presented with intrauterine growth retardation. Most other genetic testing that was performed in affected individuals (Angelman syndrome, Fragile X-syndrome) overlapped those reported previously (Martin et al., 2018).
Heterozygous carriers were mainly asymptomatic. One father was reported to have with epilepsy, and one mother migraines. Those overlapping symptoms are likely unrelated and of of different etiology.
To test whether the missense variant arose once or recurrently, we performed haplotype analyses. This revealed that the EIF3Fvariant was on an identical haplotype (minimal 7.8 kb) in 13 affected individuals of all tested pedigrees, suggesting a founder variant (Table 2).