EIF3F-related neurodevelopmental disorder: refining the phenotypic and expanding the molecular spectrum

Abstract

Background An identical homozygous missense variant in EIF3F, identified through a large-scale genome-wide sequencing approach, was reported as causative in nine individuals with a neurodevelopmental disorder, characterized by variable intellectual disability, epilepsy, behavioral problems and sensorineural hearing-loss. To refine the phenotypic and molecular spectrum of EIF3F-related neurodevelopmental disorder, we examined independent patients. Results 21 patients were homozygous and one compound heterozygous for c.694T>G/p.(Phe232Val) in EIF3F. Haplotype analyses in 15 families suggested that c.694T>G/p.(Phe232Val) was a founder variant. All affected individuals had developmental delays including delayed speech development. About half of the affected individuals had behavioral problems, altered muscular tone, hearing loss, and short stature. Moreover, this study suggests that microcephaly, reduced sensitivity to pain, cleft lip/palate, gastrointestinal symptoms and ophthalmological symptoms are part of the phenotypic spectrum. Minor dysmorphic features were observed, although neither the individuals’ facial nor general appearance were obviously distinctive. Symptoms in the compound heterozygous individual with an additional truncating variant were at the severe end of the spectrum in regard to motor milestones, speech delay, organic problems and pre- and postnatal growth of body and head, suggesting some genotype–phenotype correlation. Conclusions Our study refines the phenotypic and expands the molecular spectrum of EIF3F-related syndromic neurodevelopmental disorder.

Two Genetic Mechanisms in Two Siblings with Intellectual Disability, Autism Spectrum Disorder, and Psychosis

“…The EIF3F protein is involved in IRES-dependent viral translational initiation, protein deubiquitination, and translational initiation. Mutations of the EIF3F gene were associated with recessive developmental disorders characterized by ID, epilepsy, behavioral problems, and various physical abnormalities [ 61 , 62 ].…”

Clinical and genetic association studies reveal within-individual variability as an integral part of Huntington disease

“…Interestingly, EIF3F , which was identified through gene-based analysis and encodes a subunit of the eukaryotic translation initiation factor eIF3, has also been linked to neurodevelopmental defects. 44 Importantly, eIF3F favors repeat-associated non-ATG (RAN) translation, a key mechanism through which repeat expansions could induce neurodegeneration, with its knockdown reducing the levels of RAN proteins. 45 Given that both BMI and its variability could reflect the rate of neuropathology as argued above, these loci thus do not necessarily need to be involved in systemic energy regulation per se, but may also exert their influence by affecting neurodegeneration in HD.…”

Routine Diagnostics Confirm Novel Neurodevelopmental Disorders

“…Identification of rare variants in routine diagnostics can also facilitate research through the sharing of these results via matchmaking databases, such as GeneMatcher [ 40 ]. With this approach, several individuals from our cohort could be included in larger studies, such as GNAI1 [ 41 ], RIPPLY2 [ 42 ] and EIF3F [ 43 ]. Further case reports or the inclusion of our affected individual in larger cohorts are planned for RAB11B , RHEB , ADARB1 , GABRB1 and TCF7L2 to provide additional support for weak GDAs, expand the phenotypic spectrum or validate OMIM phenotypes.…”