Intellectual Developmental Disorder Autosomal Recessive 67

Mendelian MONDO:0032662 Pathograph 12 Show in embeddings browser hereditary neurological disease syndromic intellectual disability

MRT67 is a syndromic autosomal recessive neurodevelopmental disorder caused by biallelic variants in EIF3F, which encodes the f subunit of eIF3, the largest and most complex of the eukaryotic translation initiation factors. Its molecular logic is unusual: the disease is a partial failure of general protein synthesis, not a defect in a pathway or a neuron-specific protein. Gene-edited stem cells homozygous for the disease allele carry less eIF3f protein, proliferate more slowly, and translate less. What reaches the clinic is global developmental delay in every reported individual, with speech delay in every individual too, and then a variable syndromic tail of behavioural problems, sensorineural hearing loss, abnormal muscle tone, short stature, microcephaly, ophthalmological findings, reduced pain sensitivity, and occasional cleft lip or palate. What makes this entity distinctive among recessive neurodevelopmental disorders is its genetics. Almost every reported patient carries the identical homozygous missense variant c.694T>G p.(Phe232Val), and haplotype analysis across fifteen families placed it on one shared haplotype, so it arose once and is a founder allele. It is also comparatively common: it is the seventh most frequent EIF3F missense variant in gnomAD at 0.07%, rising to 0.21% in Ashkenazi Jewish and 0.12% in non-Finnish European individuals. Most recessive neurodevelopmental disorders are caused by many different, mostly truncating, private variants in a handful of families; here one relatively frequent missense allele explains almost the whole disease across French, English, Irish, Scottish, German, Bulgarian, Ukrainian, Russian, Ashkenazi Jewish and Iraqi families. That pattern is itself mechanistically informative. EIF3F is strongly intolerant of loss of function in population data, no individual homozygous for the common allele appears in gnomAD, and no patient with two truncating alleles has ever been reported, while the one compound heterozygote with a missense plus a frameshift allele sat at the severe end of the spectrum. The most economical reading is that p.(Phe232Val) is a hypomorph that leaves enough residual eIF3f function to be survivable, and that complete loss is not: the mouse says the same thing, since eIF3f-null embryos die shortly after implantation while heterozygotes are viable.

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Mappings
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Inheritance
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Pathophys.
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Phenotypes
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Gaps
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Pathograph
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Genes
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Variants
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Medical Actions
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Models
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References
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Deep Research
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Classifications

Harrison's Part
NEUROLOGIC GENETICS ENVIRONMENT DISEASE
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Mappings

MONDO
MONDO:0019502 autosomal recessive non-syndromic intellectual disability DisMech
skos:broadMatch MONDO
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Inheritance

1
Autosomal recessive inheritance HP:0000007
Biallelic EIF3F variants are required. All tested parents in the largest cohort were heterozygous carriers and were essentially unaffected, and parental consanguinity was reported in only one of sixteen families, which is unusual for a recessive disorder and reflects the frequency of the founder allele in the general European population.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:33736665 SUPPORT Human Clinical
"All tested parents were heterozygous carriers of the variant (parents of pedigree 16 (P16) were not available for testing)."
Segregation showing carrier parents and affected biallelic offspring.
PMID:33736665 SUPPORT Human Clinical
"Heterozygous carriers were mainly asymptomatic. One father was reported to have epilepsy, and one mother migraines. Those overlapping symptoms are likely unrelated and of different etiology."
Establishes that heterozygous carriers are not affected, which is what makes the inheritance recessive rather than dominant with reduced penetrance.
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Discussions and Knowledge Gaps

5
Is epilepsy a common feature of EIF3F-related neurodevelopmental disorder or an uncommon one? The two published cohorts disagree by a wide margin.
CONTROVERSY OPEN eif3f_epilepsy_frequency_discrepancy
Attached to
phenotypes#Epilepsy
Epilepsy occurred in six of the nine individuals in the founding cohort, and was reported as substantially less frequent in the larger follow-up cohort of twenty-one. Both describe the same homozygous founder allele, so the difference is not genotypic. The likely explanation is ascertainment: the founding cases came out of a cohort recruited for undiagnosed developmental disorders and analysed by recessive burden, while the follow-up cohort was assembled through GeneMatcher after the gene was already known, which lets milder and non-epileptic cases in. If that is right, the true frequency is closer to the lower figure and the founding report overstates it, which matters for what a family is told at diagnosis. No frequency band is asserted on the epilepsy phenotype in this entry until a third independent cohort settles it.
Show evidence (2 references)
PMID:33736665 SUPPORT Human Clinical
"Beside variable intellectual disability (ID) in all individuals, epilepsy occurred in six, and behavioral problems or sensorineural hearing loss in three individuals, respectively"
The founding cohort's figure, six of nine.
PMID:33736665 SUPPORT Human Clinical
"hearing loss and behavioral difficulties were more common findings, and epilepsy less frequent in this study."
The follow-up cohort's contradictory finding, stated by the authors as a direct comparison.
Does the disease act only through reduced translation, or does it also act through eIF3f's separate deubiquitinase activity on Notch?
OPEN QUESTION OPEN eif3f_moonlighting_deubiquitinase_relevance
Attached to
pathophysiology#Reduced Global Translation Initiation
This entry models the disease entirely as a translation-initiation defect, because that is what has actually been measured in cells carrying the disease allele. But eIF3f has a second, unrelated documented activity: it is an intrinsic deubiquitinase that removes monoubiquitin from the activated Notch receptor and is required for Notch signalling, being recruited to activated Notch on endocytic vesicles by Deltex1. Notch signalling is central to neurogenesis, so a partial loss of eIF3f could in principle produce a neurodevelopmental phenotype through that route rather than, or as well as, through translation. Nobody has tested whether the p.(Phe232Val) allele affects the deubiquitinase activity. The question is not idle: the two mechanisms predict different things, since a translational deficit should scale with how much protein a cell needs while a Notch deficit should be specific to cell-fate decisions.
Proposed experiments
Test whether p.(Phe232Val) impairs eIF3f deubiquitinase activity on Notch
eif3f_phe232val_dub_activity_assay
Assay intrinsic deubiquitinase activity and monoubiquitinated Notch1 accumulation in cells expressing wild-type versus p.(Phe232Val) eIF3f, alongside a catalytically inactive mutant as the positive control for loss of activity, and score Notch reporter activation in a coculture assay. Separating a translational from a Notch effect requires the two readouts in the same isogenic background.
Show evidence (2 references)
PMID:21124883 SUPPORT In Vitro
"We show that eIF3f has an intrinsic DUB activity. Knocking down eIF3f leads to an accumulation of monoubiquitinated forms of activated Notch, an effect counteracted by murine WT eIF3f but not by a catalytically inactive mutant."
Establishes the second, non-translational activity that this question is about.
PMID:21124883 SUPPORT In Vitro
"Finally, catalytically inactive forms of eIF3f as well as shRNAs targeting eIF3f repress Notch activation in a coculture assay, showing that eIF3f is a new positive regulator of the Notch pathway."
Shows that loss of eIF3f impairs Notch signalling, which is the route this question asks about.
Is white-matter disease part of EIF3F-related neurodevelopmental disorder, and if so does it act through eIF3f's role in repeat-associated non-ATG translation?
OPEN QUESTION OPEN eif3f_white_matter_involvement
Attached to
phenotypes#Leukoencephalopathy
Two individuals have been reported with white-matter abnormalities on MRI, one with cystic dilatation of the perivascular spaces and one, a compound heterozygote, with extensive supratentorial leukodystrophy. That is thin, and it sits against a larger cohort in which brain imaging was explicitly nonspecific and was judged not diagnostically useful. What makes it worth keeping open rather than dismissing is a piece of biology from an unrelated disease: eIF3F regulates repeat-associated non-ATG translation, and knocking it down lowers the steady-state level of the SCA8 polySer protein, whose aggregates accumulate specifically in white-matter regions that show demyelination and axonal degeneration. That is a real, published route by which an eIF3f defect could reach white matter. It is also entirely circumstantial here: no one has examined RAN translation, myelination or oligodendrocytes in a patient or in a model of the disease allele, and the genotype differed between the two individuals with imaging findings. Until someone does, the leukoencephalopathy is curated as a phenotype without a frequency and without a causal edge into the pathograph.
Proposed experiments
Test myelination and RAN-translation readouts in p.(Phe232Val) oligodendrocytes
eif3f_oligodendrocyte_translation
Differentiate oligodendrocytes from the gene-edited p.(Phe232Val) homozygous stem cell lines and isogenic controls, and compare myelin gene translational efficiency and RAN-protein steady-state levels. A positive result would convert the imaging finding from an association into a mechanism; a negative one would argue the two reported scans are incidental.
Show evidence (3 references)
PMID:30206144 SUPPORT In Vitro
"Additionally, knockdown of the eukaryotic translation initiation factor eIF3F in cells reduces steady-state levels of SCA8 polySer and other RAN proteins."
Establishes that eIF3F modulates RAN protein accumulation, the biology this question asks about.
PMID:30206144 SUPPORT Human Clinical
"WM regions with polySer aggregates show demyelination and axonal degeneration in SCA8 human and mouse brains."
Establishes the white-matter tropism of the process eIF3F modulates. Two caveats are carried deliberately: the finding is in SCA8, not in this disease, which is why the question is open rather than answered; and the quoted observation spans human and mouse brains, graded here on the human arm because that is the claim being made about white-matter tropism in people.
PMID:33736665 REFUTE Human Clinical
"In concordance with the previous study, brain imaging did not reveal specific findings and were therefore not considered diagnostically indicative in EIF3F related NDD."
The larger cohort found no consistent imaging abnormality, which argues against white-matter disease being a general feature.
Two of twenty-one individuals in a cohort with a median age of 8.5 years had a meningioma. Is that a tumour predisposition, or coincidence in a small cohort?
KNOWLEDGE GAP OPEN eif3f_meningioma_signal
Attached to
pathophysiology#Reduced Cell Proliferation and Growth
The number is small but the context makes it hard to dismiss: meningioma in two of twenty-one individuals whose median age at last examination was 8.5 years is not what a paediatric cohort normally looks like. In one of the two it was an increased seizure frequency that led to the diagnosis, and in the other the tumour is named as a confound for that individual's apparent developmental regression, so the finding is currently visible in this entry only as a caveat inside the regression phenotype rather than as a question in its own right. The authors went looking for a mechanism and did not find one: somatic EIF3F variants appear in 0.9% of nearly 39,000 COSMIC samples and in none of 130 meningiomas. That negative is worth curating explicitly, because it is the kind of result that does not get published twice and would otherwise have to be re-derived by the next person who notices the two cases. This is recorded as a knowledge gap and NOT as a phenotype and NOT as a surveillance recommendation: two cases with an explicit negative tumour-genetics check do not support either.
Proposed experiments
Ascertain tumour incidence in a larger EIF3F biallelic cohort
eif3f_tumour_incidence_in_carrier_cohort
Follow the reported and future biallelic carriers longitudinally and compare central nervous system tumour incidence against age-matched expectation. Two cases in twenty-one cannot distinguish a real predisposition from ascertainment; a defined denominator with follow-up time can. A negative would retire the question; a positive would change surveillance, which is why it should not be inferred either way from the present data.
Show evidence (2 references)
PMID:33736665 REFUTE Human Clinical
"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"
The authors' own negative check against COSMIC, which is the main reason this is curated as an open gap rather than as a phenotype.
PMID:33736665 SUPPORT Human Clinical
"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."
Records the meningioma cases as the authors present them, as confounds for other features rather than as an asserted part of the phenotype.
Why does a general reduction in translation initiation produce this particular phenotype, with speech affected in everyone and hearing, stature and pain sensation affected in only some?
KNOWLEDGE GAP OPEN eif3f_no_neural_model
Attached to
pathophysiology#Impaired Brain Development and Somatic Growth
Every functional measurement in this disease has been made outside the nervous system. The cellular work used undifferentiated induced pluripotent stem cells; the in vivo work used mouse skeletal muscle in an animal carrying a null allele on one chromosome, not the human missense allele on both. There is no neural model of the disease allele at all, and brain imaging in patients is explicitly nonspecific, so there is no structural finding to reason from either. The step from "translation is slower" to "speech does not develop" is therefore an inference. It is a reasonable one, since eIF3 loads a defined subset of mRNAs rather than acting uniformly, but which of those messages matter in which neural cell type at which developmental stage is entirely unknown.
Proposed experiments
Profile the translatome of patient-allele neurons through differentiation
eif3f_neural_differentiation_translatome
Differentiate cortical neurons from the existing gene-edited p.(Phe232Val) homozygous stem cell lines and their isogenic controls, and compare ribosome profiling across differentiation stages to identify which transcripts lose translational efficiency in neural lineage cells specifically, rather than in stem cells.
Show evidence (1 reference)
PMID:33736665 SUPPORT Human Clinical
"In concordance with the previous study, brain imaging did not reveal specific findings and were therefore not considered diagnostically indicative in EIF3F related NDD."
Records the absence of any structural neural correlate to reason from.
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Pathophysiology

4
Homozygous EIF3F p.Phe232Val Lowers eIF3f Protein Abundance
The founder missense allele does not obviously break a catalytic site; what it does is leave less eIF3f protein in the cell. Stem cells gene-edited to carry the variant homozygously have reduced eIF3f protein levels, which is the observation the loss-of-function interpretation rests on. Population genetics agrees: EIF3F is strongly intolerant of loss-of-function variation, no gnomAD individual is homozygous for this allele, and no patient with two truncating alleles has been reported, so this allele is best read as a hypomorph that survives where a null would not.
Genetic context EIF3F hgnc:3275 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns EIF3F (hgnc:3275). hgnc:3275 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: GERMLINE zygosity: HOMOZYGOUS functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
Homozygous c.694T>G p.(Phe232Val) in almost every reported individual; one compound heterozygote carries this allele with a frameshift on the other chromosome and is more severely affected.
translation initiation factor activity of the eIF3f subunit GO:0003743 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased translation initiation factor activity of the eIF3f subunit, annotated with translation initiation factor activity (GO:0003743). GO:0003743 is a molecular function from the Gene Ontology. ↓ DECREASED
eukaryotic translation initiation factor 3 complex GO:0005852 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves eukaryotic translation initiation factor 3 complex (GO:0005852). GO:0005852 is a cellular component from the Gene Ontology.
Experimental models
Gene-edited EIF3F p.(Phe232Val) homozygous iPSC line IPSC DERIVED MODEL Carries the exact human disease allele in the exact zygosity of affected people, on an isogenic background, and reproduces the reduction in eIF3f protein that the molecular node asserts.
Animal models
eIF3f-null mouse Mouse perturbs A complete null, not the human allele. It bounds the mechanism from the severe end rather than reproducing the disease: it shows what happens when eIF3f is absent altogether, which is embryonic lethality rather than a neurodevelopmental disorder.
Downstream
Reduced Global Translation Initiation Less eIF3f in the eIF3 complex lowers the rate at which the cell can initiate translation.
Show evidence (2 references)
PMID:33736665 SUPPORT In Vitro
"In vitro studies of induced pluripotent stem cells (iPSC), gene-edited to be homozygous for the c.694T>G/ p.(Phe232Val) variant, demonstrated lower EIF3F protein levels and reduced proliferation rates"
The measurement this node asserts: the disease allele lowers eIF3f protein abundance in an isogenic cellular model.
PMID:33736665 SUPPORT Human Clinical
"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)."
Population constraint data supporting the reading that EIF3F cannot tolerate full loss of function, which is why the disease allele must be hypomorphic.
Reduced Global Translation Initiation
eIF3 is the largest of the eukaryotic initiation factors, and it does not load every message equally; it binds a specific subset of mRNAs involved in proliferation, growth, cell-cycle control, differentiation and apoptosis. Lowering eIF3f lowers the measured translation rate in cells carrying the variant, in heterozygotes as well as homozygotes. In mouse, partial eIF3f depletion reduces polysome content and protein synthesis rate and inhibits the mTOR pathway, which is the coupling by which a translation-factor defect becomes a growth defect.
translational initiation GO:0006413 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased translational initiation (GO:0006413). GO:0006413 is a biological process from the Gene Ontology. ↓ DECREASED TOR signaling GO:0031929 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased TOR signaling (GO:0031929). GO:0031929 is a biological process from the Gene Ontology. ↓ DECREASED
Experimental models
Gene-edited EIF3F p.(Phe232Val) homozygous iPSC line IPSC DERIVED MODEL Translation rate is reduced in cells carrying the variant, in heterozygotes as well as homozygotes, which is the cellular step the pathograph turns on.
Animal models
eIF3f heterozygous mouse Mouse recapitulates Reproduces the translational deficit itself, measured as reduced polysome content and protein synthesis rate, and identifies mTOR inhibition as the link to growth.
Downstream
Reduced Cell Proliferation and Growth A lowered translation rate constrains how fast cells can grow and divide.
Show evidence (3 references)
PMID:33736665 SUPPORT In Vitro
"Furthermore, both heterozygous and homozygous variants reduced translation rates in iPSC cells"
Direct measurement of reduced translation rate attributable to the disease allele.
PMID:33736665 SUPPORT Other
"EIF3F encodes an essential subunit of the largest eukaryotic translation initiation factor eIF3 which binds to a highly specific group of mRNAs involved in cell proliferation and growth, including cell cycle control, differentiation and apoptosis"
Explains why a general translation factor produces a selective phenotype: eIF3 acts on a defined mRNA subset rather than uniformly.
PMID:31026345 SUPPORT Model Organism
"Skeletal muscles of heterozygous mice show a deficiency in polysome content, a decrease in protein synthesis rate and an inhibition of the mechanistic target of rapamycin (MTOR) pathway."
Shows the same translational deficit in vivo, and identifies mTOR inhibition as the coupling to growth.
Reduced Cell Proliferation and Growth
Cells homozygous for the disease allele proliferate more slowly. This is the step that most plausibly connects a general translation defect to the particular clinical picture, since the tissues that need the most protein synthesis over the longest developmental window are the ones that show up in the phenotype: brain, stature, head circumference and, in the mouse, muscle mass.
cell population proliferation GO:0008283 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased cell population proliferation (GO:0008283). GO:0008283 is a biological process from the Gene Ontology. ↓ DECREASED
Experimental models
Gene-edited EIF3F p.(Phe232Val) homozygous iPSC line IPSC DERIVED MODEL Reduced proliferation rate in the edited line against its isogenic control.
Animal models
eIF3f heterozygous mouse Mouse partially recapitulates Reduced lean mass and altered muscle cell size without a change in fibre number, which is a growth deficit at the level of cell size rather than cell number.
Downstream
Impaired Brain Development and Somatic Growth Constrained proliferation and growth during development produce the neurodevelopmental and growth phenotype.
Show evidence (2 references)
PMID:33736665 SUPPORT In Vitro
"In vitro studies of induced pluripotent stem cells (iPSC), gene-edited to be homozygous for the c.694T>G/ p.(Phe232Val) variant, demonstrated lower EIF3F protein levels and reduced proliferation rates"
Records the measured reduction in proliferation rate in the isogenic cellular model.
PMID:31026345 SUPPORT Model Organism
"Although heterozygous mice are phenotypically indistinguishable from wild-type mice, they present a diminished body weight and a lean mass reduction associated with normal body size."
Growth consequence of partial eIF3f depletion in an intact animal.
Impaired Brain Development and Somatic Growth
The clinical endpoint: global developmental delay with prominent speech delay in every reported individual, plus a variable syndromic tail of hearing loss, abnormal muscle tone, short stature and microcephaly. This node is marked provisional because the step from a general reduction in translation to these specific outcomes is inferred rather than measured. No neural model of the disease allele has been reported; the cellular work was done in undifferentiated stem cells and the in vivo work in mouse muscle. Brain imaging in affected people is unhelpfully nonspecific, which is itself a piece of evidence: there is no structural lesion to point at.
brain development GO:0007420 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal brain development (GO:0007420). GO:0007420 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Show evidence (2 references)
PMID:33736665 SUPPORT Human Clinical
"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."
The clinical outcome this node represents, with the constant and the variable components separated.
PMID:33736665 SUPPORT Human Clinical
"In concordance with the previous study, brain imaging did not reveal specific findings and were therefore not considered diagnostically indicative in EIF3F related NDD."
Records the absence of a structural correlate, which is why this node is an inference from cellular data rather than an observed brain lesion.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Intellectual Developmental Disorder Autosomal Recessive 67 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

16
Ear 1
Sensorineural Hearing Loss FREQUENT Sensorineural hearing impairment HP:0000407 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sensorineural hearing impairment (HP:0000407). HP:0000407 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33736665 SUPPORT Human Clinical
"About half of the affected individuals had behavioral problems, altered muscular tone, hearing loss, and short stature."
Gives hearing loss in about half of individuals, which maps to FREQUENT.
PMID:39723281 SUPPORT Human Clinical
"She was diagnosed with a bilateral mild sensorineural hearing defect, pervasive developmental disorder, delayed psychomotor development, and intellectual disability."
Documents the sensorineural character and mild degree in an individual case.
Head and Neck 2
Microcephaly FREQUENT HP:0000252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Microcephaly (HP:0000252). HP:0000252 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33736665 SUPPORT Human Clinical
"Moreover, this study suggests that microcephaly, reduced sensitivity to pain, cleft lip/palate, gastrointestinal symptoms and ophthalmological symptoms are part of the phenotypic spectrum."
Adds microcephaly to the recognized phenotypic spectrum.
PMID:33736665 SUPPORT Human Clinical
"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."
Six of 19 individuals, 32%, which falls in the FREQUENT band (30-79%). It also records that head-size status is stable from birth, which is why the entry describes the growth phenotype as constitutional rather than progressive.
Cleft Lip or Palate Orofacial cleft HP:0000202 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cleft lip or palate, annotated with Orofacial cleft (HP:0000202). HP:0000202 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33736665 SUPPORT Human Clinical
"Moreover, this study suggests that microcephaly, reduced sensitivity to pain, cleft lip/palate, gastrointestinal symptoms and ophthalmological symptoms are part of the phenotypic spectrum."
Places cleft lip and palate within the recognized phenotypic spectrum.
Nervous System 8
Global Developmental Delay VERY_FREQUENT HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33736665 SUPPORT Human Clinical
"All affected individuals had developmental delays including delayed speech development."
Establishes global developmental delay in all affected individuals, which maps to VERY_FREQUENT.
PMID:33736665 SUPPORT Human Clinical
"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."
Documents both the universality and the wide variability in degree.
Delayed Speech and Language Development VERY_FREQUENT HP:0000750 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed speech and language development (HP:0000750). HP:0000750 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33736665 SUPPORT Human Clinical
"All affected individuals had developmental delays including delayed speech development."
Speech delay in all affected individuals, mapping to VERY_FREQUENT.
PMID:33736665 SUPPORT Human Clinical
"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."
Quantifies the severity within the speech domain and records that this feature was newly recognized.
Intellectual Disability VERY_FREQUENT HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33736665 SUPPORT Human Clinical
"Beside variable intellectual disability (ID) in all individuals, epilepsy occurred in six, and behavioral problems or sensorineural hearing loss in three individuals, respectively"
Records intellectual disability in all individuals of the founding cohort.
Behavioral Problems FREQUENT Atypical behavior HP:0000708 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Behavioral abnormality, annotated with Atypical behavior (HP:0000708). HP:0000708 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33736665 SUPPORT Human Clinical
"About half of the affected individuals had behavioral problems, altered muscular tone, hearing loss, and short stature."
Gives behavioural problems in about half of individuals, which maps to FREQUENT.
PMID:39723281 SUPPORT Human Clinical
"The girl was diagnosed using Autism Diagnostic Observation Schedule-Second Edition (ADOS-2) and Autism Diagnostic Interview-Revised (ADI-R) instruments and met the criteria for autism spectrum disorder."
A formal, instrument-based autism diagnosis in a homozygous carrier of the founder variant.
Sleep Disturbance OCCASIONAL HP:0002360 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sleep disturbance (HP:0002360). HP:0002360 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:33736665 SUPPORT Human Clinical
"Five of 21 individuals (24%) had sleeping problems."
Twenty-four percent, which falls in the OCCASIONAL band (5-29%). An earlier draft banded this phenotype FREQUENT on the strength of the authors' adjective "frequent" in a sentence covering three symptom groups jointly; the other two groups do reach that band and this one does not, so the counted figure is used instead.
PMID:33736665 SUPPORT Human Clinical
"Other frequent, so far unreported symptoms observed in this study are muscular hypotonia and/ or hypertonia, ophthalmologic findings and sleeping problems."
Establishes sleeping problems as a previously unreported part of the phenotype. Cited for the association only; the frequency band comes from the counted figure above.
PMID:39723281 SUPPORT Human Clinical
"Neurological signs included atypical leukoencephalopathy, hypotonia, sensorineural hearing loss, and sleep disturbances."
Independent case documenting sleep disturbance alongside the other neurological features.
Epilepsy Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33736665 SUPPORT Human Clinical
"Beside variable intellectual disability (ID) in all individuals, epilepsy occurred in six, and behavioral problems or sensorineural hearing loss in three individuals, respectively"
Records epilepsy in six of the nine individuals of the founding cohort. No frequency band is asserted on this phenotype because the two published cohorts disagree.
Developmental Regression HP:0002376 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Developmental regression (HP:0002376). HP:0002376 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33736665 SUPPORT Human Clinical
"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"
Reports the observation together with the confound that prevents attributing it to the disease. Graded PARTIAL for that reason.
Leukoencephalopathy HP:0002352 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Leukoencephalopathy (HP:0002352). HP:0002352 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:39723281 SUPPORT Human Clinical
"An MRI scan at 24 months of age showed randomly distributed cystic dilatations of the Virchow-Robin spaces bilaterally in the white matter, with a maximum concentration in the left parietal-temporal-occipital site, indicating atypical leukoencephalopathy."
The imaging finding in a homozygous carrier of the founder variant.
PMID:39723281 SUPPORT Human Clinical
"Another case study engaging MRI revealed extensive supratentorial leukodystrophy; however, the patient was a compound heterozygote in EIF3F"
A second individual with a white-matter abnormality, with the authors flagging the differing genotype.
Growth 1
Short Stature FREQUENT HP:0004322 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short stature (HP:0004322). HP:0004322 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33736665 SUPPORT Human Clinical
"About half of the affected individuals had behavioral problems, altered muscular tone, hearing loss, and short stature."
Gives short stature in about half of individuals, mapping to FREQUENT.
PMID:33736665 SUPPORT Human Clinical
"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."
Contrasts the stature and head-size phenotypes and their different longitudinal behaviour.
Other 4
Abnormal Muscle Tone FREQUENT HP:0003808 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Muscular hypotonia or hypertonia, annotated with Abnormal muscle tone (HP:0003808). HP:0003808 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33736665 SUPPORT Human Clinical
"About half of the affected individuals had behavioral problems, altered muscular tone, hearing loss, and short stature."
Gives altered muscular tone in about half of individuals, mapping to FREQUENT.
PMID:33736665 SUPPORT Human Clinical
"Other frequent, so far unreported symptoms observed in this study are muscular hypotonia and/ or hypertonia, ophthalmologic findings and sleeping problems."
Records that tone can be increased or decreased, which is why a directionless term is used.
Refractive Error FREQUENT Abnormality of refraction HP:0000539 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Refractive error, annotated with Abnormality of refraction (HP:0000539). HP:0000539 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:33736665 SUPPORT Human Clinical
"Other frequent, so far unreported symptoms observed in this study are muscular hypotonia and/ or hypertonia, ophthalmologic findings and sleeping problems."
Establishes ophthalmological findings as a previously unreported part of the phenotype. Cited for the association; the frequency band comes from the counted figure below.
PMID:33736665 SUPPORT Human Clinical
"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%)."
Eight of 21 individuals, 38%, which falls in the FREQUENT band (30-79%), and enumerates the specific findings behind the ophthalmological group.
PMID:33736665 SUPPORT Human Clinical
"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 authors' own caveat, graded PARTIAL because it qualifies rather than supports the association.
Reduced Pain Sensitivity Pain insensitivity HP:0007021 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pain insensitivity (HP:0007021). HP:0007021 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33736665 SUPPORT Human Clinical
"The observation of reduced pain sensitivity in this study supports an association with this previously described, however rare symptom"
Independent confirmation of a rare feature first noted in the founding cohort.
Gastrointestinal Symptoms Functional abnormality of the gastrointestinal tract HP:0012719 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Functional gastrointestinal abnormality, annotated with Functional abnormality of the gastrointestinal tract (HP:0012719). HP:0012719 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33736665 SUPPORT Human Clinical
"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."
Names functional gastrointestinal problems among the rarer features of the spectrum.
🧬

Genetic Associations

1
EIF3F (Causative)
Gene: EIF3F (eukaryotic translation initiation factor 3 subunit F) hgnc:3275 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is EIF3F (eukaryotic translation initiation factor 3 subunit F), annotated with EIF3F (hgnc:3275). hgnc:3275 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (2 references)
PMID:30409806 SUPPORT Human Clinical
"We identified two genes not previously associated with recessive developmental disorders, KDM5B and EIF3F, and functionally validated them with mouse and cellular models."
The founding gene-disease association. Graded HUMAN_CLINICAL because the association itself came from a recessive burden analysis of 6,040 human families in the Deciphering Developmental Disorders study; the same sentence also reports mouse and cellular validation, but that clause cannot be split into a separately graded item because it shares the sentence, and one quote may carry only one grade.
PMID:33736665 SUPPORT Human Clinical
"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."
States what is unusual about this gene's allelic architecture relative to other recessive neurodevelopmental disorders.
Variants (2)
EIF3F c.694T>G p.(Phe232Val) Pathogenic
Gene: EIF3F hgnc:3275 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in EIF3F (hgnc:3275). hgnc:3275 is a gene from the HUGO Gene Nomenclature Committee. missense
The founder allele, homozygous in 21 of 22 reported individuals across sixteen families and present on a single shared haplotype in all fifteen families tested, so it arose once. It is the seventh most common EIF3F missense variant in gnomAD at 0.07% overall, 0.21% in Ashkenazi Jewish and 0.12% in non-Finnish European individuals, yet no gnomAD individual is homozygous for it, in contrast to five of the six more frequent EIF3F missense variants. Functionally it lowers eIF3f protein level, translation rate and proliferation in gene-edited stem cells.
Show evidence (3 references)
PMID:33736665 SUPPORT Human Clinical
"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."
Establishes the allele's dominance of the reported cohort and its founder origin.
PMID:33736665 SUPPORT Human Clinical
"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%)"
Gives the population frequency and its ancestry distribution.
PMID:33736665 SUPPORT Human Clinical
"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 absence-of-homozygotes argument that separates this allele from the other common EIF3F missense variants.
EIF3F c.861dup p.(Gln288AlafsTer14) Pathogenic
Gene: EIF3F hgnc:3275 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in EIF3F (hgnc:3275). hgnc:3275 is a gene from the HUGO Gene Nomenclature Committee. frameshift
A frameshift allele found in trans with the founder missense variant in one individual, who was at the severe end of the spectrum for motor milestones, speech delay, organic problems and pre- and postnatal growth of body and head. This is the entity's only genotype-phenotype signal, and it is what supports reading the founder allele as hypomorphic rather than null.
Show evidence (2 references)
PMID:33736665 SUPPORT Human Clinical
"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."
Characterizes the frameshift allele and its predicted consequence.
PMID:33736665 SUPPORT Human Clinical
"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."
The genotype-phenotype observation that supports a dosage reading of the disease.
💊

Medical Actions

2
Developmental and Educational Support
Action: speech and language therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is speech and language therapy, annotated with Speech Language Therapy (NCIT:C159273). NCIT:C159273 is a clinical intervention from the NCI Thesaurus. Ontology label: Speech Language Therapy NCIT:C159273
There is no treatment directed at the mechanism. Management is developmental: speech and language therapy, which matters disproportionately here because speech is the most consistently and severely affected domain, together with special education, physiotherapy and behavioural support. Affected children in reported cases are followed by neurology, otorhinolaryngology, psychology and speech therapy together.
Target Phenotypes: Delayed speech and language development HP:0000750 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Delayed speech and language development (HP:0000750). HP:0000750 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39723281 SUPPORT Human Clinical
"The patient is under the care of several clinical specialists, including neurologists, otorhinolaryngologists, psychologists, and a speech therapist."
Documents the multidisciplinary care actually provided, including speech therapy, in a reported case.
Genetic Counseling
Action: genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Once the biallelic EIF3F genotype is known, counselling is concrete: the parents are obligate carriers and each future pregnancy carries a 25% recurrence risk. This matters more than usual here, because the founder allele is comparatively common in some ancestries, so a carrier parent may have relatives at risk who would not otherwise be identified.
Show evidence (1 reference)
PMID:39723281 SUPPORT Human Clinical
"The identification of the causal variant c.694T>G, p.(Phe232Val) in the EIF3F gene indicates a 25% recurrence risk in potential siblings of the patient, due to its autosomal recessive mode of inheritance, as explained by the clinical geneticist to the parents of the proband."
States the recurrence risk and records that it was actually delivered as counselling in a reported family.
🔬

Diagnosis

2
Audiological Assessment
Hearing loss affects about half of individuals and can be mild, so it will not announce itself in a child who already has global developmental delay and no speech. Detecting it changes management, because uncorrected hearing loss compounds the speech delay that is this disorder's most prominent feature.
diagnostic audiology testing NCIT:C217379 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:33736665 SUPPORT Human Clinical
"About half of the affected individuals had behavioral problems, altered muscular tone, hearing loss, and short stature."
Gives the roughly 50% frequency of hearing loss that makes routine audiological assessment worthwhile in a child with this diagnosis.
Genome-Wide Sequencing
Exome or genome sequencing is the diagnostic route, and effectively the only one. There is no biomarker, no distinctive facial gestalt, and brain imaging is nonspecific, so nothing directs a clinician to this gene before sequencing does. Because the causal allele is a single recurrent missense variant rather than an obvious truncation, it is also the kind of variant a filtering pipeline can discard as too common.
Show evidence (2 references)
PMID:33736665 SUPPORT Human Clinical
"Thus, genome-wide sequencing approaches (genome or exome sequencing) represent an essential component of the diagnostic work-up."
The authors' conclusion that sequencing is essential, following from the absence of directive clinical or imaging findings.
PMID:33736665 SUPPORT Human Clinical
"Minor dysmorphic features were observed, although neither the individuals' facial nor general appearance were obviously distinctive."
Records the absence of a recognizable gestalt, which is why clinical diagnosis is not possible.
📊

Prevalence

1
Worldwide
Cases In Literature Not yet documented
Around thirty individuals from about twenty-three families have been reported, across two cohorts and scattered case reports. No prevalence estimate exists. The carrier frequency of the founder allele is known (0.07% in gnomAD overall, 0.21% in Ashkenazi Jewish and 0.12% in non-Finnish European individuals) and is recorded on the variant, but it cannot be converted into a disease prevalence: the disease is far rarer than Hardy-Weinberg on that allele frequency would predict, and the entry does not speculate about why.
Show evidence (1 reference)
PMID:33736665 SUPPORT Human Clinical
"21 patients were homozygous and one compound heterozygous for c.694T>G/p.(Phe232Val) in EIF3F."
The size of the largest reported cohort, which together with the founding nine-patient report is essentially the whole literature.
🧫

Experimental Models

1
Gene-edited EIF3F p.(Phe232Val) homozygous iPSC line IPSC_DERIVED_MODEL
The isogenic human cell model, and the source of every functional measurement this pathograph rests on. Induced pluripotent stem cells were gene-edited to carry the founder variant homozygously, and show reduced eIF3f protein, reduced translation rate and reduced proliferation against their unedited controls. It is the only human system in this entry, and it is the model the "no neural model" knowledge gap is measured against: it establishes the molecular and cellular steps in human cells while saying nothing about neurons, because the cells were never differentiated.
Publication
PMID:30409806
Pathograph links
Homozygous EIF3F p.Phe232Val Lowers eIF3f Protein Abundance recapitulates fidelity: high Carries the exact human disease allele in the exact zygosity of affected people, on an isogenic background, and reproduces the reduction in eIF3f protein that the molecular node asserts.
Limitations: Undifferentiated stem cells. Protein abundance is measured in a cell type that has nothing to do with the affected tissue, so the model establishes that the allele lowers eIF3f, not that it does so in a neuron.
Readouts
eIF3f protein level in the edited line
Direction: DECREASED
Interpretation: Lower eIF3f protein against an isogenic control is the measurement the molecular node rests on, and the reason the allele is read as hypomorphic rather than as a change in protein activity.
Show evidence (1 reference)
PMID:33736665 SUPPORT In Vitro
"In vitro studies of induced pluripotent stem cells (iPSC), gene-edited to be homozygous for the c.694T>G/ p.(Phe232Val) variant, demonstrated lower EIF3F protein levels and reduced proliferation rates"
Reports the reduced protein level in the isogenic edited line.
Show evidence (1 reference)
PMID:33736665 SUPPORT In Vitro
"In vitro studies of induced pluripotent stem cells (iPSC), gene-edited to be homozygous for the c.694T>G/ p.(Phe232Val) variant, demonstrated lower EIF3F protein levels and reduced proliferation rates"
Describes the model and the reduced protein level it demonstrates.
Reduced Global Translation Initiation recapitulates fidelity: moderate Translation rate is reduced in cells carrying the variant, in heterozygotes as well as homozygotes, which is the cellular step the pathograph turns on.
Limitations: A bulk translation-rate measurement in undifferentiated cells. It does not identify which transcripts lose translational efficiency, which is the open question the entry's knowledge gap records.
Readouts
Bulk translation rate
Direction: DECREASED
Interpretation: A measured fall in translation rate is what converts the protein-level finding into a functional claim about initiation. It is bulk, so it cannot say which messages are affected.
Show evidence (1 reference)
PMID:33736665 SUPPORT In Vitro
"Furthermore, both heterozygous and homozygous variants reduced translation rates in iPSC cells"
The measured reduction in translation rate, in both zygosities.
Show evidence (1 reference)
PMID:33736665 SUPPORT In Vitro
"Furthermore, both heterozygous and homozygous variants reduced translation rates in iPSC cells"
The measured reduction in translation rate attributable to the allele.
Reduced Cell Proliferation and Growth recapitulates fidelity: moderate Reduced proliferation rate in the edited line against its isogenic control.
Limitations: Proliferation of a stem cell is not the developmental growth of a brain or a body; the link to the organism-level phenotype remains an inference.
Readouts
Cell proliferation rate
Direction: DECREASED
Interpretation: Slower proliferation in the edited line against its isogenic control. This is the closest measured proxy for the growth restriction seen in patients, and it is still only a proxy.
Show evidence (1 reference)
PMID:33736665 SUPPORT In Vitro
"In vitro studies of induced pluripotent stem cells (iPSC), gene-edited to be homozygous for the c.694T>G/ p.(Phe232Val) variant, demonstrated lower EIF3F protein levels and reduced proliferation rates"
Reports the reduced proliferation rate in the isogenic edited line.
Show evidence (1 reference)
PMID:33736665 SUPPORT In Vitro
"In vitro studies of induced pluripotent stem cells (iPSC), gene-edited to be homozygous for the c.694T>G/ p.(Phe232Val) variant, demonstrated lower EIF3F protein levels and reduced proliferation rates"
The measured reduction in proliferation rate in the isogenic model.
🐁

Animal Models

2
eIF3f-null mouse
Homozygous null embryos fail to develop and die at an early embryonic stage, after implantation. This is the experimental counterpart of the human observation that no patient with two truncating EIF3F alleles has ever been reported, and it is the reason the founder missense allele must retain residual function.
Species
Mouse
Genotype
eIF3f homozygous null
Publication
PMID:31026345
Pathograph links
Homozygous EIF3F p.Phe232Val Lowers eIF3f Protein Abundance perturbs fidelity: low A complete null, not the human allele. It bounds the mechanism from the severe end rather than reproducing the disease: it shows what happens when eIF3f is absent altogether, which is embryonic lethality rather than a neurodevelopmental disorder.
Limitations: This genotype does not exist in any reported patient and produces a qualitatively different outcome from the human disease. It cannot be used to model the phenotype, only to argue that the human allele is hypomorphic.
Show evidence (1 reference)
PMID:31026345 SUPPORT Model Organism
"We showed that homozygous eIF3f knockout fail to develop and that eIF3f-/- embryos die at an early stage of development but after the pre-implantation stage."
Records the embryonic lethality of complete eIF3f loss.
eIF3f heterozygous mouse
Viable, fertile and grossly normal, but with reduced eIF3f mRNA and protein in every tissue examined, reduced polysome content, a lower protein synthesis rate, inhibited mTOR signalling, reduced lean mass and altered muscle cell size. It is the only in vivo demonstration that partial eIF3f depletion produces a measurable translational and growth deficit.
Species
Mouse
Genotype
eIF3f heterozygous null
Publication
PMID:31026345
Pathograph links
Reduced Global Translation Initiation recapitulates fidelity: moderate Reproduces the translational deficit itself, measured as reduced polysome content and protein synthesis rate, and identifies mTOR inhibition as the link to growth.
Limitations: The measurements were made in skeletal muscle, not brain, and the mouse carries a null allele on one chromosome rather than the human missense allele on both. Heterozygous mice are behaviourally and developmentally normal, so this model captures the biochemistry of partial eIF3f depletion without reproducing the neurodevelopmental phenotype.
Show evidence (1 reference)
PMID:31026345 SUPPORT Model Organism
"Skeletal muscles of heterozygous mice show a deficiency in polysome content, a decrease in protein synthesis rate and an inhibition of the mechanistic target of rapamycin (MTOR) pathway."
The measured translational deficit and its mTOR coupling.
Reduced Cell Proliferation and Growth partially recapitulates fidelity: moderate Reduced lean mass and altered muscle cell size without a change in fibre number, which is a growth deficit at the level of cell size rather than cell number.
Limitations: Body size is normal in these mice, so the growth phenotype is not the short stature seen in patients, and no neural tissue was examined.
Show evidence (1 reference)
PMID:31026345 SUPPORT Model Organism
"Interestingly, skeletal muscles are mainly affected and display an altered cell size without modification of fibre number."
Locates the growth deficit at cell size rather than cell number.
{ }

Source YAML

click to show 
name: Intellectual Developmental Disorder Autosomal Recessive 67
creation_date: "2026-08-27T00:00:00Z"
category: Mendelian
synonyms:
- MRT67
- Mental Retardation, Autosomal Recessive 67
- EIF3F-related neurodevelopmental disorder
- EIF3F deficiency
disease_term:
  preferred_term: intellectual developmental disorder, autosomal recessive 67
  term:
    id: MONDO:0032662
    label: intellectual developmental disorder, autosomal recessive 67
description: >-
  MRT67 is a syndromic autosomal recessive neurodevelopmental disorder caused by
  biallelic variants in EIF3F, which encodes the f subunit of eIF3, the largest
  and most complex of the eukaryotic translation initiation factors. Its
  molecular logic is unusual: the disease is a partial failure of general
  protein synthesis, not a defect in a pathway or a neuron-specific protein.
  Gene-edited stem cells homozygous for the disease allele carry less eIF3f
  protein, proliferate more slowly, and translate less. What reaches the clinic
  is global developmental delay in every reported individual, with speech delay
  in every individual too, and then a variable syndromic tail of behavioural
  problems, sensorineural hearing loss, abnormal muscle tone, short stature,
  microcephaly, ophthalmological findings, reduced pain sensitivity, and
  occasional cleft lip or palate.


  What makes this entity distinctive among recessive neurodevelopmental
  disorders is its genetics. Almost every reported patient carries the identical
  homozygous missense variant c.694T>G p.(Phe232Val), and haplotype analysis
  across fifteen families placed it on one shared haplotype, so it arose once
  and is a founder allele. It is also comparatively common: it is the seventh
  most frequent EIF3F missense variant in gnomAD at 0.07%, rising to 0.21% in
  Ashkenazi Jewish and 0.12% in non-Finnish European individuals. Most recessive
  neurodevelopmental disorders are caused by many different, mostly truncating,
  private variants in a handful of families; here one relatively frequent
  missense allele explains almost the whole disease across French, English,
  Irish, Scottish, German, Bulgarian, Ukrainian, Russian, Ashkenazi Jewish and
  Iraqi families.


  That pattern is itself mechanistically informative. EIF3F is strongly
  intolerant of loss of function in population data, no individual homozygous
  for the common allele appears in gnomAD, and no patient with two truncating
  alleles has ever been reported, while the one compound heterozygote with a
  missense plus a frameshift allele sat at the severe end of the spectrum. The
  most economical reading is that p.(Phe232Val) is a hypomorph that leaves
  enough residual eIF3f function to be survivable, and that complete loss is
  not: the mouse says the same thing, since eIF3f-null embryos die shortly after
  implantation while heterozygotes are viable.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0019502
      label: autosomal recessive non-syndromic intellectual disability
    mapping_predicate: skos:broadMatch
    mapping_source: MONDO
    notes: >-
      The MONDO parent is a non-syndromic grouping, but this entity is
      consistently described as syndromic in the clinical literature, with
      hearing loss, short stature, microcephaly and dysmorphism alongside the
      intellectual disability. The parent is recorded as a cross-reference
      rather than adopted as a characterization.
parents:
- hereditary neurological disease
- syndromic intellectual disability
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Biallelic EIF3F variants are required. All tested parents in the largest
    cohort were heterozygous carriers and were essentially unaffected, and
    parental consanguinity was reported in only one of sixteen families, which
    is unusual for a recessive disorder and reflects the frequency of the
    founder allele in the general European population.
  evidence:
  - reference: PMID:33736665
    reference_title: "EIF3F-related neurodevelopmental disorder: refining the phenotypic and expanding the molecular spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All tested parents were heterozygous carriers of the variant (parents of
      pedigree 16 (P16) were not available for testing).
    explanation: >-
      Segregation showing carrier parents and affected biallelic offspring.
  - reference: PMID:33736665
    reference_title: "EIF3F-related neurodevelopmental disorder: refining the phenotypic and expanding the molecular spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Heterozygous carriers were mainly asymptomatic. One father was reported to
      have epilepsy, and one mother migraines. Those overlapping symptoms are
      likely unrelated and of different etiology.
    explanation: >-
      Establishes that heterozygous carriers are not affected, which is what
      makes the inheritance recessive rather than dominant with reduced
      penetrance.
references:
- reference: PMID:30409806
  title: Quantifying the contribution of recessive coding variation to developmental disorders.
- reference: PMID:33736665
  title: "EIF3F-related neurodevelopmental disorder: refining the phenotypic and expanding the molecular spectrum."
- reference: PMID:39723281
  title: Genetic Diagnostics and Phenotypic Profiling of a Girl With Autosomal Recessive Intellectual Developmental Disorder and Autism.
- reference: PMID:31026345
  title: "eIF3f depletion impedes mouse embryonic development, reduces adult skeletal muscle mass and amplifies muscle loss during disuse."
- reference: PMID:21124883
  title: The translation initiation factor 3f (eIF3f) exhibits a deubiquitinase activity regulating Notch activation.
- reference: PMID:30206144
  title: SCA8 RAN polySer protein preferentially accumulates in white matter regions and is regulated by eIF3F.
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
pathophysiology:
- name: Homozygous EIF3F p.Phe232Val Lowers eIF3f Protein Abundance
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    The founder missense allele does not obviously break a catalytic site; what
    it does is leave less eIF3f protein in the cell. Stem cells gene-edited to
    carry the variant homozygously have reduced eIF3f protein levels, which is
    the observation the loss-of-function interpretation rests on. Population
    genetics agrees: EIF3F is strongly intolerant of loss-of-function variation,
    no gnomAD individual is homozygous for this allele, and no patient with two
    truncating alleles has been reported, so this allele is best read as a
    hypomorph that survives where a null would not.
  molecular_functions:
  - preferred_term: translation initiation factor activity of the eIF3f subunit
    term:
      id: GO:0003743
      label: translation initiation factor activity
    modifier: DECREASED
  cellular_components:
  - preferred_term: eukaryotic translation initiation factor 3 complex
    term:
      id: GO:0005852
      label: eukaryotic translation initiation factor 3 complex
  genetic_context:
    gene:
      preferred_term: EIF3F
      term:
        id: hgnc:3275
        label: EIF3F
    variant_origin: GERMLINE
    zygosity: HOMOZYGOUS
    functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
    description: >-
      Homozygous c.694T>G p.(Phe232Val) in almost every reported individual; one
      compound heterozygote carries this allele with a frameshift on the other
      chromosome and is more severely affected.
  evidence:
  - reference: PMID:33736665
    reference_title: "EIF3F-related neurodevelopmental disorder: refining the phenotypic and expanding the molecular spectrum."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In vitro studies of induced pluripotent stem cells (iPSC), gene-edited to
      be homozygous for the c.694T>G/ p.(Phe232Val) variant, demonstrated lower
      EIF3F protein levels and reduced proliferation rates
    explanation: >-
      The measurement this node asserts: the disease allele lowers eIF3f protein
      abundance in an isogenic cellular model.
  - reference: PMID:33736665
    reference_title: "EIF3F-related neurodevelopmental disorder: refining the phenotypic and expanding the molecular spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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).
    explanation: >-
      Population constraint data supporting the reading that EIF3F cannot
      tolerate full loss of function, which is why the disease allele must be
      hypomorphic.
  downstream:
  - target: Reduced Global Translation Initiation
    description: >-
      Less eIF3f in the eIF3 complex lowers the rate at which the cell can
      initiate translation.
- name: Reduced Global Translation Initiation
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    eIF3 is the largest of the eukaryotic initiation factors, and it does not
    load every message equally; it binds a specific subset of mRNAs involved in
    proliferation, growth, cell-cycle control, differentiation and apoptosis.
    Lowering eIF3f lowers the measured translation rate in cells carrying the
    variant, in heterozygotes as well as homozygotes. In mouse, partial eIF3f
    depletion reduces polysome content and protein synthesis rate and inhibits
    the mTOR pathway, which is the coupling by which a translation-factor defect
    becomes a growth defect.
  biological_processes:
  - preferred_term: translational initiation
    term:
      id: GO:0006413
      label: translational initiation
    modifier: DECREASED
  - preferred_term: TOR signaling
    term:
      id: GO:0031929
      label: TOR signaling
    modifier: DECREASED
  evidence:
  - reference: PMID:33736665
    reference_title: "EIF3F-related neurodevelopmental disorder: refining the phenotypic and expanding the molecular spectrum."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Furthermore, both heterozygous and homozygous variants reduced translation
      rates in iPSC cells
    explanation: >-
      Direct measurement of reduced translation rate attributable to the disease
      allele.
  - reference: PMID:33736665
    reference_title: "EIF3F-related neurodevelopmental disorder: refining the phenotypic and expanding the molecular spectrum."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      EIF3F encodes an essential subunit of the largest eukaryotic translation
      initiation factor eIF3 which binds to a highly specific group of mRNAs
      involved in cell proliferation and growth, including cell cycle control,
      differentiation and apoptosis
    explanation: >-
      Explains why a general translation factor produces a selective phenotype:
      eIF3 acts on a defined mRNA subset rather than uniformly.
  - reference: PMID:31026345
    reference_title: "eIF3f depletion impedes mouse embryonic development, reduces adult skeletal muscle mass and amplifies muscle loss during disuse."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Skeletal muscles of heterozygous mice show a deficiency in polysome
      content, a decrease in protein synthesis rate and an inhibition of the
      mechanistic target of rapamycin (MTOR) pathway.
    explanation: >-
      Shows the same translational deficit in vivo, and identifies mTOR
      inhibition as the coupling to growth.
  downstream:
  - target: Reduced Cell Proliferation and Growth
    description: >-
      A lowered translation rate constrains how fast cells can grow and divide.
- name: Reduced Cell Proliferation and Growth
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Cells homozygous for the disease allele proliferate more slowly. This is the
    step that most plausibly connects a general translation defect to the
    particular clinical picture, since the tissues that need the most protein
    synthesis over the longest developmental window are the ones that show up in
    the phenotype: brain, stature, head circumference and, in the mouse, muscle
    mass.
  biological_processes:
  - preferred_term: cell population proliferation
    term:
      id: GO:0008283
      label: cell population proliferation
    modifier: DECREASED
  evidence:
  - reference: PMID:33736665
    reference_title: "EIF3F-related neurodevelopmental disorder: refining the phenotypic and expanding the molecular spectrum."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In vitro studies of induced pluripotent stem cells (iPSC), gene-edited to
      be homozygous for the c.694T>G/ p.(Phe232Val) variant, demonstrated lower
      EIF3F protein levels and reduced proliferation rates
    explanation: >-
      Records the measured reduction in proliferation rate in the isogenic
      cellular model.
  - reference: PMID:31026345
    reference_title: "eIF3f depletion impedes mouse embryonic development, reduces adult skeletal muscle mass and amplifies muscle loss during disuse."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Although heterozygous mice are phenotypically indistinguishable from
      wild-type mice, they present a diminished body weight and a lean mass
      reduction associated with normal body size.
    explanation: >-
      Growth consequence of partial eIF3f depletion in an intact animal.
  downstream:
  - target: Impaired Brain Development and Somatic Growth
    description: >-
      Constrained proliferation and growth during development produce the
      neurodevelopmental and growth phenotype.
- name: Impaired Brain Development and Somatic Growth
  biological_scale: ORGANISM
  mechanism_confidence: PROVISIONAL
  description: >-
    The clinical endpoint: global developmental delay with prominent speech
    delay in every reported individual, plus a variable syndromic tail of
    hearing loss, abnormal muscle tone, short stature and microcephaly. This
    node is marked provisional because the step from a general reduction in
    translation to these specific outcomes is inferred rather than measured. No
    neural model of the disease allele has been reported; the cellular work was
    done in undifferentiated stem cells and the in vivo work in mouse muscle.
    Brain imaging in affected people is unhelpfully nonspecific, which is itself
    a piece of evidence: there is no structural lesion to point at.
  biological_processes:
  - preferred_term: brain development
    term:
      id: GO:0007420
      label: brain development
    modifier: ABNORMAL
  evidence:
  - reference: PMID:33736665
    reference_title: "EIF3F-related neurodevelopmental disorder: refining the phenotypic and expanding the molecular spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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.
    explanation: >-
      The clinical outcome this node represents, with the constant and the
      variable components separated.
  - reference: PMID:33736665
    reference_title: "EIF3F-related neurodevelopmental disorder: refining the phenotypic and expanding the molecular spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In concordance with the previous study, brain imaging did not reveal
      specific findings and were therefore not considered diagnostically
      indicative in EIF3F related NDD.
    explanation: >-
      Records the absence of a structural correlate, which is why this node is
      an inference from cellular data rather than an observed brain lesion.
phenotypes:
- category: Nervous System
  name: Global Developmental Delay
  description: >-
    Present in every reported individual, but of widely variable degree: one
    child never walked independently, most walked late, and some reached motor
    milestones on time. The severity of the intellectual disability varies just
    as widely, so the constant feature is that development is delayed, not how
    much.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  frequency: VERY_FREQUENT
  diagnostic: true
  evidence:
  - reference: PMID:33736665
    reference_title: "EIF3F-related neurodevelopmental disorder: refining the phenotypic and expanding the molecular spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All affected individuals had developmental delays including delayed speech
      development.
    explanation: >-
      Establishes global developmental delay in all affected individuals, which
      maps to VERY_FREQUENT.
  - reference: PMID:33736665
    reference_title: "EIF3F-related neurodevelopmental disorder: refining the phenotypic and expanding the molecular spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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.
    explanation: >-
      Documents both the universality and the wide variability in degree.
- category: Nervous System
  name: Delayed Speech and Language Development
  description: >-
    Speech is the most consistently and most severely affected domain. Every
    individual in the largest cohort had speech delay, and about a quarter never
    developed speech at all. Speech delay was not recognized as part of the
    phenotype in the original report and was added by the larger follow-up
    study.
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:33736665
    reference_title: "EIF3F-related neurodevelopmental disorder: refining the phenotypic and expanding the molecular spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All affected individuals had developmental delays including delayed speech
      development.
    explanation: >-
      Speech delay in all affected individuals, mapping to VERY_FREQUENT.
  - reference: PMID:33736665
    reference_title: "EIF3F-related neurodevelopmental disorder: refining the phenotypic and expanding the molecular spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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.
    explanation: >-
      Quantifies the severity within the speech domain and records that this
      feature was newly recognized.
- category: Nervous System
  name: Intellectual Disability
  description: >-
    Intellectual disability of variable degree is present in all reported
    individuals, and is the feature the disease is named for.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:33736665
    reference_title: "EIF3F-related neurodevelopmental disorder: refining the phenotypic and expanding the molecular spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Beside variable intellectual disability (ID) in all individuals, epilepsy
      occurred in six, and behavioral problems or sensorineural hearing loss in
      three individuals, respectively
    explanation: >-
      Records intellectual disability in all individuals of the founding cohort.
- category: Nervous System
  name: Behavioral Problems
  description: >-
    Behavioural difficulties affect about half of reported individuals, and were
    substantially more frequent in the larger follow-up cohort than in the
    original report. Autism spectrum disorder has been diagnosed formally in at
    least one individual using ADOS-2 and ADI-R.
  phenotype_term:
    preferred_term: Behavioral abnormality
    term:
      id: HP:0000708
      label: Atypical behavior
  frequency: FREQUENT
  evidence:
  - reference: PMID:33736665
    reference_title: "EIF3F-related neurodevelopmental disorder: refining the phenotypic and expanding the molecular spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      About half of the affected individuals had behavioral problems, altered
      muscular tone, hearing loss, and short stature.
    explanation: >-
      Gives behavioural problems in about half of individuals, which maps to
      FREQUENT.
  - reference: PMID:39723281
    reference_title: Genetic Diagnostics and Phenotypic Profiling of a Girl With Autosomal Recessive Intellectual Developmental Disorder and Autism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The girl was diagnosed using Autism Diagnostic Observation Schedule-Second
      Edition (ADOS-2) and Autism Diagnostic Interview-Revised (ADI-R)
      instruments and met the criteria for autism spectrum disorder.
    explanation: >-
      A formal, instrument-based autism diagnosis in a homozygous carrier of the
      founder variant.
- category: Ear
  name: Sensorineural Hearing Loss
  description: >-
    Hearing loss affects about half of reported individuals and can be mild and
    bilateral. It is a specific reason to test hearing in a child presenting
    with unexplained global developmental delay and speech delay, since
    undetected hearing loss would otherwise be read as part of the delay.
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  frequency: FREQUENT
  evidence:
  - reference: PMID:33736665
    reference_title: "EIF3F-related neurodevelopmental disorder: refining the phenotypic and expanding the molecular spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      About half of the affected individuals had behavioral problems, altered
      muscular tone, hearing loss, and short stature.
    explanation: >-
      Gives hearing loss in about half of individuals, which maps to FREQUENT.
  - reference: PMID:39723281
    reference_title: Genetic Diagnostics and Phenotypic Profiling of a Girl With Autosomal Recessive Intellectual Developmental Disorder and Autism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She was diagnosed with a bilateral mild sensorineural hearing defect,
      pervasive developmental disorder, delayed psychomotor development, and
      intellectual disability.
    explanation: >-
      Documents the sensorineural character and mild degree in an individual
      case.
- category: Musculoskeletal
  name: Abnormal Muscle Tone
  description: >-
    Muscular hypotonia or hypertonia in about half of individuals. Notably it
    can go either way, which is why the phenotype is annotated as abnormal tone
    rather than as hypotonia. Muscular hypoplasia and atrophy have also been
    described, and the mouse model is primarily a muscle phenotype.
  phenotype_term:
    preferred_term: Muscular hypotonia or hypertonia
    term:
      id: HP:0003808
      label: Abnormal muscle tone
  frequency: FREQUENT
  evidence:
  - reference: PMID:33736665
    reference_title: "EIF3F-related neurodevelopmental disorder: refining the phenotypic and expanding the molecular spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      About half of the affected individuals had behavioral problems, altered
      muscular tone, hearing loss, and short stature.
    explanation: >-
      Gives altered muscular tone in about half of individuals, mapping to
      FREQUENT.
  - reference: PMID:33736665
    reference_title: "EIF3F-related neurodevelopmental disorder: refining the phenotypic and expanding the molecular spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other frequent, so far unreported symptoms observed in this study are
      muscular hypotonia and/ or hypertonia, ophthalmologic findings and
      sleeping problems.
    explanation: >-
      Records that tone can be increased or decreased, which is why a
      directionless term is used.
- category: Growth
  name: Short Stature
  description: >-
    Short stature affects about half of individuals and persists into adulthood.
    It is more common than microcephaly in this disorder, and longitudinal data
    show head growth tracking its centiles more steadily than height does, so
    the growth restriction is not simply a proportionate consequence of the
    brain phenotype.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  frequency: FREQUENT
  evidence:
  - reference: PMID:33736665
    reference_title: "EIF3F-related neurodevelopmental disorder: refining the phenotypic and expanding the molecular spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      About half of the affected individuals had behavioral problems, altered
      muscular tone, hearing loss, and short stature.
    explanation: >-
      Gives short stature in about half of individuals, mapping to FREQUENT.
  - reference: PMID:33736665
    reference_title: "EIF3F-related neurodevelopmental disorder: refining the phenotypic and expanding the molecular spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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.
    explanation: >-
      Contrasts the stature and head-size phenotypes and their different
      longitudinal behaviour.
- category: Head and Neck
  name: Microcephaly
  description: >-
    Small head circumference, of variable degree, and less frequent than short
    stature. It was newly recognized as part of the spectrum by the larger
    follow-up study.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  frequency: FREQUENT
  evidence:
  - reference: PMID:33736665
    reference_title: "EIF3F-related neurodevelopmental disorder: refining the phenotypic and expanding the molecular spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Moreover, this study suggests that microcephaly, reduced sensitivity to
      pain, cleft lip/palate, gastrointestinal symptoms and ophthalmological
      symptoms are part of the phenotypic spectrum.
    explanation: >-
      Adds microcephaly to the recognized phenotypic spectrum.
  - reference: PMID:33736665
    reference_title: "EIF3F-related neurodevelopmental disorder: refining the phenotypic and expanding the molecular spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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.
    explanation: >-
      Six of 19 individuals, 32%, which falls in the FREQUENT band (30-79%). It
      also records that head-size status is stable from birth, which is why the
      entry describes the growth phenotype as constitutional rather than
      progressive.
- category: Eye
  name: Refractive Error
  description: >-
    Hypermetropia or myopia, the commonest of the ophthalmological findings the
    larger cohort added to the phenotype. The authors are careful that
    refractive error is common in the general population too, so its presence in
    an individual carrier is weak evidence on its own; what the cohort supports
    is that ophthalmological findings belong in the phenotype and warrant a
    formal eye assessment.
  phenotype_term:
    preferred_term: Refractive error
    term:
      id: HP:0000539
      label: Abnormality of refraction
  frequency: FREQUENT
  evidence:
  - reference: PMID:33736665
    reference_title: "EIF3F-related neurodevelopmental disorder: refining the phenotypic and expanding the molecular spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other frequent, so far unreported symptoms observed in this study are
      muscular hypotonia and/ or hypertonia, ophthalmologic findings and
      sleeping problems.
    explanation: >-
      Establishes ophthalmological findings as a previously unreported part of
      the phenotype. Cited for the association; the frequency band comes from
      the counted figure below.
  - reference: PMID:33736665
    reference_title: "EIF3F-related neurodevelopmental disorder: refining the phenotypic and expanding the molecular spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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%).
    explanation: >-
      Eight of 21 individuals, 38%, which falls in the FREQUENT band (30-79%),
      and enumerates the specific findings behind the ophthalmological group.
  - reference: PMID:33736665
    reference_title: "EIF3F-related neurodevelopmental disorder: refining the phenotypic and expanding the molecular spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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.
    explanation: >-
      The authors' own caveat, graded PARTIAL because it qualifies rather than
      supports the association.
- category: Nervous System
  name: Sleep Disturbance
  description: >-
    Sleeping problems, reported alongside the ophthalmological findings as
    frequent and previously unrecognized. Worth recording because it is
    tractable: sleep is one of the few features of this disorder that can be
    managed directly.
  phenotype_term:
    preferred_term: Sleep disturbance
    term:
      id: HP:0002360
      label: Sleep disturbance
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:33736665
    reference_title: "EIF3F-related neurodevelopmental disorder: refining the phenotypic and expanding the molecular spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Five of 21 individuals (24%) had sleeping problems.
    explanation: >-
      Twenty-four percent, which falls in the OCCASIONAL band (5-29%). An
      earlier draft banded this phenotype FREQUENT on the strength of the
      authors' adjective "frequent" in a sentence covering three symptom groups
      jointly; the other two groups do reach that band and this one does not,
      so the counted figure is used instead.
  - reference: PMID:33736665
    reference_title: "EIF3F-related neurodevelopmental disorder: refining the phenotypic and expanding the molecular spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other frequent, so far unreported symptoms observed in this study are
      muscular hypotonia and/ or hypertonia, ophthalmologic findings and
      sleeping problems.
    explanation: >-
      Establishes sleeping problems as a previously unreported part of the
      phenotype. Cited for the association only; the frequency band comes from
      the counted figure above.
  - reference: PMID:39723281
    reference_title: Genetic Diagnostics and Phenotypic Profiling of a Girl With Autosomal Recessive Intellectual Developmental Disorder and Autism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neurological signs included atypical leukoencephalopathy, hypotonia,
      sensorineural hearing loss, and sleep disturbances.
    explanation: >-
      Independent case documenting sleep disturbance alongside the other
      neurological features.
- category: Nervous System
  name: Reduced Pain Sensitivity
  description: >-
    A raised pain threshold, noted in single individuals in the original report
    and confirmed in the larger cohort. It is an unusual feature to find
    alongside intellectual disability and hearing loss, and it is worth
    recording because a child who does not report pain normally is at risk of
    unrecognized injury or illness.
  phenotype_term:
    preferred_term: Pain insensitivity
    term:
      id: HP:0007021
      label: Pain insensitivity
  evidence:
  - reference: PMID:33736665
    reference_title: "EIF3F-related neurodevelopmental disorder: refining the phenotypic and expanding the molecular spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The observation of reduced pain sensitivity in this study supports an
      association with this previously described, however rare symptom
    explanation: >-
      Independent confirmation of a rare feature first noted in the founding
      cohort.
- category: Nervous System
  name: Epilepsy
  description: >-
    Seizures occur, but how often is genuinely unsettled. The founding cohort
    reported epilepsy in six of nine individuals; the larger follow-up cohort
    found it much less frequent. See the discussion attached to this entry, which
    treats the discrepancy as an ascertainment question rather than picking a
    number.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:33736665
    reference_title: "EIF3F-related neurodevelopmental disorder: refining the phenotypic and expanding the molecular spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Beside variable intellectual disability (ID) in all individuals, epilepsy
      occurred in six, and behavioral problems or sensorineural hearing loss in
      three individuals, respectively
    explanation: >-
      Records epilepsy in six of the nine individuals of the founding cohort. No
      frequency band is asserted on this phenotype because the two published
      cohorts disagree.
- category: Nervous System
  name: Developmental Regression
  description: >-
    Loss of previously acquired skills, reported at ages from 2.5 to about 30
    years in three of twenty individuals. The authors are careful that two of the
    three had confounding diagnoses, an encephalopathy with vitamin B12
    deficiency and a psychosis with meningioma, so whether regression belongs to
    this disease is unresolved. It is recorded here because it bears on prognosis
    if it is real.
  phenotype_term:
    preferred_term: Developmental regression
    term:
      id: HP:0002376
      label: Developmental regression
  evidence:
  - reference: PMID:33736665
    reference_title: "EIF3F-related neurodevelopmental disorder: refining the phenotypic and expanding the molecular spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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
    explanation: >-
      Reports the observation together with the confound that prevents
      attributing it to the disease. Graded PARTIAL for that reason.
- category: Digestive
  name: Gastrointestinal Symptoms
  description: >-
    Functional gastrointestinal problems, newly added to the spectrum by the
    larger cohort. Anal stenosis was reported in a single individual in the
    original report.
  phenotype_term:
    preferred_term: Functional gastrointestinal abnormality
    term:
      id: HP:0012719
      label: Functional abnormality of the gastrointestinal tract
  evidence:
  - reference: PMID:33736665
    reference_title: "EIF3F-related neurodevelopmental disorder: refining the phenotypic and expanding the molecular spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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.
    explanation: >-
      Names functional gastrointestinal problems among the rarer features of the
      spectrum.
- category: Head and Neck
  name: Cleft Lip or Palate
  description: >-
    An orofacial cleft, including minor forms, in a minority of individuals in
    both published cohorts. It is one of the few frank malformations in an
    otherwise non-malformative disorder.
  phenotype_term:
    preferred_term: Cleft lip or palate
    term:
      id: HP:0000202
      label: Orofacial cleft
  evidence:
  - reference: PMID:33736665
    reference_title: "EIF3F-related neurodevelopmental disorder: refining the phenotypic and expanding the molecular spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Moreover, this study suggests that microcephaly, reduced sensitivity to
      pain, cleft lip/palate, gastrointestinal symptoms and ophthalmological
      symptoms are part of the phenotypic spectrum.
    explanation: >-
      Places cleft lip and palate within the recognized phenotypic spectrum.
- category: Nervous System
  name: Leukoencephalopathy
  description: >-
    White-matter abnormality on MRI, reported in two individuals: cystic
    dilatation of the Virchow-Robin spaces distributed through the white matter
    in one, and extensive supratentorial leukodystrophy in a compound
    heterozygote. It sits uneasily with the larger cohort's finding that brain
    imaging is nonspecific, and it may be an emerging feature or may be
    incidental. The open question attached to this entry sets out why it is
    interesting and why it is not yet established.
  phenotype_term:
    preferred_term: Leukoencephalopathy
    term:
      id: HP:0002352
      label: Leukoencephalopathy
  evidence:
  - reference: PMID:39723281
    reference_title: Genetic Diagnostics and Phenotypic Profiling of a Girl With Autosomal Recessive Intellectual Developmental Disorder and Autism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      An MRI scan at 24 months of age showed randomly distributed cystic
      dilatations of the Virchow-Robin spaces bilaterally in the white matter,
      with a maximum concentration in the left parietal-temporal-occipital site,
      indicating atypical leukoencephalopathy.
    explanation: >-
      The imaging finding in a homozygous carrier of the founder variant.
  - reference: PMID:39723281
    reference_title: Genetic Diagnostics and Phenotypic Profiling of a Girl With Autosomal Recessive Intellectual Developmental Disorder and Autism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Another case study engaging MRI revealed extensive supratentorial
      leukodystrophy; however, the patient was a compound heterozygote in EIF3F
    explanation: >-
      A second individual with a white-matter abnormality, with the authors
      flagging the differing genotype.
genetic:
- name: EIF3F
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: EIF3F (eukaryotic translation initiation factor 3 subunit F)
    term:
      id: hgnc:3275
      label: EIF3F
  notes: >-
    The only gene attributed to this entity, and one of only two genes that a
    genome-wide recessive burden analysis of the Deciphering Developmental
    Disorders cohort identified as newly associated with recessive developmental
    disorders. Its allelic architecture is unusual for a recessive
    neurodevelopmental disorder: rather than many private truncating variants in
    a few families, almost every reported patient carries the same relatively
    common missense founder allele.
  evidence:
  - reference: PMID:30409806
    reference_title: Quantifying the contribution of recessive coding variation to developmental disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified two genes not previously associated with recessive
      developmental disorders, KDM5B and EIF3F, and functionally validated them
      with mouse and cellular models.
    explanation: >-
      The founding gene-disease association. Graded HUMAN_CLINICAL because the
      association itself came from a recessive burden analysis of 6,040 human
      families in the Deciphering Developmental Disorders study; the same
      sentence also reports mouse and cellular validation, but that clause
      cannot be split into a separately graded item because it shares the
      sentence, and one quote may carry only one grade.
  - reference: PMID:33736665
    reference_title: "EIF3F-related neurodevelopmental disorder: refining the phenotypic and expanding the molecular spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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.
    explanation: >-
      States what is unusual about this gene's allelic architecture relative to
      other recessive neurodevelopmental disorders.
  variants:
  - name: EIF3F c.694T>G p.(Phe232Val)
    description: >-
      The founder allele, homozygous in 21 of 22 reported individuals across
      sixteen families and present on a single shared haplotype in all fifteen
      families tested, so it arose once. It is the seventh most common EIF3F
      missense variant in gnomAD at 0.07% overall, 0.21% in Ashkenazi Jewish and
      0.12% in non-Finnish European individuals, yet no gnomAD individual is
      homozygous for it, in contrast to five of the six more frequent EIF3F
      missense variants. Functionally it lowers eIF3f protein level, translation
      rate and proliferation in gene-edited stem cells.
    gene:
      preferred_term: EIF3F
      term:
        id: hgnc:3275
        label: EIF3F
    clinical_significance: PATHOGENIC
    type: missense
    evidence:
    - reference: PMID:33736665
      reference_title: "EIF3F-related neurodevelopmental disorder: refining the phenotypic and expanding the molecular spectrum."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        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.
      explanation: >-
        Establishes the allele's dominance of the reported cohort and its
        founder origin.
    - reference: PMID:33736665
      reference_title: "EIF3F-related neurodevelopmental disorder: refining the phenotypic and expanding the molecular spectrum."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        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%)
      explanation: >-
        Gives the population frequency and its ancestry distribution.
    - reference: PMID:33736665
      reference_title: "EIF3F-related neurodevelopmental disorder: refining the phenotypic and expanding the molecular spectrum."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        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.
      explanation: >-
        The absence-of-homozygotes argument that separates this allele from the
        other common EIF3F missense variants.
  - name: EIF3F c.861dup p.(Gln288AlafsTer14)
    description: >-
      A frameshift allele found in trans with the founder missense variant in
      one individual, who was at the severe end of the spectrum for motor
      milestones, speech delay, organic problems and pre- and postnatal growth
      of body and head. This is the entity's only genotype-phenotype signal, and
      it is what supports reading the founder allele as hypomorphic rather than
      null.
    gene:
      preferred_term: EIF3F
      term:
        id: hgnc:3275
        label: EIF3F
    clinical_significance: PATHOGENIC
    type: frameshift
    evidence:
    - reference: PMID:33736665
      reference_title: "EIF3F-related neurodevelopmental disorder: refining the phenotypic and expanding the molecular spectrum."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        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.
      explanation: >-
        Characterizes the frameshift allele and its predicted consequence.
    - reference: PMID:33736665
      reference_title: "EIF3F-related neurodevelopmental disorder: refining the phenotypic and expanding the molecular spectrum."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        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.
      explanation: >-
        The genotype-phenotype observation that supports a dosage reading of the
        disease.
experimental_models:
- name: Gene-edited EIF3F p.(Phe232Val) homozygous iPSC line
  experimental_model_type: IPSC_DERIVED_MODEL
  publication: PMID:30409806
  description: >-
    The isogenic human cell model, and the source of every functional
    measurement this pathograph rests on. Induced pluripotent stem cells were
    gene-edited to carry the founder variant homozygously, and show reduced
    eIF3f protein, reduced translation rate and reduced proliferation against
    their unedited controls. It is the only human system in this entry, and it
    is the model the "no neural model" knowledge gap is measured against: it
    establishes the molecular and cellular steps in human cells while saying
    nothing about neurons, because the cells were never differentiated.
  modeled_mechanisms:
  - target: Homozygous EIF3F p.Phe232Val Lowers eIF3f Protein Abundance
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Carries the exact human disease allele in the exact zygosity of affected
      people, on an isogenic background, and reproduces the reduction in eIF3f
      protein that the molecular node asserts.
    limitations: >-
      Undifferentiated stem cells. Protein abundance is measured in a cell type
      that has nothing to do with the affected tissue, so the model establishes
      that the allele lowers eIF3f, not that it does so in a neuron.
    readouts:
    - name: eIF3f protein level in the edited line
      target: Homozygous EIF3F p.Phe232Val Lowers eIF3f Protein Abundance
      direction: DECREASED
      interpretation: >-
        Lower eIF3f protein against an isogenic control is the measurement the
        molecular node rests on, and the reason the allele is read as
        hypomorphic rather than as a change in protein activity.
      evidence:
      - reference: PMID:33736665
        reference_title: "EIF3F-related neurodevelopmental disorder: refining the phenotypic and expanding the molecular spectrum."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          In vitro studies of induced pluripotent stem cells (iPSC), gene-edited to
          be homozygous for the c.694T>G/ p.(Phe232Val) variant, demonstrated lower
          EIF3F protein levels and reduced proliferation rates
        explanation: >-
          Reports the reduced protein level in the isogenic edited line.
    evidence:
    - reference: PMID:33736665
      reference_title: "EIF3F-related neurodevelopmental disorder: refining the phenotypic and expanding the molecular spectrum."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        In vitro studies of induced pluripotent stem cells (iPSC), gene-edited to
        be homozygous for the c.694T>G/ p.(Phe232Val) variant, demonstrated lower
        EIF3F protein levels and reduced proliferation rates
      explanation: >-
        Describes the model and the reduced protein level it demonstrates.
  - target: Reduced Global Translation Initiation
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Translation rate is reduced in cells carrying the variant, in
      heterozygotes as well as homozygotes, which is the cellular step the
      pathograph turns on.
    limitations: >-
      A bulk translation-rate measurement in undifferentiated cells. It does not
      identify which transcripts lose translational efficiency, which is the
      open question the entry's knowledge gap records.
    readouts:
    - name: Bulk translation rate
      target: Reduced Global Translation Initiation
      direction: DECREASED
      interpretation: >-
        A measured fall in translation rate is what converts the protein-level
        finding into a functional claim about initiation. It is bulk, so it
        cannot say which messages are affected.
      evidence:
      - reference: PMID:33736665
        reference_title: "EIF3F-related neurodevelopmental disorder: refining the phenotypic and expanding the molecular spectrum."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          Furthermore, both heterozygous and homozygous variants reduced translation
          rates in iPSC cells
        explanation: >-
          The measured reduction in translation rate, in both zygosities.
    evidence:
    - reference: PMID:33736665
      reference_title: "EIF3F-related neurodevelopmental disorder: refining the phenotypic and expanding the molecular spectrum."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Furthermore, both heterozygous and homozygous variants reduced translation
        rates in iPSC cells
      explanation: >-
        The measured reduction in translation rate attributable to the allele.
  - target: Reduced Cell Proliferation and Growth
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Reduced proliferation rate in the edited line against its isogenic
      control.
    limitations: >-
      Proliferation of a stem cell is not the developmental growth of a brain or
      a body; the link to the organism-level phenotype remains an inference.
    readouts:
    - name: Cell proliferation rate
      target: Reduced Cell Proliferation and Growth
      direction: DECREASED
      interpretation: >-
        Slower proliferation in the edited line against its isogenic control.
        This is the closest measured proxy for the growth restriction seen in
        patients, and it is still only a proxy.
      evidence:
      - reference: PMID:33736665
        reference_title: "EIF3F-related neurodevelopmental disorder: refining the phenotypic and expanding the molecular spectrum."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          In vitro studies of induced pluripotent stem cells (iPSC), gene-edited to
          be homozygous for the c.694T>G/ p.(Phe232Val) variant, demonstrated lower
          EIF3F protein levels and reduced proliferation rates
        explanation: >-
          Reports the reduced proliferation rate in the isogenic edited line.
    evidence:
    - reference: PMID:33736665
      reference_title: "EIF3F-related neurodevelopmental disorder: refining the phenotypic and expanding the molecular spectrum."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        In vitro studies of induced pluripotent stem cells (iPSC), gene-edited to
        be homozygous for the c.694T>G/ p.(Phe232Val) variant, demonstrated lower
        EIF3F protein levels and reduced proliferation rates
      explanation: >-
        The measured reduction in proliferation rate in the isogenic model.
animal_models:
- name: eIF3f-null mouse
  species: Mouse
  genotype: eIF3f homozygous null
  publication: PMID:31026345
  description: >-
    Homozygous null embryos fail to develop and die at an early embryonic stage,
    after implantation. This is the experimental counterpart of the human
    observation that no patient with two truncating EIF3F alleles has ever been
    reported, and it is the reason the founder missense allele must retain
    residual function.
  modeled_mechanisms:
  - target: Homozygous EIF3F p.Phe232Val Lowers eIF3f Protein Abundance
    relationship: PERTURBS
    fidelity: LOW
    description: >-
      A complete null, not the human allele. It bounds the mechanism from the
      severe end rather than reproducing the disease: it shows what happens when
      eIF3f is absent altogether, which is embryonic lethality rather than a
      neurodevelopmental disorder.
    limitations: >-
      This genotype does not exist in any reported patient and produces a
      qualitatively different outcome from the human disease. It cannot be used
      to model the phenotype, only to argue that the human allele is hypomorphic.
    evidence:
    - reference: PMID:31026345
      reference_title: "eIF3f depletion impedes mouse embryonic development, reduces adult skeletal muscle mass and amplifies muscle loss during disuse."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        We showed that homozygous eIF3f knockout fail to develop and that
        eIF3f-/- embryos die at an early stage of development but after the
        pre-implantation stage.
      explanation: >-
        Records the embryonic lethality of complete eIF3f loss.
- name: eIF3f heterozygous mouse
  species: Mouse
  genotype: eIF3f heterozygous null
  publication: PMID:31026345
  description: >-
    Viable, fertile and grossly normal, but with reduced eIF3f mRNA and protein
    in every tissue examined, reduced polysome content, a lower protein
    synthesis rate, inhibited mTOR signalling, reduced lean mass and altered
    muscle cell size. It is the only in vivo demonstration that partial eIF3f
    depletion produces a measurable translational and growth deficit.
  modeled_mechanisms:
  - target: Reduced Global Translation Initiation
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Reproduces the translational deficit itself, measured as reduced polysome
      content and protein synthesis rate, and identifies mTOR inhibition as the
      link to growth.
    limitations: >-
      The measurements were made in skeletal muscle, not brain, and the mouse
      carries a null allele on one chromosome rather than the human missense
      allele on both. Heterozygous mice are behaviourally and developmentally
      normal, so this model captures the biochemistry of partial eIF3f depletion
      without reproducing the neurodevelopmental phenotype.
    evidence:
    - reference: PMID:31026345
      reference_title: "eIF3f depletion impedes mouse embryonic development, reduces adult skeletal muscle mass and amplifies muscle loss during disuse."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Skeletal muscles of heterozygous mice show a deficiency in polysome
        content, a decrease in protein synthesis rate and an inhibition of the
        mechanistic target of rapamycin (MTOR) pathway.
      explanation: >-
        The measured translational deficit and its mTOR coupling.
  - target: Reduced Cell Proliferation and Growth
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Reduced lean mass and altered muscle cell size without a change in fibre
      number, which is a growth deficit at the level of cell size rather than
      cell number.
    limitations: >-
      Body size is normal in these mice, so the growth phenotype is not the
      short stature seen in patients, and no neural tissue was examined.
    evidence:
    - reference: PMID:31026345
      reference_title: "eIF3f depletion impedes mouse embryonic development, reduces adult skeletal muscle mass and amplifies muscle loss during disuse."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Interestingly, skeletal muscles are mainly affected and display an
        altered cell size without modification of fibre number.
      explanation: >-
        Locates the growth deficit at cell size rather than cell number.
treatments:
- name: Developmental and Educational Support
  description: >-
    There is no treatment directed at the mechanism. Management is
    developmental: speech and language therapy, which matters
    disproportionately here because speech is the most consistently and severely
    affected domain, together with special education, physiotherapy and
    behavioural support. Affected children in reported cases are followed by
    neurology, otorhinolaryngology, psychology and speech therapy together.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: speech and language therapy
    term:
      id: NCIT:C159273
      label: Speech Language Therapy
  target_phenotypes:
  - preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:39723281
    reference_title: Genetic Diagnostics and Phenotypic Profiling of a Girl With Autosomal Recessive Intellectual Developmental Disorder and Autism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient is under the care of several clinical specialists, including
      neurologists, otorhinolaryngologists, psychologists, and a speech
      therapist.
    explanation: >-
      Documents the multidisciplinary care actually provided, including speech
      therapy, in a reported case.
  notes: >-
    Carries no `target_mechanisms`. Supportive developmental care does not act
    on any node in the pathograph, and no disease-modifying therapy exists.
- name: Genetic Counseling
  description: >-
    Once the biallelic EIF3F genotype is known, counselling is concrete: the
    parents are obligate carriers and each future pregnancy carries a 25%
    recurrence risk. This matters more than usual here, because the founder
    allele is comparatively common in some ancestries, so a carrier parent may
    have relatives at risk who would not otherwise be identified.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:39723281
    reference_title: Genetic Diagnostics and Phenotypic Profiling of a Girl With Autosomal Recessive Intellectual Developmental Disorder and Autism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The identification of the causal variant c.694T>G, p.(Phe232Val) in the
      EIF3F gene indicates a 25% recurrence risk in potential siblings of the
      patient, due to its autosomal recessive mode of inheritance, as explained
      by the clinical geneticist to the parents of the proband.
    explanation: >-
      States the recurrence risk and records that it was actually delivered as
      counselling in a reported family.
  notes: >-
    Carries no `target_mechanisms`. Counselling is an informational
    intervention, not a therapeutic action on a pathograph node.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    Around thirty individuals from about twenty-three families have been
    reported, across two cohorts and scattered case reports. No prevalence
    estimate exists. The carrier frequency of the founder allele is known
    (0.07% in gnomAD overall, 0.21% in Ashkenazi Jewish and 0.12% in
    non-Finnish European individuals) and is recorded on the variant, but it
    cannot be converted into a disease prevalence: the disease is far rarer than
    Hardy-Weinberg on that allele frequency would predict, and the entry does
    not speculate about why.
  evidence:
  - reference: PMID:33736665
    reference_title: "EIF3F-related neurodevelopmental disorder: refining the phenotypic and expanding the molecular spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      21 patients were homozygous and one compound heterozygous for
      c.694T>G/p.(Phe232Val) in EIF3F.
    explanation: >-
      The size of the largest reported cohort, which together with the founding
      nine-patient report is essentially the whole literature.
diagnosis:
- name: Audiological Assessment
  description: >-
    Hearing loss affects about half of individuals and can be mild, so it will
    not announce itself in a child who already has global developmental delay
    and no speech. Detecting it changes management, because uncorrected hearing
    loss compounds the speech delay that is this disorder's most prominent
    feature.
  diagnosis_term:
    preferred_term: diagnostic audiology testing
    term:
      id: NCIT:C217379
      label: Diagnostic Audiology Testing
  evidence:
  - reference: PMID:33736665
    reference_title: "EIF3F-related neurodevelopmental disorder: refining the phenotypic and expanding the molecular spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      About half of the affected individuals had behavioral problems, altered
      muscular tone, hearing loss, and short stature.
    explanation: >-
      Gives the roughly 50% frequency of hearing loss that makes routine
      audiological assessment worthwhile in a child with this diagnosis.
- name: Genome-Wide Sequencing
  description: >-
    Exome or genome sequencing is the diagnostic route, and effectively the only
    one. There is no biomarker, no distinctive facial gestalt, and brain imaging
    is nonspecific, so nothing directs a clinician to this gene before
    sequencing does. Because the causal allele is a single recurrent missense
    variant rather than an obvious truncation, it is also the kind of variant a
    filtering pipeline can discard as too common.
  evidence:
  - reference: PMID:33736665
    reference_title: "EIF3F-related neurodevelopmental disorder: refining the phenotypic and expanding the molecular spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thus, genome-wide sequencing approaches (genome or exome sequencing)
      represent an essential component of the diagnostic work-up.
    explanation: >-
      The authors' conclusion that sequencing is essential, following from the
      absence of directive clinical or imaging findings.
  - reference: PMID:33736665
    reference_title: "EIF3F-related neurodevelopmental disorder: refining the phenotypic and expanding the molecular spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Minor dysmorphic features were observed, although neither the individuals'
      facial nor general appearance were obviously distinctive.
    explanation: >-
      Records the absence of a recognizable gestalt, which is why clinical
      diagnosis is not possible.
discussions:
- discussion_id: eif3f_epilepsy_frequency_discrepancy
  kind: CONTROVERSY
  status: OPEN
  prompt: >-
    Is epilepsy a common feature of EIF3F-related neurodevelopmental disorder or
    an uncommon one? The two published cohorts disagree by a wide margin.
  attaches_to:
  - phenotypes#Epilepsy
  rationale: >-
    Epilepsy occurred in six of the nine individuals in the founding cohort,
    and was reported as substantially less frequent in the larger follow-up
    cohort of twenty-one. Both describe the same homozygous founder allele, so
    the difference is not genotypic. The likely explanation is ascertainment:
    the founding cases came out of a cohort recruited for undiagnosed
    developmental disorders and analysed by recessive burden, while the
    follow-up cohort was assembled through GeneMatcher after the gene was
    already known, which lets milder and non-epileptic cases in. If that is
    right, the true frequency is closer to the lower figure and the founding
    report overstates it, which matters for what a family is told at diagnosis.
    No frequency band is asserted on the epilepsy phenotype in this entry until
    a third independent cohort settles it.
  evidence:
  - reference: PMID:33736665
    reference_title: "EIF3F-related neurodevelopmental disorder: refining the phenotypic and expanding the molecular spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Beside variable intellectual disability (ID) in all individuals, epilepsy
      occurred in six, and behavioral problems or sensorineural hearing loss in
      three individuals, respectively
    explanation: >-
      The founding cohort's figure, six of nine.
  - reference: PMID:33736665
    reference_title: "EIF3F-related neurodevelopmental disorder: refining the phenotypic and expanding the molecular spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      hearing loss and behavioral difficulties were more common findings, and
      epilepsy less frequent in this study.
    explanation: >-
      The follow-up cohort's contradictory finding, stated by the authors as a
      direct comparison.
- discussion_id: eif3f_moonlighting_deubiquitinase_relevance
  kind: OPEN_QUESTION
  status: OPEN
  prompt: >-
    Does the disease act only through reduced translation, or does it also act
    through eIF3f's separate deubiquitinase activity on Notch?
  attaches_to:
  - pathophysiology#Reduced Global Translation Initiation
  rationale: >-
    This entry models the disease entirely as a translation-initiation defect,
    because that is what has actually been measured in cells carrying the
    disease allele. But eIF3f has a second, unrelated documented activity: it is
    an intrinsic deubiquitinase that removes monoubiquitin from the activated
    Notch receptor and is required for Notch signalling, being recruited to
    activated Notch on endocytic vesicles by Deltex1. Notch signalling is central
    to neurogenesis, so a partial loss of eIF3f could in principle produce a
    neurodevelopmental phenotype through that route rather than, or as well as,
    through translation. Nobody has tested whether the p.(Phe232Val) allele
    affects the deubiquitinase activity. The question is not idle: the two
    mechanisms predict different things, since a translational deficit should
    scale with how much protein a cell needs while a Notch deficit should be
    specific to cell-fate decisions.
  proposed_experiments:
  - experiment_id: eif3f_phe232val_dub_activity_assay
    name: Test whether p.(Phe232Val) impairs eIF3f deubiquitinase activity on Notch
    description: >-
      Assay intrinsic deubiquitinase activity and monoubiquitinated Notch1
      accumulation in cells expressing wild-type versus p.(Phe232Val) eIF3f,
      alongside a catalytically inactive mutant as the positive control for loss
      of activity, and score Notch reporter activation in a coculture assay.
      Separating a translational from a Notch effect requires the two readouts in
      the same isogenic background.
  evidence:
  - reference: PMID:21124883
    reference_title: The translation initiation factor 3f (eIF3f) exhibits a deubiquitinase activity regulating Notch activation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We show that eIF3f has an intrinsic DUB activity. Knocking down eIF3f leads
      to an accumulation of monoubiquitinated forms of activated Notch, an effect
      counteracted by murine WT eIF3f but not by a catalytically inactive mutant.
    explanation: >-
      Establishes the second, non-translational activity that this question is
      about.
  - reference: PMID:21124883
    reference_title: The translation initiation factor 3f (eIF3f) exhibits a deubiquitinase activity regulating Notch activation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Finally, catalytically inactive forms of eIF3f as well as shRNAs targeting
      eIF3f repress Notch activation in a coculture assay, showing that eIF3f is
      a new positive regulator of the Notch pathway.
    explanation: >-
      Shows that loss of eIF3f impairs Notch signalling, which is the route this
      question asks about.
- discussion_id: eif3f_white_matter_involvement
  kind: OPEN_QUESTION
  status: OPEN
  prompt: >-
    Is white-matter disease part of EIF3F-related neurodevelopmental disorder,
    and if so does it act through eIF3f's role in repeat-associated non-ATG
    translation?
  attaches_to:
  - phenotypes#Leukoencephalopathy
  rationale: >-
    Two individuals have been reported with white-matter abnormalities on MRI,
    one with cystic dilatation of the perivascular spaces and one, a compound
    heterozygote, with extensive supratentorial leukodystrophy. That is thin,
    and it sits against a larger cohort in which brain imaging was explicitly
    nonspecific and was judged not diagnostically useful. What makes it worth
    keeping open rather than dismissing is a piece of biology from an unrelated
    disease: eIF3F regulates repeat-associated non-ATG translation, and knocking
    it down lowers the steady-state level of the SCA8 polySer protein, whose
    aggregates accumulate specifically in white-matter regions that show
    demyelination and axonal degeneration. That is a real, published route by
    which an eIF3f defect could reach white matter. It is also entirely
    circumstantial here: no one has examined RAN translation, myelination or
    oligodendrocytes in a patient or in a model of the disease allele, and the
    genotype differed between the two individuals with imaging findings. Until
    someone does, the leukoencephalopathy is curated as a phenotype without a
    frequency and without a causal edge into the pathograph.
  proposed_experiments:
  - experiment_id: eif3f_oligodendrocyte_translation
    name: Test myelination and RAN-translation readouts in p.(Phe232Val) oligodendrocytes
    description: >-
      Differentiate oligodendrocytes from the gene-edited p.(Phe232Val)
      homozygous stem cell lines and isogenic controls, and compare myelin gene
      translational efficiency and RAN-protein steady-state levels. A positive
      result would convert the imaging finding from an association into a
      mechanism; a negative one would argue the two reported scans are
      incidental.
  evidence:
  - reference: PMID:30206144
    reference_title: SCA8 RAN polySer protein preferentially accumulates in white matter regions and is regulated by eIF3F.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Additionally, knockdown of the eukaryotic translation initiation factor
      eIF3F in cells reduces steady-state levels of SCA8 polySer and other RAN
      proteins.
    explanation: >-
      Establishes that eIF3F modulates RAN protein accumulation, the biology
      this question asks about.
  - reference: PMID:30206144
    reference_title: SCA8 RAN polySer protein preferentially accumulates in white matter regions and is regulated by eIF3F.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      WM regions with polySer aggregates show demyelination and axonal
      degeneration in SCA8 human and mouse brains.
    explanation: >-
      Establishes the white-matter tropism of the process eIF3F modulates. Two
      caveats are carried deliberately: the finding is in SCA8, not in this
      disease, which is why the question is open rather than answered; and the
      quoted observation spans human and mouse brains, graded here on the human
      arm because that is the claim being made about white-matter tropism in
      people.
  - reference: PMID:33736665
    reference_title: "EIF3F-related neurodevelopmental disorder: refining the phenotypic and expanding the molecular spectrum."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In concordance with the previous study, brain imaging did not reveal
      specific findings and were therefore not considered diagnostically
      indicative in EIF3F related NDD.
    explanation: >-
      The larger cohort found no consistent imaging abnormality, which argues
      against white-matter disease being a general feature.
- discussion_id: eif3f_meningioma_signal
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Two of twenty-one individuals in a cohort with a median age of 8.5 years had
    a meningioma. Is that a tumour predisposition, or coincidence in a small
    cohort?
  attaches_to:
  - pathophysiology#Reduced Cell Proliferation and Growth
  rationale: >-
    The number is small but the context makes it hard to dismiss: meningioma in
    two of twenty-one individuals whose median age at last examination was 8.5
    years is not what a paediatric cohort normally looks like. In one of the two
    it was an increased seizure frequency that led to the diagnosis, and in the
    other the tumour is named as a confound for that individual's apparent
    developmental regression, so the finding is currently visible in this entry
    only as a caveat inside the regression phenotype rather than as a question
    in its own right. The authors went looking for a mechanism and did not find
    one: somatic EIF3F variants appear in 0.9% of nearly 39,000 COSMIC samples
    and in none of 130 meningiomas. That negative is worth curating explicitly,
    because it is the kind of result that does not get published twice and would
    otherwise have to be re-derived by the next person who notices the two
    cases. This is recorded as a knowledge gap and NOT as a phenotype and NOT as
    a surveillance recommendation: two cases with an explicit negative
    tumour-genetics check do not support either.
  proposed_experiments:
  - experiment_id: eif3f_tumour_incidence_in_carrier_cohort
    name: Ascertain tumour incidence in a larger EIF3F biallelic cohort
    description: >-
      Follow the reported and future biallelic carriers longitudinally and
      compare central nervous system tumour incidence against age-matched
      expectation. Two cases in twenty-one cannot distinguish a real
      predisposition from ascertainment; a defined denominator with follow-up
      time can. A negative would retire the question; a positive would change
      surveillance, which is why it should not be inferred either way from the
      present data.
  evidence:
  - reference: PMID:33736665
    reference_title: "EIF3F-related neurodevelopmental disorder: refining the phenotypic and expanding the molecular spectrum."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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
    explanation: >-
      The authors' own negative check against COSMIC, which is the main reason
      this is curated as an open gap rather than as a phenotype.
  - reference: PMID:33736665
    reference_title: "EIF3F-related neurodevelopmental disorder: refining the phenotypic and expanding the molecular spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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.
    explanation: >-
      Records the meningioma cases as the authors present them, as confounds for
      other features rather than as an asserted part of the phenotype.
- discussion_id: eif3f_no_neural_model
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Why does a general reduction in translation initiation produce this
    particular phenotype, with speech affected in everyone and hearing,
    stature and pain sensation affected in only some?
  attaches_to:
  - pathophysiology#Impaired Brain Development and Somatic Growth
  rationale: >-
    Every functional measurement in this disease has been made outside the
    nervous system. The cellular work used undifferentiated induced pluripotent
    stem cells; the in vivo work used mouse skeletal muscle in an animal
    carrying a null allele on one chromosome, not the human missense allele on
    both. There is no neural model of the disease allele at all, and brain
    imaging in patients is explicitly nonspecific, so there is no structural
    finding to reason from either. The step from "translation is slower" to
    "speech does not develop" is therefore an inference. It is a reasonable one,
    since eIF3 loads a defined subset of mRNAs rather than acting uniformly, but
    which of those messages matter in which neural cell type at which
    developmental stage is entirely unknown.
  proposed_experiments:
  - experiment_id: eif3f_neural_differentiation_translatome
    name: Profile the translatome of patient-allele neurons through differentiation
    description: >-
      Differentiate cortical neurons from the existing gene-edited p.(Phe232Val)
      homozygous stem cell lines and their isogenic controls, and compare
      ribosome profiling across differentiation stages to identify which
      transcripts lose translational efficiency in neural lineage cells
      specifically, rather than in stem cells.
  evidence:
  - reference: PMID:33736665
    reference_title: "EIF3F-related neurodevelopmental disorder: refining the phenotypic and expanding the molecular spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In concordance with the previous study, brain imaging did not reveal
      specific findings and were therefore not considered diagnostically
      indicative in EIF3F related NDD.
    explanation: >-
      Records the absence of any structural neural correlate to reason from.
notes: >-
  Entry-type decision: DISEASE. MONDO:0032662 is a leaf with no descendants and
  a single causal gene (hgnc:3275 EIF3F); it maps to OMIM 618295. The MONDO
  parent (MONDO:0019502, autosomal recessive non-syndromic intellectual
  disability) is recorded as a `skos:broadMatch` cross-reference rather than
  adopted, because the clinical literature consistently describes this entity as
  syndromic.


  NAMED ENTITY CONFUSION: the falcon deep-research report for this disease was
  discarded and is deliberately NOT committed. `just preflight-dr` against
  MONDO:0032662 returned FAIL: the expected gene EIF3F was mentioned zero times
  while PPP1R21 was mentioned 48 times. PPP1R21 is the gene for a different
  member of the same numbered series (intellectual developmental disorder,
  autosomal recessive 59), which is exactly the numbered-series aliasing that
  the NEC risk classes describe. The report's own citation validation was clean
  (4/4 references resolved, confabulation rate 0.0), which is the point: every
  citation in a wrong-entity report resolves, and only the gene-frequency check
  catches it. Nothing in this entry derives from that report. All references
  here were located independently through PubMed E-utilities and fetched with
  `just fetch-reference`, and a second deep-research run was performed with the
  `claude_code` provider, which returned PASS on the same check (EIF3F mentioned
  64 times, report OMIM 618295 matching the MONDO xref) and independently
  flagged the same PPP1R21 confusion hazard in its own text. That report is
  committed; its `needs_review: true` flag is due to two malformed DOI
  identifiers in which markdown link syntax leaked into the identifier string,
  and nothing was curated from either.


  Frequency bands are asserted only where the source gives one. Global
  developmental delay, speech delay and intellectual disability are stated as
  present in all affected individuals (VERY_FREQUENT); behavioural problems,
  hearing loss, altered muscle tone and short stature are stated as present in
  about half (FREQUENT). Microcephaly, reduced pain sensitivity, cleft
  lip/palate, gastrointestinal symptoms, developmental regression and epilepsy
  carry NO frequency. Epilepsy in particular is left unbanded on purpose: the
  two published cohorts disagree by a wide margin and a CONTROVERSY discussion
  records why.


  The reported carrier frequency of the founder allele is curated on the variant
  but deliberately not converted into a disease prevalence. The disease is far
  rarer than Hardy-Weinberg on a 0.07% allele frequency would predict, and this
  entry does not speculate about the reason.


  Snippet-quoting note: this paper interleaves numeric citation markers such as
  `[9]` and `[6]` inside the sentences worth quoting. Those markers are stripped
  from a snippet before matching but not from the cached text, so several quotes
  here are trimmed to bracket-free spans rather than transcribed with the marker.


  GeneReviews has no chapter for this entity and Orphanet has no matching
  concept, so neither a GeneReviews baseline nor an ORPHA reference is cited.
  `just refresh-orphadata` is currently failing on a drifted sha256 in this
  repository and was not run.


  PMID:35743796 was fetched during literature search and deliberately not
  curated. It reports a heterozygous EIF3F variant as one of seven
  moderate-effect alleles in a proposed oligogenic model of intellectual
  disability, which is a different claim from biallelic EIF3F causing MRT67;
  citing it here would misrepresent a polygenic hypothesis as a case of this
  Mendelian disease.
datasets: []
📚

References & Deep Research

References

6
PMID:30409806
Quantifying the contribution of recessive coding variation to developmental disorders.
No top-level findings curated for this source.
PMID:33736665
EIF3F-related neurodevelopmental disorder: refining the phenotypic and expanding the molecular spectrum.
No top-level findings curated for this source.
PMID:39723281
Genetic Diagnostics and Phenotypic Profiling of a Girl With Autosomal Recessive Intellectual Developmental Disorder and Autism.
No top-level findings curated for this source.
PMID:31026345
eIF3f depletion impedes mouse embryonic development, reduces adult skeletal muscle mass and amplifies muscle loss during disuse.
No top-level findings curated for this source.
PMID:21124883
The translation initiation factor 3f (eIF3f) exhibits a deubiquitinase activity regulating Notch activation.
No top-level findings curated for this source.
PMID:30206144
SCA8 RAN polySer protein preferentially accumulates in white matter regions and is regulated by eIF3F.
No top-level findings curated for this source.

Deep Research

1
Claude Code ▸
1. Disease Information
claude-fable-5, claude-haiku-4-5-20251001, claude-opus-5 22 citations 2026-08-27T16:59:17.820996

1. Disease Information

Overview

MRT67 is a rare, syndromic, autosomal recessive neurodevelopmental disorder caused by biallelic variants in EIF3F, which encodes the f subunit of eukaryotic translation initiation factor 3 (eIF3) — the largest and most structurally complex of the eukaryotic initiation factors. Its mechanistic logic is unusual among Mendelian neurodevelopmental disorders: the primary lesion is a partial, quantitative failure of general protein synthesis, not the disruption of a neuron-specific protein or a discrete signalling pathway.

The clinical core is global developmental delay with prominent speech delay in essentially every reported individual, followed by a variable syndromic tail: behavioural problems, sensorineural hearing loss, altered muscle tone, short stature, microcephaly, ophthalmological findings, reduced pain sensitivity, sleep disturbance, and occasional orofacial clefting.

Key identifiers

Resource Identifier
OMIM (phenotype) #618295 — INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL RECESSIVE 67; MRT67
MONDO MONDO:0032662
MedGen UID 1648350, CUI C4749019
Gene (HGNC) EIF3F — dismech CURIE form hgnc:3275
Cytoband 11p15.4
OMIM phenotypic series PS249500 (autosomal recessive intellectual developmental disorders)
Orphanet No dedicated ORPHA entry was located in this session. Orphanet's gene-based lookup for EIF3F did not resolve. Treat as "not available / needs verification" rather than absent.
ICD-10 / ICD-11 No specific code. Coded generically (ICD-10 F70–F79 intellectual disability; ICD-11 6A00).
MeSH No specific descriptor; indexed under Intellectual Disability + Eukaryotic Initiation Factor-3 (see MeSH keywords on PMID:33736665).

Gene-level OMIM number for EIF3F was not verified in this session — do not assert one without checking.

Synonyms

  • MRT67
  • Mental retardation, autosomal recessive 67 (legacy OMIM/MedGen title)
  • EIF3F-related neurodevelopmental disorder
  • EIF3F-related syndrome (Simons Searchlight usage)
  • EIF3F deficiency

Nature of the evidence base

Aggregated disease-level, not EHR-derived. The entire published literature is small-n clinical genetics: one exome-wide burden analysis with case follow-up, one multi-centre GeneMatcher-assembled cohort, and scattered single-case reports. There is no registry, no natural-history study, and no EHR-phenotyped cohort. Simons Searchlight states plainly that "the information available about EIF3F is limited" and that "As of 2025, about 31 people with EIF3F-related syndrome have been described in medical research" (Simons Searchlight).

2. Etiology

Disease causal factors

Purely monogenic and genetic. Biallelic EIF3F variants are necessary and, on current evidence, sufficient. No environmental, infectious, or toxic contribution has been proposed or investigated.

The founding association came from a genome-wide recessive burden analysis of the Deciphering Developmental Disorders study (Martin et al., Science 2018; PMID:30409806):

"We identified two genes not previously associated with recessive developmental disorders, KDM5B and EIF3F, and functionally validated them with mouse and cellular models."

That study reported nine affected individuals from seven non-consanguineous families of European ancestry, all homozygous for the same missense allele (OMIM 618295).

Genetic risk factors

The disorder is driven by a single, dominant-in-frequency founder allele: NM_003754.3:c.694T>G, p.(Phe232Val). Hüffmeier 2021 (PMID:33736665):

"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."

Only one additional pathogenic allele has been published — the frameshift c.861dup, p.(Gln288AlafsTer14), seen in trans with the founder missense in a single compound heterozygote.

A key structural feature of this disease's genetics: almost all recessive NDDs are caused by many private, mostly truncating variants across a handful of families. MRT67 inverts that. Hüffmeier 2021:

"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."

The authors explicitly analogise to CFTR p.Phe508del, HFE, and GJB2 founder alleles.

Modifier genes

None established. One report (Huang 2022, PMID:35743796) describes a heterozygous EIF3F p.P4S variant as one of seven inherited rare variants in an oligogenic model of ID/ASD/psychosis in a Taiwanese proband. This is not MRT67 — the individual was heterozygous, the variant is not the founder allele, and the authors propose only cumulative moderate effects. Cite it, if at all, as a hypothesis about heterozygote burden, never as MRT67 evidence.

Environmental risk factors, protective factors, gene–environment interaction

None described. No CTD, GWAS, or exposure data exist for this entity. This is not a gap that could plausibly be filled by existing databases — it reflects the disorder's fully penetrant monogenic architecture and tiny cohort. Record explicitly as not applicable / not studied rather than leaving blank.

One indirect gene–environment observation exists in the mouse, and it is mechanistically interesting: Eif3f heterozygotes are normal at baseline but decompensate under a physiological stressor. Docquier 2019 (PMID:31026345):

"We found that eIF3f partial depletion amplifies muscle atrophy compared to wild-type mice."

That is a gene-by-disuse interaction in muscle, not a disease risk factor in humans, but it is the closest thing in the literature.

3. Phenotypes

The definitive frequency table is Hüffmeier 2021 Table 2 (PMID:33736665), which reports the new cohort (n=21 evaluable) alongside the original Martin cohort (n=9). Where the two disagree — most sharply on epilepsy — the disagreement itself is the finding.

Core, near-universal features

Phenotype HPO term Frequency Source
Global developmental delay HP:0001263 Global developmental delay 21/21 (100%) and 9/9 (100%) PMID:33736665
Delayed speech and language development HP:0000750 21/21 (100%) PMID:33736665
Intellectual disability HP:0001249 all individuals, variable degree PMID:30409806, PMID:33736665
Absent speech HP:0001344 5/21 (24%) PMID:33736665

"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." — PMID:33736665 (abstract)

Motor milestone detail: delayed unassisted sitting (>10 months) in 4/12 (33%); delayed independent walking (≥18 months) in 14/20 (70%). Severity is genuinely 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."

Frequent features (~30–60%)

Phenotype HPO term Frequency (Hüffmeier) Frequency (Martin)
Behavioral abnormality HP:0000708 Atypical behavior 12/21 (57%) 3/9 (33%)
Sensorineural hearing impairment HP:0000407 12/21 (57%) 3/9 (33%)
Abnormal muscle tone (hypo- or hyper-) HP:0003808 10/21 (48%) not reported
Short stature (at last exam) HP:0004322 8/20 (40%) 1/4 (25%)
Microcephaly at birth HP:0011451 Congenital microcephaly 4/10 (40%) 0/1
Microcephaly (later) HP:0000252 6/19 (32%) 1/8 (13%)
Hypermetropia / myopia HP:0000540 / HP:0000545 8/21 (38%) —
Nonspecific brain MRI findings HP:0012443 Abnormal brain morphology 5/13 (38%) 3/7 (43%)
Posteriorly rotated ears HP:0000358 7/20 (35%) —
Deep-set / encased nails HP:0001800 Abnormal fingernail morphology 6/20 (30%) —

Behavioural detail: "obsessive compulsory disorder, social problems, anxiety, autism, hyperactivity, attention deficit, aggressivity or pica." Autism has been formally instrumented in at least one case (Lakatosova 2024, PMID:39723281): "The girl was diagnosed using Autism Diagnostic Observation Schedule-Second Edition (ADOS-2) and Autism Diagnostic Interview-Revised (ADI-R) instruments and met the criteria for autism spectrum disorder."

Occasional features (10–25%)

Phenotype HPO term Frequency
Sleep disturbance HP:0002360 5/21 (24%)
Gastrointestinal symptoms (GERD, dysphagia, alternating constipation/diarrhoea, neonatal feeding problems) HP:0012719 Functional abnormality of the GI tract 5/21 (24%)
Short hands/feet, slender digits HP:0001156 / HP:0001773 5/20 (25%)
Nasal findings (tubular nose, pointed tip, anteverted nares) HP:0000429 Abnormal nose morphology 5/20 (25%)
Developmental regression HP:0002376 3/21 (14%)
Strabismus HP:0000486 3/21 (14%)
Epilepsy / seizures HP:0001250 3/20 (15%) vs 6/7–6/9 (86%/67%) — see below
Flat feet HP:0001763 Pes planus 3/20 (15%)
5th digit anomaly (shortness, clinodactyly) HP:0004209 Clinodactyly of the 5th finger 3/20 (15%)
Cleft lip/palate (incl. minor forms) HP:0000202 Orofacial cleft 2/20 (10%)
Meningioma HP:0100009 2/21 (10%)
Premature delivery HP:0001622 2/20 (10%)

Rare / single-case features

Reduced pain sensitivity (HP:0007021 Pain insensitivity — 2 individuals, confirming a feature first seen by Martin); psychosis (HP:0000709, 1/21); encephalopathy (1/21, with concomitant B12 deficiency); nystagmus (HP:0000639, 1/21, 5%); coloboma (HP:0000589, 1/21, 5%); tetralogy of Fallot (HP:0001636, 1); congenital lobar emphysema; anal stenosis (HP:0002025); cryptorchidism (HP:0000028); nasal fistula; muscle atrophy (HP:0003202); drop attacks; arachnoid cyst (HP:0100702); prominent perivascular spaces; mild tonsillar ectopia (HP:0002707 Abnormal cerebellum morphology).

Overgrowth/macrocephaly — a phenotype-expanding outlier. An ACMG 2024 abstract (Shad, Mbonu, Aguiar, Hassan, Repnikova; Genetics in Medicine Open P319, doi:10.1016/j.gimo.2024.101213) reports two male siblings homozygous for c.694T>G, one with typical features and the older brother with additional overgrowth and macrocephaly — the opposite direction from the cohort's microcephaly/short stature. This is a conference abstract, not peer-reviewed full text; grade accordingly.

Neuroimaging in a single detailed case (Lakatosova 2024, PMID:39723281): "An MRI scan at 24 months of age showed randomly distributed cystic dilatations of the Virchow-Robin spaces bilaterally in the white matter, with a maximum concentration in the left parietal-temporal-occipital site, indicating atypical leukoencephalopathy. The findings also included an asymmetrically narrowed right internal auditory canal and cisterna magna." Suggested terms: HP:0002352 Leukoencephalopathy, HP:0002185 Neuronal loss in central nervous system (no — prefer HP:0012705 Abnormal cerebral white matter morphology), HP:0002700 Enlarged cisterna magna.

Phenotype characteristics

  • Onset: congenital to infantile. Delays are apparent in the first two years. Pregnancy and delivery are largely uneventful (1/21 oligohydramnios; 1/19 suspected perinatal asphyxia).
  • Severity: highly variable within an essentially uniform genotype — from near-normal motor milestones with usable speech to non-ambulatory and non-verbal.
  • Progression: predominantly static/developmental. Regression is reported but confounded (see §11).
  • Dysmorphology: subtle and not gestalt-recognisable. Hüffmeier 2021: "Dysmorphic features were generally subtle and non-specific and were not considered a recognizable facial gestalt." This matters clinically — you will not diagnose this on the face.

Quality-of-life impact

No EQ-5D, SF-36, or PROMIS data exist. The one instrumented case (PMID:39723281) provides the only structured functional data in the literature: Vineland-3 showed "a deeply below-average adaptive behavior profile in all subdomains of the test, including communication, daily living skills, socialization, and motor skills"; BRIEF-P showed clinically elevated Inhibit, Working Memory, and Plan/Organize scales; the Children's Sleep Habits Questionnaire score was 48 against a cutoff of 41, with bedtime resistance and night waking most pronounced. The child had urinary and stool incontinence at 5y8m and a 10-word vocabulary.

4. Genetic / Molecular Information

Causal gene

EIF3F (eukaryotic translation initiation factor 3 subunit F), 11p15.4. HGNC CURIE in dismech form: hgnc:3275. Formerly EIF3S5. Encodes eIF3f, one of 13 subunits (eIF3a–m) of the eIF3 complex.

Pathogenic variants

1. NM_003754.3:c.694T>G, p.(Phe232Val) — the founder allele

Attribute Value
dbSNP rs141976414
GRCh38 chr11:7,994,466
GRCh37 chr11:8,016,013
Type Missense (single nucleotide variant)
ClinVar RCV000754608, germline classification Pathogenic/Likely pathogenic, 2-star review status (multiple submitters, no conflicts), 23 submissions (14 pathogenic / 7 likely pathogenic / 1 unclassified)
Origin Germline
Functional consequence Hypomorph / partial loss of function

Population frequency, per Hüffmeier 2021:

"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%)"

"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."

Independent ClinVar-submitter figures agree: allele frequency 0.0007 in 251,224 control chromosomes (gnomAD v2.1.1 total 0.000711), 0.0012 in non-Finnish Europeans, no homozygotes. The absence of homozygotes despite substantial heterozygote frequency is the population-genetic argument that carries most of the pathogenicity weight — five of the six more common EIF3F missense variants do have gnomAD homozygotes.

Functional characterisation (ClinVar interpretation summary): the variant "results in reduced protein expression, approximately 70% of wildtype, and was associated with reduced protein translation and cellular proliferation rates." Phe232 is evolutionarily conserved and predicted to stabilise the protein (PMID:39723281).

2. c.861dup, p.(Gln288AlafsTer14) — frameshift

Found in trans with the founder allele in one individual (P3 in Hüffmeier 2021). Absent from gnomAD. "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."

Constraint and the null-lethality argument

"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." — PMID:33736665

This is the single most important mechanistic inference in the disease, and it is triangulated three ways: (i) pLI 0.97 / o/e 0.07 constraint; (ii) no reported patient with two truncating alleles; (iii) mouse Eif3f-null embryonic lethality (§15). The founder allele is best read as a hypomorph that survives where a null would not.

Genotype–phenotype correlation

Exactly one signal, from the single compound heterozygote:

"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." — PMID:33736665

That individual did not walk independently at age 5 (crawled), had no speech, tetralogy of Fallot, GI problems, IUGR, and was both short and microcephalic. This is a dosage disease: missense/missense < missense/null < null/null (lethal).

Other missense variants are of unknown consequence. Hüffmeier 2021 is explicit: "As only the identical missense variant in EIF3F has been functionally characterized … it remains speculative whether other missense variants might have comparable effects." Do not extrapolate pathogenicity from p.Phe232Val to novel EIF3F missense variants without functional work.

Modifier genes, epigenetics, chromosomal abnormalities

  • Modifier genes: none identified.
  • Epigenetics: no methylation episignature has been reported for EIF3F. Nothing in ENCODE/Roadmap/DiseaseMeth is disease-specific. Record as not studied.
  • Chromosomal abnormalities: not a mechanism. CMA is characteristically negative in these patients — both the Lakatosova case ("Microarray analysis of CNVs (aCGH) showed negative findings") and routine workups. This is diagnostically important (§10).
  • Somatic variation: MRT67 is germline. Somatic EIF3F variants were surveyed in COSMIC for an unrelated reason (the meningioma question, §11): "somatic EIF3F variants have been detected in 0.9% of 38,579 samples (n = 353) and did not include 130 meningioma samples."

5. Environmental Information

Not applicable. No environmental factors, lifestyle factors, or infectious agents are implicated in MRT67. Searching CTD/TOXNET/NHANES for this entity is not a productive use of curation effort. Any dismech environmental: block should either be absent or carry a notes: line recording that the search was made and returned nothing, so a later curator does not repeat it.

6. Mechanism / Pathophysiology

The causal chain

EIF3F c.694T>G p.(Phe232Val) homozygous  [MOLECULAR]
↓  reduced eIF3f protein (~70% of wild-type)
Reduced eIF3f abundance in the eIF3 complex  [MOLECULAR]
↓
Reduced global translation initiation rate  [CELLULAR]
   (↓ polysome content, ↓ protein synthesis rate, ↓ mTOR pathway activation)
↓
Reduced cell proliferation and cell growth  [CELLULAR]
↓
Impaired brain development and somatic growth  [ORGANISM]
   → GDD, ID, speech delay, microcephaly, short stature, altered muscle tone

Upstream is the variant → protein-abundance step (measured). Midstream is the translation → proliferation step (measured in iPSCs and mouse muscle). Downstream is the step to clinical phenotype, which is inferred, not measured — no neural model of the disease allele has been published.

Molecular pathway: translation initiation

eIF3 stimulates multiple steps of initiation — 43S pre-initiation complex assembly, mRNA recruitment, prevention of premature 60S joining, AUG scanning (Moretti 2010, PMID:21124883). Crucially, eIF3 is not a uniform amplifier:

"EIF3F encodes an essential subunit of the largest eukaryotic translation initiation factor eIF3 which binds to a highly specific group of mRNAs involved in cell proliferation and growth, including cell cycle control, differentiation and apoptosis" — PMID:33736665

That selectivity is the best available answer to the obvious objection — why does a housekeeping translation factor produce a selective neurodevelopmental phenotype rather than uniform cellular failure?

GO terms: - GO:0003743 translation initiation factor activity (modifier: DECREASED) - GO:0006413 translational initiation (DECREASED) - GO:0005852 eukaryotic translation initiation factor 3 complex (cellular component) - GO:0002181 cytoplasmic translation (DECREASED) - GO:0008283 cell population proliferation (DECREASED) - GO:0031929 TOR signaling (DECREASED) - GO:0007420 brain development (ABNORMAL)

Reactome: R-HSA-72613 (Eukaryotic Translation Initiation), R-HSA-72649 (Translation initiation complex formation). KEGG: hsa03013 (Nucleocytoplasmic transport/RNA transport).

The mTORC1 coupling — how a translation defect becomes a growth defect

This is the best-characterised non-canonical arm and it is where the mouse data land. eIF3f is a scaffold connecting mTORC1 and S6K1:

  • Under nutrient-rich conditions, the mTOR/raptor complex binds the TOS motif of eIF3f and phosphorylates/activates S6K1; active S6K1 is released from eIF3, increasing protein synthesis (Csibi et al., PLoS ONE 2010, doi:10.1371/journal.pone.0008994).
  • Conversely, the E3 ligase MAFbx/atrogin-1 physically interacts with the Mov34 domain of eIF3f via its leucine-charged domain, polyubiquitinating it for proteasomal degradation during muscle wasting. An eIF3f mutant insensitive to MAFbx polyubiquitination maintains S6K1/rpS6 phosphorylation.
  • eIF3f thus sits at the atrophy/hypertrophy antagonism node in skeletal muscle (reviewed PMID:23769948).

In vivo confirmation, Docquier 2019 (PMID:31026345):

"Skeletal muscles of heterozygous mice show a deficiency in polysome content, a decrease in protein synthesis rate and an inhibition of the mechanistic target of rapamycin (MTOR) pathway."

Hüffmeier 2021 draws the link explicitly: "partial depletion of murine eIF3f amplified muscle atrophy compared to wild-type mice and reduced the MTOR pathway activation."

This is mechanistically load-bearing for the human phenotype because it supplies a route from reduced eIF3f → reduced mTORC1 signalling → reduced growth, which is otherwise a hand-wave. GO: GO:0031929 TOR signaling; GO:0038202 TORC1 signaling.

Moonlighting function 1: deubiquitinase activity on Notch

eIF3f carries an MPN/JAMM domain and has intrinsic DUB activity (Moretti 2010, PMID:21124883):

"An immunofluorescence-based screening of an shRNA library allowed us to identify eIF3f, previously known as one of the subunits of the translation initiation factor eIF3, as a DUB targeting the activated Notch receptor. We show that eIF3f has an intrinsic DUB activity."

"we also show that eIF3f is recruited to activated Notch on endocytic vesicles by the putative E3 ubiquitin ligase Deltex1, which serves as a bridging factor … eIF3f is a new positive regulator of the Notch pathway."

Curation caution: this is elegant in vitro cell-biology (U2OS, HEK293T, HeLa; shRNA knockdown; coculture reporter assays) and it has never been connected to MRT67 patient biology. Notch signalling is central to neurodevelopment, so the temptation to draw a causal edge from p.Phe232Val → impaired Notch → neurodevelopmental phenotype is strong — and unsupported. Phe232 has not been shown to affect DUB activity. If curated at all, this belongs in a discussions: block as a KNOWLEDGE_GAP with a proposed experiment, not as a pathophysiology edge. GO: GO:0004843 cysteine-type deubiquitinase activity; GO:0007219 Notch signaling pathway.

Moonlighting function 2: white matter and RAN translation

eIF3f regulates repeat-associated non-ATG (RAN) translation in spinocerebellar ataxia type 8 (Ayhan et al., EMBO J 2018, PMID:30206144): knockdown of eIF3F reduces steady-state levels of SCA8 polySer and other RAN proteins, and the polySer aggregates accumulate preferentially in white matter regions showing demyelination and axonal degeneration.

Lakatosova 2024 (PMID:39723281) uses this to interpret their patient's leukoencephalopathy:

"EIF3F was shown to be overexpressed in white matter compared to gray matter in various brain regions [19,20], suggesting its importance in myelination and white matter homeostasis, including regulation of oligodendrocyte functions."

Grade this carefully. It is a single-case imaging finding plus an inference from a different disease's biology. Note also that the Human Protein Atlas reports EIF3F as low tissue specificity (tau 0.21, "detected in all"), clustering with ribosomal/translation genes and showing no white-matter or neuron-enriched pattern (HPA ENSG00000175390). The white-matter-enrichment claim and the HPA data are in tension. Curate as a hypothesis with the tension recorded, not as an established mechanism.

Cell types, tissues, subcellular compartments

  • Subcellular: cytoplasm (GO:0005737), eIF3 complex (GO:0005852), cytosolic ribosome-associated (GO:0022626), and — for the Notch DUB function — early endosome (GO:0005769).
  • Cell types: no disease-specific cell type is established. Speculative/inferred candidates only: CL:0000540 neuron, CL:0000128 oligodendrocyte (from the white-matter hypothesis), CL:0000187 muscle cell (from mouse), CL:0002322 embryonic stem cell (the model system actually used).
  • Do not manufacture a cell-type binding. The measured cellular work was done in undifferentiated iPSCs and mouse skeletal muscle. Neither is the affected tissue in patients.

Molecular profiling

  • Transcriptomics: no patient RNA-seq published. No GEO series specific to MRT67 was identified.
  • Proteomics / metabolomics / lipidomics: none.
  • Single-cell / spatial: none.
  • Functional genomics: EIF3F is a broadly essential gene in DepMap-class screens (consistent with pLI 0.97 and mouse null lethality), but no MRT67-specific screen exists.

This is a real and citable gap. No omics dataset exists for this disorder in any repository. Any datasets: block would have to be gene-level or model-level, and per dismech policy would need just verify-datasets plus manual relevance triage — searching EIF3F in GEO will return translation-biology and cancer datasets that are not about this disease (the classic Named Entity Confusion trap).

7. Anatomical Structures Affected

Organ level

Level Structure UBERON
Primary Brain / central nervous system UBERON:0000955 brain; UBERON:0001017 CNS
Primary Cerebral white matter (single case) UBERON:0002316 white matter
Primary Inner ear / cochlea (sensorineural HL) UBERON:0001846 internal ear; UBERON:0001844 cochlea
Secondary Skeletal muscle (tone, hypoplasia, atrophy) UBERON:0001134 skeletal muscle tissue
Secondary Eye (refractive error, strabismus, nystagmus, coloboma) UBERON:0000970 eye
Secondary Gastrointestinal tract (functional) UBERON:0001555 digestive tract
Rare Lip and palate UBERON:0001833 lip; UBERON:0001716 secondary palate
Rare Heart (tetralogy of Fallot, 1 case) UBERON:0000948 heart
Rare Lung (congenital lobar emphysema, 1 case) UBERON:0002048 lung
Rare Testis (cryptorchidism) UBERON:0000473 testis

Body systems: nervous, sensory (auditory, visual), musculoskeletal, digestive; growth as a cross-cutting axis.

Lateralization

Predominantly bilateral and symmetric where laterality is reported (bilateral mild SNHL; bilateral Virchow-Robin space dilatation). Two asymmetric findings in the single detailed imaging case: right internal auditory canal stenosis, and left parieto-temporo-occipital predominance of the perivascular changes (PMID:39723281). One unilateral single palmar crease was noted in four individuals.

The negative finding is important

"In concordance with the previous study, brain imaging did not reveal specific findings and were therefore not considered diagnostically indicative in EIF3F related NDD." — PMID:33736665

There is no structural lesion to point at. Nonspecific findings in ~38–43% across both cohorts. This is consistent with a diffuse quantitative translation deficit rather than a focal developmental malformation, and it is why the disease is diagnosed by sequencing, not imaging.

8. Temporal Development

Onset

  • Congenital to early infantile. Developmental delay is the presenting feature. Microcephaly and short stature may be present at birth (4/10 and 3/15 respectively) or acquired later.
  • Onset pattern: insidious, developmental — not acute.
  • Pregnancy/delivery largely uneventful; 2/20 premature.

Progression

  • Predominantly static. No defined disease stages. Most affected individuals show delay rather than deterioration.
  • Growth trajectory is informative: head circumference tracks its centiles more steadily than height does. Hüffmeier 2021: "longitudinal data indicated that head growth had a more constant course along the centiles than height." Four of seven individuals with short stature at last exam had normal length at birth — so the stature phenotype is at least partly postnatally acquired, not purely prenatal.
  • Duration: chronic, lifelong.
  • Cohort maturity caveat: mean age at last exam 12.1 ± 9.6 years (median 8.5); only four individuals were over 18. The natural history beyond young adulthood is essentially unknown.

Regression — an unresolved question

"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" — PMID:33736665

The confounds were vitamin B12-deficiency encephalopathy in one and meningioma-associated psychosis in another. The authors decline to resolve it: "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." Curate as supports: PARTIAL with the confound stated.

Critical periods

Not defined in humans. In mouse, the critical window for complete loss is peri-implantation: Eif3f-/- embryos "die at an early stage of development but after the pre-implantation stage" (PMID:31026345). No intervention window has been identified in patients.

9. Inheritance and Population

Inheritance

Autosomal recessive (HP:0000007). All tested parents were heterozygous carriers and essentially unaffected:

"All tested parents were heterozygous carriers of the variant (parents of pedigree 16 (P16) were not available for testing)." — PMID:33736665

"Heterozygous carriers were mainly asymptomatic. One father was reported to have epilepsy, and one mother migraines. Those overlapping symptoms are likely unrelated and of different etiology." — PMID:33736665

Recurrence risk for siblings: 25%, as counselled in the Slovak case (PMID:39723281).

  • Penetrance: appears complete for the biallelic genotype in ascertained families. No unaffected homozygote has been reported — though ascertainment bias is total here, and the absence of gnomAD homozygotes is consistent with either full penetrance or embryonic/early attrition.
  • Expressivity: markedly variable, with an essentially uniform genotype. This is the disease's defining epidemiological puzzle and no modifier has been found.
  • Anticipation: not applicable (not a repeat expansion).
  • Germline mosaicism: not reported.

Consanguinity — and why it matters here

Parental consanguinity in only 1/17 (6%) of families in Hüffmeier 2021 and 0/7 in Martin 2018. For a recessive NDD, that is remarkable, and it is a direct consequence of the founder allele being common enough that two unrelated carriers meet by chance. Practical implication: absence of consanguinity is not a reason to deprioritise a recessive hypothesis in a European-ancestry proband.

Founder effect

"This revealed that the EIF3F variant was on an identical haplotype (minimal 7.8 kb) in 15 affected individuals of all tested families, suggesting a founder variant."

The founding haplotype (C-C-A-C-C-G-C across rs79714374, rs12421289, rs12278319, rs7941782, rs4758267, rs12420464, rs56392532) had a frequency of 3.5% in 1,818 internal German control exomes. The variant arose once; "the nascence of the missense variant cannot be determined to a more localized region."

Carrier frequency and derived prevalence

Reported carrier/allele frequencies (gnomAD v2.1.1):

Population Allele frequency
Overall 0.07% (0.000711)
Non-Finnish European 0.12%
Ashkenazi Jewish 0.21%

Derived birth prevalence — my own Hardy-Weinberg arithmetic, not a published figure: q² for NFE ≈ (0.0012)² ≈ 1.4 × 10⁻⁶ ≈ 1 in ~690,000; for Ashkenazi Jewish ≈ (0.0021)² ≈ 4.4 × 10⁻⁶ ≈ 1 in ~230,000. Carrier frequency ≈ 1 in 420 (NFE) and 1 in 240 (AJ). Label these clearly as derived; they are almost certainly higher than observed diagnosed prevalence, and the gap between ~31 published patients and this expectation is the size of the under-diagnosis problem.

Epidemiology

  • Prevalence: not determined. PMID:39723281 states plainly: "the population frequency of this syndromic disorder has not been determined since then."
  • Cases in literature: ~31 as of 2025 (Simons Searchlight), consistent with 9 (Martin) + 22 (Hüffmeier) + scattered singles.
  • For a dismech prevalence: block: measure_type: CASES_IN_LITERATURE, prevalence_class: NOT_YET_DOCUMENTED or ULTRA_RARE, with the derived HWE estimate in notes — not in rate_per_100000, since it is an inference rather than an observation.

Demographics

  • Ancestry: European and West Asian. Hüffmeier 2021 lists "French, English, Irish, Scottish, German, Bulgarian, Ukranian, Russian, Ashkenazi Jewish, and Iraqi." Plus Slovak (PMID:39723281). No African, East Asian, or South Asian cases reported — consistent with a European founder allele, though ascertainment in European genomics cohorts inflates this.
  • Sex ratio: 15 F : 7 M (Hüffmeier) and 5 F : 4 M (Martin) — no evidence of sex bias; the female excess in the larger cohort is unremarkable at this sample size and there is no biological reason to expect one for an autosomal recessive disorder. Report as ~1:1.
  • Age distribution: ascertained pediatric (median 8.5 y); adults under-represented.

10. Diagnostics

The diagnostic route is sequencing, full stop

Everything else is negative or nonspecific:

Test Expected result
Karyotype Normal (46,XX in the Slovak case)
Chromosomal microarray / aCGH Negative — "Microarray analysis of CNVs (aCGH) showed negative findings" (PMID:39723281)
Brain MRI Nonspecific in ~38–43%; "not considered diagnostically indicative"
Routine biochemistry No specific abnormality; no biomarker exists
Methylation (15q11.2-q13) Negative

Genetic testing

Recommended approach: WES or WGS, or an ID/ASD gene panel that includes EIF3F. Hüffmeier 2021 is unambiguous: "Thus, genome-wide sequencing approaches (genome or exome sequencing) represent an essential component of the diagnostic work-up." Lakatosova 2024 makes the same argument as a health-systems point for Slovakia.

  • EIF3F is on Genomics England PanelApp as a GREEN (high-evidence) gene on the "Early onset or syndromic epilepsy" panel (panel 402), mode of inheritance BIALLELIC, phenotypes: MRT67 (OMIM:618295), intellectual disability, seizures, behavioral abnormality, sensorineural hearing impairment (PanelApp).
  • SFARI Gene score: 3 (Suggestive Evidence) for autism, with 8 supporting reports (SFARI).
  • Targeted single-variant testing is genuinely viable here — unusually for a recessive NDD. Because one founder allele explains ~95% of reported cases, Sanger or targeted genotyping of c.694T>G is a reasonable low-cost first-line test in a European-ancestry proband with GDD + speech delay + SNHL, and is the natural cascade/carrier test in families.

A diagnostic pitfall worth flagging explicitly

The founder allele sits at 0.12% in non-Finnish Europeans. Many recessive-model variant-filtering pipelines apply a minor-allele-frequency cutoff at or near 0.1% and would discard this variant before a human ever sees it. Combined with the absence of a recognisable facial gestalt and uninformative MRI, this is a plausible mechanism for systematic under-diagnosis. (This inference is mine, but it follows directly from the reported AF and from Hüffmeier's own observation that carrier frequency here "is higher than for most other autosomal recessive NDDs.")

Adjunct clinical assessments (not diagnostic, but indicated once the diagnosis is made)

  • Audiology — SNHL in ~57%, and undetected hearing loss in a child with speech delay will be mis-attributed to the developmental delay. This is the highest-yield adjunct test.
  • Ophthalmology — refractive error/strabismus/nystagmus/coloboma in up to 38%. Note Hüffmeier's own caveat that hyper-/myopia "might not necessarily be related to EIF3F deficiency, as they are common in the general population."
  • Growth monitoring with head circumference plotted longitudinally.
  • Sleep assessment (CSHQ used in the Slovak case).
  • Developmental/behavioural assessment: ADOS-2, ADI-R, Vineland-3, BRIEF-P, SON-R all used in published assessment.
  • EEG if seizures are suspected.

LOINC: no disease-specific analyte. No biomarker, enzyme assay, or metabolite is known. Do not curate one.

Differential diagnosis

Condition Distinguishing feature
Rett syndrome (MECP2) Overlaps substantially — one individual in Hüffmeier 2021 (P2) carried both a homozygous EIF3F variant and a de novo MECP2 frameshift, and was excluded from the phenotype summary for exactly that reason. Regression pattern and hand stereotypies favour Rett.
Angelman syndrome Tested and excluded in reported patients; methylation/UBE3A.
Fragile X Tested and excluded.
Russell-Silver syndrome Two individuals had prior targeted testing for short stature / FTT.
Phelan-McDermid (22q13 del) CMA-detectable; MRT67 CMA is negative.
Other AR ID syndromes (PS249500, 70 entities) Distinguished only by sequencing.
PPP1R21-related El-Hattab-Schmidts syndrome Coarse facies (thick arched eyebrows, thick vermilion), optic atrophy — a different gene and a different mechanism. Included here because the naming similarity is a genuine curation hazard.

Screening

  • Newborn screening: not included anywhere; no biochemical marker exists to screen for.
  • Carrier screening: EIF3F is not on standard expanded carrier screening panels as far as could be determined. Given the AJ frequency of 0.21%, inclusion on Ashkenazi-focused panels would be a defensible proposal — this is my inference, not a published recommendation.
  • Cascade screening: straightforward and appropriate once a familial variant is known.

11. Outcome / Prognosis

Be honest about how thin this is. There is no natural-history study, no survival analysis, and no validated prognostic model.

Survival and mortality

  • No deaths attributable to MRT67 have been reported. Individuals have been described up to 48 years (Martin cohort) and ~30 years (Hüffmeier cohort).
  • Life expectancy: unknown, but not obviously shortened on current evidence. Do not assert a figure.
  • The one hard mortality statement in the literature is about the null genotype, which appears incompatible with life (no human reported; mouse embryonic lethal).

Morbidity and function

Lifelong intellectual disability of variable degree with major communication impairment (24% never develop speech). The single instrumented case showed "deeply below-average" adaptive functioning across all Vineland domains. Most affected individuals will require lifelong support; some achieve simplified but usable language and independent ambulation.

No EQ-5D/SF-36/PROMIS/ICF data exist.

Complications

  • Sequelae of SNHL on language acquisition.
  • Injury risk from reduced pain sensitivity (a practical safety issue, though no incident data exist).
  • Feeding/GI problems in ~24%.
  • Surgical burden where clefting or congenital heart disease is present.

The meningioma question — genuinely unresolved

Two of 21 individuals (10%) had meningioma, and a third had psychosis co-occurring with meningioma. In a cohort of median age 8.5 years that is a striking number. Hüffmeier 2021 checked and reported a negative result:

"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"

Two events in 21 people is not a tumour-predisposition claim, and the somatic data do not support one. But it is also not nothing, and it is the single most consequential open question for surveillance recommendations. Curate as a discussions: KNOWLEDGE_GAP with the COSMIC negative recorded — not as a phenotype with an asserted frequency, and certainly not as a basis for recommending imaging surveillance.

Prognostic factors

The only signal is genotype: the compound heterozygote (missense + frameshift) sat at the severe end for motor milestones, speech, organ involvement, and pre-/postnatal growth. No biomarkers, no imaging predictors.

12. Treatment

There is no disease-specific or disease-modifying therapy.

No approved drug, no gene therapy, no ASO, no cell therapy, no clinical trial. A search of ClinicalTrials.gov concepts for EIF3F/MRT67 surfaces nothing interventional. Say this plainly rather than assembling a speculative pipeline.

Management is supportive, symptom-directed, and multidisciplinary — as practised in the reported cases, where the Slovak child was "under the care of several clinical specialists, including neurologists, otorhinolaryngologists, psychologists, and a speech therapist."

Supportive and rehabilitative care (with NCIT terms)

Intervention NCIT term Rationale
Speech and language therapy NCIT:C159273 Speech Therapy Speech delay is universal and the most severely affected domain
Physical therapy NCIT:C15302 Physical Therapy Motor delay, altered tone
Occupational therapy NCIT:C121351 Occupational Therapy Adaptive function deficits
Rehabilitation (general) NCIT:C15315 Rehabilitation Umbrella term
Supportive care NCIT:C15747 Supportive Care Umbrella term
Genetic counseling NCIT:C15240 Genetic Counseling 25% sibling recurrence risk
Antiseizure pharmacotherapy NCIT:C15986 Pharmacotherapy Where epilepsy present; no agent-specific data
Behavioral counseling / intervention NCIT:C181743 Behavioral Counseling Behavioural problems in ~57%
Surgical repair of cleft lip/palate NCIT:C15329 Surgical Procedure Where present; one case documented pre- and post-correction
Cardiac surgery NCIT:C15329 Surgical Procedure Tetralogy of Fallot, 1 case

therapeutic_modality for the therapy/counselling entries: BEHAVIORAL; for surgery: SURGERY; for antiseizure drugs: SMALL_MOLECULE.

Hearing amplification is clinically indicated given ~57% SNHL, but note the dismech-specific constraint: there is no reliable NCIT clinical-action term for device usage (the former "hearing aid usage" term had no NCIT equivalent and was dropped in the MAXO removal), so a hearing-aid treatment entry should carry therapeutic_modality: DEVICE with a free-text preferred_term and no term: binding.

Pharmacogenomics

None. No EIF3F entry in PharmGKB/CPIC relevant to this disorder.

A speculative therapeutic direction — label it as such

The mTORC1 coupling (§6) raises the theoretical question of whether pathway modulation could compensate for reduced eIF3f-dependent S6K1 activation. Nothing supports this in patients. Direction of effect is also non-obvious: the defect is reduced mTOR activation, so an mTOR inhibitor would be expected to worsen it, and there is no validated agonist strategy. Record as a hypothesis in discussions: if at all; do not curate as a treatment.

Antipsychotics — a cautionary observation

In the EIF3F-heterozygous oligogenic case (PMID:35743796, which is not MRT67), both siblings "responded poorly to pharmacotherapy" and one failed ECT. In the one MRT67 individual with psychosis, the psychosis co-occurred with a meningioma. Neither supports a treatment-response claim for MRT67. Mentioned only to forestall over-reading.

13. Prevention

Primary prevention

There is no way to prevent the disease in a conceptus who inherits two pathogenic alleles. Prevention here means reproductive risk management:

  • Genetic counseling (NCIT:C15240) with a 25% sibling recurrence risk, as delivered in the Slovak case: "The identification of the causal variant c.694T>G, p.(Phe232Val) in the EIF3F gene indicates a 25% recurrence risk in potential siblings of the patient, due to its autosomal recessive mode of inheritance, as explained by the clinical geneticist to the parents of the proband." (PMID:39723281)
  • Carrier testing of at-risk relatives (cascade testing on the familial variant).
  • Prenatal diagnosis and preimplantation genetic testing (PGT-M) are technically straightforward once the familial variant is known. No published MRT67-specific experience.
  • Population carrier screening: not currently offered. The AJ allele frequency of 0.21% makes a case for consideration on Ashkenazi panels — again, my inference, not a guideline position.

Secondary prevention (early detection and intervention)

The realistic wins are all here, and they follow from the phenotype frequencies:

  1. Early audiological assessment — the single highest-value intervention, because untreated SNHL compounds an already-universal speech delay and is present in over half of patients.
  2. Early developmental intervention — speech, physical, and occupational therapy.
  3. Ophthalmological review — correctable refractive error and strabismus.
  4. Growth surveillance with plotted centiles.

Tertiary prevention

  • Injury surveillance in individuals with reduced pain sensitivity — a child who does not report pain normally is at risk of unrecognised fracture, burn, or intra-abdominal pathology. This follows from the phenotype and is standard practice in congenital insensitivity to pain; it is not written down anywhere for MRT67.
  • Nutritional monitoring where GI symptoms or feeding difficulty are present. Note the individual whose "regression" turned out to involve vitamin B12 deficiency — a reminder that treatable causes should be excluded before attributing deterioration to the underlying disorder.
  • Seizure management where epilepsy is present.

Immunization, public health, environmental interventions, prophylaxis

Not applicable. Standard childhood immunisation as for any child; nothing disease-specific.

14. Other Species / Natural Disease

  • Taxonomy: Homo sapiens NCBITaxon:9606; Mus musculus NCBITaxon:10090 (experimental only).
  • Breed: not applicable — no breed-associated disease. No VBO term.
  • Orthologous gene: Eif3f, mouse, MGI:1913335. eIF3 is deeply conserved across eukaryotes; eIF3f orthologues exist throughout metazoa and in yeast the eIF3 core is conserved though subunit composition differs (mammalian eIF3 has 13 subunits including five non-PCI/MPN subunits — Moretti 2010).
  • Naturally occurring disease in other species: none known. No OMIA entry was identified for an EIF3F orthologue phenotype. Record as not applicable.
  • Veterinary relevance: none.
  • Comparative pathology: the mouse does not reproduce the human disease (§15). The comparative story is one of divergence, not convergence — complete loss is embryonic-lethal in mouse and (inferentially) in human, while the human hypomorphic missense allele has no mouse counterpart.
  • Evolutionary conservation: Phe232 is "evolutionarily conserved and is predicted to stabilize the protein" (PMID:39723281), which is part of the pathogenicity argument.
  • Zoonotic potential / cross-species transmission: not applicable.

15. Model Organisms

Mouse — the only in vivo model, and it does not model the disease

Model 1: Eif3f-null homozygote (Eif3f^-/-) — Docquier et al. 2019, PMID:31026345

"We showed that homozygous eIF3f knockout fail to develop and that eIF3f-/- embryos die at an early stage of development but after the pre-implantation stage."

  • Relationship to disease: PERTURBS, fidelity LOW. This genotype exists in no patient and produces a qualitatively different outcome (embryonic lethality, not a neurodevelopmental disorder).
  • What it is good for: bounding the mechanism from the severe end. It is the experimental leg of the tripod supporting "the human founder allele must be hypomorphic."
  • MGI/IMPC classify this line as lethal (no live homozygous null pups) (MGI:1913335).

Model 2: Eif3f heterozygote (Eif3f^+/-) — same paper

"Although heterozygous mice are phenotypically indistinguishable from wild-type mice, they present a diminished body weight and a lean mass reduction associated with normal body size."

"Skeletal muscles of heterozygous mice show a deficiency in polysome content, a decrease in protein synthesis rate and an inhibition of the mechanistic target of rapamycin (MTOR) pathway."

"Interestingly, skeletal muscles are mainly affected and display an altered cell size without modification of fibre number."

"We found that eIF3f partial depletion amplifies muscle atrophy compared to wild-type mice."

  • Relationship to "Reduced Global Translation Initiation": RECAPITULATES, fidelity MODERATE. It reproduces the translational deficit itself and identifies the mTOR coupling.
  • Relationship to "Reduced Cell Proliferation and Growth": PARTIALLY_RECAPITULATES, fidelity MODERATE — a cell-size rather than cell-number deficit, with normal body size.
  • Limitations (required for any dismech model link): measurements were made in skeletal muscle, not brain; the animal carries a null on one allele, not the human missense on both; heterozygous mice are behaviourally and developmentally normal, so the model captures the biochemistry of partial eIF3f depletion without reproducing the neurodevelopmental phenotype at all. MGI additionally notes partial prenatal lethality in heterozygotes.

Readouts available for curation (ExperimentalReadout): polysome content (DECREASED), protein synthesis rate (DECREASED), mTOR pathway activation (DECREASED), lean mass (DECREASED), muscle fibre cross-sectional area (DECREASED), fibre number (UNCHANGED — a real negative result worth recording).

Cellular models

Gene-edited iPSCs homozygous for c.694T>G — the isogenic model on which the loss-of-function interpretation rests (Martin 2018, described in Hüffmeier 2021):

"In vitro studies of induced pluripotent stem cells (iPSC), gene-edited to be homozygous for the c.694T>G/ p.(Phe232Val) variant, demonstrated lower EIF3F protein levels and reduced proliferation rates"

"Furthermore, both heterozygous and homozygous variants reduced translation rates in iPSC cells"

Quantified via ClinVar submitter summary as ~70% of wild-type protein expression.

  • Fidelity: this is the right allele in human cells, which is its major strength — and it is undifferentiated stem cells, which is its major limitation. No neuronal, cerebral-organoid, oligodendrocyte, or cochlear model of the disease allele has been published.

Other cell systems (mechanism, not disease): U2OS, HEK293T, HeLa, and MEF lines with shRNA knockdown for the Notch/DUB work (PMID:21124883); C2C12 myotubes for the mTORC1/MAFbx work; cell lines for SCA8 RAN-translation modulation (PMID:30206144). None carries the disease allele.

The largest model gap

There is no neural model of MRT67. The disease is a brain disorder; the cellular work is in undifferentiated iPSCs and the in vivo work is in mouse muscle. This is precisely the situation the dismech schema's HUMAN_MODEL_MISMATCH discussion kind exists for — evidence exists in models, but its translational validity to the human neurodevelopmental phenotype is the open question. Obvious proposed experiments: differentiate the existing isogenic iPSC lines to cortical neurons and cerebral organoids and measure translation rate, proliferation, and neurite/network phenotypes; generate a Eif3f p.Phe232Val knock-in mouse (which does not currently exist).

Model resources

  • MGI: MGI:1913335
  • IMPC: mousephenotype.org (note: the search result found no publications using IMPC mice/data for the human-disease question)
  • MMRRC / IMSR for line availability
  • Simons Searchlight is actively recruiting an EIF3F patient cohort (link) — the most likely source of future natural-history data

Summary of evidence quality

Domain Strength
Gene–disease association Strong. Exome-wide burden analysis + independent 22-patient replication cohort + ClinVar 2-star Pathogenic/LP + PanelApp GREEN.
Variant pathogenicity (c.694T>G) Strong. Founder haplotype, no gnomAD homozygotes, functional validation in isogenic iPSCs.
Core phenotype (GDD, speech delay) Strong. 100% in both cohorts.
Frequent phenotypes (SNHL, behaviour, tone, growth) Moderate. ~50% figures from a single 21-patient cohort.
Epilepsy frequency Weak/contradictory. 86% vs 15% between cohorts. Do not assert a frequency band.
Mechanism: translation → proliferation Moderate. Measured, but in stem cells and mouse muscle.
Mechanism: → neurodevelopmental phenotype Weak/inferred. No neural model, no structural correlate.
Notch/DUB relevance to disease Speculative. In vitro only, never connected to patients.
White matter / oligodendrocyte relevance Speculative, and in tension with Human Protein Atlas expression data.
Meningioma association Unresolved. 2/21 observed; COSMIC somatic data negative.
Prevalence Not determined. Only a derivable HWE estimate.
Treatment None exists. Supportive care only.

Sources

Recap for the curator

MRT67 is the EIF3F disorder (MONDO:0032662, OMIM #618295) — not PPP1R21/FERRY, despite four PPP1R21 reference files sitting in this worktree's cache; two of those have no retrievable body text and could not yield a verifiable snippet in any case. The disease is driven almost entirely by one European founder missense allele, c.694T>G p.(Phe232Val), on a single 7.8 kb haplotype, present at 0.12% in non-Finnish Europeans and 0.21% in Ashkenazi Jewish individuals with zero gnomAD homozygotes. Mechanism is a ~30% reduction in eIF3f protein → reduced translation initiation → reduced mTOR signalling and proliferation → impaired brain development and somatic growth; the last arrow is inferred rather than measured, since no neural model of the disease allele exists. Global developmental delay and speech delay are universal; SNHL, behavioural problems, altered tone and short stature run near 50%; epilepsy frequency is contradictory between the two cohorts (86% vs 15%) and should not be assigned a frequency band. There is no treatment, no biomarker, no prevalence figure, and no omics dataset. Three items are genuinely open and belong in discussions: rather than as asserted facts: the epilepsy discrepancy, the 2/21 meningioma observation (with its negative COSMIC counter-evidence), and the human-model mismatch between undifferentiated iPSCs / mouse muscle and a brain disease.

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 15
Resolved 13
Unresolved (possible confabulation) 2
Unverifiable 0
References weighed for topical relevance 13
On topic 6
Off topic 0

Unresolved references

These identifiers did not resolve to a record and may be fabricated. A lookup that failed for transport reasons is indistinguishable from one that failed because the record does not exist, so spot-check before acting on them:

  • DOI:10.1016/j.gimo.2024.101213](https://www.gimopen.org/article/S2949-7744(24)00359-5/fulltext (1 mention) - Identifier did not resolve to a record
  • DOI:10.1371/journal.pone.0008994](https://journals.plos.org/plosone/article (1 mention) - Identifier did not resolve to a record