A recessive endolysosomal disorder caused by germline missense variants in the FYVE domain of RBSN, presenting with progressive muscle weakness, facial dysmorphism, ophthalmoplegia and intellectual disability. RBSN encodes rabenosyn-5, a Rab5 effector that is recruited to early endosomes by binding phosphatidylinositol 3-phosphate through that FYVE domain, and which tethers the Sec1-like protein hVPS45 to Rab5 - hVPS45 does not bind Rab5 itself. What makes this entry worth reading is not the phenotype but the allele mechanism. The two causal variants, p.Arg180Gly and p.Gly183Arg, abolish PI3P binding and so prevent rabenosyn-5 reaching the early endosome at all - and yet the endosomal recycling pathway is unaffected. What accumulates in patient fibroblasts is cargo tagged for lysosomal degradation. The reporting authors call these separation-of-function alleles: they delay endosomal maturation while leaving recycling intact, splitting apart two functions of one protein that had not previously been separable. That is also why this is a distinct disease rather than a variant of the other RBSN disorder. A different germline RBSN allele, p.Gly97Arg, causes congenital myelofibrosis with anemia, neutropenia, developmental delay and ocular abnormalities - a haematological phenotype with essentially no overlap with this one. The authors' conclusion is that distinct germline RBSN mutations cause non-overlapping phenotypes with specific and discrete endolysosomal cellular defects, and this entry follows that split.
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name: Kariminejad Neurodevelopmental Syndrome
creation_date: "2026-09-21T00:00:00Z"
description: >-
A recessive endolysosomal disorder caused by germline missense variants in the
FYVE domain of RBSN, presenting with progressive muscle weakness, facial
dysmorphism, ophthalmoplegia and intellectual disability. RBSN encodes
rabenosyn-5, a Rab5 effector that is recruited to early endosomes by binding
phosphatidylinositol 3-phosphate through that FYVE domain, and which tethers the
Sec1-like protein hVPS45 to Rab5 - hVPS45 does not bind Rab5 itself.
What makes this entry worth reading is not the phenotype but the allele
mechanism. The two causal variants, p.Arg180Gly and p.Gly183Arg, abolish PI3P
binding and so prevent rabenosyn-5 reaching the early endosome at all - and yet
the endosomal recycling pathway is unaffected. What accumulates in patient
fibroblasts is cargo tagged for lysosomal degradation. The reporting authors call
these separation-of-function alleles: they delay endosomal maturation while
leaving recycling intact, splitting apart two functions of one protein that had
not previously been separable.
That is also why this is a distinct disease rather than a variant of the other
RBSN disorder. A different germline RBSN allele, p.Gly97Arg, causes congenital
myelofibrosis with anemia, neutropenia, developmental delay and ocular
abnormalities - a haematological phenotype with essentially no overlap with this
one. The authors' conclusion is that distinct germline RBSN mutations cause
non-overlapping phenotypes with specific and discrete endolysosomal cellular
defects, and this entry follows that split.
category: Mendelian
parents:
- Neurodevelopmental Disorder
- Endosomal trafficking disorder
disease_term:
preferred_term: Kariminejad neurodevelopmental syndrome
term:
id: MONDO:0975795
label: Kariminejad neurodevelopmental syndrome
synonyms:
- RBSN-related neurodevelopmental syndrome
- rabenosyn-5 FYVE-domain disorder
notes: >-
Entry scope, and the lump/split decision this entry exists to make. The stub
(stubs/Kariminejad_Neurodevelopmental_Syndrome.yaml) left `entry_type:
UNDECIDED` and set out the question: RBSN has two named Mendelian disorders,
and whether the second is a distinct DISEASE or a `has_subtypes` row on the
first had not been settled. It is curated here as a DISEASE, on three grounds
that are independent of each other:
1. The alleles segregate cleanly by phenotype. ClinVar keys p.Arg180Gly and
p.Gly183Arg to this condition and p.Gly97Arg to MONDO:0975797, and that
assignment is recorded in the already-curated sibling entry
kb/disorders/Congenital_Myelofibrosis_With_Anemia_Neutropenia_Developmental_Delay_And_Ocular_Abnormalities.yaml,
whose curator read the ClinVar records through the NCBI E-utilities esummary
API on 2026-09-19. This entry did not re-derive that; it relies on it and says so.
2. The phenotypes do not overlap. This disorder is neuromuscular and cognitive;
the sibling is a congenital bone marrow failure syndrome with myelofibrosis,
neutropenia and anemia. They share developmental delay and little else.
3. The cellular defects are different and were measured in the same paper.
PMID:35652444 shows that the FYVE-domain alleles leave endosomal recycling
intact and impair lysosomal delivery, and concludes explicitly that distinct
germline RBSN mutations cause non-overlapping phenotypes with discrete
endolysosomal defects.
MONDO agrees: the two are separate terms, and neither is a descendant of the
other. Curating this as a `has_subtypes` row on the sibling would have asserted
a hierarchy the ontology does not carry - the same error that
`Usmani-Riazuddin_Syndrome_Autosomal_Dominant` records having avoided, and for
the same reason.
What is NOT settled, and is carried forward rather than resolved here: a third
RBSN patient, homozygous p.Gly425Arg (PMID:25233840), fits neither disorder
cleanly. The sibling entry analyses this at length in its
`rbsn_allelic_series_nosology` discussion and declines to count her as a case of
either. This entry takes the same position and does not re-argue it; see that
discussion rather than duplicating it.
Evidence base. One paper, two families, two alleles - PMID:35652444 is the
defining and essentially the only clinical source. Everything phenotypic in this
entry traces to it. The supporting cell-biology references describe rabenosyn-5
in normal cells, not in patients.
Module conformance checked and left unset. `just list-modules` was read and
`kb/modules/` grepped for `endosom`, `lysosom`, `traffick`, `vesicle`, `Rab`,
`autophag` and `sorting`. There is no endosomal-maturation or membrane-trafficking
module. The lysosomal storage modules are not applicable: this is a delivery
defect upstream of the lysosome with no storage material described, and
conforming to one would assert accumulation of an undegraded substrate that
nobody has reported.
No GeneReviews chapter exists for this disorder. Checked offline with
`just check-genereviews kb/disorders/Kariminejad_Neurodevelopmental_Syndrome.yaml`
against the committed Bookshelf index; NO_CHAPTER for GeneReviews.
Deep research. `just preflight-dr` returns PASS against MONDO:0975795 (RBSN
mentioned 31 times, no rival gene above 5, and the report's OMIM 620937 matches
the MONDO xref). Its single most useful contribution was PMID:26192890 -
Kariminejad et al. 2015, the founding clinical description the syndrome is named
after, published seven years before the gene was identified. This entry did not
cite it. It supplies the electrophysiological myopathy with non-specific
biopsies, the leukoencephalopathy and delayed myelination on MRI, the unilateral
abduction deficit behind the ophthalmoplegia, and the only enumeration of the
facial features anywhere in the literature - every other source calls them
dysmorphic and stops.
Two things in the report's own validation output were checked rather than
accepted. All three of its "terms named as a different term" findings are
artifacts of the validator reading a phenotype table's *frequency* column as the
term name ("All (6/6)", "Frequent", "1 patient"); none is a wrong binding. It
also flags `GO:0017137` as obsolete, replaced by `GO:0031267` - this entry uses
neither, so nothing followed from it.
Pathograph wiring. All fourteen phenotypes are wired from
`Delayed Endosomal Maturation with Preserved Recycling`, and the reason they are
all wired the same way is that they all rest on the same kind of claim. Four come
from one sentence in PMID:35652444 naming the features that constitute the
disorder; two are the founding paper's imaging findings; eight are the individual
facial features that same paper enumerates. Not one of the fourteen has a
published mechanism connecting it to the endosomal defect, which is exactly what
the `rbsn_cellular_defect_to_tissue_phenotype` discussion records. Every edge is
therefore `directness: INDIRECT` and says so. Wiring two of the four defining
features and leaving the other two isolated, which is how this entry first stood,
asserted a distinction between them that no source makes.
The facial features are curated individually rather than folded into the coarse
`Abnormal facial shape` node, and the two coexist deliberately. The coarse node
carries the gene paper's sentence, which names dysmorphism and characterises it
no further - that, and only that, is what makes its `SOURCE_UNSPECIFIED` basis
true. An earlier revision of this entry attached the founding paper's enumerating
sentence to that same node, which falsified the declared basis: a source there
plainly did characterise it further, in the snippet directly below the
declaration. `just check-coarse-phenotypes` cannot catch that, because it checks
that a basis is declared rather than that it is the right one. The remedy was the
one the `coarse-phenotype-bindings` skill prescribes - if you can list the
findings, they are phenotypes - so the eight are curated beside the coarse node
and the enumerating quote moved onto them. `PATHOGRAPH_HUB` was considered and
rejected: a hub is defined by convergence, and this node is one arm of a
fourteen-way fan-out from a single upstream node, which is the pattern that skill
warns is not a hub.
references:
- reference: PMID:35652444
title: "RABENOSYN separation-of-function mutations uncouple endosomal recycling from lysosomal degradation, causing a distinct Mendelian disorder."
tags: []
findings:
- statement: >-
The defining report. Clinical, genetic, cellular and biochemical evidence
that the recessive FYVE-domain alleles p.Arg180Gly and p.Gly183Arg cause a
novel Mendelian disorder of progressive muscle weakness, facial dysmorphism,
ophthalmoplegia and intellectual disability, by abolishing PI3P binding and
preventing rabenosyn-5 from reaching the early endosome - while leaving
endosomal recycling intact.
- reference: PMID:26192890
title: "Intellectual disability, muscle weakness and characteristic face in three siblings: A newly described recessive syndrome mapping to 3p24.3-p25.3."
tags: []
findings:
- statement: >-
The founding clinical description, seven years before the gene was found, and
the paper the syndrome is named after. Three Iranian siblings with mild
intellectual disability, progressive muscle weakness and a characteristic
face; electrophysiological signs of myopathy with non-specific muscle
biopsies; leukoencephalopathy with delayed myelination on MRI in two of them;
and homozygosity mapping to a single identical-by-descent block at
3p24.3-p25.3 containing 57 genes - the interval that later yielded RBSN. It
is also the only source that enumerates the facial features rather than
calling them dysmorphic.
- reference: PMID:11062261
title: "Rabenosyn-5, a novel Rab5 effector, is complexed with hVPS45 and recruited to endosomes through a FYVE finger domain."
tags: []
findings:
- statement: >-
Characterises the protein and the domain this disease disrupts: rabenosyn-5
is a Rab5 effector recruited to early endosomes through its FYVE finger in a
PI3-kinase-dependent manner, and is the molecular link between Rab5 and
hVPS45, which does not bind Rab5 directly.
- reference: PMID:22308388
title: "Rabenosyn-5 defines the fate of the transferrin receptor following clathrin-mediated endocytosis."
tags: []
findings:
- statement: >-
Establishes that rabenosyn-5 determines whether internalised cargo is recycled
or routed onward - which is the function the disease alleles split in two.
- reference: PMID:15020713
title: "Rabenosyn-5 and EHD1 interact and sequentially regulate protein recycling to the plasma membrane."
tags: []
findings:
- statement: >-
The recycling arm of rabenosyn-5 function, cited here for the contrast: this
is the pathway the FYVE-domain disease alleles leave working.
- reference: PMID:29784638
title: "Syndromic congenital myelofibrosis associated with a loss-of-function variant in RBSN."
tags: []
findings:
- statement: >-
The other RBSN disorder, cited only to mark the boundary of this entry. A
different germline allele produces a haematological syndrome with essentially
no phenotypic overlap with this one.
inheritance:
- name: Autosomal recessive
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
description: >-
Recessively acting germline RBSN alleles in the FYVE domain. Both reported
variants behave recessively; no heterozygous carrier phenotype has been
described.
evidence:
- reference: PMID:35652444
reference_title: "RABENOSYN separation-of-function mutations uncouple endosomal recycling from lysosomal degradation, causing a distinct Mendelian disorder."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Using exome sequencing, we identified recessively acting germline alleles p.Arg180Gly and p.Gly183Arg, which are both situated in the FYVE domain of RBSN."
explanation: "States the inheritance mode, the two alleles, and the domain they share."
pathophysiology:
- name: RBSN FYVE-Domain Missense Variant
biological_scale: MOLECULAR
role: Initiating genetic lesion
description: >-
One of two recessive missense alleles, p.Arg180Gly or p.Gly183Arg, three
residues apart in the FYVE finger of rabenosyn-5. The FYVE domain is the
module through which the protein reads phosphatidylinositol 3-phosphate on
endosomal membranes, so a lesion here is a targeting lesion rather than a
catalytic one.
genetic_context:
gene:
preferred_term: RBSN
term:
id: hgnc:20759
label: RBSN
variant_origin: GERMLINE
allele_type: SNV
zygosity: HOMOZYGOUS
functional_impact_category: LOSS_OF_FUNCTION
description: >-
Recorded as LOSS_OF_FUNCTION because PI3P binding is abolished, but the
enum cannot express what is distinctive here: the loss is selective. One of
the protein's two downstream functions is lost and the other is retained, on
the same allele, which is what the authors mean by separation-of-function.
See `discussions`.
genes:
- preferred_term: RBSN
term:
id: hgnc:20759
label: RBSN
evidence:
- reference: PMID:35652444
reference_title: "RABENOSYN separation-of-function mutations uncouple endosomal recycling from lysosomal degradation, causing a distinct Mendelian disorder."
supports: SUPPORT
directness: DIRECT
evidence_source: HUMAN_CLINICAL
snippet: "Using exome sequencing, we identified recessively acting germline alleles p.Arg180Gly and p.Gly183Arg, which are both situated in the FYVE domain of RBSN."
explanation: "The alleles and their location in the domain this node is about."
downstream:
- target: Loss of PI3P Binding and Failure of Endosomal Recruitment
description: The FYVE lesion removes the protein's membrane-targeting capability.
evidence:
- reference: PMID:35652444
reference_title: "RABENOSYN separation-of-function mutations uncouple endosomal recycling from lysosomal degradation, causing a distinct Mendelian disorder."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "We find that these variants abrogate binding to its cognate substrate phosphatidylinositol 3-phosphate (PI3P) and thus prevent its translocation to early endosomes."
explanation: "The biochemical consequence measured for both alleles."
- name: Loss of PI3P Binding and Failure of Endosomal Recruitment
biological_scale: MOLECULAR
role: Core molecular lesion
description: >-
The mutant protein no longer binds phosphatidylinositol 3-phosphate and
therefore never translocates to the early endosome. Rabenosyn-5 is normally
recruited there in a PI3-kinase-dependent manner through the FYVE finger, and
it is what links Rab5 to hVPS45. So the failure is not of rabenosyn-5's
activity but of its localisation - the protein is present in the cell and
absent from the membrane where it works.
molecular_functions:
- preferred_term: phosphatidylinositol-3-phosphate binding by the RBSN FYVE domain
term:
id: GO:0032266
label: phosphatidylinositol-3-phosphate binding
modifier: DECREASED
cellular_components:
- preferred_term: early endosome
term:
id: GO:0005769
label: early endosome
evidence:
- reference: PMID:35652444
reference_title: "RABENOSYN separation-of-function mutations uncouple endosomal recycling from lysosomal degradation, causing a distinct Mendelian disorder."
supports: SUPPORT
directness: DIRECT
evidence_source: IN_VITRO
snippet: "We find that these variants abrogate binding to its cognate substrate phosphatidylinositol 3-phosphate (PI3P) and thus prevent its translocation to early endosomes."
explanation: "Both halves of this node - lost PI3P binding, and the failure of translocation that follows."
- reference: PMID:11062261
reference_title: "Rabenosyn-5, a novel Rab5 effector, is complexed with hVPS45 and recruited to endosomes through a FYVE finger domain."
supports: SUPPORT
directness: INDIRECT
evidence_source: IN_VITRO
snippet: "This complex includes a novel protein, Rabenosyn-5, which, like the previously characterized Rab5 effector early endosome antigen 1 (EEA1), contains an FYVE finger domain and is recruited in a phosphatidylinositol-3-kinase-dependent fashion to early endosomes."
explanation: "Establishes the normal recruitment mechanism the disease alleles break. INDIRECT because it describes wild-type cell biology, not the patient alleles."
downstream:
- target: Delayed Endosomal Maturation with Preserved Recycling
description: >-
The selective consequence: lysosomal delivery fails while the recycling route
continues to work.
evidence:
- reference: PMID:35652444
reference_title: "RABENOSYN separation-of-function mutations uncouple endosomal recycling from lysosomal degradation, causing a distinct Mendelian disorder."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Although the endosomal recycling pathway was unaltered, mutant p.Gly183Arg patient fibroblasts show accumulation of cargo tagged for lysosomal degradation."
explanation: "The measured dissociation, in patient cells: recycling intact, lysosomal cargo accumulating."
- name: Delayed Endosomal Maturation with Preserved Recycling
biological_scale: CELLULAR
role: Cellular phenotype, and the disease's distinguishing feature
description: >-
In patient fibroblasts, cargo destined for lysosomal degradation accumulates
while recycling to the plasma membrane proceeds normally. The authors read this
as a delay in endosomal maturation rather than a block: the early endosome
still forms and still recycles, it just does not progress efficiently toward the
degradative route.
The reason to curate this as its own node rather than folding it into the
molecular lesion is that it is the claim on which the whole nosology rests. If
the FYVE alleles impaired both arms, there would be no principled reason to
separate this disorder from the RBSN myelofibrosis syndrome; it is the
selectivity that makes the two diseases mechanistically distinct rather than
merely clinically different.
biological_processes:
- preferred_term: endosome to lysosome transport
term:
id: GO:0008333
label: endosome to lysosome transport
modifier: DECREASED
cellular_components:
- preferred_term: endolysosome
term:
id: GO:0036019
label: endolysosome
evidence:
- reference: PMID:35652444
reference_title: "RABENOSYN separation-of-function mutations uncouple endosomal recycling from lysosomal degradation, causing a distinct Mendelian disorder."
supports: SUPPORT
directness: DIRECT
evidence_source: IN_VITRO
snippet: "Our results suggest that these variants are separation-of-function alleles, which cause a delay in endosomal maturation without affecting cargo recycling."
explanation: "The authors' own statement of the cellular phenotype, including the hedge - a delay, not a block."
- reference: PMID:22308388
reference_title: "Rabenosyn-5 defines the fate of the transferrin receptor following clathrin-mediated endocytosis."
supports: SUPPORT
directness: INDIRECT
evidence_source: IN_VITRO
snippet: "Depletion of Rabenosyn-5, but not of other early endosomal proteins such as early endosome antigen 1, resulted in impaired transferrin uptake and lysosomal degradation of transferrin receptors."
explanation: "Shows that removing rabenosyn-5 disturbs the fate of internalised cargo between recycling and lysosomal degradation - the decision these disease alleles bisect - and that the effect is specific to rabenosyn-5 rather than general to early-endosomal proteins. INDIRECT because it is depletion in normal cells, not a patient allele."
downstream:
- target: Progressive muscle weakness
description: >-
The neuromuscular arm. No mechanism links impaired lysosomal delivery to
muscle specifically; see `discussions`.
evidence:
- reference: PMID:35652444
reference_title: "RABENOSYN separation-of-function mutations uncouple endosomal recycling from lysosomal degradation, causing a distinct Mendelian disorder."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "Here, we present clinical, genetic, cellular and biochemical evidence that two distinct RBSN missense variants are responsible for a novel Mendelian disorder consisting of progressive muscle weakness, facial dysmorphisms, ophthalmoplegia and intellectual disability."
explanation: "Establishes the phenotype as a consequence of the variants. INDIRECT for this edge specifically: the paper does not connect the cellular defect to muscle."
- target: Intellectual disability
description: The cognitive arm, on the same footing as the neuromuscular one.
evidence:
- reference: PMID:35652444
reference_title: "RABENOSYN separation-of-function mutations uncouple endosomal recycling from lysosomal degradation, causing a distinct Mendelian disorder."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "Here, we present clinical, genetic, cellular and biochemical evidence that two distinct RBSN missense variants are responsible for a novel Mendelian disorder consisting of progressive muscle weakness, facial dysmorphisms, ophthalmoplegia and intellectual disability."
explanation: "Same sentence, same limitation: the phenotype is attributed to the variants, not derived from the cellular defect."
- target: Ophthalmoplegia
description: >-
The ocular arm, on the same footing as the neuromuscular and cognitive ones.
Named in the same sentence that defines the disorder, and no mechanism links
the endosomal defect to extraocular muscle specifically; see `discussions`.
evidence:
- reference: PMID:35652444
reference_title: "RABENOSYN separation-of-function mutations uncouple endosomal recycling from lysosomal degradation, causing a distinct Mendelian disorder."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "a novel Mendelian disorder consisting of progressive muscle weakness, facial dysmorphisms, ophthalmoplegia and intellectual disability"
explanation: "Names ophthalmoplegia as one of the four features constituting the disorder this variant causes."
- target: Abnormal facial shape
description: >-
The dysmorphism, wired on the same footing as the other three defining
features. A developmental claim with no mechanism behind it - nothing links
delayed endosomal maturation to craniofacial patterning here.
evidence:
- reference: PMID:35652444
reference_title: "RABENOSYN separation-of-function mutations uncouple endosomal recycling from lysosomal degradation, causing a distinct Mendelian disorder."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "a novel Mendelian disorder consisting of progressive muscle weakness, facial dysmorphisms, ophthalmoplegia and intellectual disability"
explanation: "Names the facial dysmorphism as one of the four features constituting the disorder."
- target: Leukoencephalopathy
description: >-
The white-matter finding, wired as a further consequence of the same
cell-biological defect. Inferential in exactly the way the other arms are.
evidence:
- reference: PMID:26192890
reference_title: "Intellectual disability, muscle weakness and characteristic face in three siblings: A newly described recessive syndrome mapping to 3p24.3-p25.3."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "Brain MRIs in two of the sibs showed leukencephalopathy with delayed myelination, frontal and parietal hyperintensities, and hippocampal atrophy in one."
explanation: "The imaging finding in the founding pedigree. INDIRECT because the sentence reports the observation without deriving it from the endosomal defect."
- target: Delayed myelination
description: >-
Delayed myelination alongside the white-matter change, from the same imaging.
evidence:
- reference: PMID:26192890
reference_title: "Intellectual disability, muscle weakness and characteristic face in three siblings: A newly described recessive syndrome mapping to 3p24.3-p25.3."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "Brain MRIs in two of the sibs showed leukencephalopathy with delayed myelination, frontal and parietal hyperintensities, and hippocampal atrophy in one."
explanation: "The same MRI sentence, curated here for the myelination arm."
- target: Highly arched eyebrow
description: >-
A constituent of the facial phenotype, wired from the mechanism on the same
footing as the coarse dysmorphism node and everything else in this entry. No
published mechanism connects the endosomal defect to craniofacial patterning.
evidence:
- reference: PMID:26192890
reference_title: "Intellectual disability, muscle weakness and characteristic face in three siblings: A newly described recessive syndrome mapping to 3p24.3-p25.3."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "including highly arched eyebrows, down-slanting palpebral fissures, prominent nasal bridge, prominent nose, columella extending below alae nasi, narrow mouth, narrow palate, and dental caries"
explanation: "Records the feature in affected siblings. INDIRECT because the sentence enumerates the face without deriving it from the endosomal defect."
- target: Downslanted palpebral fissures
description: >-
A constituent of the facial phenotype, wired from the mechanism on the same
footing as the coarse dysmorphism node and everything else in this entry. No
published mechanism connects the endosomal defect to craniofacial patterning.
evidence:
- reference: PMID:26192890
reference_title: "Intellectual disability, muscle weakness and characteristic face in three siblings: A newly described recessive syndrome mapping to 3p24.3-p25.3."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "including highly arched eyebrows, down-slanting palpebral fissures, prominent nasal bridge, prominent nose, columella extending below alae nasi, narrow mouth, narrow palate, and dental caries"
explanation: "Records the feature in affected siblings. INDIRECT because the sentence enumerates the face without deriving it from the endosomal defect."
- target: Prominent nasal bridge
description: >-
A constituent of the facial phenotype, wired from the mechanism on the same
footing as the coarse dysmorphism node and everything else in this entry. No
published mechanism connects the endosomal defect to craniofacial patterning.
evidence:
- reference: PMID:26192890
reference_title: "Intellectual disability, muscle weakness and characteristic face in three siblings: A newly described recessive syndrome mapping to 3p24.3-p25.3."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "including highly arched eyebrows, down-slanting palpebral fissures, prominent nasal bridge, prominent nose, columella extending below alae nasi, narrow mouth, narrow palate, and dental caries"
explanation: "Records the feature in affected siblings. INDIRECT because the sentence enumerates the face without deriving it from the endosomal defect."
- target: Prominent nose
description: >-
A constituent of the facial phenotype, wired from the mechanism on the same
footing as the coarse dysmorphism node and everything else in this entry. No
published mechanism connects the endosomal defect to craniofacial patterning.
evidence:
- reference: PMID:26192890
reference_title: "Intellectual disability, muscle weakness and characteristic face in three siblings: A newly described recessive syndrome mapping to 3p24.3-p25.3."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "including highly arched eyebrows, down-slanting palpebral fissures, prominent nasal bridge, prominent nose, columella extending below alae nasi, narrow mouth, narrow palate, and dental caries"
explanation: "Records the feature in affected siblings. INDIRECT because the sentence enumerates the face without deriving it from the endosomal defect."
- target: Low hanging columella
description: >-
A constituent of the facial phenotype, wired from the mechanism on the same
footing as the coarse dysmorphism node and everything else in this entry. No
published mechanism connects the endosomal defect to craniofacial patterning.
evidence:
- reference: PMID:26192890
reference_title: "Intellectual disability, muscle weakness and characteristic face in three siblings: A newly described recessive syndrome mapping to 3p24.3-p25.3."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "including highly arched eyebrows, down-slanting palpebral fissures, prominent nasal bridge, prominent nose, columella extending below alae nasi, narrow mouth, narrow palate, and dental caries"
explanation: "Records the feature in affected siblings. INDIRECT because the sentence enumerates the face without deriving it from the endosomal defect."
- target: Narrow mouth
description: >-
A constituent of the facial phenotype, wired from the mechanism on the same
footing as the coarse dysmorphism node and everything else in this entry. No
published mechanism connects the endosomal defect to craniofacial patterning.
evidence:
- reference: PMID:26192890
reference_title: "Intellectual disability, muscle weakness and characteristic face in three siblings: A newly described recessive syndrome mapping to 3p24.3-p25.3."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "including highly arched eyebrows, down-slanting palpebral fissures, prominent nasal bridge, prominent nose, columella extending below alae nasi, narrow mouth, narrow palate, and dental caries"
explanation: "Records the feature in affected siblings. INDIRECT because the sentence enumerates the face without deriving it from the endosomal defect."
- target: Narrow palate
description: >-
A constituent of the facial phenotype, wired from the mechanism on the same
footing as the coarse dysmorphism node and everything else in this entry. No
published mechanism connects the endosomal defect to craniofacial patterning.
evidence:
- reference: PMID:26192890
reference_title: "Intellectual disability, muscle weakness and characteristic face in three siblings: A newly described recessive syndrome mapping to 3p24.3-p25.3."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "including highly arched eyebrows, down-slanting palpebral fissures, prominent nasal bridge, prominent nose, columella extending below alae nasi, narrow mouth, narrow palate, and dental caries"
explanation: "Records the feature in affected siblings. INDIRECT because the sentence enumerates the face without deriving it from the endosomal defect."
- target: Carious teeth
description: >-
A constituent of the facial phenotype, wired from the mechanism on the same
footing as the coarse dysmorphism node and everything else in this entry. No
published mechanism connects the endosomal defect to craniofacial patterning.
evidence:
- reference: PMID:26192890
reference_title: "Intellectual disability, muscle weakness and characteristic face in three siblings: A newly described recessive syndrome mapping to 3p24.3-p25.3."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "including highly arched eyebrows, down-slanting palpebral fissures, prominent nasal bridge, prominent nose, columella extending below alae nasi, narrow mouth, narrow palate, and dental caries"
explanation: "Records the feature in affected siblings. INDIRECT because the sentence enumerates the face without deriving it from the endosomal defect."
phenotypes:
- name: Progressive muscle weakness
category: Clinical
description: >-
Progressive weakness, one of the four features in the disorder's defining
description. The source does not specify distribution, severity or age of
onset, so none is asserted here.
diagnostic: true
phenotype_term:
preferred_term: Progressive muscle weakness
term:
id: HP:0003323
label: Progressive muscle weakness
evidence:
- reference: PMID:35652444
reference_title: "RABENOSYN separation-of-function mutations uncouple endosomal recycling from lysosomal degradation, causing a distinct Mendelian disorder."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "a novel Mendelian disorder consisting of progressive muscle weakness, facial dysmorphisms, ophthalmoplegia and intellectual disability"
explanation: "Progressive muscle weakness named as a defining feature."
- reference: PMID:26192890
reference_title: "Intellectual disability, muscle weakness and characteristic face in three siblings: A newly described recessive syndrome mapping to 3p24.3-p25.3."
supports: SUPPORT
directness: DIRECT
evidence_source: HUMAN_CLINICAL
snippet: "Electrophysiological studies showed signs of myopathy, and muscle biopsies demonstrated only nonspecific signs."
explanation: "The electrophysiological correlate of the weakness, with the negative biopsy finding recorded alongside it."
- name: Leukoencephalopathy
category: Radiographic
description: >-
White-matter signal abnormality on brain MRI in two of the three siblings in
the founding pedigree, reported together with frontal and parietal
hyperintensities. Non-specific, and explicitly variable across the cohort.
phenotype_term:
preferred_term: Leukoencephalopathy
term:
id: HP:0002352
label: Leukoencephalopathy
evidence:
- reference: PMID:26192890
reference_title: "Intellectual disability, muscle weakness and characteristic face in three siblings: A newly described recessive syndrome mapping to 3p24.3-p25.3."
supports: SUPPORT
directness: DIRECT
evidence_source: HUMAN_CLINICAL
snippet: "Brain MRIs in two of the sibs showed leukencephalopathy with delayed myelination, frontal and parietal hyperintensities, and hippocampal atrophy in one."
explanation: "The imaging finding in the founding pedigree, in two of three siblings."
- name: Delayed myelination
category: Radiographic
description: >-
Delayed myelination accompanying the white-matter change, from the same
imaging in the same two siblings.
phenotype_term:
preferred_term: Delayed myelination
term:
id: HP:0012448
label: Delayed myelination
evidence:
- reference: PMID:26192890
reference_title: "Intellectual disability, muscle weakness and characteristic face in three siblings: A newly described recessive syndrome mapping to 3p24.3-p25.3."
supports: SUPPORT
directness: DIRECT
evidence_source: HUMAN_CLINICAL
snippet: "Brain MRIs in two of the sibs showed leukencephalopathy with delayed myelination, frontal and parietal hyperintensities, and hippocampal atrophy in one."
explanation: "The same MRI sentence, curated here for the myelination finding specifically."
- name: Ophthalmoplegia
category: Clinical
description: >-
Impaired extraocular movement. Bound to the general ophthalmoplegia concept
rather than to external or progressive external ophthalmoplegia: the source
says only "ophthalmoplegia", and the narrower HPO terms would assert a
distribution and a course it does not report.
diagnostic: true
phenotype_term:
preferred_term: Ophthalmoplegia
term:
id: HP:0000602
label: Ophthalmoplegia
evidence:
- reference: PMID:35652444
reference_title: "RABENOSYN separation-of-function mutations uncouple endosomal recycling from lysosomal degradation, causing a distinct Mendelian disorder."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "a novel Mendelian disorder consisting of progressive muscle weakness, facial dysmorphisms, ophthalmoplegia and intellectual disability"
explanation: "Ophthalmoplegia named as a defining feature, without further qualification."
- reference: PMID:26192890
reference_title: "Intellectual disability, muscle weakness and characteristic face in three siblings: A newly described recessive syndrome mapping to 3p24.3-p25.3."
supports: SUPPORT
directness: DIRECT
evidence_source: HUMAN_CLINICAL
snippet: "and in one of them an inability to abduct the left eye"
explanation: "The concrete ocular observation behind the ophthalmoplegia, in one of the three founding siblings - a unilateral abduction deficit rather than a global ophthalmoplegia."
- name: Intellectual disability
category: Clinical
description: Cognitive impairment. Severity is not stated in the source and is not asserted.
diagnostic: true
phenotype_term:
preferred_term: Intellectual disability
term:
id: HP:0001249
label: Intellectual disability
evidence:
- reference: PMID:35652444
reference_title: "RABENOSYN separation-of-function mutations uncouple endosomal recycling from lysosomal degradation, causing a distinct Mendelian disorder."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "a novel Mendelian disorder consisting of progressive muscle weakness, facial dysmorphisms, ophthalmoplegia and intellectual disability"
explanation: "Intellectual disability named as a defining feature."
- name: Highly arched eyebrow
category: Clinical
description: >-
One of the eight facial features enumerated in the founding pedigree. Curated
individually rather than left inside the coarse dysmorphism node, because the
source does name it.
phenotype_term:
preferred_term: Highly arched eyebrow
term:
id: HP:0002553
label: Highly arched eyebrow
evidence:
- reference: PMID:26192890
reference_title: "Intellectual disability, muscle weakness and characteristic face in three siblings: A newly described recessive syndrome mapping to 3p24.3-p25.3."
supports: SUPPORT
directness: DIRECT
evidence_source: HUMAN_CLINICAL
snippet: "including highly arched eyebrows, down-slanting palpebral fissures, prominent nasal bridge, prominent nose, columella extending below alae nasi, narrow mouth, narrow palate, and dental caries"
explanation: "Enumerates highly arched eyebrows among the facial features of the three founding siblings."
- name: Downslanted palpebral fissures
category: Clinical
description: >-
One of the eight facial features enumerated in the founding pedigree. Curated
individually rather than left inside the coarse dysmorphism node, because the
source does name it.
phenotype_term:
preferred_term: Downslanted palpebral fissures
term:
id: HP:0000494
label: Downslanted palpebral fissures
evidence:
- reference: PMID:26192890
reference_title: "Intellectual disability, muscle weakness and characteristic face in three siblings: A newly described recessive syndrome mapping to 3p24.3-p25.3."
supports: SUPPORT
directness: DIRECT
evidence_source: HUMAN_CLINICAL
snippet: "including highly arched eyebrows, down-slanting palpebral fissures, prominent nasal bridge, prominent nose, columella extending below alae nasi, narrow mouth, narrow palate, and dental caries"
explanation: "Enumerates down-slanting palpebral fissures among the facial features of the three founding siblings."
- name: Prominent nasal bridge
category: Clinical
description: >-
One of the eight facial features enumerated in the founding pedigree. Curated
individually rather than left inside the coarse dysmorphism node, because the
source does name it.
phenotype_term:
preferred_term: Prominent nasal bridge
term:
id: HP:0000426
label: Prominent nasal bridge
evidence:
- reference: PMID:26192890
reference_title: "Intellectual disability, muscle weakness and characteristic face in three siblings: A newly described recessive syndrome mapping to 3p24.3-p25.3."
supports: SUPPORT
directness: DIRECT
evidence_source: HUMAN_CLINICAL
snippet: "including highly arched eyebrows, down-slanting palpebral fissures, prominent nasal bridge, prominent nose, columella extending below alae nasi, narrow mouth, narrow palate, and dental caries"
explanation: "Enumerates prominent nasal bridge among the facial features of the three founding siblings."
- name: Prominent nose
category: Clinical
description: >-
One of the eight facial features enumerated in the founding pedigree. Curated
individually rather than left inside the coarse dysmorphism node, because the
source does name it.
phenotype_term:
preferred_term: Prominent nose
term:
id: HP:0000448
label: Prominent nose
evidence:
- reference: PMID:26192890
reference_title: "Intellectual disability, muscle weakness and characteristic face in three siblings: A newly described recessive syndrome mapping to 3p24.3-p25.3."
supports: SUPPORT
directness: DIRECT
evidence_source: HUMAN_CLINICAL
snippet: "including highly arched eyebrows, down-slanting palpebral fissures, prominent nasal bridge, prominent nose, columella extending below alae nasi, narrow mouth, narrow palate, and dental caries"
explanation: "Enumerates prominent nose among the facial features of the three founding siblings."
- name: Low hanging columella
category: Clinical
description: >-
One of the eight facial features enumerated in the founding pedigree. Curated
individually rather than left inside the coarse dysmorphism node, because the
source does name it.
phenotype_term:
preferred_term: Low hanging columella
term:
id: HP:0009765
label: Low hanging columella
evidence:
- reference: PMID:26192890
reference_title: "Intellectual disability, muscle weakness and characteristic face in three siblings: A newly described recessive syndrome mapping to 3p24.3-p25.3."
supports: SUPPORT
directness: DIRECT
evidence_source: HUMAN_CLINICAL
snippet: "including highly arched eyebrows, down-slanting palpebral fissures, prominent nasal bridge, prominent nose, columella extending below alae nasi, narrow mouth, narrow palate, and dental caries"
explanation: "Enumerates columella extending below alae nasi among the facial features of the three founding siblings."
- name: Narrow mouth
category: Clinical
description: >-
One of the eight facial features enumerated in the founding pedigree. Curated
individually rather than left inside the coarse dysmorphism node, because the
source does name it.
phenotype_term:
preferred_term: Narrow mouth
term:
id: HP:0000160
label: Narrow mouth
evidence:
- reference: PMID:26192890
reference_title: "Intellectual disability, muscle weakness and characteristic face in three siblings: A newly described recessive syndrome mapping to 3p24.3-p25.3."
supports: SUPPORT
directness: DIRECT
evidence_source: HUMAN_CLINICAL
snippet: "including highly arched eyebrows, down-slanting palpebral fissures, prominent nasal bridge, prominent nose, columella extending below alae nasi, narrow mouth, narrow palate, and dental caries"
explanation: "Enumerates narrow mouth among the facial features of the three founding siblings."
- name: Narrow palate
category: Clinical
description: >-
One of the eight facial features enumerated in the founding pedigree. Curated
individually rather than left inside the coarse dysmorphism node, because the
source does name it.
phenotype_term:
preferred_term: Narrow palate
term:
id: HP:0000189
label: Narrow palate
evidence:
- reference: PMID:26192890
reference_title: "Intellectual disability, muscle weakness and characteristic face in three siblings: A newly described recessive syndrome mapping to 3p24.3-p25.3."
supports: SUPPORT
directness: DIRECT
evidence_source: HUMAN_CLINICAL
snippet: "including highly arched eyebrows, down-slanting palpebral fissures, prominent nasal bridge, prominent nose, columella extending below alae nasi, narrow mouth, narrow palate, and dental caries"
explanation: "Enumerates narrow palate among the facial features of the three founding siblings."
- name: Carious teeth
category: Clinical
description: >-
One of the eight facial features enumerated in the founding pedigree. Curated
individually rather than left inside the coarse dysmorphism node, because the
source does name it.
phenotype_term:
preferred_term: Carious teeth
term:
id: HP:0000670
label: Carious teeth
evidence:
- reference: PMID:26192890
reference_title: "Intellectual disability, muscle weakness and characteristic face in three siblings: A newly described recessive syndrome mapping to 3p24.3-p25.3."
supports: SUPPORT
directness: DIRECT
evidence_source: HUMAN_CLINICAL
snippet: "including highly arched eyebrows, down-slanting palpebral fissures, prominent nasal bridge, prominent nose, columella extending below alae nasi, narrow mouth, narrow palate, and dental caries"
explanation: "Enumerates dental caries among the facial features of the three founding siblings."
- name: Abnormal facial shape
category: Clinical
description: >-
Facial dysmorphism as the gene paper states it - one of the four features it
names as constituting this disorder, characterised no further. That sentence is
this node's only evidence, which is what makes SOURCE_UNSPECIFIED true of it.
The eight individual features are known, from the founding clinical report, and
are curated as their own phenotypes beside this node rather than folded into it.
phenotype_term:
preferred_term: Abnormal facial shape
term:
id: HP:0001999
label: Abnormal facial shape
coarse_binding_basis: SOURCE_UNSPECIFIED
evidence:
- reference: PMID:35652444
reference_title: "RABENOSYN separation-of-function mutations uncouple endosomal recycling from lysosomal degradation, causing a distinct Mendelian disorder."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "a novel Mendelian disorder consisting of progressive muscle weakness, facial dysmorphisms, ophthalmoplegia and intellectual disability"
explanation: "Facial dysmorphism named as a defining feature, with no individual features itemised."
genetic:
- name: RBSN
gene_term:
preferred_term: RBSN
term:
id: hgnc:20759
label: RBSN
relationship_type: CAUSATIVE
variant_origin: GERMLINE
association: Recessive FYVE-domain missense alleles p.Arg180Gly and p.Gly183Arg
presence: Positive
inheritance:
- name: Autosomal recessive
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
notes: >-
RBSN is one gene with two named Mendelian disorders, and which one a patient
has depends on which residue is hit. The two alleles curated here sit in the
FYVE domain, three residues apart, and give this neuromuscular-cognitive
phenotype; p.Gly97Arg gives congenital myelofibrosis with anemia, neutropenia,
developmental delay and ocular abnormalities (MONDO:0975797), curated
separately. A third homozygous allele, p.Gly425Arg (PMID:25233840), fits
neither and is analysed in the sibling entry's `rbsn_allelic_series_nosology`
discussion rather than re-argued here.
Practical consequence: an RBSN variant report cannot be interpreted without
the residue. "Pathogenic variant in RBSN" does not name a disease.
evidence:
- reference: PMID:35652444
reference_title: "RABENOSYN separation-of-function mutations uncouple endosomal recycling from lysosomal degradation, causing a distinct Mendelian disorder."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Using exome sequencing, we identified recessively acting germline alleles p.Arg180Gly and p.Gly183Arg, which are both situated in the FYVE domain of RBSN."
explanation: "The two causal alleles and their shared domain."
- reference: PMID:35652444
reference_title: "RABENOSYN separation-of-function mutations uncouple endosomal recycling from lysosomal degradation, causing a distinct Mendelian disorder."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We conclude that distinct germline mutations in RBSN cause non-overlapping phenotypes with specific and discrete endolysosomal cellular defects."
explanation: "The authors' conclusion that RBSN alleles partition by phenotype, which is the basis for curating this as a separate disease."
diagnosis:
- name: Exome Sequencing
description: >-
The diagnosis is molecular; the disorder was defined by exome sequencing and
there is no biochemical or imaging marker for it. Because the two RBSN
disorders are distinguished by residue rather than by gene, the report must be
read at variant level.
diagnosis_term:
preferred_term: exome sequencing
term:
id: NCIT:C101295
label: Whole Exome Sequencing
evidence:
- reference: PMID:35652444
reference_title: "RABENOSYN separation-of-function mutations uncouple endosomal recycling from lysosomal degradation, causing a distinct Mendelian disorder."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Using exome sequencing, we identified recessively acting germline alleles p.Arg180Gly and p.Gly183Arg, which are both situated in the FYVE domain of RBSN."
explanation: "Exome sequencing as the method that identified the disorder."
prevalence:
- population: Worldwide
measure_type: CASES_IN_LITERATURE
prevalence_class: ULTRA_RARE
notes: >-
One report, two alleles. PubMed was searched on 2026-09-21 for RBSN,
rabenosyn-5 and ZFYVE20; no case series, cohort or second clinical report of
this disorder was returned beyond the defining paper. No rate is recorded, and
no case count is asserted either, because the abstract states the number of
alleles rather than the number of patients.
evidence:
- reference: PMID:35652444
reference_title: "RABENOSYN separation-of-function mutations uncouple endosomal recycling from lysosomal degradation, causing a distinct Mendelian disorder."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Here, we present clinical, genetic, cellular and biochemical evidence that two distinct RBSN missense variants are responsible for a novel Mendelian disorder consisting of progressive muscle weakness, facial dysmorphisms, ophthalmoplegia and intellectual disability."
explanation: "Describes the disorder as novel and reports two variants, which is the whole of the clinical literature and the basis for the ULTRA_RARE band."
clinical_burden:
burden_level: VARIABLE
rationale: >-
Set as VARIABLE to record uncertainty rather than measured variability, and
that distinction is the point. The disorder combines progressive muscle
weakness with intellectual disability, which is a high-burden combination in
principle. But the single defining report gives no severity grading, no age of
onset, no rate of progression and no survival data, and it describes two
alleles rather than a case series. There is not enough here to place the
burden on the scale honestly, and an assertion of SEVERE would be a guess
dressed as a finding.
evidence:
- reference: PMID:35652444
reference_title: "RABENOSYN separation-of-function mutations uncouple endosomal recycling from lysosomal degradation, causing a distinct Mendelian disorder."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "a novel Mendelian disorder consisting of progressive muscle weakness, facial dysmorphisms, ophthalmoplegia and intellectual disability"
explanation: "The only characterisation of the phenotype available. INDIRECT with respect to burden: it names features without grading any of them."
discussions:
- discussion_id: rbsn_separation_of_function_not_expressible
status: OPEN
kind: CURATION_TODO
attaches_to:
- pathophysiology#RBSN FYVE-Domain Missense Variant
- pathophysiology#Delayed Endosomal Maturation with Preserved Recycling
prompt: >-
`FunctionalImpactEnum` has no value for a separation-of-function allele. Is
that a gap worth a schema change, or is `LOSS_OF_FUNCTION` plus prose the right
answer?
rationale: >-
The genetic_context on the lesion node records `LOSS_OF_FUNCTION`, which is
true and loses the point. What these alleles do is abolish one downstream
function of rabenosyn-5 while leaving another intact, on the same allele, in
the same cell - the authors' term is separation-of-function, and it is the
finding the paper exists to report. A query over the KB for
`LOSS_OF_FUNCTION` will return this variant next to alleles that simply
destroy their gene product, and nothing in the structured record distinguishes
them.
The available enum values do not help: `PARTIAL_LOSS_OF_FUNCTION` means
reduced activity, not selectively lost activity, and would be a different and
wrong claim here. `HYPOMORPHIC` has the same problem.
Whether this warrants a schema change is genuinely open - the pattern may be
rare enough that prose is adequate, and the `extend-schema` skill's first
question is whether a curation need warrants one at all. Recorded so that the
next curator who meets a separation-of-function allele finds a precedent
rather than inventing a convention.
- discussion_id: rbsn_cellular_defect_to_tissue_phenotype
status: OPEN
kind: KNOWLEDGE_GAP
attaches_to:
- pathophysiology#Delayed Endosomal Maturation with Preserved Recycling
- phenotypes#Progressive muscle weakness
prompt: >-
How does delayed endosome-to-lysosome delivery produce progressive muscle
weakness, ophthalmoplegia and intellectual disability specifically?
rationale: >-
The cellular defect was measured in fibroblasts, which are not an affected
tissue. Nothing connects it to muscle, to extraocular muscle in particular, or
to the developing brain, and the defining paper does not attempt the
connection - it establishes the allele, the biochemistry and the cell
phenotype, and reports the clinical features alongside them.
The edges from the cellular node to the phenotypes are therefore marked
INDIRECT rather than omitted: the phenotypes are certainly caused by the
variants, and the route from the measured cellular defect to them is not
established. That distinction is what the `directness` axis is for, and it is
worth being explicit that these edges assert attribution, not mechanism.
proposed_experiments:
- experiment_id: rbsn_patient_myotube_cargo_trafficking
name: Lysosomal cargo delivery in patient-derived myotubes
description: >-
Repeat the fibroblast cargo-accumulation assay in myotubes differentiated
from patient cells, and in an unaffected cell type from the same patient as a
within-individual control. If the defect is larger in muscle than in
fibroblasts, tissue vulnerability is quantitative; if it is the same, the
explanation lies elsewhere and the fibroblast result is not informative about
why muscle fails.
readouts:
- name: Accumulation of lysosomally-tagged cargo in myotubes
target: pathophysiology#Delayed Endosomal Maturation with Preserved Recycling
direction: INCREASED
interpretation: >-
Greater accumulation in myotubes than in autologous fibroblasts would
support differential tissue vulnerability as the explanation for the
neuromuscular phenotype.
- discussion_id: rbsn_single_report_evidence_base
status: OPEN
kind: KNOWLEDGE_GAP
attaches_to:
- disease#Kariminejad Neurodevelopmental Syndrome
prompt: >-
Has any second family with FYVE-domain RBSN disease been reported, and does the
phenotype hold up?
rationale: >-
Every clinical statement in this entry comes from one paper. That paper is
unusually strong for a first report - it carries genetic, cellular and
biochemical evidence rather than segregation alone - but it is still one
report, and the phenotype description is four features in a single sentence
with no severity, onset or course attached. A second family would either
confirm the syndrome or reveal that the four features are the ascertainable
tip of something broader.
Relevant to how this entry should be read: the sparseness of the phenotype
section here is a property of the literature, not of the curation. Nothing was
left out.
- discussion_id: rbsn_aggregator_phenotypes_include_a_disputed_patient
status: OPEN
kind: CONTROVERSY
attaches_to:
- disease#Kariminejad Neurodevelopmental Syndrome
- genetic#RBSN
prompt: >-
Monarch's HPO annotation set for MONDO:0975795 is sourced in part to
PMID:25233840 - the p.Gly425Arg patient that the sibling RBSN entry
deliberately declined to assign to either named disorder. Should that
patient's phenotypes be counted as phenotypes of this disease?
rationale: >-
This is a disagreement between an automated aggregator and a careful read of
the primary sources, and it is worth recording because a curator working from
the aggregated list would not see it.
The sibling entry
(kb/disorders/Congenital_Myelofibrosis_With_Anemia_Neutropenia_Developmental_Delay_And_Ocular_Abnormalities.yaml)
analysed the p.Gly425Arg patient in its `rbsn_allelic_series_nosology`
discussion and declined to count her as a case of either RBSN disorder,
because ClinVar does not classify that allele under either named condition and
her phenotype - intractable seizures, developmental delay, dysmorphism and a
mild marrow phenotype - fits neither cleanly. Meanwhile some cross-referencing
pipeline has provisionally pulled her into this disease's phenotype profile.
The practical consequence is specific. A phenotype list taken from that
aggregated set would import intention tremor, ptosis, coxa valga and several
dysmorphic features into this entry on the strength of a patient whose
membership is disputed, and nothing in the list itself would say which
phenotypes came from which paper.
Scope of this entry's `phenotypes` section, which is wider than it first was.
It now carries the four features PMID:35652444 names as constituting the
disorder, plus the imaging findings and the eight enumerated facial features
from the founding clinical report PMID:26192890 - every one with an exact quote
from the paper it came from.
A second class of phenotype is excluded, and for a different reason from the
disputed patient. Aggregated sources and the deep-research report attribute
global developmental delay, hypotonia, spastic paraplegia, sensorimotor
peripheral neuropathy, short stature, elevated creatine kinase and hippocampal
atrophy to this disease, drawing on the second family and on OMIM's clinical
synopsis. Those are probably real. They are omitted because none is quotable:
the relevant caches here are abstract-only, and an OMIM clinical synopsis is
not a citable source in this repository. That is a limit of what can be
verified, not a judgement that the features are absent, and it is recorded so
a future curator does not re-derive the question from scratch.
Resolving it means reading PMID:25233840 against both disorders and deciding
where, if anywhere, that patient belongs, then updating the sibling entry's
discussion node with the answer rather than leaving two entries carrying
different provisional positions.
notes: >-
Raised by the automated second-opinion comment on the claim issue
(dismech#12393), which surfaced the aggregator's sourcing. The identifiers it
supplied - OMIM:620937, DOID:0061158, MedGen:1874901, UMLS:C5975371, and the
ClinVar accessions VCV003340064 (p.Arg180Gly) and VCV003340063 (p.Gly183Arg) -
are recorded here rather than curated into `mappings`, because none of them was
independently retrieved during this curation.
Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.
Record notes
Entry scope, and the lump/split decision this entry exists to make. The stub (stubs/Kariminejad_Neurodevelopmental_Syndrome.yaml) left `entry_type: UNDECIDED` and set out the question: RBSN has two named Mendelian disorders, and whether the second is a distinct DISEASE or a `has_subtypes` row on the first had not been settled. It is curated here as a DISEASE, on three grounds that are independent of each other: 1. The alleles segregate cleanly by phenotype. ClinVar keys p.Arg180Gly and p.Gly183Arg to this condition and p.Gly97Arg to MONDO:0975797, and that assignment is recorded in the already-curated sibling entry kb/disorders/Congenital_Myelofibrosis_With_Anemia_Neutropenia_Developmental_Delay_And_Ocular_Abnormalities.yaml, whose curator read the ClinVar records through the NCBI E-utilities esummary API on 2026-09-19. This entry did not re-derive that; it relies on it and says so. 2. The phenotypes do not overlap. This disorder is neuromuscular and cognitive; the sibling is a congenital bone marrow failure syndrome with myelofibrosis, neutropenia and anemia. They share developmental delay and little else. 3. The cellular defects are different and were measured in the same paper. PMID:35652444 shows that the FYVE-domain alleles leave endosomal recycling intact and impair lysosomal delivery, and concludes explicitly that distinct germline RBSN mutations cause non-overlapping phenotypes with discrete endolysosomal defects. MONDO agrees: the two are separate terms, and neither is a descendant of the other. Curating this as a `has_subtypes` row on the sibling would have asserted a hierarchy the ontology does not carry - the same error that `Usmani-Riazuddin_Syndrome_Autosomal_Dominant` records having avoided, and for the same reason. What is NOT settled, and is carried forward rather than resolved here: a third RBSN patient, homozygous p.Gly425Arg (PMID:25233840), fits neither disorder cleanly. The sibling entry analyses this at length in its `rbsn_allelic_series_nosology` discussion and declines to count her as a case of either. This entry takes the same position and does not re-argue it; see that discussion rather than duplicating it. Evidence base. One paper, two families, two alleles - PMID:35652444 is the defining and essentially the only clinical source. Everything phenotypic in this entry traces to it. The supporting cell-biology references describe rabenosyn-5 in normal cells, not in patients. Module conformance checked and left unset. `just list-modules` was read and `kb/modules/` grepped for `endosom`, `lysosom`, `traffick`, `vesicle`, `Rab`, `autophag` and `sorting`. There is no endosomal-maturation or membrane-trafficking module. The lysosomal storage modules are not applicable: this is a delivery defect upstream of the lysosome with no storage material described, and conforming to one would assert accumulation of an undegraded substrate that nobody has reported. No GeneReviews chapter exists for this disorder. Checked offline with `just check-genereviews kb/disorders/Kariminejad_Neurodevelopmental_Syndrome.yaml` against the committed Bookshelf index; NO_CHAPTER for GeneReviews. Deep research. `just preflight-dr` returns PASS against MONDO:0975795 (RBSN mentioned 31 times, no rival gene above 5, and the report's OMIM 620937 matches the MONDO xref). Its single most useful contribution was PMID:26192890 - Kariminejad et al. 2015, the founding clinical description the syndrome is named after, published seven years before the gene was identified. This entry did not cite it. It supplies the electrophysiological myopathy with non-specific biopsies, the leukoencephalopathy and delayed myelination on MRI, the unilateral abduction deficit behind the ophthalmoplegia, and the only enumeration of the facial features anywhere in the literature - every other source calls them dysmorphic and stops. Two things in the report's own validation output were checked rather than accepted. All three of its "terms named as a different term" findings are artifacts of the validator reading a phenotype table's *frequency* column as the term name ("All (6/6)", "Frequent", "1 patient"); none is a wrong binding. It also flags `GO:0017137` as obsolete, replaced by `GO:0031267` - this entry uses neither, so nothing followed from it. Pathograph wiring. All fourteen phenotypes are wired from `Delayed Endosomal Maturation with Preserved Recycling`, and the reason they are all wired the same way is that they all rest on the same kind of claim. Four come from one sentence in PMID:35652444 naming the features that constitute the disorder; two are the founding paper's imaging findings; eight are the individual facial features that same paper enumerates. Not one of the fourteen has a published mechanism connecting it to the endosomal defect, which is exactly what the `rbsn_cellular_defect_to_tissue_phenotype` discussion records. Every edge is therefore `directness: INDIRECT` and says so. Wiring two of the four defining features and leaving the other two isolated, which is how this entry first stood, asserted a distinction between them that no source makes. The facial features are curated individually rather than folded into the coarse `Abnormal facial shape` node, and the two coexist deliberately. The coarse node carries the gene paper's sentence, which names dysmorphism and characterises it no further - that, and only that, is what makes its `SOURCE_UNSPECIFIED` basis true. An earlier revision of this entry attached the founding paper's enumerating sentence to that same node, which falsified the declared basis: a source there plainly did characterise it further, in the snippet directly below the declaration. `just check-coarse-phenotypes` cannot catch that, because it checks that a basis is declared rather than that it is the right one. The remedy was the one the `coarse-phenotype-bindings` skill prescribes - if you can list the findings, they are phenotypes - so the eight are curated beside the coarse node and the enumerating quote moved onto them. `PATHOGRAPH_HUB` was considered and rejected: a hub is defined by convergence, and this node is one arm of a fourteen-way fan-out from a single upstream node, which is the pattern that skill warns is not a hub.
Review round 1 on PR #12433 · 2026-09-21T09:09:14Z · View source
Addressed the blocking finding and the suggestion from the ai4c-reviewer round on 9cbf37b9a. The blocking finding is correct and I created it in the previous round by improving the entry. Adding the founding paper's enumerating sentence to the Abnormal facial shape phenotype falsified the coarse_binding_basis SOURCE_UNSPECIFIED declared directly above it: that basis means the cited source characterises the finding no further, and the new snippet enumerated eight features. The declaration and its own evidence contradicted each other. check-coarse-phenotypes passes either way because it checks that a basis is declared, not that it is true. Remedy is the one the coarse-phenotype-bindings skill prescribes: if you can list the findings, they are phenotypes. The eight facial features are now curated individually beside the coarse node - Highly arched eyebrow HP:0002553, Downslanted palpebral fissures HP:0000494, Prominent nasal bridge HP:0000426, Prominent nose HP:0000448, Low hanging columella HP:0009765, Narrow mouth HP:0000160, Narrow palate HP:0000189, Carious teeth HP:0000670 - and the enumerating quote moved onto them. The coarse node keeps only the gene paper's sentence, which names dysmorphism and stops, so SOURCE_UNSPECIFIED is now true of the evidence that remains. Every CURIE was verified independently rather than taken from the review. Seven came from the reviewer and all seven check out against cache/hp/terms.csv with matching labels. The eighth, for columella extending below alae nasi, was not supplied: HP:0009765 Low hanging columella was found by searching and confirmed by reading its HPO definition, Columella extending inferior to the level of the nasal base when viewed from the side. PATHOGRAPH_HUB was considered for the coarse node, as the review suggested, and rejected. The skill defines a hub by convergence of incoming edges and warns specifically against declaring one on a node that is merely one arm of a wide fan-out. This node is one of fourteen targets of a single upstream node, which is the Rubinstein-Taybi pattern the skill describes. All eight new phenotypes are wired from the mechanism node on the same footing as the rest, keeping the internal consistency the previous round established. Coverage is 14/14. Suggestion taken: the rbsn_aggregator_phenotypes_include_a_disputed_patient discussion now covers the second exclusion class as well. Global developmental delay, hypotonia, spastic paraplegia, sensorimotor peripheral neuropathy, short stature, elevated creatine kinase and hippocampal atrophy are attributed to this disease by aggregated sources and by the deep-research report, drawing on the second family and OMIM's clinical synopsis. They are omitted because none is quotable - the caches are abstract-only and an OMIM synopsis is not citable here - which is a limit on verification rather than a judgement that the features are absent. Stale prose corrected in two places. The discussion said the phenotypes section was limited to the four features from PMID:35652444, which stopped being true when the imaging phenotypes were added. The notes said all six phenotypes are wired, which stopped being true at fourteen. Prose describing repository state rots, and both were rewritten rather than patched. Validation: just validate-disorders passes, 43/43 snippets verified, up from 28. check-coarse-phenotypes, check-duplicate-keys, check-entity-refs, check-causal-targets and check-qualifier-terms all clean. list-disconnected-phenotypes reports 14/14.
Reconcile OpenScientist deep-research report; wire pathograph · 2026-09-21T08:33:51Z · View source
Reconciled the OpenScientist deep-research run and fixed a pathograph inconsistency before opening the PR. preflight-dr returns PASS against MONDO:0975795: RBSN mentioned 31 times, no rival gene above 5, and the report's OMIM 620937 matches the MONDO xref. The report's single most useful contribution was PMID:26192890, Kariminejad et al. 2015 - the founding clinical description the syndrome is named after, published seven years before the gene was identified. This entry did not cite it at all, which was a real gap. It supplies four things no other source in the entry does: the electrophysiological signs of myopathy alongside non-specific muscle biopsies, the leukoencephalopathy with delayed myelination on MRI in two of the three siblings, the unilateral abduction deficit that is the concrete observation behind the ophthalmoplegia, and the only enumeration of the facial features anywhere in the literature. Every other source calls the face dysmorphic and stops. Two new phenotypes were curated from it, Leukoencephalopathy HP:0002352 and Delayed myelination HP:0012448, both looked up rather than recalled, and three existing phenotypes gained it as a second evidence item. Pathograph wiring. The entry previously wired two of its four phenotypes from Delayed Endosomal Maturation with Preserved Recycling and left the other two isolated - but all four rest on the SAME sentence in PMID:35652444, which names them as the four features constituting the disorder. Wiring two and not the other two asserted a distinction between them that no source makes. All six phenotypes are now wired, each with directness INDIRECT and a description saying plainly that no published mechanism connects it to the endosomal defect, which is what the rbsn_cellular_defect_to_tissue_phenotype discussion already records. Coverage is 6/6. Term discipline. All three of the report's terms named as a different term findings are artifacts of the validator reading a phenotype table's frequency column as the term name - All (6/6), Frequent, 1 patient - and none is a wrong binding. That is the same false-positive class reported as issue #12415, now seen in a second report. The report also flags GO:0017137 as obsolete, replaced by GO:0031267; this entry uses neither. One error caught before commit. Four new evidence items were drafted with a reference_title for PMID:35652444 written from memory rather than copied from the cache frontmatter - Rabenosyn-5 suppresses non-homologous end joining... which is not that paper. The real title is RABENOSYN separation-of-function mutations uncouple endosomal recycling from lysosomal degradation, causing a distinct Mendelian disorder. Corrected and re-checked with check-reference-titles. Two fetched references, PMID:17235359 and PMID:18685079, were pruned rather than committed: they are model-organism endosomal-trafficking papers the report cites, and nothing in this entry ended up citing them. Validation: just validate-disorders passes, 28/28 snippets verified, up from 19. check-duplicate-keys, check-entity-refs, check-causal-targets, check-qualifier-terms and check-reference-titles all clean.
Create: Kariminejad Neurodevelopmental Syndrome (RBSN FYVE-domain disorder) · 2026-09-21T05:25:54Z · View source
New DISEASE entry for MONDO:0975795, the RBSN FYVE-domain disorder. The lump/split decision this entry exists to make. The stub left entry_type UNDECIDED and set out the question: RBSN has two named Mendelian disorders and whether the second is a distinct DISEASE or a has_subtypes row on the first had not been settled. Curated as DISEASE, on three independent grounds. The alleles segregate cleanly by phenotype, with ClinVar keying p.Arg180Gly and p.Gly183Arg to this condition and p.Gly97Arg to MONDO:0975797 - an assignment recorded in the already-curated sibling entry, whose curator read the ClinVar records through the NCBI esummary API on 2026-09-19, and which this entry relies on rather than re-deriving. The phenotypes do not overlap: this disorder is neuromuscular and cognitive, the sibling is a congenital bone marrow failure syndrome. And the cellular defects are different and were measured in the same paper, which concludes explicitly that distinct germline RBSN mutations cause non-overlapping phenotypes with discrete endolysosomal defects. MONDO agrees - the two are separate terms and neither descends from the other, so a has_subtypes row would have asserted a hierarchy the ontology does not carry. The automated second-opinion comment on claim issue #12393 reached the same conclusion independently. The mechanism is unusually clean and is the reason the entry is worth reading. The two alleles sit three residues apart in the FYVE finger, abolish PI3P binding, and so prevent rabenosyn-5 reaching the early endosome at all. Yet endosomal recycling is unaffected; what accumulates in patient fibroblasts is cargo tagged for lysosomal degradation. The authors call these separation-of-function alleles. That selectivity is curated as its own node, because it is the claim the whole nosology rests on: if the FYVE alleles impaired both arms there would be no principled reason to separate this disorder from the RBSN myelofibrosis syndrome. A schema gap recorded as a CURATION_TODO rather than worked around: FunctionalImpactEnum has no value for a separation-of-function allele. The genetic_context records LOSS_OF_FUNCTION, which is true and loses the point - a query for LOSS_OF_FUNCTION returns this variant next to alleles that simply destroy their gene product. PARTIAL_LOSS_OF_FUNCTION and HYPOMORPHIC both mean reduced activity rather than selectively lost activity and would be different and wrong claims. Whether this warrants a schema change is genuinely open; recorded so the next curator meeting such an allele finds a precedent rather than inventing a convention. A live disagreement between an automated aggregator and a careful human read, carried as a CONTROVERSY discussion. Monarch's HPO annotation set for MONDO:0975795 is sourced in part to PMID:25233840 - the p.Gly425Arg patient the sibling entry deliberately declined to assign to either RBSN disorder. A phenotype list taken from that aggregated set would import intention tremor, ptosis, coxa valga and several dysmorphic features into this entry on the strength of a patient whose membership is disputed, and nothing in the list itself would say which phenotypes came from which paper. This entry's phenotypes section is therefore limited to the four features stated in PMID:35652444, each with an exact quote - which is why it is short. Surfaced by the second-opinion comment. Module conformance left unset: kb/modules/ was grepped for endosom, lysosom, traffick, vesicle, Rab, autophag and sorting, and there is no endosomal-maturation or membrane-trafficking module. The lysosomal storage modules were rejected on positive grounds - this is a delivery defect upstream of the lysosome with no storage material described, and conforming would assert accumulation of an undegraded substrate nobody has reported. The second-opinion comment independently flagged the same caution about lysosomal_substrate_accumulation. Deep research: an OpenScientist run for this entry was launched with the others in this batch and had not completed when the entry was committed. It will be reconciled in a follow-up round before the pull request is opened. Validation. just validate passes with 19/19 snippets verified. just validate-terms, check-entity-refs, check-causal-targets, check-duplicate-keys and check-coarse-phenotypes all pass. just check-genereviews reports NO_CHAPTER for both collections. One evidence defect caught by validation during drafting: a supporting cell-biology item quoted PMID:22308388's title as its snippet. Reference validation rejected it and it was replaced with a result sentence from that abstract - the depletion experiment showing the effect is specific to rabenosyn-5 rather than general to early-endosomal proteins. That is the second title-as-snippet error in this batch of five entries.
Overview. KAREVS (OMIM #620937) is a rare autosomal recessive developmental disorder featuring global developmental delay (delayed walking by a few years, speech delay), impaired intellectual development, hypotonia and progressive muscle weakness, dysmorphic facial features, and variable nonspecific brain-imaging abnormalities. It was first delineated clinically by Kariminejad et al. (2015) in three Iranian siblings and molecularly resolved (gene = RBSN) by Paul et al. (2022) [PMID 26192890; PMID 35652444].
"two distinct RBSN missense variants are responsible for a novel Mendelian disorder consisting of progressive muscle weakness, facial dysmorphisms, ophthalmoplegia and intellectual disability." — Paul et al., 2022 (PMID 35652444)
Key identifiers. - OMIM: #620937 (phenotype); *609511 (RBSN gene) - MONDO: MONDO:0975795 - MedGen: C5975371 - Orphanet: No dedicated ORPHAcode identified as of report date (Not available) - ICD-10: No specific code; maps to Q87.8 / F79 (general dysmorphic/ID categories) (no dedicated code) - ICD-11: No specific code; would fall under LD2F.1Y / 6A00 classes (no dedicated code) - MeSH: No dedicated MeSH heading (Not available)
Synonyms / alternative names. Kariminejad neurodevelopmental syndrome; KAREVS; "Intellectual disability, muscle weakness and characteristic face" (original descriptive title, 3p24.3–p25.3-linked recessive syndrome). Not to be confused with Kariminejad-Nafissi syndrome (a distinct skeletal dysplasia).
Data provenance. Disease-level aggregated resources (OMIM, MONDO, MedGen) built from individual patient case reports (2 families, n=6). No EHR/registry-scale data exist.
Causal factor — genetic (Mendelian, monogenic). KAREVS is caused by homozygous missense variants in RBSN. No environmental, infectious, or multifactorial etiology is involved.
Genetic risk factors. - Causal variants: c.547G>A (p.Gly183Arg) — Iranian family; c.538C>G (p.Arg180Gly) — Canadian Cree family (both NM_022340.3, FYVE domain) [PMID 35652444]. - Consanguinity is the dominant risk factor: both families are consanguineous and homozygous by descent. - Being a heterozygous carrier of a pathogenic RBSN allele confers risk of affected offspring only when both parents carry it (AR). - Modifier genes: none identified; phenotypic variability (below) is currently unexplained (candidate modifiers not studied).
Environmental / lifestyle / occupational risk factors. Not applicable — no non-genetic contributors are known or expected for a monogenic recessive disorder.
Protective factors. None described. In principle, absence of a second pathogenic allele (heterozygosity) is fully protective (carriers are unaffected) [PMID 26192890].
Gene–environment interactions. None described.
All phenotypes derive from n=6 patients; "frequencies" are qualitative/small-count estimates from Kariminejad 2015 (Iranian family, F1) and Paul 2022 / OMIM clinical synopsis (Cree family, F2).
| Phenotype | Type | Onset | Severity/Course | Frequency | HPO |
|---|---|---|---|---|---|
| Intellectual disability (mild–moderate; IQ 42, 53) | Cognitive/behavioral | Childhood | Stable–mild, lifelong | All (6/6) | HP:0001249 |
| Global developmental delay (motor, speech) | Sign | Infancy/early childhood | Walking 18–25 mo | All | HP:0001263 / HP:0000750 / HP:0001270 |
| Progressive muscle weakness / myopathy | Sign | Childhood | Progressive | All | HP:0003198 / HP:0001324 |
| Hypotonia | Sign | Early | Variable | Frequent | HP:0001252 |
| Distinctive facies (highly arched eyebrows, downslanting palpebral fissures, prominent nasal bridge/nose, columella below alae nasi, narrow mouth, narrow/high palate, maxillary hypoplasia, small chin) | Physical | Congenital | Stable | All | HP:0002553; HP:0000494; HP:0000426; HP:0000160; HP:0000189; HP:0000347 |
| Ophthalmoplegia / impaired eye abduction; ptosis; amblyopia; hypermetropia | Sign | Childhood | Variable | Subset (≥1 each) | HP:0000602; HP:0000508; HP:0000646; HP:0000540 |
| Dental caries | Sign | Childhood | — | Reported | HP:0000670 |
| Short stature | Growth | Childhood | — | Reported (OMIM) | HP:0004322 |
| Leukoencephalopathy / delayed myelination / white-matter hyperintensities | Lab/imaging | Childhood | Nonspecific | 2/3 F1 | HP:0002352; HP:0012448 |
| Hippocampal atrophy; enlarged ventricles | Imaging | Childhood | — | Single patients | HP:0410170; HP:0002119 |
| Spastic paraplegia | Sign | Childhood | Progressive | 2/3 F2 | HP:0001258 |
| Sensorimotor peripheral neuropathy | Sign | Childhood | — | F2 | HP:0007141 |
| Elevated serum CK; elevated lactate; hyperlipidemia; microcephaly | Lab/physical | Childhood | — | Single patients (F2) | HP:0003236; HP:0002151; HP:0003077; HP:0000252 |
| Intention tremor | Sign | Childhood | — | 1 patient | HP:0002080 |
"...mild intellectual disability, progressive muscle weakness, and characteristic facies... highly arched eyebrows, down-slanting palpebral fissures, prominent nasal bridge, prominent nose, columella extending below alae nasi, narrow mouth, narrow palate, and dental caries, and in one of them an inability to abduct the left eye." — Kariminejad et al., 2015 (PMID 26192890)
Quality-of-life impact. No formal QoL instruments (EQ-5D/SF-36/PROMIS) have been applied (Not available). Expected functional impact: lifelong intellectual disability limiting independent living, plus progressive weakness/spasticity affecting mobility and self-care.
"distinct germline mutations in RBSN cause non-overlapping phenotypes with specific and discrete endolysosomal cellular defects." — Paul et al., 2022 (PMID 35652444)
Ontology. Gene product: FYVE-domain Rab effector. GO-MF: phosphatidylinositol-3-phosphate binding GO:0032266; Rab GTPase binding GO:0017137. CHEBI: phosphatidylinositol 3-phosphate CHEBI:26034.
Not applicable. KAREVS is a monogenic recessive disorder with no established environmental factors, lifestyle contributors, or infectious agents. No toxin/radiation/occupational exposures are implicated (searches of CTD/PubMed yield no environmental modifiers).
Cell types (CL): neuron CL:0000540; skeletal muscle fiber CL:0000188; fibroblast (model) CL:0000057; oligodendrocyte (myelination, inferred) CL:0000128. Biological process (GO): endosome to lysosome transport GO:0008333; early endosome to late endosome transport GO:0045022; endosomal transport GO:0016197; regulation of endosome size/maturation; vesicle fusion GO:0006906.
"Using exome sequencing, we identified recessively acting germline alleles p.Arg180Gly and p.Gly183Arg." — Paul et al., 2022 (PMID 35652444)
NCIT: Whole Exome Sequencing; Whole Genome Sequencing; Genetic Testing; Magnetic Resonance Imaging; Electromyography.
No disease-modifying or curative therapy exists. Management is supportive, multidisciplinary, and symptom-directed (extrapolated from standard care for AR syndromic ID/myopathy; no KAREVS-specific trials).
NCIT: Physical Therapy; Occupational Therapy; Speech Therapy; Supportive Care; Rehabilitation Therapy; Baclofen.
NCIT: Genetic Counseling; Genetic Carrier Screening; Prenatal Diagnosis.
Supported: - KAREVS is caused by biallelic FYVE-domain RBSN missense variants (AR) — strongly supported (segregation in 2 families + functional data) [PMID 26192890; PMID 35652444]. - Mechanism is loss of PI3P binding → endosomal mislocalization → delayed endosomal maturation with spared recycling (separation-of-function) — supported (patient-cell biochemistry/imaging) [PMID 35652444]. - Distinct RBSN variants cause distinct disorders via distinct endolysosomal defects — supported [PMID 35652444; PMID 25233840].
Refuted / excluded: - Environmental, infectious, or chromosomal causation — excluded (purely monogenic). - Hematologic involvement as part of KAREVS — excluded in reported families (distinguishes from RBSN congenital myelofibrosis). - Complete-null mechanism — refuted (null is lethal; disease requires hypomorphic alleles).
Checked with linkml-reference-validator 0.2.1.
| Outcome | Count |
|---|---|
| References checked | 7 |
| Resolved | 7 |
| Unresolved (possible confabulation) | 0 |
| Unverifiable | 0 |
| References weighed for topical relevance | 7 |
| On topic | 3 |
| Off topic | 0 |
All extracted references resolved successfully.
Checked with linkml-term-validator 0.4.5, through the ols: adapter.
| Outcome | Count |
|---|---|
| Terms checked | 54 |
| Resolved | 51 |
| Unresolved (possible confabulation) | 0 |
| Obsolete | 1 |
| Unverifiable | 2 |
| Terms whose name was checked | 3 |
| Terms named correctly | 0 |
| Terms named as a different term | 3 |
These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:
HP:0001249 (1 mention) - the report calls it "All (6/6)"; HP calls it Intellectual disabilityHP:0001252 (1 mention) - the report calls it "Frequent"; HP calls it HypotoniaHP:0002080 (1 mention) - the report calls it "1 patient"; HP calls it Intention tremorThese terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:
GO:0017137 (GO_0017137) (1 mention) - replaced by GO:0031267Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: MGI.