CAPRIN1 Related Neurodevelopmental Disorder

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Inheritance

1

Autosomal dominant inheritance HP:0000006

Dominant by haploinsufficiency. Patient cells express only the wild-type allele, with transcript and protein at about half the normal level - which is the direct demonstration that the mechanism is dose rather than a dominant-negative product.

Autosomal dominant inheritance

Show evidence (1 reference)

PMID:35979925 SUPPORT Human Clinical

"In patient-derived lymphoblasts and fibroblasts, we showed a monoallelic expression of the wild-type allele, and a reduction of the transcript and protein compatible with a half dose"

Establishes haploinsufficiency in patient material rather than inferring it from variant class - monoallelic expression plus half-dose protein is the observation that rules out a dominant-negative product.

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Discussions and Knowledge Gaps

1

Does heterozygous CAPRIN1 loss impair dendritic mRNA localisation in human neurons, or is the localisation defect a property of complete absence that half dosage does not reproduce?

HUMAN MODEL MISMATCH caprin1_dose_gap

Attached to

pathophysiology#Impaired Dendritic mRNA Localisation animal_models#Rng105/Caprin1 knockout mouse animal_models#Rng105/Caprin1 heterozygous mouse

The mechanism at the centre of this entry - mislocalisation of AMPAR-regulator transcripts - is established only at complete loss of Caprin-1, in a conditional forebrain knockout and constitutive null neurons. The human disease is haploinsufficiency. An earlier revision of this gap said no model at the right dose existed apart from the CRISPR-edited iPSC neurons. That was wrong: a heterozygous Rng105+/- mouse has been comprehensively characterised and is curated in this entry. The gap is therefore narrower than stated, and different in kind. It is not that half dosage has never been modelled - it has, and it produces a behavioural phenotype. It is that neither dose-matched model has been assayed for the molecular step this entry's causal chain runs through: the mouse work is behavioural throughout, and the CAPRIN1+/- neurons were characterised for morphology, translation, calcium, oxidative stress and electrical activity but not for dendritic mRNA localisation. So the chain passes through a step demonstrated only at a dose the disease does not have, while the models at the right dose report the phenotype without reporting the mechanism. That is not a reason to doubt the model - reduced spiking in CAPRIN1+/- neurons and reduced sociality in Rng105+/- mice are both consistent with it - but the specific link from half dosage to transport failure is inferred rather than shown, and one experiment would close it.

Proposed experiments

Dendritic transcript localisation in CAPRIN1+/- iPSC-derived neurons

caprin1_het_localisation_assay

Genome-wide profiling of somatodendritic mRNA distribution in the existing CRISPR-edited CAPRIN1+/- cortical neurons, compared with isogenic controls, focused on the AMPAR-regulator transcripts identified in the mouse.

Would support

pathophysiology#Impaired Dendritic mRNA Localisation

Supporting outcome

Reduced dendritic localisation of the same transcript class at heterozygous dose, matching the mouse in direction if not magnitude.

Refuting outcome

Normal transcript distribution at heterozygous dose, which would mean the reduced neuronal activity arises by a route other than transport failure and the entry's central node applies only to complete loss.

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Pathophysiology

5

CAPRIN1 Haploinsufficiency

Heterozygous loss-of-function variants leave one working allele, and patient cells carry transcript and protein at about half the normal level.

CAPRIN1 hgnc:6743

Downstream

Impaired Dendritic mRNA Localisation

Show evidence (1 reference)

PMID:35979925 SUPPORT Human Clinical

"In patient-derived lymphoblasts and fibroblasts, we showed a monoallelic expression of the wild-type allele, and a reduction of the transcript and protein compatible with a half dose"

The half-dose state this node asserts, measured in patient cells.

Impaired Dendritic mRNA Localisation

Caprin-1 carries specific transcripts into dendrites. Without enough of it, the asymmetric somatodendritic distribution of mRNAs is lost. The important detail is which transcripts: those encoding regulators of AMPA-receptor surface expression. That is what makes the consequence a synaptic-scaling failure rather than a general translation deficit, and it is why the entry does not model this as "less protein made".

glutamatergic neuron CL:0000679

intracellular mRNA localization GO:0008298 ↓ DECREASED

Animal models

Rng105/Caprin1 knockout mouse Mouse recapitulates The mouse is where the mRNA-localisation mechanism was established, including the identity of the mislocalised transcript class.

Downstream

Attenuated Homeostatic AMPAR Scaling and Reduced Synaptic Strength

Show evidence (3 references)

PMID:29157358 SUPPORT Model Organism

"RNG105 deficiency impaired the asymmetric somato-dendritic localization of mRNAs"

The localisation defect this node asserts. Graded MODEL_ORGANISM: this is the mouse knockout, and the finding is not shown in patient neurons.

PMID:29157358 SUPPORT Model Organism

"RNG105 deficiency reduced the dendritic localization of mRNAs encoding regulators of AMPAR surface expression"

Names the transcript class, which is what connects a transport defect to a specific synaptic consequence rather than to translation in general.

PMID:20861386 SUPPORT Model Organism

"RNG105 knock-out in mice reduces the dendritic localization of mRNAs for Na+/K+ ATPase (NKA) subunit isoforms"

A second, independently identified cargo class. It matters here because of what accompanies it: dendritic NKA function is lost while somatic NKA function is not. That is the shape of the claim this node makes - the protein is made, and made in the wrong place.

Attenuated Homeostatic AMPAR Scaling and Reduced Synaptic Strength

With the AMPAR-regulator transcripts not reaching dendrites, homeostatic AMPAR scaling is attenuated and synaptic strength falls. In the mouse this produces severe long-term memory deficits; in patient-derived neurons the corresponding readout is reduced spiking and bursting.

Downstream

Disrupted Cortical Neuronal Development

Extraneural Consequences of Reduced Caprin-1

Show evidence (2 references)

PMID:29157358 SUPPORT Model Organism

"attenuated homeostatic AMPAR scaling in dendrites and reduced synaptic strength"

Both halves of this node, in the model where they were measured.

PMID:35979925 SUPPORT In Vitro

"measurements of activity in CAPRIN1+/- neurons via micro-electrode arrays indicated lower spike rates and bursts, with an overall reduced activity"

The human counterpart, in CRISPR-edited iPSC-derived neurons at the same heterozygous dose as patients - which is what stops this node resting on a homozygous mouse knockout alone.

Disrupted Cortical Neuronal Development

In CAPRIN1+/- human cortical neurons the cells themselves are abnormal: fewer processes, disorganised architecture, and increased degeneration, alongside altered translation, impaired calcium signalling and increased oxidative stress.

Downstream

Delayed Speech and Language Development

Intellectual Disability

Attention Deficit Hyperactivity Disorder

Autism

Global Developmental Delay

Seizure

Show evidence (2 references)

PMID:35979925 SUPPORT In Vitro

"CAPRIN1 loss caused reduced neuronal processes, overall disruption of the neuronal organization and an increased neuronal degeneration"

The morphological phenotype of this node, in human neurons carrying the patient-equivalent genotype.

PMID:35979925 SUPPORT In Vitro

"CAPRIN1+/- neurons also showed an impaired calcium signalling and increased oxidative stress"

Two further cellular abnormalities the authors identify. They are recorded on this node rather than as separate mechanism nodes because nothing cited establishes their order relative to the morphological changes.

Extraneural Consequences of Reduced Caprin-1

The respiratory, skeletal, feeding and ophthalmologic features, which occur in a third to a half of patients and which a neuronal mechanism does not account for. CAPRIN1 is ubiquitously expressed and also regulates mRNAs encoding proteins important for cell proliferation and migration in multiple cell types, so there is a plausible route to non-neural tissue. An earlier revision of this node said no cited work showed Caprin-1 operating in any extraneural organ. That was wrong, and two mouse results already in this PR's references show it: complete RNG105 knockout is neonatally lethal from respiratory failure, and targeted inner-ear deletion causes progressive hearing loss. Both are organ-specific requirements for Caprin-1 outside the brain, and the respiratory one lands on the same organ system as a phenotype reached from this node. What is genuinely absent is the dose. Both results are complete loss - homozygous null and targeted deletion - and this disease is haploinsufficiency. So the defensible claim, and the one the node now makes, is that Caprin-1 has non-neural organ requirements demonstrated at complete loss, and that nothing cited shows those requirements failing at half dosage. It remains a sibling of the neuronal arm rather than downstream of it, because routing a limb anomaly through cortical neuron development would be false.

Downstream

Respiratory Problems

Abnormal Skeletal Morphology

Feeding Difficulties

Abnormality of the Eye

Show evidence (4 references)

PMID:35979925 SUPPORT Human Clinical

"CAPRIN1 encodes a ubiquitous protein that regulates the transport and translation of neuronal mRNAs critical for synaptic plasticity, as well as mRNAs encoding proteins important for cell proliferation and migration in multiple cell types"

Supplies the general basis for extraneural involvement - ubiquitous expression and a second transcript class in other cell types.

PMID:29157358 SUPPORT Model Organism

"RNG105 homozygous KO mice are neonatally lethal because of respiratory failure (Shiina et al., 2010)"

An organ-specific requirement for Caprin-1 outside the nervous system, in the same organ system as one of this node's phenotypes. Note this is a secondary citation - the sentence is this paper's introduction restating Shiina et al. 2010, which is the primary and is not cited here. Graded SUPPORT for the node's existence, not for the respiratory phenotype: neonatal lethality in a homozygous null is not the respiratory morbidity of a surviving heterozygous patient, and the entry does not treat it as the same claim.

PMID:35165318 SUPPORT Model Organism

"targeted inner ear-deletion of Caprin1 in mice leads to an early onset, progressive hearing loss"

A second organ-specific requirement, and a tissue-restricted deletion rather than a constitutive null - so the phenotype is attributable to Caprin-1 loss in that organ. Pairs with the hearing loss reported in the expanded human spectrum.

+ 1 more reference

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

10

Digestive 1

Feeding Difficulties FREQUENT HP:0011968

Show evidence (1 reference)

PMID:35979925 SUPPORT Human Clinical

"Affected individuals also had respiratory problems (50%), limb/skeletal anomalies (50%), developmental delay (42%) feeding difficulties (33%), seizures (33%) and ophthalmologic problems (33%)"

33%, stated for feeding difficulties by name.

Nervous System 6

Delayed Speech and Language Development OBLIGATE HP:0000750

Show evidence (1 reference)

PMID:35979925 SUPPORT Human Clinical

"a neurodevelopmental phenotype characterized by language impairment/speech delay (100%), intellectual disability (83%), attention deficit hyperactivity disorder (82%) and autism spectrum disorder (67%)"

The quote states 100% for language impairment specifically, which is what licenses OBLIGATE. Every frequency in this entry is bound to a figure the source gives for that phenotype, not to a neighbouring one.

Intellectual Disability VERY_FREQUENT HP:0001249

Show evidence (1 reference)

PMID:35979925 SUPPORT Human Clinical

"a neurodevelopmental phenotype characterized by language impairment/speech delay (100%), intellectual disability (83%), attention deficit hyperactivity disorder (82%) and autism spectrum disorder (67%)"

83% falls in the VERY_FREQUENT band (80-99%), and the figure is stated for intellectual disability by name.

Attention Deficit Hyperactivity Disorder VERY_FREQUENT HP:0007018

Show evidence (1 reference)

PMID:35979925 SUPPORT Human Clinical

"a neurodevelopmental phenotype characterized by language impairment/speech delay (100%), intellectual disability (83%), attention deficit hyperactivity disorder (82%) and autism spectrum disorder (67%)"

82%, stated for ADHD by name, which is inside the VERY_FREQUENT band.

Autism FREQUENT HP:0000717

Show evidence (1 reference)

PMID:35979925 SUPPORT Human Clinical

"a neurodevelopmental phenotype characterized by language impairment/speech delay (100%), intellectual disability (83%), attention deficit hyperactivity disorder (82%) and autism spectrum disorder (67%)"

67%, stated for autism spectrum disorder by name, which falls in FREQUENT (30-79%) rather than VERY_FREQUENT.

Global Developmental Delay FREQUENT HP:0001263

Show evidence (1 reference)

PMID:35979925 SUPPORT Human Clinical

"Affected individuals also had respiratory problems (50%), limb/skeletal anomalies (50%), developmental delay (42%) feeding difficulties (33%), seizures (33%) and ophthalmologic problems (33%)"

42%, stated for developmental delay by name.

Seizure FREQUENT HP:0001250

Show evidence (1 reference)

PMID:35979925 SUPPORT Human Clinical

"Affected individuals also had respiratory problems (50%), limb/skeletal anomalies (50%), developmental delay (42%) feeding difficulties (33%), seizures (33%) and ophthalmologic problems (33%)"

33%, stated for seizures by name.

Other 3

Respiratory Problems FREQUENT Abnormality of the respiratory system HP:0002086

Show evidence (1 reference)

PMID:35979925 SUPPORT Human Clinical

"Affected individuals also had respiratory problems (50%), limb/skeletal anomalies (50%), developmental delay (42%) feeding difficulties (33%), seizures (33%) and ophthalmologic problems (33%)"

50% for respiratory problems. The HP term is deliberately general because the source phrase is general - naming a specific respiratory phenotype would assert more than the cohort description supports.

Abnormal Skeletal Morphology FREQUENT HP:0011842

Show evidence (1 reference)

PMID:35979925 SUPPORT Human Clinical

"Affected individuals also had respiratory problems (50%), limb/skeletal anomalies (50%), developmental delay (42%) feeding difficulties (33%), seizures (33%) and ophthalmologic problems (33%)"

50% for limb and skeletal anomalies, bound to a general term for the same reason as the respiratory phenotype.

Abnormality of the Eye FREQUENT HP:0000478

Show evidence (1 reference)

PMID:35979925 SUPPORT Human Clinical

"Affected individuals also had respiratory problems (50%), limb/skeletal anomalies (50%), developmental delay (42%) feeding difficulties (33%), seizures (33%) and ophthalmologic problems (33%)"

33% for ophthalmologic problems, bound to a general term because the source phrase does not name a specific ocular finding.

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Genetic Associations

1

CAPRIN1

Gene: CAPRIN1 hgnc:6743 relationship_type: CAUSATIVE variant_origin: GERMLINE

Autosomal dominant inheritance

Show evidence (3 references)

PMID:35979925 SUPPORT Human Clinical

"We identified 12 cases with loss-of-function CAPRIN1 variants"

The cohort and the variant class.

PMID:35977029 SUPPORT In Vitro

"We validated that NDD-related de novo variants in newly implicated and known NDD genes, such as CAPRIN1, disrupt the interaction of the core SG network and interfere with SG formation"

Independent functional corroboration of CAPRIN1 as an NDD gene, reached from a different direction: this study ascertained through stress-granule assembly regulators rather than through CAPRIN1, and shows that NDD variants in it disrupt stress-granule formation. Graded PARTIAL because that is a functional result about the gene, not a clinical cohort - it corroborates the gene-disease link without replicating the phenotype profile. An earlier revision quoted this paper's opening sentence instead, which describes an NDD with language problems, intellectual disability and behavioural issues. That sentence is about UBAP2L, not CAPRIN1 - the quote stopped one word before the gene name that fixes its subject, and the resemblance to this entry's three most frequent phenotypes was a coincidence between two different disorders. It verified as an exact substring throughout.

PMID:41859620 SUPPORT Human Clinical

"Mutations in the cell cycle-associated protein 1 (CAPRIN1) gene have been shown to present with language impairment, speech delay, intellectual disability, attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), respiratory problems, limb and skeletal anomalies,..."

Extends the reported spectrum by cerebellar ataxia, dysmorphic features and hearing loss beyond the twelve features in the defining cohort. Graded PARTIAL because this is a background sentence in a single case report summarising the literature, not a cohort observation with a denominator - which is also why the three added features carry no frequency and, for now, no phenotype record. The hearing loss is worth noting against the inner-ear Caprin1 deletion mouse cited on the extraneural node.

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External Assertions

1

OMIM CAPRIN1 gene record

OMIM gene record OMIM:601178

The CAPRIN1 gene record cited by the defining cohort. Recorded here because DiseaseMappings carries no OMIM slot.

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Diagnosis

1

Molecular Diagnosis by Exome Sequencing

Diagnosis is molecular; there is no biomarker and no imaging finding. The clinical picture - language impairment with intellectual disability, ADHD and autism - is shared with a large number of neurodevelopmental disorders, so the gene is reached by sequencing rather than by phenotype.

whole exome sequencing NCIT:C101295

Show evidence (1 reference)

PMID:41859620 SUPPORT Human Clinical

"Whole exome sequencing was significant for a likely pathogenic variant in the maternally inherited CAPRIN1 gene"

Exome sequencing as the diagnostic route in a reported case. Quoted only for the method: this abstract calls the same variant "maternally inherited" in one sentence and "de novo and heterozygous" in the next, so nothing about its inheritance is curated from it.

📊

Prevalence

1

Published cases worldwide

Cases In Literature Ultra Rare

Twelve cases in the defining cohort. No point prevalence has been estimated. Recorded as a case count rather than a rate; this is also the denominator behind every percentage in the phenotypes section, which is why those bands are coarse.

Show evidence (1 reference)

PMID:35979925 SUPPORT Human Clinical

"We identified 12 cases with loss-of-function CAPRIN1 variants"

The cohort size, which is the denominator for the frequency bands.

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Animal Models

2

Rng105/Caprin1 knockout mouse

Species

Mouse

Genotype

Camk2a-Cre;Rng105 conditional forebrain knockout, with constitutive Rng105-/- primary neurons for the AMPAR-scaling work

Publication

PMID:29157358

Pathograph links

Impaired Dendritic mRNA Localisation recapitulates fidelity: moderate The mouse is where the mRNA-localisation mechanism was established, including the identity of the mislocalised transcript class.

Limitations: Fidelity is MODERATE and the reason is a dose mismatch that matters for this disease specifically. This model is a complete loss - a conditional forebrain knockout, with constitutive nulls for the primary-neuron work - while the human disorder is haploinsufficiency. A null establishes what Caprin-1 does, not what half of it fails to do, and this disease is entirely a claim about half. An earlier revision of this entry said the iPSC CAPRIN1+/- neurons were the only model at the right dose. That was wrong: a heterozygous Rng105+/- mouse exists and is curated below. It does not close the gap this link records, because it was behaviourally rather than molecularly characterised and does not report dendritic mRNA localisation, but it does mean the correct statement is "no model at the right dose has been assayed for this readout" rather than "no model at the right dose exists".

Readouts

Dendritic localisation of AMPAR-regulator mRNAs

Direction: DECREASED

Interpretation: The transport failure, measured on the transcript class that connects it to synaptic scaling.

Show evidence (1 reference)

PMID:29157358 SUPPORT Model Organism

"RNG105 deficiency reduced the dendritic localization of mRNAs encoding regulators of AMPAR surface expression"

Reports the measurement and its direction.

Show evidence (1 reference)

PMID:29157358 SUPPORT Model Organism

"RNG105-deficient mice displayed unprecedentedly severe defects in long-term memory formation in spatial and contextual learning tasks"

Establishes the model as informative for the pathway. The severity language is the authors' and is quoted rather than softened.

Rng105/Caprin1 heterozygous mouse

The dose-matched model. A comprehensive behavioural battery on Rng105+/- mice - the same single-copy loss as the human disease - finds reduced sociality, a weak preference for social novelty, and reduced flexibility in reversal learning with intact memory acquisition. It is curated separately from the knockout rather than as another link on it, because the two make different claims: the null says what Caprin-1 does, this one says that losing one copy is enough to produce a social-behaviour phenotype.

Species

Mouse

Genotype

Rng105 (Caprin1) heterozygous knockout, Rng105+/-

Publication

PMID:26865403

{ }

Source YAML

click to show

name: CAPRIN1 Related Neurodevelopmental Disorder
creation_date: "2026-08-28T21:45:00Z"
category: Mendelian
description: >-
  CAPRIN1-related neurodevelopmental disorder is an autosomal dominant condition
  caused by heterozygous loss-of-function variants in CAPRIN1, acting through
  haploinsufficiency. CAPRIN1 encodes Caprin-1 (also called RNG105), a
  cytoplasmic RNA-binding protein that is a core component of neuronal RNA
  transport granules.

  Its job is positional rather than quantitative: it carries specific mRNAs out
  into dendrites so they can be translated where they are needed. Losing half of
  it impairs the somatodendritic localisation of those transcripts, and among
  them are the mRNAs encoding regulators of AMPA-receptor surface expression - so
  the downstream failure is in homeostatic AMPAR scaling and synaptic strength
  rather than in protein supply overall.

  The clinical phenotype is language impairment in every reported patient, with
  intellectual disability, ADHD and autism in most, plus respiratory,
  skeletal, feeding, seizure and ophthalmologic involvement in a third to a half.
parents:
  - Neurodevelopmental Disorder
synonyms:
  - CAPRIN1-NDD
  - CAPRIN1 haploinsufficiency
  - RNG105-related neurodevelopmental disorder
disease_term:
  preferred_term: neurodevelopmental disorder with language impairment, autism, and attention deficit-hyperactivity disorder
  term:
    id: MONDO:0968945
    label: neurodevelopmental disorder with language impairment, autism, and attention deficit-hyperactivity disorder
notes: >-
  Frequencies, and why this entry has them when its four companions do not. The
  defining cohort reports a per-phenotype frequency for every feature it lists,
  in one sentence per group. Each frequency band below is therefore bound to a
  quote stating that figure for that named phenotype. This is the discipline the
  previous curation batch failed: a band taken from a number describing a
  neighbouring phenotype in the same sentence is wrong however exactly the quote
  verifies.

  Twelve patients is a small denominator and the percentages are correspondingly
  coarse - 33% is four patients. The bands are recorded because the source states
  them, not because they are precise.

  A misattributed quote, and the correction matters. The deep-research report
  committed alongside attributes to PMID:35979925 a sentence beginning "The
  majority of reported pathogenic mutations in the CAPRIN1 gene result in
  decreased protein levels and haploinsufficiency". The report's own reference
  validation flagged it as not found in that source, and it is not in that
  abstract - so an earlier revision of this entry recorded it as a confabulated
  quote, the only one across the five reports in this batch.

  That was wrong, and it is a more interesting failure than the one it replaced.
  The sentence is real and verbatim. It belongs to PMID:41859620, a 2026 case
  report now cited in this entry for the expanded phenotype. So the defect is
  misattribution, not fabrication: a true sentence pinned to the wrong paper.

  The two failures need different defences. A confabulated quote is caught by
  any substring check against the cited source, which is what happened here. A
  misattributed one is caught by that check only because the curator happened to
  cite the wrong paper - had the report named PMID:41859620, the quote would
  have verified exactly and nothing in the pipeline would have noticed anything,
  because nothing verifies that a sentence supports the claim it is attached to.
  Quarantining the quote was still right; the reason recorded for it was not.

  General terms where the source is general. Respiratory, skeletal and
  ophthalmologic involvement are bound to high-level HP terms because the cohort
  describes them only as "respiratory problems", "limb/skeletal anomalies" and
  "ophthalmologic problems". Binding a specific phenotype would assert more than
  the source carries.

  No treatments section. Management is symptomatic and no cited reference states
  a protocol quotable exactly.
external_assertions:
  - name: OMIM CAPRIN1 gene record
    source: OMIM
    assertion_type: gene_record
    external_id: OMIM:601178
    url: https://omim.org/entry/601178
    description: >-
      The CAPRIN1 gene record cited by the defining cohort. Recorded here
      because DiseaseMappings carries no OMIM slot.
inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
    description: >-
      Dominant by haploinsufficiency. Patient cells express only the wild-type
      allele, with transcript and protein at about half the normal level - which
      is the direct demonstration that the mechanism is dose rather than a
      dominant-negative product.
    evidence:
      - reference: PMID:35979925
        reference_title: "CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          In patient-derived lymphoblasts and fibroblasts, we showed a
          monoallelic expression of the wild-type allele, and a reduction of the
          transcript and protein compatible with a half dose
        explanation: >-
          Establishes haploinsufficiency in patient material rather than
          inferring it from variant class - monoallelic expression plus half-dose
          protein is the observation that rules out a dominant-negative product.
pathophysiology:
  - name: CAPRIN1 Haploinsufficiency
    biological_scale: MOLECULAR
    description: >-
      Heterozygous loss-of-function variants leave one working allele, and
      patient cells carry transcript and protein at about half the normal level.
    genes:
      - preferred_term: CAPRIN1
        term:
          id: hgnc:6743
          label: CAPRIN1
    downstream:
      - target: Impaired Dendritic mRNA Localisation
    evidence:
      - reference: PMID:35979925
        reference_title: "CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          In patient-derived lymphoblasts and fibroblasts, we showed a
          monoallelic expression of the wild-type allele, and a reduction of the
          transcript and protein compatible with a half dose
        explanation: >-
          The half-dose state this node asserts, measured in patient cells.
  - name: Impaired Dendritic mRNA Localisation
    biological_scale: CELLULAR
    description: >-
      Caprin-1 carries specific transcripts into dendrites. Without enough of
      it, the asymmetric somatodendritic distribution of mRNAs is lost.

      The important detail is which transcripts: those encoding regulators of
      AMPA-receptor surface expression. That is what makes the consequence a
      synaptic-scaling failure rather than a general translation deficit, and it
      is why the entry does not model this as "less protein made".
    cell_types:
      - preferred_term: glutamatergic neuron
        term:
          id: CL:0000679
          label: glutamatergic neuron
    biological_processes:
      - preferred_term: intracellular mRNA localization
        term:
          id: GO:0008298
          label: intracellular mRNA localization
        modifier: DECREASED
    downstream:
      - target: Attenuated Homeostatic AMPAR Scaling and Reduced Synaptic Strength
    evidence:
      - reference: PMID:29157358
        reference_title: "RNG105/caprin1, an RNA granule protein for dendritic mRNA localization, is essential for long-term memory formation."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          RNG105 deficiency impaired the asymmetric somato-dendritic
          localization of mRNAs
        explanation: >-
          The localisation defect this node asserts. Graded MODEL_ORGANISM: this
          is the mouse knockout, and the finding is not shown in patient
          neurons.
      - reference: PMID:29157358
        reference_title: "RNG105/caprin1, an RNA granule protein for dendritic mRNA localization, is essential for long-term memory formation."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          RNG105 deficiency reduced the dendritic localization of mRNAs encoding
          regulators of AMPAR surface expression
        explanation: >-
          Names the transcript class, which is what connects a transport defect
          to a specific synaptic consequence rather than to translation in
          general.
      - reference: PMID:20861386
        reference_title: "RNG105 deficiency impairs the dendritic localization of mRNAs for Na+/K+ ATPase subunit isoforms and leads to the degeneration of neuronal networks."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          RNG105 knock-out in mice reduces the dendritic localization of mRNAs
          for Na+/K+ ATPase (NKA) subunit isoforms
        explanation: >-
          A second, independently identified cargo class. It matters here
          because of what accompanies it: dendritic NKA function is lost while
          somatic NKA function is not. That is the shape of the claim this node
          makes - the protein is made, and made in the wrong place.
  - name: Attenuated Homeostatic AMPAR Scaling and Reduced Synaptic Strength
    biological_scale: CELLULAR
    description: >-
      With the AMPAR-regulator transcripts not reaching dendrites, homeostatic
      AMPAR scaling is attenuated and synaptic strength falls. In the mouse this
      produces severe long-term memory deficits; in patient-derived neurons the
      corresponding readout is reduced spiking and bursting.
    downstream:
      - target: Disrupted Cortical Neuronal Development
      - target: Extraneural Consequences of Reduced Caprin-1
    evidence:
      - reference: PMID:29157358
        reference_title: "RNG105/caprin1, an RNA granule protein for dendritic mRNA localization, is essential for long-term memory formation."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          attenuated homeostatic AMPAR scaling in dendrites and reduced synaptic
          strength
        explanation: >-
          Both halves of this node, in the model where they were measured.
      - reference: PMID:35979925
        reference_title: "CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          measurements of activity in CAPRIN1+/- neurons via micro-electrode
          arrays indicated lower spike rates and bursts, with an overall reduced
          activity
        explanation: >-
          The human counterpart, in CRISPR-edited iPSC-derived neurons at the
          same heterozygous dose as patients - which is what stops this node
          resting on a homozygous mouse knockout alone.
  - name: Disrupted Cortical Neuronal Development
    biological_scale: CELLULAR
    description: >-
      In CAPRIN1+/- human cortical neurons the cells themselves are abnormal:
      fewer processes, disorganised architecture, and increased degeneration,
      alongside altered translation, impaired calcium signalling and increased
      oxidative stress.
    downstream:
      - target: Delayed Speech and Language Development
      - target: Intellectual Disability
      - target: Attention Deficit Hyperactivity Disorder
      - target: Autism
      - target: Global Developmental Delay
      - target: Seizure
    evidence:
      - reference: PMID:35979925
        reference_title: "CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          CAPRIN1 loss caused reduced neuronal processes, overall disruption of
          the neuronal organization and an increased neuronal degeneration
        explanation: >-
          The morphological phenotype of this node, in human neurons carrying
          the patient-equivalent genotype.
      - reference: PMID:35979925
        reference_title: "CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          CAPRIN1+/- neurons also showed an impaired calcium signalling and
          increased oxidative stress
        explanation: >-
          Two further cellular abnormalities the authors identify. They are
          recorded on this node rather than as separate mechanism nodes because
          nothing cited establishes their order relative to the morphological
          changes.
  - name: Extraneural Consequences of Reduced Caprin-1
    biological_scale: ORGANISM
    description: >-
      The respiratory, skeletal, feeding and ophthalmologic features, which
      occur in a third to a half of patients and which a neuronal mechanism does
      not account for.

      CAPRIN1 is ubiquitously expressed and also regulates mRNAs encoding
      proteins important for cell proliferation and migration in multiple cell
      types, so there is a plausible route to non-neural tissue.

      An earlier revision of this node said no cited work showed Caprin-1
      operating in any extraneural organ. That was wrong, and two mouse results
      already in this PR's references show it: complete RNG105 knockout is
      neonatally lethal from respiratory failure, and targeted inner-ear
      deletion causes progressive hearing loss. Both are organ-specific
      requirements for Caprin-1 outside the brain, and the respiratory one lands
      on the same organ system as a phenotype reached from this node.

      What is genuinely absent is the dose. Both results are complete loss -
      homozygous null and targeted deletion - and this disease is
      haploinsufficiency. So the defensible claim, and the one the node now
      makes, is that Caprin-1 has non-neural organ requirements demonstrated at
      complete loss, and that nothing cited shows those requirements failing at
      half dosage. It remains a sibling of the neuronal arm rather than
      downstream of it, because routing a limb anomaly through cortical neuron
      development would be false.
    downstream:
      - target: Respiratory Problems
      - target: Abnormal Skeletal Morphology
      - target: Feeding Difficulties
      - target: Abnormality of the Eye
    evidence:
      - reference: PMID:35979925
        reference_title: "CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          CAPRIN1 encodes a ubiquitous protein that regulates the transport and
          translation of neuronal mRNAs critical for synaptic plasticity, as
          well as mRNAs encoding proteins important for cell proliferation and
          migration in multiple cell types
        explanation: >-
          Supplies the general basis for extraneural involvement - ubiquitous
          expression and a second transcript class in other cell types.
      - reference: PMID:29157358
        reference_title: "RNG105/caprin1, an RNA granule protein for dendritic mRNA localization, is essential for long-term memory formation."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          RNG105 homozygous KO mice are neonatally lethal because of respiratory
          failure (Shiina et al., 2010)
        explanation: >-
          An organ-specific requirement for Caprin-1 outside the nervous system,
          in the same organ system as one of this node's phenotypes. Note this is
          a secondary citation - the sentence is this paper's introduction
          restating Shiina et al. 2010, which is the primary and is not cited
          here. Graded SUPPORT for the node's existence, not for the respiratory
          phenotype:
          neonatal lethality in a homozygous null is not the respiratory
          morbidity of a surviving heterozygous patient, and the entry does not
          treat it as the same claim.
      - reference: PMID:35165318
        reference_title: "Targeted deletion of the RNA-binding protein Caprin1 leads to progressive hearing loss and impairs recovery from noise exposure in mice."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          targeted inner ear-deletion of Caprin1 in mice leads to an early onset,
          progressive hearing loss
        explanation: >-
          A second organ-specific requirement, and a tissue-restricted deletion
          rather than a constitutive null - so the phenotype is attributable to
          Caprin-1 loss in that organ. Pairs with the hearing loss reported in
          the expanded human spectrum.
      - reference: PMID:35979925
        reference_title: "CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          Affected individuals also had respiratory problems (50%),
          limb/skeletal anomalies (50%), developmental delay (42%) feeding
          difficulties (33%), seizures (33%) and ophthalmologic problems (33%)
        explanation: >-
          Establishes that these features occur in the cohort, which is what the
          edges below assert.
phenotypes:
  - name: Delayed Speech and Language Development
    category: Neurologic
    frequency: OBLIGATE
    description: >-
      Present in every reported patient, and the most consistent feature of the
      disorder.
    phenotype_term:
      preferred_term: Delayed speech and language development
      term:
        id: HP:0000750
        label: Delayed speech and language development
    evidence:
      - reference: PMID:35979925
        reference_title: "CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          a neurodevelopmental phenotype characterized by language
          impairment/speech delay (100%), intellectual disability (83%),
          attention deficit hyperactivity disorder (82%) and autism spectrum
          disorder (67%)
        explanation: >-
          The quote states 100% for language impairment specifically, which is what
          licenses OBLIGATE. Every frequency in this entry is bound to a figure
          the source gives for that phenotype, not to a neighbouring one.
  - name: Intellectual Disability
    category: Neurologic
    frequency: VERY_FREQUENT
    phenotype_term:
      preferred_term: Intellectual disability
      term:
        id: HP:0001249
        label: Intellectual disability
    evidence:
      - reference: PMID:35979925
        reference_title: "CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          a neurodevelopmental phenotype characterized by language
          impairment/speech delay (100%), intellectual disability (83%),
          attention deficit hyperactivity disorder (82%) and autism spectrum
          disorder (67%)
        explanation: >-
          83% falls in the VERY_FREQUENT band (80-99%), and the figure is stated for
          intellectual disability by name.
  - name: Attention Deficit Hyperactivity Disorder
    category: Behavioral
    frequency: VERY_FREQUENT
    phenotype_term:
      preferred_term: Attention deficit hyperactivity disorder
      term:
        id: HP:0007018
        label: Attention deficit hyperactivity disorder
    evidence:
      - reference: PMID:35979925
        reference_title: "CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          a neurodevelopmental phenotype characterized by language
          impairment/speech delay (100%), intellectual disability (83%),
          attention deficit hyperactivity disorder (82%) and autism spectrum
          disorder (67%)
        explanation: >-
          82%, stated for ADHD by name, which is inside the VERY_FREQUENT band.
  - name: Autism
    category: Behavioral
    frequency: FREQUENT
    phenotype_term:
      preferred_term: Autism
      term:
        id: HP:0000717
        label: Autism
    evidence:
      - reference: PMID:35979925
        reference_title: "CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          a neurodevelopmental phenotype characterized by language
          impairment/speech delay (100%), intellectual disability (83%),
          attention deficit hyperactivity disorder (82%) and autism spectrum
          disorder (67%)
        explanation: >-
          67%, stated for autism spectrum disorder by name, which falls in FREQUENT
          (30-79%) rather than VERY_FREQUENT.
  - name: Respiratory Problems
    category: Respiratory
    frequency: FREQUENT
    description: >-
      Bound to the system-level term rather than the physiology term. The source
      says only "respiratory problems", which does not distinguish a functional
      abnormality from a structural one, and HP:0002795 would have asserted the
      former.
    phenotype_term:
      preferred_term: Respiratory problems
      term:
        id: HP:0002086
        label: Abnormality of the respiratory system
    evidence:
      - reference: PMID:35979925
        reference_title: "CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          Affected individuals also had respiratory problems (50%),
          limb/skeletal anomalies (50%), developmental delay (42%) feeding
          difficulties (33%), seizures (33%) and ophthalmologic problems (33%)
        explanation: >-
          50% for respiratory problems. The HP term is deliberately general because
          the source phrase is general - naming a specific respiratory phenotype
          would assert more than the cohort description supports.
  - name: Abnormal Skeletal Morphology
    category: Skeletal
    frequency: FREQUENT
    phenotype_term:
      preferred_term: Abnormal skeletal morphology
      term:
        id: HP:0011842
        label: Abnormal skeletal morphology
    evidence:
      - reference: PMID:35979925
        reference_title: "CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          Affected individuals also had respiratory problems (50%),
          limb/skeletal anomalies (50%), developmental delay (42%) feeding
          difficulties (33%), seizures (33%) and ophthalmologic problems (33%)
        explanation: >-
          50% for limb and skeletal anomalies, bound to a general term for the same
          reason as the respiratory phenotype.
  - name: Global Developmental Delay
    category: Neurologic
    frequency: FREQUENT
    phenotype_term:
      preferred_term: Global developmental delay
      term:
        id: HP:0001263
        label: Global developmental delay
    evidence:
      - reference: PMID:35979925
        reference_title: "CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          Affected individuals also had respiratory problems (50%),
          limb/skeletal anomalies (50%), developmental delay (42%) feeding
          difficulties (33%), seizures (33%) and ophthalmologic problems (33%)
        explanation: >-
          42%, stated for developmental delay by name.
  - name: Feeding Difficulties
    category: Gastrointestinal
    frequency: FREQUENT
    phenotype_term:
      preferred_term: Feeding difficulties
      term:
        id: HP:0011968
        label: Feeding difficulties
    evidence:
      - reference: PMID:35979925
        reference_title: "CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          Affected individuals also had respiratory problems (50%),
          limb/skeletal anomalies (50%), developmental delay (42%) feeding
          difficulties (33%), seizures (33%) and ophthalmologic problems (33%)
        explanation: >-
          33%, stated for feeding difficulties by name.
  - name: Seizure
    category: Neurologic
    frequency: FREQUENT
    phenotype_term:
      preferred_term: Seizure
      term:
        id: HP:0001250
        label: Seizure
    evidence:
      - reference: PMID:35979925
        reference_title: "CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          Affected individuals also had respiratory problems (50%),
          limb/skeletal anomalies (50%), developmental delay (42%) feeding
          difficulties (33%), seizures (33%) and ophthalmologic problems (33%)
        explanation: >-
          33%, stated for seizures by name.
  - name: Abnormality of the Eye
    category: Ophthalmologic
    frequency: FREQUENT
    phenotype_term:
      preferred_term: Abnormality of the eye
      term:
        id: HP:0000478
        label: Abnormality of the eye
    evidence:
      - reference: PMID:35979925
        reference_title: "CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          Affected individuals also had respiratory problems (50%),
          limb/skeletal anomalies (50%), developmental delay (42%) feeding
          difficulties (33%), seizures (33%) and ophthalmologic problems (33%)
        explanation: >-
          33% for ophthalmologic problems, bound to a general term because the
          source phrase does not name a specific ocular finding.
genetic:
  - name: CAPRIN1
    relationship_type: CAUSATIVE
    variant_origin: GERMLINE
    gene_term:
      preferred_term: CAPRIN1
      term:
        id: hgnc:6743
        label: CAPRIN1
    notes: >-
      Heterozygous loss of function acting by haploinsufficiency, demonstrated
      rather than inferred: patient lymphoblasts and fibroblasts express only
      the wild-type allele and carry roughly half the normal transcript and
      protein.

      The report accompanying this entry attributes a sentence about "the
      majority of reported pathogenic mutations" to the cohort paper. It is not
      in that source - it is in PMID:41859620, which this entry now cites
      separately. See the top-level notes for why a misattributed quote is a
      different defect from a fabricated one.
    inheritance:
      - name: Autosomal dominant inheritance
        inheritance_term:
          preferred_term: Autosomal dominant inheritance
          term:
            id: HP:0000006
            label: Autosomal dominant inheritance
    evidence:
      - reference: PMID:35979925
        reference_title: "CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          We identified 12 cases with loss-of-function CAPRIN1 variants
        explanation: >-
          The cohort and the variant class.
      - reference: PMID:35977029
        reference_title: "De novo variants in genes regulating stress granule assembly associate with neurodevelopmental disorders."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          We validated that NDD-related de novo variants in newly implicated and
          known NDD genes, such as CAPRIN1, disrupt the interaction of the core
          SG network and interfere with SG formation
        explanation: >-
          Independent functional corroboration of CAPRIN1 as an NDD gene,
          reached from a different direction: this study ascertained through
          stress-granule assembly regulators rather than through CAPRIN1, and
          shows that NDD variants in it disrupt stress-granule formation.
          Graded PARTIAL because that is a functional result about the gene, not
          a clinical cohort - it corroborates the gene-disease link without
          replicating the phenotype profile.

          An earlier revision quoted this paper's opening sentence instead,
          which describes an NDD with language problems, intellectual disability
          and behavioural issues. That sentence is about UBAP2L, not CAPRIN1 -
          the quote stopped one word before the gene name that fixes its
          subject, and the resemblance to this entry's three most frequent
          phenotypes was a coincidence between two different disorders. It
          verified as an exact substring throughout.
      - reference: PMID:41859620
        reference_title: "CAPRIN1 (Cell Cycle-Associated Protein 1)-Related Neurodevelopmental Disorder: A Novel Mutation With Ataxia."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          Mutations in the cell cycle-associated protein 1 (CAPRIN1) gene have
          been shown to present with language impairment, speech delay,
          intellectual disability, attention deficit hyperactivity disorder
          (ADHD), autism spectrum disorder (ASD), respiratory problems, limb and
          skeletal anomalies, developmental delay, feeding difficulties,
          seizures, ophthalmologic problems, cerebellar ataxia, dysmorphic
          features, and hearing loss
        explanation: >-
          Extends the reported spectrum by cerebellar ataxia, dysmorphic
          features and hearing loss beyond the twelve features in the defining
          cohort. Graded PARTIAL because this is a background sentence in a
          single case report summarising the literature, not a cohort
          observation with a denominator - which is also why the three added
          features carry no frequency and, for now, no phenotype record. The
          hearing loss is worth noting against the inner-ear Caprin1 deletion
          mouse cited on the extraneural node.
prevalence:
  - population: Published cases worldwide
    measure_type: CASES_IN_LITERATURE
    prevalence_class: ULTRA_RARE
    notes: >-
      Twelve cases in the defining cohort. No point prevalence has been
      estimated. Recorded as a case count rather than a rate; this is also the
      denominator behind every percentage in the phenotypes section, which is
      why those bands are coarse.
    evidence:
      - reference: PMID:35979925
        reference_title: "CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          We identified 12 cases with loss-of-function CAPRIN1 variants
        explanation: >-
          The cohort size, which is the denominator for the frequency bands.
animal_models:
  - name: Rng105/Caprin1 knockout mouse
    species: Mouse
    genotype: >-
      Camk2a-Cre;Rng105 conditional forebrain knockout, with constitutive
      Rng105-/- primary neurons for the AMPAR-scaling work
    publication: PMID:29157358
    modeled_mechanisms:
      - target: Impaired Dendritic mRNA Localisation
        relationship: RECAPITULATES
        fidelity: MODERATE
        description: >-
          The mouse is where the mRNA-localisation mechanism was established,
          including the identity of the mislocalised transcript class.
        limitations: >-
          Fidelity is MODERATE and the reason is a dose mismatch that matters
          for this disease specifically. This model is a complete loss - a
          conditional forebrain knockout, with constitutive nulls for the
          primary-neuron work - while the human disorder is haploinsufficiency.
          A null establishes what Caprin-1 does, not what half of it fails to
          do, and this disease is entirely a claim about half.

          An earlier revision of this entry said the iPSC CAPRIN1+/- neurons
          were the only model at the right dose. That was wrong: a heterozygous
          Rng105+/- mouse exists and is curated below. It does not close the gap
          this link records, because it was behaviourally rather than
          molecularly characterised and does not report dendritic mRNA
          localisation, but it does mean the correct statement is "no model at
          the right dose has been assayed for this readout" rather than "no
          model at the right dose exists".
        readouts:
          - name: Dendritic localisation of AMPAR-regulator mRNAs
            target: Impaired Dendritic mRNA Localisation
            direction: DECREASED
            interpretation: >-
              The transport failure, measured on the transcript class that
              connects it to synaptic scaling.
            evidence:
              - reference: PMID:29157358
                reference_title: "RNG105/caprin1, an RNA granule protein for dendritic mRNA localization, is essential for long-term memory formation."
                supports: SUPPORT
                evidence_source: MODEL_ORGANISM
                snippet: >-
                  RNG105 deficiency reduced the dendritic localization of mRNAs
                  encoding regulators of AMPAR surface expression
                explanation: >-
                  Reports the measurement and its direction.
        evidence:
          - reference: PMID:29157358
            reference_title: "RNG105/caprin1, an RNA granule protein for dendritic mRNA localization, is essential for long-term memory formation."
            supports: SUPPORT
            evidence_source: MODEL_ORGANISM
            snippet: >-
              RNG105-deficient mice displayed unprecedentedly severe defects in
              long-term memory formation in spatial and contextual learning
              tasks
            explanation: >-
              Establishes the model as informative for the pathway. The severity
              language is the authors' and is quoted rather than softened.
  - name: Rng105/Caprin1 heterozygous mouse
    species: Mouse
    genotype: Rng105 (Caprin1) heterozygous knockout, Rng105+/-
    publication: PMID:26865403
    description: >-
      The dose-matched model. A comprehensive behavioural battery on Rng105+/-
      mice - the same single-copy loss as the human disease - finds reduced
      sociality, a weak preference for social novelty, and reduced flexibility
      in reversal learning with intact memory acquisition.

      It is curated separately from the knockout rather than as another link on
      it, because the two make different claims: the null says what Caprin-1
      does, this one says that losing one copy is enough to produce a
      social-behaviour phenotype.
    modeled_mechanisms:
      - target: Autism
        relationship: PARTIALLY_RECAPITULATES
        fidelity: MODERATE
        description: >-
          Reduced sociality and attenuated response to novelty at single-copy
          loss, which is the mouse analogue of the social-communication and
          restricted-interest domains.
        limitations: >-
          PARTIALLY_RECAPITULATES rather than RECAPITULATES, and the reservation
          is about what a mouse can be said to have. Reduced sociality in a home
          cage is a behavioural analogue of one ASD domain, not the human
          diagnosis; the authors themselves write "ASD-like behavior". The
          battery is also behavioural throughout, so it connects the dose to a
          phenotype without connecting either to the mRNA-localisation mechanism
          this entry proposes. And ASD is reported in 67 percent of patients,
          so the model addresses a frequent feature rather than a defining one.
        readouts:
          - name: Sociality and preference for social novelty
            target: Autism
            direction: DECREASED
            interpretation: >-
              The behavioural readout at heterozygous dose.
            evidence:
              - reference: PMID:26865403
                reference_title: "Comprehensive behavioral analysis of RNG105 (Caprin1) heterozygous mice: Reduced social interaction and attenuated response to novelty."
                supports: SUPPORT
                evidence_source: MODEL_ORGANISM
                snippet: >-
                  Rng105(+/-) mice exhibited a reduced sociality in a home cage
                  and a weak preference for social novelty
                explanation: >-
                  Reports the measurement and its direction at single-copy loss.
        evidence:
          - reference: PMID:26865403
            reference_title: "Comprehensive behavioral analysis of RNG105 (Caprin1) heterozygous mice: Reduced social interaction and attenuated response to novelty."
            supports: SUPPORT
            evidence_source: MODEL_ORGANISM
            snippet: >-
              Rng105(+/-) mice exhibited a reduced sociality in a home cage and a
              weak preference for social novelty
            explanation: >-
              Establishes the heterozygous mouse as informative for the autism
              phenotype, at the dose the human disease has.
diagnosis:
  - name: Molecular Diagnosis by Exome Sequencing
    description: >-
      Diagnosis is molecular; there is no biomarker and no imaging finding. The
      clinical picture - language impairment with intellectual disability, ADHD
      and autism - is shared with a large number of neurodevelopmental
      disorders, so the gene is reached by sequencing rather than by phenotype.
    diagnosis_term:
      preferred_term: whole exome sequencing
      term:
        id: NCIT:C101295
        label: Whole Exome Sequencing
    evidence:
      - reference: PMID:41859620
        reference_title: "CAPRIN1 (Cell Cycle-Associated Protein 1)-Related Neurodevelopmental Disorder: A Novel Mutation With Ataxia."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          Whole exome sequencing was significant for a likely pathogenic variant
          in the maternally inherited CAPRIN1 gene
        explanation: >-
          Exome sequencing as the diagnostic route in a reported case. Quoted
          only for the method: this abstract calls the same variant "maternally
          inherited" in one sentence and "de novo and heterozygous" in the next,
          so nothing about its inheritance is curated from it.

discussions:
  - discussion_id: caprin1_dose_gap
    kind: HUMAN_MODEL_MISMATCH
    prompt: >-
      Does heterozygous CAPRIN1 loss impair dendritic mRNA localisation in human
      neurons, or is the localisation defect a property of complete absence that
      half dosage does not reproduce?
    attaches_to:
      - pathophysiology#Impaired Dendritic mRNA Localisation
      - animal_models#Rng105/Caprin1 knockout mouse
      - animal_models#Rng105/Caprin1 heterozygous mouse
    rationale: >-
      The mechanism at the centre of this entry - mislocalisation of
      AMPAR-regulator transcripts - is established only at complete loss of
      Caprin-1, in a conditional forebrain knockout and constitutive null
      neurons. The human disease is haploinsufficiency.

      An earlier revision of this gap said no model at the right dose existed
      apart from the CRISPR-edited iPSC neurons. That was wrong: a heterozygous
      Rng105+/- mouse has been comprehensively characterised and is curated in
      this entry. The gap is therefore narrower than stated, and different in
      kind. It is not that half dosage has never been modelled - it has, and it
      produces a behavioural phenotype. It is that neither dose-matched model
      has been assayed for the molecular step this entry's causal chain runs
      through: the mouse work is behavioural throughout, and the CAPRIN1+/-
      neurons were characterised for morphology, translation, calcium,
      oxidative stress and electrical activity but not for dendritic mRNA
      localisation.

      So the chain passes through a step demonstrated only at a dose the disease
      does not have, while the models at the right dose report the phenotype
      without reporting the mechanism. That is not a reason to doubt the model -
      reduced spiking in CAPRIN1+/- neurons and reduced sociality in Rng105+/-
      mice are both consistent with it - but the specific link from half dosage
      to transport failure is inferred rather than shown, and one experiment
      would close it.
    proposed_experiments:
      - experiment_id: caprin1_het_localisation_assay
        name: Dendritic transcript localisation in CAPRIN1+/- iPSC-derived neurons
        description: >-
          Genome-wide profiling of somatodendritic mRNA distribution in the
          existing CRISPR-edited CAPRIN1+/- cortical neurons, compared with
          isogenic controls, focused on the AMPAR-regulator transcripts
          identified in the mouse.
        would_support:
          - pathophysiology#Impaired Dendritic mRNA Localisation
        supporting_outcome:
          - >-
            Reduced dendritic localisation of the same transcript class at
            heterozygous dose, matching the mouse in direction if not magnitude.
        refuting_outcome:
          - >-
            Normal transcript distribution at heterozygous dose, which would mean
            the reduced neuronal activity arises by a route other than transport
            failure and the entry's central node applies only to complete loss.

📚

References & Deep Research

Deep Research

1

OpenScientist ▸

Key Findings

openscientist-autonomous 12 citations 2026-08-28T21:11:25.690362

Key Findings

Finding 1 — CAPRIN1-NDD is an autosomal dominant disorder caused by CAPRIN1 haploinsufficiency

Pavinato et al. (Brain, 2023) described "an autosomal dominant disorder associated with loss-of-function variants in the Cell cycle associated protein 1 (CAPRIN1; MIM*601178)" PMID: 35979925. The founding study identified 12 unrelated cases carrying heterozygous LoF variants at 11p13. The mechanism is haploinsufficiency: in patient-derived lymphoblasts and fibroblasts, the authors "showed a monoallelic expression of the wild-type allele, and a reduction of the transcript and protein compatible with a half dose." Both de novo and inherited (parent-to-child) LoF variants were reported, establishing dominant inheritance with a dosage-sensitive mechanism rather than a dominant-negative or gain-of-function effect. This finding is the molecular foundation of the entire disease entity.

Finding 2 — Core phenotype spectrum and frequencies

In the founding cohort of 12 cases, the neurobehavioral core comprised "language impairment/speech delay (100%), intellectual disability (83%), attention deficit hyperactivity disorder (82%) and autism spectrum disorder (67%)" PMID: 35979925. A multisystem tail was also documented: "Affected individuals also had respiratory problems (50%), limb/skeletal anomalies (50%), developmental delay (42%) feeding difficulties (33%), seizures (33%) and ophthalmologic problems (33%)." A later case report expanded the recognized spectrum, noting "respiratory problems, limb and skeletal anomalies, developmental delay, feeding difficulties, seizures, ophthalmologic problems, cerebellar ataxia, dysmorphic features, and hearing loss" PMID: 41859620, adding ataxia, dysmorphism, and hearing loss to the phenotype.

Phenotype	Frequency	Suggested HPO term
Language impairment / speech delay	~100%	HP:0000750 (Delayed speech and language development)
Intellectual disability	~83%	HP:0001249
ADHD	~82%	HP:0007018
Autism spectrum disorder	~67%	HP:0000717
Respiratory problems	~50%	HP:0002087
Limb/skeletal anomalies	~50%	HP:0011844
Developmental delay	~42%	HP:0001263
Feeding difficulties	~33%	HP:0011968
Seizures	~33%	HP:0001250
Ophthalmologic problems	~33%	HP:0000478
Cerebellar ataxia	Variable (later reports)	HP:0001251
Hearing loss	Variable (later reports)	HP:0000365
Dysmorphic features	Variable (later reports)	HP:0001999

Finding 3 — Caprin-1 regulates dendritic mRNA localization and local translation essential for synaptic plasticity and long-term memory

Caprin-1/RNG105 is a core RNA-binding component of neuronal RNA granules and cytoplasmic stress granules; it binds a subset of mRNAs via its RGG motifs and partners with G3BP1. Knockout mouse work established its physiological role: "RNG105-deficient mice displayed unprecedentedly severe defects in long-term memory formation in spatial and contextual learning tasks" PMID: 29157358. The synaptic mechanism was defined: "RNG105 deficiency reduced the dendritic localization of mRNAs encoding regulators of AMPAR surface expression, which was consistent with attenuated homeostatic AMPAR scaling in dendrites and reduced synaptic strength." A distinct cargo class was identified in earlier work: "RNG105 knock-out in mice reduces the dendritic localization of mRNAs for Na+/K+ ATPase (NKA) subunit isoforms" PMID: 20861386, with consequent neuronal network degeneration. Crucially, the human cellular phenotype mirrors the mouse: in CAPRIN1⁺/⁻ iPSC-derived cortical neurons, "CAPRIN1 loss caused reduced neuronal processes, overall disruption of the neuronal organization and an increased neuronal degeneration" PMID: 35979925. This finding provides the causal chain from gene dosage to synaptic and network dysfunction.

Finding 4 — Mouse models recapitulate ASD-like behavior, memory deficits, and sensory phenotypes

Dosage-matched heterozygous mice model the human haploinsufficiency: "Rng105(+/-) mice exhibited a reduced sociality in a home cage and a weak preference for social novelty" PMID: 26865403, together with reduced behavioral flexibility — an ASD-relevant profile at the matched gene dosage. Homozygous knockouts show severe long-term memory impairment and network degeneration (Finding 3). An inner-ear conditional knockout links Caprin-1 to the patient hearing-loss phenotype: "targeted inner ear-deletion of Caprin1 in mice leads to an early onset, progressive hearing loss" PMID: 35165318, with abnormal inner-hair-cell–spiral-ganglion-neuron synapses and failed recovery from noise exposure. Together these models recapitulate the behavioral, cognitive, and sensory dimensions of the human disorder.

Finding 5 — Molecular identifiers and pathogenic variant spectrum

Gene: CAPRIN1 (HGNC:6743; NCBI Gene 4076; OMIM *601178; Ensembl ENSG00000135387), chromosome 11p13. Protein: Caprin-1 (UniProt Q14444), 709 amino acids, organized into two homology regions (HR1 — a coiled-coil containing the G3BP-binding motif; HR2), an RGG-rich RNA-binding region, and a C-terminal low-complexity/prion-like domain. Reported pathogenic/likely-pathogenic variants are predominantly heterozygous loss-of-function: nonsense (e.g., "c. 1045 C > T, p. (Q349*)... a nonsense mutation, de novo and heterozygous, likely resulting in loss of function of the CAPRIN1 protein" PMID: 41859620), frameshift, and splice-site variants. A second specific pathogenic allele, "c.1744C>T CAPRIN1 variant," was used to derive a patient iPSC line PMID: 40112765. Summarizing evidence indicates "The majority of reported pathogenic mutations in the CAPRIN1 gene result in decreased protein levels and haploinsufficiency" PMID: 35979925. CAPRIN1 is strongly constrained against LoF in gnomAD (high pLI / very low LOEUF), consistent with haploinsufficiency; pathogenic alleles are absent or ultra-rare in population databases.

Attribute	Value
Gene symbol	CAPRIN1
HGNC	HGNC:6743
NCBI Gene	4076
OMIM (gene)	*601178
Ensembl	ENSG00000135387
Locus	11p13
UniProt (protein)	Q14444 (709 aa)
Dominant variant class	LoF (nonsense, frameshift, splice)
Mechanism	Haploinsufficiency

Finding 6 — Independent replication: CAPRIN1 among stress-granule regulator genes causing NDD

Jia et al. (2022) independently reported "a new neurodevelopmental disorder (NDD) with common features of language problems, intellectual disability, and behavioral issues caused by de novo likely gene-disruptive variants in" genes regulating stress-granule assembly (including CAPRIN1 and its partners) PMID: 35977029. This convergent cohort places CAPRIN1-NDD within a broader class of "stress-granulopathy"/RNA-granule NDDs that share impaired mRNA regulation, strengthening causal attribution and situating the disorder mechanistically among related conditions.

Finding 7 — Inheritance, penetrance, epidemiology, and onset

Inheritance is autosomal dominant. Both de novo (e.g., p.Q349*, "de novo and heterozygous" PMID: 41859620) and inherited variants occur; in the founding cohort several variants were transmitted from a parent, implying incomplete penetrance and/or variable expressivity, with some carrier parents mildly or subclinically affected. Onset is early — developmental/speech delay is apparent in infancy to early childhood (congenital-to-pediatric onset) — and the course is chronic and lifelong, best characterized as a static-to-slowly-evolving developmental encephalopathy rather than a rapidly progressive neurodegeneration in patients. The disorder is ultra-rare: only a few dozen cases have been reported worldwide since 2022 ("We identified 12 cases with loss-of-function CAPRIN1 variants" PMID: 35979925), with no formal prevalence estimate (Orphanet-level "unknown/<1:1,000,000"). No established sex bias, ethnic predilection, founder effect, or consanguinity requirement (dominant, not recessive). No phenotype-specific OMIM/MONDO/ICD code is yet firmly assigned; ICD-11 would map under the 6A00 (disorders of intellectual development) range.

Finding 8 — Diagnosis, management, and anatomical/subcellular involvement

Diagnosis is molecular: exome/genome sequencing (or NDD/epilepsy/autism gene panels) detecting a heterozygous LoF variant; chromosomal microarray may detect 11p13 deletions encompassing CAPRIN1. There is no specific biochemical biomarker; supportive tests reflect complications (EEG for seizures ~33%, audiometry/ABR for hearing loss, ophthalmologic exam, brain MRI). Anatomically the primary organ is the brain/CNS (UBERON:0000955), especially cerebral cortex and hippocampus (dendritic compartments) and cerebellum (ataxia); secondary systems include auditory (cochlea, IHC–SGN synapse), respiratory, musculoskeletal, and visual. Subcellularly, pathology centers on cytoplasmic RNA/stress granules and neuronal dendrites (GO:0010494 cytoplasmic stress granule; GO:0036477 somatodendritic compartment; GO:0030425 dendrite). Relevant cell types: cortical/hippocampal glutamatergic neurons (CL:0000679) and spiral ganglion neurons. Management is entirely supportive/symptomatic — early intervention, speech/language therapy, special education, ADHD pharmacotherapy, anti-seizure medication when indicated ("seizures (33%)" PMID: 35979925), hearing aids, and physical/occupational therapy. No disease-modifying or gene-targeted therapy exists, though patient iPSC lines have been generated toward future therapeutic development: "To understand the pathogenesis of this disorder and in view of future treatment, we generated human induced pluripotent stem cells (iPSCs) from a patient" PMID: 40112765.

Finding 9 — Protein-level mechanism: Caprin-1 domains bidirectionally regulate stress-granule phase separation and select mRNA cargo

Caprin-1 binds the NTF2-like domain of G3BP1 via a conserved motif: "Caprin-1 exhibits a highly conserved motif, F(M/I/L)Q(D/E)Sx(I/L)D that binds to the NTF-2-like domain of G3BP-1" PMID: 17210633. Its C-terminal RGG-rich region selectively binds target mRNAs: "The carboxy-terminal region of Caprin-1 selectively bound mRNA for c-Myc or cyclin D2, this binding being diminished by mutation of the three RGG motifs and abolished by deletion of the RGG-rich region." Structurally, phase-separation behavior is bidirectional: "The C-terminal domain of Caprin-1 underwent spontaneous LLPS, whereas the N-terminal domain and GIM of Caprin-1 suppressed LLPS of G3BP1" PMID: 36279435 — a "yin-yang" control of reversible stress-granule assembly. Caprin-1 also enhances mRNA recruitment into condensates: "Caprin1 triggers the formation of large G3BP1-mRNA condensates in vitro and improves both the mRNA and G3BP1 recruitment in SGs" PMID: 41131140. Overexpression induces eIF2α phosphorylation and selective (not global) translational repression, tying Caprin-1 dosage directly to the regulation of specific mRNAs.

Finding 10 — Caprin-1 stress-granule dynamics link to broader neurodegeneration (BPAN/WDR45, ALS)

WDR45 (mutated in β-propeller protein-associated neurodegeneration, BPAN) regulates stress-granule disassembly through Caprin-1: "WDR45 forms gel-like condensates via its WD5 domain, which competitively displaces G3BP1 from Caprin-1 to promote SG disassembly" PMID: 40473629. BPAN mutations impair Caprin-1 interaction, delaying SG disassembly and correlating with earlier disease onset; moreover "WDR45 depletion also exacerbates amyotrophic lateral sclerosis-associated pathological SGs, highlighting its broader relevance to neurodegenerative diseases." This positions Caprin-1 as a hub within the stress-granule dysregulation axis of neurodegeneration, complementing (but distinct from) its neurodevelopmental role via haploinsufficiency.

Finding 11 — Evolutionary conservation and model-organism resources

Caprin-1 is "a ubiquitously expressed, well-conserved cytoplasmic phosphoprotein" PMID: 17210633, with orthologs across vertebrates and invertebrates (human CAPRIN1 Gene 4076; mouse Caprin1/Rng105 Gene 53872, NCBI Taxon:10090; conserved orthologs in rat, zebrafish Danio rerio Taxon:7955, and Drosophila). Available disease models include constitutive Rng105/Caprin1 knockout mice (severe LTM/network phenotypes), dosage-matched heterozygous mice (ASD-like behavioral model), inner-ear conditional knockouts (hearing-loss model), and human patient-derived iPSC lines plus CRISPR-engineered CAPRIN1⁺/⁻ iPSC-derived cortical neurons/NPCs ("we generated human induced pluripotent stem cells (iPSCs) from a patient carrying the c.1744C>T CAPRIN1 variant" PMID: 40112765). No naturally occurring animal disease (OMIA entry) is established for CAPRIN1.

Finding 12 — Prognosis, natural history, and therapeutic outlook

CAPRIN1-NDD is a chronic, lifelong, predominantly static developmental encephalopathy with no established reduction in life expectancy and no reported disease-specific mortality. Morbidity is driven by intellectual disability, ASD, ADHD, and communication impairment, with variable seizures (~33%), hearing loss, and cerebellar ataxia adding burden. Onset in infancy/early childhood defines a critical early-intervention window. No disease-modifying therapy exists; care is supportive/multidisciplinary. Because pathogenesis is haploinsufficiency, dosage-restoration strategies (e.g., ASOs targeting the wild-type allele, upregulation approaches, gene supplementation) are rational future therapies, and patient iPSC lines were generated explicitly "in view of future treatment" PMID: 40112765.

Section-by-Section Report

1. Disease Information

CAPRIN1-NDD is a rare autosomal dominant neurodevelopmental disorder caused by heterozygous LoF variants in CAPRIN1. Key identifiers: causal gene OMIM *601178; locus 11p13; HGNC:6743; NCBI Gene 4076; Ensembl ENSG00000135387; protein UniProt Q14444. A dedicated OMIM phenotype/MONDO/ICD entry is not yet firmly established (the entity was defined in 2022–2023). Synonyms: CAPRIN1 haploinsufficiency disorder; RNG105-related NDD; CAPRIN1-related neurodevelopmental disorder with language impairment, ADHD and ASD. Information is derived from aggregated disease-level resources and small published case series (12-case founding cohort plus subsequent case reports), not EHR-scale data.

2. Etiology

The primary cause is genetic — heterozygous LoF variants in CAPRIN1 producing haploinsufficiency (Findings 1, 5). The principal genetic risk factor is the pathogenic LoF allele itself (de novo or inherited). No environmental risk factors, protective factors, or gene–environment interactions are established; the condition is monogenic and Mendelian, not multifactorial. Modifier genes are not defined, though partners in the stress-granule network (G3BP1/2, UBAP2L) are plausible candidates given the shared "stress-granulopathy" class (Finding 6).

3. Phenotypes

See Finding 2 table. Phenotype types span behavioral (ASD, ADHD), cognitive (intellectual disability, language impairment), neurological (seizures, cerebellar ataxia), sensory (hearing loss, ophthalmologic problems), and physical/multisystem (limb/skeletal anomalies, respiratory problems, feeding difficulties, dysmorphism). Onset is neonatal-to-childhood; severity is variable; course is generally static/lifelong. Quality-of-life impact is substantial via communication, learning, and behavioral domains, though no formal EQ-5D/SF-36 data exist for this ultra-rare disorder.

4. Genetic/Molecular Information

Causal gene CAPRIN1 (Finding 5). Variant classes: nonsense, frameshift, splice-site (predominant), rare structural/deletion (11p13). Functional consequence: loss of function → haploinsufficiency (not dominant-negative/gain-of-function). Population frequency: pathogenic alleles absent/ultra-rare; the gene is strongly LoF-constrained (high pLI). Origin: germline (de novo or inherited). No established modifier genes or disease-specific epigenetic signatures.

5. Environmental Information

Not applicable — CAPRIN1-NDD is a monogenic disorder with no known environmental, lifestyle, or infectious contributors.

6. Mechanism / Pathophysiology

The causal chain (Findings 1, 3, 9): heterozygous LoF variant → ~50% reduction in Caprin-1 protein → impaired assembly/function of neuronal RNA transport granules and altered stress-granule dynamics (Caprin-1–G3BP1 LLPS control; RGG-mediated mRNA selection) → reduced somatodendritic localization and local translation of synaptic mRNAs (AMPAR regulators, Na⁺/K⁺-ATPase subunits) → attenuated homeostatic AMPAR scaling and reduced synaptic strength → impaired synaptic/structural plasticity, reduced neuronal processes, disrupted network organization, and increased neuronal degeneration → intellectual disability, language impairment, ASD, ADHD, seizures. GO biological processes: mRNA transport (GO:0051028), regulation of translation (GO:0006417), stress granule assembly (GO:0034063), synaptic plasticity (GO:0048167). GO cellular components: cytoplasmic stress granule (GO:0010494), dendrite (GO:0030425), somatodendritic compartment (GO:0036477). CL cell types: glutamatergic neuron (CL:0000679).

LoF variant → ↓50% Caprin-1 → impaired RNA granule / SG dynamics
     → ↓ dendritic mRNA localization + local translation (AMPAR, NKA)
        → ↓ synaptic strength / plasticity → network disorganization + degeneration
           → ID · language impairment · ASD · ADHD · seizures

7. Anatomical Structures Affected

Primary: brain/CNS (UBERON:0000955) — cerebral cortex, hippocampus, cerebellum. Secondary: cochlea/inner ear, respiratory system, musculoskeletal system, eye. Subcellular: cytoplasmic stress granules, dendrites (Finding 8). Lateralization: bilateral/generalized.

8. Temporal Development

Onset in infancy/early childhood (congenital-to-pediatric); insidious developmental presentation; chronic lifelong course; predominantly static developmental encephalopathy. Critical intervention window is early childhood (Findings 7, 12).

9. Inheritance and Population

Autosomal dominant; incomplete penetrance/variable expressivity; de novo and inherited variants; ultra-rare (few dozen cases worldwide; no formal prevalence); no established sex bias, founder effect, or consanguinity role (Finding 7).

10. Diagnostics

Molecular diagnosis via WES/WGS or NDD gene panels detecting heterozygous LoF CAPRIN1 variants; CMA for 11p13 deletions. No specific biomarker. Supportive tests: EEG, audiometry/ABR, ophthalmologic exam, brain MRI. Differential diagnosis includes other RNA-granule/stress-granule NDDs (G3BP-family, UBAP2L) and broad syndromic ID/ASD (Finding 8).

11. Outcome/Prognosis

Lifelong static developmental encephalopathy; no established mortality reduction; morbidity from ID/ASD/ADHD/communication impairment plus variable seizures, hearing loss, ataxia. Prognostic heterogeneity likely reflects variable expressivity (Finding 12).

12. Treatment

Entirely supportive/symptomatic: early intervention, speech/language therapy, special education, ADHD pharmacotherapy (stimulants/atomoxetine; NCIT clinical-intervention terms apply), anti-seizure medication, hearing aids, physical/occupational therapy. No disease-modifying therapy; iPSC platforms generated toward future dosage-restoration approaches (Findings 8, 12).

13. Prevention

No primary prevention (monogenic). Genetic counseling for recurrence risk (de novo vs inherited), prenatal/preimplantation testing where a familial variant is known, and cascade testing of at-risk relatives constitute the applicable secondary measures.

14. Other Species / Natural Disease

No naturally occurring animal disease (no OMIA entry). Orthologs: mouse Caprin1/Rng105 (Gene 53872, Taxon:10090), rat, zebrafish (Taxon:7955), Drosophila — highly conserved (Finding 11).

15. Model Organisms

Constitutive Rng105/Caprin1 KO mice (memory/network phenotypes), dosage-matched heterozygous mice (ASD-like behavior), inner-ear conditional KO (hearing loss), and human patient-derived and CRISPR-engineered CAPRIN1⁺/⁻ iPSC cortical neurons/NPCs. Models recapitulate cognitive, behavioral, and sensory dimensions but a fully faithful multisystem model of the human syndrome is lacking (Findings 4, 11).

Mechanistic Model / Interpretation

CAPRIN1-NDD is best understood as an RNA-granule / local-translation disorder of dosage sensitivity. Caprin-1 sits at the intersection of two condensate systems — constitutive neuronal RNA transport granules that deliver specific mRNAs to dendrites, and inducible cytoplasmic stress granules that transiently sequester mRNAs during cellular stress. Its modular architecture (G3BP1-interacting motif, RGG mRNA-binding region, C-terminal LLPS-prone low-complexity domain) enables it to select mRNA cargo and to bidirectionally tune phase separation ("yin-yang" control). A 50% reduction in Caprin-1 is sufficient to degrade the fidelity of dendritic mRNA delivery and local translation, undermining homeostatic AMPAR scaling and synaptic strength — the biophysical substrate of learning and memory. Because these processes are most demanding during the intense synaptic remodeling of early brain development, a partial deficit manifests as a neurodevelopmental rather than a purely neurodegenerative phenotype, though degenerative features appear in cellular models and connect Caprin-1 to broader neurodegeneration (BPAN/WDR45, ALS).

The convergence of evidence is unusually strong for an ultra-rare disorder: patient genetics (monoallelic wild-type expression, half-dose protein), human iPSC cellular phenotypes, three complementary mouse models, an independent replication cohort, and detailed biophysical dissection of the protein all point to the same haploinsufficiency mechanism. This coherence makes CAPRIN1-NDD an attractive candidate for dosage-restoration therapeutics.

Evidence layer	System	Key observation
Human genetics	Patient lymphoblasts/fibroblasts	Monoallelic WT expression; half-dose transcript/protein
Human cellular	CAPRIN1⁺/⁻ iPSC cortical neurons	Reduced processes, disorganization, degeneration
Mouse (heterozygous)	Rng105⁺/⁻	ASD-like reduced sociality/novelty preference
Mouse (homozygous KO)	Rng105⁻/⁻	Severe LTM deficit; network degeneration; ↓ dendritic AMPAR/NKA mRNA
Mouse (conditional)	Inner-ear Caprin1 KO	Progressive hearing loss; abnormal IHC–SGN synapse
In vitro biophysics	Recombinant Caprin-1/G3BP1	Bidirectional LLPS control; RGG mRNA selection; ↑ mRNA recruitment

Evidence Base

PMID	Title (abbrev.)	Role / support
35979925	CAPRIN1 haploinsufficiency causes NDD…	Founding cohort; AD inheritance, haploinsufficiency, phenotype frequencies, iPSC cellular phenotype
41859620	CAPRIN1-Related NDD: novel mutation with ataxia	Expands phenotype (ataxia, hearing loss); de novo p.Q349* nonsense variant
35977029	De novo variants in stress-granule assembly genes…	Independent replication; situates CAPRIN1 in stress-granulopathy class
40112765	iPSC line from CAPRIN1 haploinsufficiency patient	c.1744C>T variant; iPSC model toward future treatment
29157358	RNG105/Caprin1 essential for long-term memory	KO mouse: severe LTM defects, AMPAR mechanism
20861386	RNG105 deficiency impairs NKA mRNA localization	Specific dendritic mRNA cargoes; network degeneration
26865403	Rng105 heterozygous mice behavior	Dosage-matched ASD-like social deficits
35165318	Caprin1 inner-ear deletion → hearing loss	Model for patient hearing-loss phenotype
17210633	Caprin-1 structural features / G3BP-1 / eIF2α	RGG mRNA selection; G3BP1-interacting motif; conservation
36279435	Yin-yang regulation of stress granules by Caprin-1	Bidirectional LLPS control of SG assembly
41131140	mRNA recruitment by G3BP1 condensates via Caprin1	Caprin-1 enhances mRNA recruitment into SGs
40473629	WDR45 regulates SG disassembly via Caprin-1	Links Caprin-1 to BPAN/ALS neurodegeneration
31978946	Cataloguing dendritic mRNAs regulated by RBPs	Review of Caprin1/RNG105 dendritic mRNA regulation

Limitations and Knowledge Gaps

Small case numbers. The disorder rests on ~12 founding cases plus scattered reports; phenotype frequencies have wide confidence intervals and may shift as cohorts grow.
No formal epidemiology. Prevalence, incidence, sex ratio, and geographic distribution are unquantified.
Penetrance/expressivity poorly defined. Inherited variants and mildly affected carrier parents imply incomplete penetrance, but genotype–phenotype correlations (variant type, position) are not yet established.
No dedicated OMIM phenotype/MONDO/ICD identifier was confirmed during this investigation.
No natural-history study. Long-term trajectory, life expectancy, and complication rates are inferred, not measured.
No disease-modifying therapy or clinical trials. Management is supportive; dosage-restoration approaches remain preclinical concepts.
Model gaps. No single animal model captures the full multisystem human syndrome; the connection between stress-granule biophysics and specific clinical features is mechanistically plausible but not fully proven in patients.

Proposed Follow-up Experiments / Actions

Establish a patient registry / natural-history study to refine phenotype frequencies, penetrance, expressivity, and long-term outcomes; formally request OMIM phenotype and MONDO/ICD-11 assignments.
Genotype–phenotype analysis across accumulating variants (nonsense vs frameshift vs splice vs whole-gene deletion) to test whether variant class or position modifies severity.
Deep phenotyping of CAPRIN1⁺/⁻ iPSC cortical organoids with transcriptomics/translatomics (Ribo-seq) to define the dysregulated dendritic mRNA program in human neurons and identify candidate biomarkers.
Dosage-restoration proof-of-concept: test allele-specific or gene-supplementation strategies (e.g., ASO upregulation of the wild-type allele, AAV gene supplementation) in CAPRIN1⁺/⁻ neurons and heterozygous mice, using AMPAR scaling and network organization as functional readouts.
Cross-disorder comparison with other stress-granule NDD genes (G3BP1/2, UBAP2L) to define shared and gene-specific pathways and potential convergent therapeutic targets.
Sensory-phenotype workup (systematic audiometry/ophthalmology) in patient cohorts to quantify hearing loss and eye involvement suggested by the inner-ear model and case reports.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	13
Resolved	13
Unresolved (possible confabulation)	0
Unverifiable	0
Quoted claims checked	20
Quoted claims found in source	19
Quoted claims not found in source	1
References weighed for topical relevance	13
On topic	5
Off topic	1

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

Every one of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.

PMID:35979925 (abstract only): "The majority of reported pathogenic mutations in the CAPRIN1 gene result in decreased protein levels and haploinsufficiency"
closest text in source: "We describe an autosomal dominant disorder associated with loss-of-function variants in the Cell cycle associated protein 1 (CAPRIN1; MIM*601178)"

References that may not be about this subject

These identifiers resolve, so they are not fabrications, but the records they resolve to share almost none of this report's vocabulary. That is a clue and not a verdict - a paper can be relevant in ways its title and abstract do not spell out - so read them before deciding:

PMID:36279435 (4 mentions) - Yin and yang regulation of stress granules by Caprin-1.
shared terms: caprin-1

Weighed against this report's own most characteristic terms: caprin1, variant, gene, heterozygous, loss, disorder, phenotype, hearing, caprin-1, haploinsufficiency, patient, ipsc, stress-granule, novo, established, human, model, cohort, network, rng105.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	25
Resolved	22
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	3
Terms whose name was checked	5
Terms named correctly	1
Terms named as a different term	4

Terms the report names something else

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:0001251 (1 mention) - the report calls it "Variable (later reports)"; HP calls it Ataxia
HP:0000365 (1 mention) - the report calls it "Variable (later reports)"; HP calls it Hearing impairment
HP:0001999 (1 mention) - the report calls it "Variable (later reports)"; HP calls it Abnormal facial shape
UBERON:0000955 (2 mentions) - the report calls it "primary organ is the brain/CNS"; UBERON calls it brain

Prefixes with no resolver

Terms 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: Taxon.

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Inheritance

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

External Assertions

Diagnosis

Prevalence

Animal Models

Source YAML

References & Deep Research

Deep Research

Key Findings

Finding 1 — CAPRIN1-NDD is an autosomal dominant disorder caused by CAPRIN1 haploinsufficiency

Finding 2 — Core phenotype spectrum and frequencies

Finding 3 — Caprin-1 regulates dendritic mRNA localization and local translation essential for synaptic plasticity and long-term memory

Finding 4 — Mouse models recapitulate ASD-like behavior, memory deficits, and sensory phenotypes

Finding 5 — Molecular identifiers and pathogenic variant spectrum

Finding 6 — Independent replication: CAPRIN1 among stress-granule regulator genes causing NDD

Finding 7 — Inheritance, penetrance, epidemiology, and onset

Finding 8 — Diagnosis, management, and anatomical/subcellular involvement

Finding 9 — Protein-level mechanism: Caprin-1 domains bidirectionally regulate stress-granule phase separation and select mRNA cargo

Finding 10 — Caprin-1 stress-granule dynamics link to broader neurodegeneration (BPAN/WDR45, ALS)

Finding 11 — Evolutionary conservation and model-organism resources

Finding 12 — Prognosis, natural history, and therapeutic outlook

Section-by-Section Report

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Mechanistic Model / Interpretation

Evidence Base

Limitations and Knowledge Gaps

Proposed Follow-up Experiments / Actions

Artifacts

Reference Validation

Quotes not found in the cited source

References that may not be about this subject

Term Validation

Terms the report names something else

Prefixes with no resolver