CAPRIN1 Related Neurodevelopmental Disorder

Mendelian MONDO:0968945 Pathograph 53 Show in embeddings browser Neurodevelopmental Disorder

CAPRIN1-related neurodevelopmental disorder is associated with heterozygous loss-of-function variants and reduced Caprin-1 dosage. Language impairment, intellectual or learning disability, ADHD and autism dominate the reported spectrum; motor delay, seizures and variable respiratory, skeletal, ocular and auditory findings also occur. Expressivity varies and unaffected variant carriers are documented. ClinGen classified the gene–disease relationship as Moderate in February 2026. Human heterozygous neuronal models show altered global and local translation, calcium signaling, oxidative stress, neurite development and network activity. Dendritic mRNA transport and AMPA-receptor mechanisms are best established in mouse null models and cannot be assumed to operate identically at human heterozygous dosage. The recurrent p.Pro512Leu aggregation-associated neurodegenerative disorder is a distinct allelic condition.

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Inheritance

Autosomal dominant inheritance HP:0000006

Autosomal dominant inheritance with variable expressivity and incomplete penetrance. De novo alleles and transmission from both affected and reportedly unaffected parents are documented. An affected father and son carried p.Arg458Ter, whereas a clinically unaffected mother carried c.279+1G>T. Observed case-series proportions cannot estimate population penetrance.

Autosomal dominant inheritance

Show evidence (2 references)

url:https://oup.silverchair-cdn.com/article-minimal/6650380 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Case 2 had ... variant inherited from his mother, reported healthy and without history of intellectual disability, speech delay, neurodevelopmental/behavioural concerns or other medical issues; she had a college education."

Publisher full text of Pavinato et al., Brain 2023, PMID:35979925: CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD. Documents a reportedly unaffected transmitting parent.

url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_688d0e25-04f0-4160-a53a-00a6b423cafa-2026-02-02T110000.000Z SUPPORT DIRECT REVIEW SYNTHESIS Other

"Twelve PTVs occurred ... de novo ... nine were inherited (including one inherited from an affected father), and one was of unknown inheritance."

Expert synthesis of 22 probands distinguishes inheritance from penetrance.

Discussions and Knowledge Gaps

Does human heterozygous CAPRIN1 loss reduce dendritic delivery of the same mRNAs affected in mouse null neurons?

HUMAN MODEL MISMATCH caprin1_dose_gap

Attached to

pathophysiology#Impaired Dendritic mRNA Localisation experimental_models#Isogenic CAPRIN1 heterozygous human cortical neurons experimental_models#Heterozygous Caprin1 primary cortical neurons

Dendritic transcript mislocalization is directly established in complete-loss mouse models. Human heterozygous neurons have altered local puromycin labeling, which measures translation rather than RNA transport. Heterozygous mouse neurons were assayed for surface GluR1, but the downward trend was not significant; their study was therefore not exclusively behavioral. Testing transcript localization and gene-dosage rescue in the same human background would distinguish a conserved transport defect from other routes to altered translation and network activity.

Proposed experiments

Dendritic RNA localization and dosage rescue in human heterozygous neurons

caprin1_het_localisation_assay

Measure somatodendritic distributions of AMPA-regulator and NKA-subunit transcripts in heterozygous and isogenic control neurons, with physiological CAPRIN1 restoration. Pair RNA localization with local translation and electrophysiology.

Would support

pathophysiology#Impaired Dendritic mRNA Localisation

Supporting outcome

A concordant dendritic RNA deficit reversed by physiological CAPRIN1 restoration.

Refuting outcome

Preserved RNA distributions despite reproducible local-translation and network abnormalities.

Show evidence (2 references)

url:https://oup.silverchair-cdn.com/article-minimal/6650380 SUPPORT DIRECT PRIMARY RESULT In Vitro

"These data suggest that ... CAPRIN1 ... haploinsufficiency might also affect local protein synthesis."

PMID:26865403 REFUTE DIRECT PRIMARY RESULT In Vitro

"GluR1 surface distribution in dendrites tended to be less in Rng105+/− mice than in wild-type mice, though statistically not significant"

The heterozygous comparison limits claims of a proven same-dose effect.

Which stress-granule abnormalities occur in human loss-of-function neurons at physiological dosage?

HUMAN MODEL MISMATCH caprin1_stress_granule_context

Attached to

pathophysiology#Context-Dependent Impairment of Stress-Granule Assembly

CAPRIN1-null HeLa cells and an Ile373Lys add-back assay show impaired granule assembly, whereas null cochlear explants retain marker-positive granules. Normal-protein biophysical studies show opposing domain effects and enhanced G3BP1-dependent mRNA recruitment; these establish molecular capabilities, not a proven universal disease mechanism. WDR45-associated granule disassembly and p.Pro512Leu aggregation belong to distinct disease contexts. Physiological-dose neuronal experiments should measure granule composition and recovery, not only granule number.

Show evidence (4 references)

PMID:35977029 SUPPORT DIRECT PRIMARY RESULT In Vitro

"We observed a significant reduction of SG numbers in KO cell lines"

CAPRIN1 knockout perturbs granule formation in HeLa cells.

PMID:35165318 REFUTE DIRECT PRIMARY RESULT In Vitro

"These data suggest that stress granule formation in native cochlear cells is not dependent on Caprin1."

Null cochlear explants retain stress-granule formation.

PMID:36279435 SUPPORT INDIRECT BACKGROUND In Vitro

"The C-terminal domain of Caprin-1 underwent spontaneous LLPS, whereas the N-terminal domain and GIM of Caprin-1 suppressed LLPS of G3BP1."

Domain biophysics provides context without establishing the effects of patient loss-of-function alleles.

+ 1 more reference

What determines whether a carrier of a CAPRIN1 protein-truncating variant develops neurodevelopmental impairment?

OPEN QUESTION caprin1_penetrance

Attached to

genetic#CAPRIN1

ClinGen downgraded the relationship to Moderate because truncating alleles were also present in reportedly unaffected parents, siblings and controls. Ascertainment, depth of parental phenotyping, allele-specific consequences and additional genetic factors could contribute. Existing series do not support a numerical penetrance estimate or a validated modifier gene.

Show evidence (1 reference)

url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_688d0e25-04f0-4160-a53a-00a6b423cafa-2026-02-02T110000.000Z SUPPORT DIRECT REVIEW SYNTHESIS Other

"The classification was downgraded from strong to moderate due to multiple instances of truncating variants inherited from unaffected parents or present in unaffected siblings and controls."

The expert panel explicitly qualifies the strength of the gene–disease relationship.

⚙

Pathophysiology

Heterozygous Coding Nonsense Substitutions

Mechanism confidence: Established

Heterozygous single-nucleotide substitutions introduce premature termination codons, including p.Gln399Ter and p.Gln582Ter. These alleles were functionally investigated in patient fibroblasts.

CAPRIN1 hgnc:6743

Genetic context CAPRIN1 hgnc:6743 Variant type: single nucleotide variant Genomic context: coding sequence variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: LOSS_OF_FUNCTION

Downstream

Decay of Premature-Termination CAPRIN1 Transcripts Tested nonsense alleles produce decay-sensitive transcripts.

Show evidence (1 reference)

url:https://oup.silverchair-cdn.com/article-minimal/6650380 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Sanger sequencing of the cDNA containing the c.1195C... p.Gln399Ter and c.1744C... p.Gln582Ter shows that the mutant allele is probably degraded by NMD"

Intronic CAPRIN1 Splice-Donor Substitution

Mechanism confidence: Established

The heterozygous c.279+1G>T substitution affects the intron 3 donor and produces in-frame exon 3 skipping. The variant was transmitted by a reportedly unaffected mother.

CAPRIN1 hgnc:6743

Genetic context CAPRIN1 hgnc:6743 Variant type: single nucleotide variant Genomic context: intron variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: LOSS_OF_FUNCTION

Downstream

Aberrant CAPRIN1 Splicing The two substitutions alter exon inclusion in patient RNA.

Show evidence (1 reference)

url:https://oup.silverchair-cdn.com/article-minimal/6650380 SUPPORT DIRECT PRIMARY RESULT In Vitro

"The c.279+1G... change causes an in-frame 84 bp exon 3 skipping"

Publisher full text of Pavinato et al., Brain 2023, PMID:35979925: CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD. Allele-specific RNA analysis identifies the consequence of the donor alteration.

Exon-Terminal CAPRIN1 Splice-Altering Substitution

Mechanism confidence: Established

The heterozygous synonymous c.879G>A substitution affects the final nucleotide of exon 8 and disrupts donor recognition. Patient RNA shows out-of-frame exon 8 skipping.

CAPRIN1 hgnc:6743

Genetic context CAPRIN1 hgnc:6743 Variant type: single nucleotide variant Genomic context: coding sequence variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: LOSS_OF_FUNCTION

Downstream

Aberrant CAPRIN1 Splicing The two substitutions alter exon inclusion in patient RNA.

Show evidence (1 reference)

url:https://oup.silverchair-cdn.com/article-minimal/6650380 SUPPORT DIRECT PRIMARY RESULT In Vitro

"The c.879G... affects the last base of exon 8 and causes out-of-frame skipping of exon 8 and a degradation by NMD."

Heterozygous Small Coding Deletion

Mechanism confidence: Established

The c.1493_1496del allele removes four coding nucleotides and predicts p.Ser498AsnfsTer10. Allele-specific RNA decay was not demonstrated for this particular deletion.

CAPRIN1 hgnc:6743

Genetic context CAPRIN1 hgnc:6743 Variant type: deletion Genomic context: coding sequence variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: LOSS_OF_FUNCTION

Downstream

Decay of Premature-Termination CAPRIN1 Transcripts Frameshift alleles predict premature termination; their decay was not directly assayed.

Show evidence (2 references)

url:https://oup.silverchair-cdn.com/article-minimal/6650380 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Overall, they include two splicing ... and 10 nonsense/frameshift changes."

url:https://broadinstitute.atlassian.net/wiki/spaces/BCLGC/pages/4871684098/CAPRIN1+Gene+Curation SUPPORT DIRECT REVIEW SYNTHESIS Other

"Case 11: c.1493_1496del, p.Ser498AsnfsTer10 ... 3 year old male"

The expert case summary names the allele reported in the primary clinical supplement.

Heterozygous Coding Deletion-Insertion

Mechanism confidence: Established

The c.1103delinsTATGT allele replaces a coding nucleotide with five bases and predicts p.Gly368ValfsTer5. It is a compound deletion-insertion rather than a simple nucleotide substitution; RNA decay was not directly assayed for this allele.

CAPRIN1 hgnc:6743

Genetic context CAPRIN1 hgnc:6743 Genomic context: coding sequence variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: LOSS_OF_FUNCTION

Single-base replacement by TATGT at c.1103, creating a frameshift.

Downstream

Decay of Premature-Termination CAPRIN1 Transcripts Frameshift alleles predict premature termination; their decay was not directly assayed.

Show evidence (2 references)

url:https://oup.silverchair-cdn.com/article-minimal/6650380 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Overall, they include two splicing ... and 10 nonsense/frameshift changes."

url:https://broadinstitute.atlassian.net/wiki/spaces/BCLGC/pages/4871684098/CAPRIN1+Gene+Curation SUPPORT DIRECT REVIEW SYNTHESIS Other

"Case 7: c.1103delinsTATGT, p.Gly368ValfsTer5 ... 6 year old male"

The expert case summary names the allele reported in the primary clinical supplement.

Heterozygous CAPRIN1 Gene Deletion

Mechanism confidence: Established

A de novo 11p13 deletion encompasses CAPRIN1 and seven other genes. It supports a dosage hypothesis but the individual phenotype cannot be attributed solely to CAPRIN1.

CAPRIN1 hgnc:6743

Genetic context CAPRIN1 hgnc:6743 Variant type: deletion Genomic context: coding sequence Genomic context: intron variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: LOSS_OF_FUNCTION

Downstream

Reduced CAPRIN1 Protein Abundance Deletion removes one CAPRIN1 copy; reduced transcript was measured in the deletion carrier.

Show evidence (1 reference)

url:https://oup.silverchair-cdn.com/article-minimal/6650380 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The deletion spans eight genes, including ... CAPRIN1"

Publisher full text of Pavinato et al., Brain 2023, PMID:35979925: CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD. Defines the multigene deletion, which is not an isolated CAPRIN1 deletion.

Aberrant CAPRIN1 Splicing

Mechanism confidence: Established

Patient-derived lymphoblastoid cells showed exon 3 skipping with c.279+1G>T and exon 8 skipping with c.879G>A. The exon 3 event preserves the reading frame and is associated with reduced protein abundance; the exon 8 event introduces a frameshift and a decay-sensitive transcript.

mRNA splicing, via spliceosome GO:0000398 ⚠ ABNORMAL

Experimental models

Patient fibroblasts and lymphoblastoid cells PRIMARY CELL CULTURE Exon skipping differs between the two splice variants.

Downstream

Decay of Premature-Termination CAPRIN1 Transcripts The out-of-frame exon 8 product undergoes decay; this link does not apply to the in-frame exon 3 product.

Reduced CAPRIN1 Protein Abundance The in-frame splice carrier also has reduced protein; altered stability is proposed.

Show evidence (1 reference)

url:https://oup.silverchair-cdn.com/article-minimal/6650380 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Analysis of the cDNA showed skipping of exon 3 ... and of exon 8"

Publisher full text of Pavinato et al., Brain 2023, PMID:35979925: CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD. RNA analysis distinguishes the two splice outcomes.

Decay of Premature-Termination CAPRIN1 Transcripts

Mechanism confidence: Established

Mutant transcripts were depleted in tested nonsense and out-of-frame splice carriers. Cycloheximide partly restored their detection, supporting nonsense-mediated decay. This was not demonstrated for every truncating allele and does not describe the in-frame exon 3 product.

nuclear-transcribed mRNA catabolic process, nonsense-mediated decay GO:0000184 ↑ INCREASED

Experimental models

Patient fibroblasts and lymphoblastoid cells PRIMARY CELL CULTURE Cycloheximide partly restores mutant transcript detection.

Downstream

Reduced CAPRIN1 Protein Abundance Reduced productive RNA accompanies reduced protein in tested patient cells.

Show evidence (1 reference)

url:https://oup.silverchair-cdn.com/article-minimal/6650380 SUPPORT DIRECT PRIMARY RESULT In Vitro

"To investigate the occurrence of nonsense-mediated decay (NMD) for premature stop codons, we treated fibroblasts with CHX and showed a partial rescue in the expression of the mutant allele by Sanger sequencing"

Publisher full text of Pavinato et al., Brain 2023, PMID:35979925: CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD. Pharmacological inhibition partially restores the mutant RNA.

Reduced CAPRIN1 Protein Abundance

Mechanism confidence: Established

Reduced CAPRIN1 abundance was measured in patient cells. Dosage is cell- and allele-dependent: fibroblast immunoblots for p.Gln399Ter and p.Gln582Ter were approximately 26% and 36% of normalized control abundance. The genetic mechanism is loss of function, but a universal precisely 50% protein level is not established.

Experimental models

Patient fibroblasts and lymphoblastoid cells PRIMARY CELL CULTURE Patient cells have reduced CAPRIN1 abundance.

Downstream

Impaired Dendritic mRNA Localisation Loss-of-function models support this consequence; cellular intermediates and genotype-dose equivalence remain incompletely defined.

Increased Global Neuronal Translation Loss-of-function models support this consequence; cellular intermediates and genotype-dose equivalence remain incompletely defined.

Reduced Distal Dendritic Translation Loss-of-function models support this consequence; cellular intermediates and genotype-dose equivalence remain incompletely defined.

Impaired Neurite Development Loss-of-function models support this consequence; cellular intermediates and genotype-dose equivalence remain incompletely defined.

Increased Intracellular Calcium Signals Loss-of-function models support this consequence; cellular intermediates and genotype-dose equivalence remain incompletely defined.

Increased Neuronal Oxidative Stress Loss-of-function models support this consequence; cellular intermediates and genotype-dose equivalence remain incompletely defined.

Neuronal Process Degeneration Loss-of-function models support this consequence; cellular intermediates and genotype-dose equivalence remain incompletely defined.

Reduced Neuronal Network Activity Loss-of-function models support this consequence; cellular intermediates and genotype-dose equivalence remain incompletely defined.

Context-Dependent Impairment of Stress-Granule Assembly Loss-of-function models support this consequence; cellular intermediates and genotype-dose equivalence remain incompletely defined.

Abnormal Cochlear Postsynaptic Structure Loss-of-function models support this consequence; cellular intermediates and genotype-dose equivalence remain incompletely defined.

Show evidence (1 reference)

url:https://oup.silverchair-cdn.com/article-minimal/6650380 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Overall, CAPRIN1 protein levels were clearly reduced in all samples analysed, supporting haploinsufficiency as the disease mechanism."

Publisher full text of Pavinato et al., Brain 2023, PMID:35979925: CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD. Direct patient-cell expression studies support reduced protein abundance.

Impaired Dendritic mRNA Localisation

Mechanism confidence: Provisional

Mouse forebrain conditional deletion and constitutive null neurons show reduced dendritic localization of selected transcripts, including AMPA-receptor regulators and Na+/K+-ATPase subunits. AMPA-receptor subunit transcripts themselves were not generally depleted from dendrites. This transport step has not been directly measured in human heterozygous neurons.

neuron CL:0000540

intracellular mRNA localization GO:0008298 ↓ DECREASED

Experimental models

Constitutive Caprin1-null primary cortical neurons PRIMARY CELL CULTURE NKA-related reporter RNA localization and movement are reduced.

Animal models

Rng105/Caprin1 forebrain conditional knockout mouse Mouse partially recapitulates Somatodendritic localization of selected regulator mRNAs is reduced.

Downstream

Reduced Dendritic Sodium-Potassium Pump Activity Mislocalization of NKA-related transcripts accompanies a compartment-specific pump deficit in null neurons.

Reduced Dendritic AMPA-Receptor Surface Expression Loss of regulator-transcript localization is proposed to alter AMPA-receptor trafficking.

Impaired Homeostatic AMPA-Receptor Scaling The transport defect and impaired homeostatic scaling coexist in null models; a transcript-specific rescue was not shown.

Show evidence (2 references)

PMID:29157358 SUPPORT DIRECT PRIMARY RESULT Model Organism

"These results indicated that various mRNAs, encoding AMPAR regulators involved in AMPAR surface expression and retention to postsynapses, were localized to dendrites in an RNG105-dependent manner."

In vivo somatodendritic RNA profiling identifies affected regulator transcripts.

PMID:20861386 SUPPORT DIRECT PRIMARY RESULT In Vitro

"their localization was limited to the cell soma and proximal dendrites and their motility was reduced in Rng105−/− neurons"

Cultured null neurons show altered movement and distribution of NKA-related reporter transcripts.

Increased Global Neuronal Translation

Mechanism confidence: Established

In CRISPR-edited CAPRIN1+/− human cortical neurons, puromycin incorporation indicated increased global protein synthesis at 14 days after neuronal differentiation. The earlier four-day difference was not significant. The finding contradicts a purely positional defect with preserved global translation in all contexts.

neuron CL:0000540

translation GO:0006412 ↑ INCREASED

Experimental models

Isogenic CAPRIN1 heterozygous human cortical neurons IPSC DERIVED MODEL Global translation is increased at day 14, with no significant increase at day 4.

Show evidence (1 reference)

url:https://oup.silverchair-cdn.com/article-minimal/6650380 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Treatment of hiPSCs-derived neurons with 1 µg/ml puromycin for 30 min resulted in a slightly increased global translation ... neurons 4 days post-ND ... which became significantly higher 14 days post-ND"

Reduced Distal Dendritic Translation

Mechanism confidence: Established

The dendritic puromycin signal declined more rapidly with distance from the soma in heterozygous human neurons than in controls, supporting altered local protein synthesis. This readout measures local translation and does not directly establish which mRNAs are mislocalized.

neuron CL:0000540

translation GO:0006412 ↓ DECREASED

Experimental models

Isogenic CAPRIN1 heterozygous human cortical neurons IPSC DERIVED MODEL Distal dendritic puromycin labeling declines more steeply.

Show evidence (1 reference)

url:https://oup.silverchair-cdn.com/article-minimal/6650380 SUPPORT DIRECT PRIMARY RESULT In Vitro

"These data suggest that ... CAPRIN1 ... haploinsufficiency might also affect local protein synthesis."

Reduced Dendritic Sodium-Potassium Pump Activity

Mechanism confidence: Provisional

In cultured mouse null neurons, NKA subunit proteins were depleted from dendrites despite similar total abundance. K+-dependent Na+ efflux was reduced in dendrites while somatic activity was preserved. The corresponding pump defect has not been directly measured in human heterozygous neurons.

neuron CL:0000540

P-type sodium:potassium-exchanging transporter activity GO:0005391 ↓ DECREASED

Experimental models

Constitutive Caprin1-null primary cortical neurons PRIMARY CELL CULTURE Dendritic pump activity is reduced while somatic activity is preserved.

Downstream

Increased Intracellular Calcium Signals A pump-to-calcium pathway is proposed from mouse and human results; it has not been tested directly in human heterozygous neurons.

Show evidence (1 reference)

PMID:20861386 SUPPORT DIRECT PRIMARY RESULT In Vitro

"These results suggest that NKA activity was decreased in dendrites but not in the cell soma of Rng105−/− neurons"

Functional imaging localizes the deficit to dendrites.

Reduced Dendritic AMPA-Receptor Surface Expression

Mechanism confidence: Provisional

Dendritic surface GluR1 was reduced in mouse null neurons. A heterozygous primary-neuron comparison showed a downward trend that was not statistically significant. Reduced surface expression is therefore established for complete loss, with uncertainty at the human genotype dosage.

neuron CL:0000540

Experimental models

Constitutive Caprin1-null primary cortical neurons PRIMARY CELL CULTURE Dendritic surface GluR1 is significantly reduced.

Heterozygous Caprin1 primary cortical neurons PRIMARY CELL CULTURE The heterozygous surface-GluR1 difference was not statistically significant.

Downstream

Reduced Excitatory Synaptic Strength Reduced postsynaptic receptor availability is a proposed contributor to lower excitatory responses.

Show evidence (2 references)

PMID:26865403 SUPPORT DIRECT PRIMARY RESULT In Vitro

"quantification revealed that the ratio of surface/total GluR1 puncta number in dendrites was significantly reduced in the Rng105−/− neurons"

Complete-loss cultures show a significant surface-receptor deficit.

PMID:26865403 REFUTE DIRECT PRIMARY RESULT In Vitro

"GluR1 surface distribution in dendrites tended to be less in Rng105+/− mice than in wild-type mice, though statistically not significant"

The heterozygous comparison limits claims of a proven same-dose effect.

Impaired Homeostatic AMPA-Receptor Scaling

Mechanism confidence: Provisional

Activity deprivation with TTX/APV increased dendritic AMPA-receptor surface puncta in wild-type cortical neurons but failed to induce the corresponding response in Caprin1-null cultures. This experimental scaling defect has not been demonstrated in patient neurons.

neuron CL:0000540

Experimental models

Constitutive Caprin1-null primary cortical neurons PRIMARY CELL CULTURE The TTX/APV-induced scaling response is impaired.

Downstream

Reduced Excitatory Synaptic Strength Impaired scaling may lower the synaptic set point, but the assays use distinct null preparations.

Show evidence (1 reference)

PMID:29157358 SUPPORT DIRECT PRIMARY RESULT In Vitro

"By contrast, the activity deprivation-dependent increase in surface GluR1 expression was not observed in Rng105−/− dendrites"

Direct activity-deprivation experiment in primary null neurons.

Reduced Excitatory Synaptic Strength

Mechanism confidence: Provisional

Forebrain conditional knockout mice had reduced absolute hippocampal excitatory postsynaptic responses. Relative potentiation from the lower baseline was preserved, so reduced synaptic strength should not be equated with abolished LTP induction.

neuron CL:0000540

chemical synaptic transmission GO:0007268 ↓ DECREASED

Animal models

Rng105/Caprin1 forebrain conditional knockout mouse Mouse partially recapitulates Absolute excitatory responses are reduced while relative LTP gain is retained.

Show evidence (2 references)

PMID:29157358 SUPPORT DIRECT PRIMARY RESULT Model Organism

"RNG105 deficiency reduced both the amplitude and slope of fEPSP to about half of those of control mice"

Hippocampal physiology measures the lower absolute response.

PMID:29157358 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Theta-burst-induced LTP in CA1 neurons revealed that fEPSP was increased from baseline by ~100%, which was comparable between Rng105f/f and Camk2a-Cre;Rng105f/f mice"

Supports the distinction between reduced absolute synaptic strength and preserved relative LTP gain.

Impaired Neurite Development

Mechanism confidence: Established

Human heterozygous cortical neurons developed shorter processes and disorganized neuronal architecture. Early neuronal rosettes and progenitor morphology were preserved; the effect emerged during neuronal differentiation rather than gross failure of progenitor formation.

neuron CL:0000540

dendrite development GO:0016358 ↓ DECREASED

Experimental models

Isogenic CAPRIN1 heterozygous human cortical neurons IPSC DERIVED MODEL Neurite length and organization are impaired.

Isogenic CAPRIN1 heterozygous neuronal progenitors IPSC DERIVED MODEL Early rosette size and progenitor morphology were not detectably altered.

Constitutive Caprin1-null primary cortical neurons PRIMARY CELL CULTURE Dendritic length and arborization are reduced.

Downstream

Reduced Neuronal Network Activity Altered neurite architecture may contribute to reduced network activity.

Show evidence (1 reference)

url:https://oup.silverchair-cdn.com/article-minimal/6650380 SUPPORT DIRECT PRIMARY RESULT In Vitro

"immature neurons showed an alteration of neuronal structure, accompanied by reduced neurites length"

Increased Intracellular Calcium Signals

Mechanism confidence: Established

Live imaging of heterozygous human neurons showed elevated intracellular calcium signals at days 10 and 14, before overt degeneration. The assay does not identify the responsible channel or establish that a dendritic NKA defect causes this change.

neuron CL:0000540

intracellular calcium ion homeostasis GO:0006874 ⚠ ABNORMAL

Experimental models

Isogenic CAPRIN1 heterozygous human cortical neurons IPSC DERIVED MODEL Calcium signals are elevated before overt degeneration.

Downstream

Increased Neuronal Oxidative Stress Calcium elevation precedes oxidative stress; causal direction has not been established.

Show evidence (1 reference)

url:https://oup.silverchair-cdn.com/article-minimal/6650380 SUPPORT DIRECT PRIMARY RESULT In Vitro

"showed an increase in ... signals in ... compared to control neurons, both at 10 and 14 days post-ND"

Publisher full text of Pavinato et al., Brain 2023, PMID:35979925: CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD. Calcium imaging precedes overt degeneration. The quoted comparison identifies the two time points of the increased calcium-signal finding.

Increased Neuronal Oxidative Stress

Mechanism confidence: Established

CellROX signal was increased in human heterozygous neurons at day 18, near the onset of degeneration. The study did not distinguish ROS species or demonstrate that antioxidant treatment rescues the phenotype.

neuron CL:0000540

Experimental models

Isogenic CAPRIN1 heterozygous human cortical neurons IPSC DERIVED MODEL Oxidative-stress signal is elevated near degeneration onset.

Downstream

Neuronal Process Degeneration Oxidative stress accompanies degeneration without a demonstrated rescue experiment.

Show evidence (1 reference)

url:https://oup.silverchair-cdn.com/article-minimal/6650380 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Notably, we observed a significant increase in CellROX signal ... cells compared to controls"

Neuronal Process Degeneration

Mechanism confidence: Established

CAPRIN1+/− cortical cultures developed shrinking cell clusters and progressive process degeneration beginning around days 17–19. This in vitro finding does not establish progressive neurodegeneration as the natural history of human loss-of-function disease.

neuron CL:0000540

Experimental models

Isogenic CAPRIN1 heterozygous human cortical neurons IPSC DERIVED MODEL Neuronal processes degenerate around days 17–19.

Downstream

Reduced Neuronal Network Activity Degeneration may worsen network function, but reduced activity also precedes overt cell loss.

Show evidence (1 reference)

url:https://oup.silverchair-cdn.com/article-minimal/6650380 SUPPORT DIRECT PRIMARY RESULT In Vitro

"we observed a progressive degeneration of neuronal processes ... which began with the formation of small clusters of shrinking neuronal cells ... between Days 17 and 19 post-ND in five independent cultures"

Reduced Neuronal Network Activity

Mechanism confidence: Established

Human heterozygous neurons showed reduced spike rates/counts and, at later sampled time points, reduced burst counts on microelectrode arrays. These network readouts are distinct from the AMPA-receptor scaling and hippocampal synaptic assays performed in mouse null models.

neuron CL:0000540

chemical synaptic transmission GO:0007268 ↓ DECREASED

Experimental models

Isogenic CAPRIN1 heterozygous human cortical neurons IPSC DERIVED MODEL Spike and burst activity are reduced.

Show evidence (1 reference)

url:https://oup.silverchair-cdn.com/article-minimal/6650380 SUPPORT DIRECT PRIMARY RESULT In Vitro

"The spike rate and spike count were significantly lower in ... neurons versus controls"

Publisher full text of Pavinato et al., Brain 2023, PMID:35979925: CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD. Microelectrode recordings directly demonstrate reduced network activity.

Context-Dependent Impairment of Stress-Granule Assembly

Mechanism confidence: Provisional

CAPRIN1 knockout reduced arsenite-induced stress-granule numbers in HeLa cells. Re-expression experiments showed that the candidate p.Ile373Lys variant disrupts G3BP1/2 binding and granule recruitment, but this does not demonstrate the mechanism of all heterozygous truncating alleles. Cochlear null explants still formed TIA1/HuR-positive granules, demonstrating cell-context dependence.

cytoplasmic stress granule assembly GO:0034063 ↓ DECREASED

Experimental models

CAPRIN1 knockout and missense add-back HeLa cells CELL LINE CAPRIN1 loss and p.Ile373Lys perturb stress-granule assembly.

Caprin1 conditional-null cochlear explants OTHER Granule formation persisted in Caprin1-deficient cochlear cells.

Show evidence (2 references)

PMID:35977029 SUPPORT DIRECT PRIMARY RESULT In Vitro

"We observed a significant reduction of SG numbers in KO cell lines"

CAPRIN1 knockout perturbs granule formation in HeLa cells.

PMID:35165318 REFUTE DIRECT PRIMARY RESULT In Vitro

"These data suggest that stress granule formation in native cochlear cells is not dependent on Caprin1."

Null cochlear explants retain stress-granule formation.

Abnormal Cochlear Postsynaptic Structure

Mechanism confidence: Provisional

Sox10-Cre Caprin1 conditional knockout mice showed enlarged postsynaptic GluA2-positive areas at inner-hair-cell–spiral-ganglion synapses, reduced auditory-nerve responses and impaired recovery from noise. Hair cells and their bundles were preserved; synapse loss and hair-cell death were not established explanations. The specific postsynaptic defect has not been shown in human heterozygotes.

Animal models

Sox10-Cre Caprin1 conditional knockout mouse Mouse partially recapitulates Postsynaptic GluA2 areas are enlarged with reduced auditory-nerve responses.

Show evidence (1 reference)

PMID:35165318 SUPPORT DIRECT PRIMARY RESULT Model Organism

"the GluA2-positive post-synaptic densities were almost twofold larger in Caprin1tm3d/tm3d mice compared to wildtypes"

Morphometry identifies altered postsynaptic structure.

⬡

Pathograph

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

●

Phenotypes

Digestive 1

Feeding Difficulties OCCASIONAL HP:0011968

Show evidence (1 reference)

url:https://oup.silverchair-cdn.com/article-minimal/6650380 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Gastrointestinal issues (2/12), feeding difficulties (2/12) and ocular anomalies (4/12) were reported"

Ear 1

Hearing Impairment OCCASIONAL HP:0000365

Show evidence (1 reference)

url:https://oup.silverchair-cdn.com/article-minimal/6650380 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Notably, mild hearing loss has been observed in Cases 3 and 10."

Eye 4

Strabismus HP:0000486

Show evidence (1 reference)

url:https://broadinstitute.atlassian.net/wiki/spaces/BCLGC/pages/4871684098/CAPRIN1+Gene+Curation SUPPORT DIRECT REVIEW SYNTHESIS Other

"10 year old male - hypermetropic and had strabismus"

Expert case summary matches the detailed primary clinical supplement.

Astigmatism HP:0000483

Show evidence (1 reference)

url:https://broadinstitute.atlassian.net/wiki/spaces/BCLGC/pages/4871684098/CAPRIN1+Gene+Curation SUPPORT DIRECT REVIEW SYNTHESIS Other

"mild astigmatism and myopia, generalized anxiety disorder, difficulties with language comprehension"

Expert case summary matches the detailed primary clinical supplement.

Myopia HP:0000545

Show evidence (1 reference)

url:https://broadinstitute.atlassian.net/wiki/spaces/BCLGC/pages/4871684098/CAPRIN1+Gene+Curation SUPPORT DIRECT REVIEW SYNTHESIS Other

"mild astigmatism and myopia, generalized anxiety disorder, difficulties with language comprehension"

Expert case summary matches the detailed primary clinical supplement.

Hypermetropia HP:0000540

Show evidence (1 reference)

url:https://broadinstitute.atlassian.net/wiki/spaces/BCLGC/pages/4871684098/CAPRIN1+Gene+Curation SUPPORT DIRECT REVIEW SYNTHESIS Other

"10 year old male - hypermetropic and had strabismus"

Expert case summary matches the detailed primary clinical supplement.

Head and Neck 3

Bulbous Nose HP:0000414

Show evidence (1 reference)

url:https://oup.silverchair-cdn.com/article-minimal/6650380 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"broad nasal tip, low hanging columella and thin lip recurred in different cases"

Low Hanging Columella HP:0009765

Show evidence (1 reference)

url:https://oup.silverchair-cdn.com/article-minimal/6650380 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"broad nasal tip, low hanging columella and thin lip recurred in different cases"

Thin Upper Lip Vermilion HP:0000219

Show evidence (1 reference)

url:https://oup.silverchair-cdn.com/article-minimal/6650380 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"broad nasal tip, low hanging columella and thin lip recurred in different cases"

Immune 1

Asthma HP:0002099

Show evidence (1 reference)

url:https://oup.silverchair-cdn.com/article-minimal/6650380 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Respiratory concerns were reported in six cases, and included foetal respiratory distress, post-natal saturation dips, obstructive sleep apnoea, sudden chocking spells and asthma"

Limbs 1

Clinodactyly HP:0030084

Show evidence (1 reference)

url:https://oup.silverchair-cdn.com/article-minimal/6650380 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Six patients also showed mild skeletal limb malformations, with fifth digit clinodactyly as the prevalent feature"

Publisher full text of Pavinato et al., Brain 2023, PMID:35979925: CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD. Supports clinodactyly without assigning the aggregate limb-anomaly frequency.

Musculoskeletal 3

Hypotonia HP:0001252

Show evidence (1 reference)

PMID:41859620 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"On neurologic exam, the patient demonstrated mild global hypotonia."

Direct neurological examination.

Scoliosis OCCASIONAL HP:0002650

Show evidence (1 reference)

url:https://oup.silverchair-cdn.com/article-minimal/6650380 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"two patients had scoliosis and mild kyphoscoliosis."

Joint Hypermobility HP:0001382

Show evidence (1 reference)

url:https://broadinstitute.atlassian.net/wiki/spaces/BCLGC/pages/4871684098/CAPRIN1+Gene+Curation SUPPORT DIRECT REVIEW SYNTHESIS Other

"flexible joints of hands and feet, autism, food selectivity, late/normal motor development milestones, ADHD"

Case 5 provides joint-laxity evidence.

Nervous System 20

Delayed Speech and Language Development HP:0000750

Show evidence (1 reference)

url:https://oup.silverchair-cdn.com/article-minimal/6650380 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Language impairment was observed in all cases, with most cases speaking very few words at the last evaluations."

Publisher full text of Pavinato et al., Brain 2023, PMID:35979925: CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD. All 12 clinically ascertained cases had language impairment.

Intellectual Disability HP:0001249

Show evidence (1 reference)

url:https://oup.silverchair-cdn.com/article-minimal/6650380 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Intellectual and/or learning disabilities from mild to very severe were reported for all but Cases 1 and 6"

Specific Learning Disability HP:0001328

Show evidence (1 reference)

url:https://broadinstitute.atlassian.net/wiki/spaces/BCLGC/pages/4871684098/CAPRIN1+Gene+Curation SUPPORT DIRECT REVIEW SYNTHESIS Other

"9 year old female - history of developmental delay (particularly in speech), ADHD, dyslexia"

Expert case summary corroborates dyslexia in the primary clinical supplement.

Attention Deficit Hyperactivity Disorder VERY_FREQUENT HP:0007018

Show evidence (1 reference)

url:https://oup.silverchair-cdn.com/article-minimal/6650380 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Nine of eleven patients (82%) met the diagnostic criteria for attention deficit hyperactivity disorder (ADHD)."

Autism FREQUENT HP:0000717

Show evidence (1 reference)

url:https://oup.silverchair-cdn.com/article-minimal/6650380 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"ASD was diagnosed in eight patients (67%)."

Global Developmental Delay HP:0001263

Show evidence (1 reference)

url:https://broadinstitute.atlassian.net/wiki/spaces/BCLGC/pages/4871684098/CAPRIN1+Gene+Curation SUPPORT DIRECT REVIEW SYNTHESIS Other

"Case 9: 12 year old male - mild ID, global developmental delay, moderate language impairment, ADHD"

Case-level evidence explicitly identifies global delay.

Delayed Gross Motor Development HP:0002194

Show evidence (1 reference)

PMID:41859620 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"We present the case of a patient with ASD, gross motor delay, fine motor delay, speech delay, mixed receptive-expressive language disorder, incontinence, and ADHD."

Case-level motor development findings.

Delayed Fine Motor Development HP:0010862

Show evidence (1 reference)

PMID:41859620 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"We present the case of a patient with ASD, gross motor delay, fine motor delay, speech delay, mixed receptive-expressive language disorder, incontinence, and ADHD."

Case-level motor development findings.

Developmental Regression HP:0002376

Show evidence (1 reference)

url:https://broadinstitute.atlassian.net/wiki/spaces/BCLGC/pages/4871684098/CAPRIN1+Gene+Curation SUPPORT DIRECT REVIEW SYNTHESIS Other

"6 year old male - ASD, stagnation/decline in development and is now only able to use a few words"

Case 7 had early loss or stagnation of acquired language.

Speech Apraxia HP:0011098

Show evidence (2 references)

url:https://broadinstitute.atlassian.net/wiki/spaces/BCLGC/pages/4871684098/CAPRIN1+Gene+Curation SUPPORT DIRECT REVIEW SYNTHESIS Other

"severe language delay, ASD, severe speech apraxia, fine motor skills deficit"

Primary cohort deletion case has speech apraxia; the multigene deletion limits gene specificity.

PMID:41859620 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"On the Goldman-Fristoe Test of Articulation-3 (GFTA-3), the patient scored 28%, which is indicative of Apraxia."

The later case reports speech apraxia assessment.

Seizures HP:0001250

Show evidence (1 reference)

url:https://oup.silverchair-cdn.com/article-minimal/6650380 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Four patients had epileptic seizures with different severity"

Infantile Spasms HP:0012469

Show evidence (1 reference)

url:https://broadinstitute.atlassian.net/wiki/spaces/BCLGC/pages/4871684098/CAPRIN1+Gene+Curation SUPPORT DIRECT REVIEW SYNTHESIS Other

"3 year old male - infantile spasms, global developmental delay and speech delay, epilepsy, gait instability, ASD, stereotyped movements, ID, signs of ADHD and aggressivity"

Case-level evidence for infantile spasms.

Ataxia HP:0001251

Show evidence (1 reference)

PMID:41859620 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"a wide-based gait with an ataxic quality to movement"

Direct examination in a nonsense-variant carrier.

Motor Stereotypy HP:0000733

Show evidence (1 reference)

url:https://oup.silverchair-cdn.com/article-minimal/6650380 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Stereotyped movements and behaviours were also observed in some of the patients"

Aggressive Behavior HP:0000718

Show evidence (1 reference)

PMID:41859620 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"the school expressed significant concerns regarding aggression, poor focus, self-isolation, and limited interaction with others"

School observations in the 2026 case.

Self-Injurious Behavior HP:0100716

Show evidence (1 reference)

PMID:41859620 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"including self-injurious behavior such as hitting himself"

Direct case description.

Anxiety HP:0000739

Show evidence (1 reference)

url:https://broadinstitute.atlassian.net/wiki/spaces/BCLGC/pages/4871684098/CAPRIN1+Gene+Curation SUPPORT DIRECT REVIEW SYNTHESIS Other

"generalized anxiety disorder, difficulties with language comprehension"

Case 4 had generalized anxiety.

Obstructive Sleep Apnea HP:0002870

Show evidence (1 reference)

url:https://oup.silverchair-cdn.com/article-minimal/6650380 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Respiratory concerns were reported in six cases, and included foetal respiratory distress, post-natal saturation dips, obstructive sleep apnoea, sudden chocking spells and asthma"

Absence Seizures Generalized non-motor (absence) seizure HP:0002121

Show evidence (1 reference)

url:https://oup.silverchair-cdn.com/article-minimal/6650380 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Case 11 had infantile spams beginning at 9 months of age, which became absence epilepsy"

Focal Seizures Focal-onset seizure HP:0007359

Show evidence (1 reference)

url:https://broadinstitute.atlassian.net/wiki/spaces/BCLGC/pages/4871684098/CAPRIN1+Gene+Curation SUPPORT DIRECT REVIEW SYNTHESIS Other

"repeated focal seizures evolving into a focal status epilepticus"

The clinical description identifies the seizure type without supplying a robust population frequency.

Respiratory 1

Respiratory Distress HP:0002098

Show evidence (1 reference)

url:https://oup.silverchair-cdn.com/article-minimal/6650380 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Respiratory concerns were reported in six cases, and included foetal respiratory distress, post-natal saturation dips, obstructive sleep apnoea, sudden chocking spells and asthma"

Constitutional 1

Urinary Incontinence HP:0000020

Show evidence (1 reference)

PMID:41859620 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"He was in the process of toilet training, wearing diapers only at night, and voiding approximately once per hour during the day."

The case characterizes delayed continence in its developmental context.

🧬

Genetic Associations

CAPRIN1 (Loss-of-function gene–disease association with Moderate ClinGen validity and incompletely quantified penetrance.)

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

Autosomal dominant inheritance

Show evidence (3 references)

url:https://oup.silverchair-cdn.com/article-minimal/6650380 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"we identified by exome or genome sequencing 11 additional cases with nonsense or splicing variants affecting donor/acceptor sites"

url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_688d0e25-04f0-4160-a53a-00a6b423cafa-2026-02-02T110000.000Z SUPPORT DIRECT REVIEW SYNTHESIS Other

"The classification was downgraded from strong to moderate due to multiple instances of truncating variants inherited from unaffected parents or present in unaffected siblings and controls."

The expert panel explicitly qualifies the strength of the gene–disease relationship.

PMID:41859620 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Trio whole-exome sequencing analysis identified a heterozygous, maternally inherited, likely pathogenic variant in CAPRIN1, c. 1045 C > T/p. Q349*"

The case body resolves the inheritance used here; the abstract is internally inconsistent.

🗃️

External Assertions

OMIM NEDLAAD phenotype record

OMIM disease record OMIM:620782

Phenotype record for the developmental disorder; OMIM:601178 is the CAPRIN1 gene record.

💊

Medical Actions

Speech and language therapy

Action: Speech Language Therapy NCIT:C159273

Platform: Behavioral / lifestyle

Speech-language support was used in affected children. Therapy addresses communication and speech motor difficulties; the reports do not establish a CAPRIN1-specific treatment effect.

Target Phenotypes: Delayed speech and language development HP:0000750 Speech apraxia HP:0011098

Show evidence (1 reference)

PMID:41859620 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"He received physical, occupational, and speech therapy through the school system and used an augmentative and alternative communication device."

Documents supportive interventions in the 2026 case; efficacy was not measured in a controlled comparison.

Augmentative and alternative communication

Action: Therapeutic Procedure NCIT:C49236

Platform: Device

An augmentative communication device and a personal picture agenda were used in reported cases. Such aids support communication; device type, adherence and comparative outcomes were not systematically evaluated.

Target Phenotypes: Delayed speech and language development HP:0000750

Show evidence (2 references)

PMID:41859620 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"He received physical, occupational, and speech therapy through the school system and used an augmentative and alternative communication device."

Documents supportive interventions in the 2026 case; efficacy was not measured in a controlled comparison.

url:https://oup.silverchair-cdn.com/article-minimal/6650380 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Case 1, who was helped using a personal picture agenda"

Physical therapy

Action: Physical Therapy NCIT:C15302

Platform: Behavioral / lifestyle

School-based physical therapy was reported for motor difficulties in the 2026 case. The paper does not quantify improvement attributable to therapy.

Target Phenotypes: Delayed gross motor development HP:0002194 Ataxia HP:0001251

Show evidence (1 reference)

PMID:41859620 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"He received physical, occupational, and speech therapy through the school system and used an augmentative and alternative communication device."

Documents supportive interventions in the 2026 case; efficacy was not measured in a controlled comparison.

Occupational therapy

Action: Occupational Therapy NCIT:C121351

Platform: Behavioral / lifestyle

School-based occupational therapy addressed functional and fine motor needs. No disorder-specific comparative benefit was measured.

Target Phenotypes: Delayed fine motor development HP:0010862

Show evidence (1 reference)

PMID:41859620 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"He received physical, occupational, and speech therapy through the school system and used an augmentative and alternative communication device."

Documents supportive interventions in the 2026 case; efficacy was not measured in a controlled comparison.

Antiseizure medication

Action: Pharmacotherapy NCIT:C15986

Agent: Oxcarbazepine NCIT:C47643 Valproate Sodium NCIT:C48029 Carbamazepine NCIT:C341

Platform: Small molecule

Reported regimens include oxcarbazepine in one child and sodium valproate with carbamazepine in another; valproate provided some control in a child with nocturnal seizures. These are individual treatment histories, not evidence of a preferred regimen for all CAPRIN1-associated seizure types.

Target Phenotypes: Seizure HP:0001250 Infantile spasms HP:0012469

Show evidence (3 references)

url:https://oup.silverchair-cdn.com/article-minimal/6650380 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Cases 2 and 4 showed absence type seizures, which resolved after oxcarbazepine and ADHD treatment, respectively."

url:https://oup.silverchair-cdn.com/article-minimal/6650380 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"was treated with sodium valproate and carbamazepine."

url:https://oup.silverchair-cdn.com/article-minimal/6650380 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Case 12 suffered from secondary generalized epileptic seizures during sleep, and was treated with valproate with discrete control."

Publisher full text of Pavinato et al., Brain 2023, PMID:35979925: CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD. Individual response description without comparative efficacy data.

Genetic counseling

Action: Genetic Counseling NCIT:C15240

Platform: Other

Counseling should distinguish variant transmission from clinical penetrance, address variable expression and consider testing of parents and relatives. A heterozygous carrier can transmit the allele with a 50% probability per pregnancy, but the probability and severity of clinical manifestations are not quantified by the available series.

Show evidence (1 reference)

url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_688d0e25-04f0-4160-a53a-00a6b423cafa-2026-02-02T110000.000Z SUPPORT INDIRECT REVIEW SYNTHESIS Other

"More evidence is needed to determine the penetrance and phenotypic spectrum of ... CAPRIN1 ... haploinsufficiency."

The expert assessment supports counseling about uncertainty rather than assuming every carrier is affected.

ADHD pharmacotherapy

Action: Pharmacotherapy NCIT:C15986

Platform: Small molecule

ADHD medication was used in Case 4 of the defining cohort, with resolution of staring spells that the detailed clinical assessment considered nonepileptic. This single treatment history does not establish a CAPRIN1-specific drug response or a preferred regimen.

Target Phenotypes: Attention deficit hyperactivity disorder HP:0007018

Show evidence (1 reference)

url:https://oup.silverchair-cdn.com/article-minimal/6650380 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Cases 2 and 4 showed absence type seizures, which resolved after oxcarbazepine and ADHD treatment, respectively."

Publisher full text of Pavinato et al., Brain 2023, PMID:35979925: CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD. The cohort reports ADHD treatment in Case 4. The detailed supplement considered the staring spells nonepileptic, so their resolution is not evidence of an antiseizure effect. ADHD symptom improvement was not separately quantified, so this records treatment use rather than efficacy for ADHD.

🔬

Diagnosis

Molecular genetic testing

Exome or genome sequencing can identify coding and splice-region alleles; chromosomal microarray detected the multigene deletion. Interpretation should include segregation and variant-specific functional evidence where available, the Moderate gene–disease classification, and the distinct p.Pro512Leu mechanism.

Genetic Testing NCIT:C15709

Show evidence (1 reference)

url:https://oup.silverchair-cdn.com/article-minimal/6650380 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"we identified by exome or genome sequencing 11 additional cases with nonsense or splicing variants affecting donor/acceptor sites"

RNA analysis of splice and truncating variants

Patient RNA studies demonstrated exon skipping or decay-sensitive mutant transcripts in selected alleles. These are variant-interpretation assays, not a validated standalone diagnostic biomarker; absence of one particular readout would not exclude every CAPRIN1-associated mechanism.

RNA Analysis NCIT:C18473

Show evidence (2 references)

url:https://oup.silverchair-cdn.com/article-minimal/6650380 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Analysis of the cDNA showed skipping of exon 3 ... and of exon 8"

url:https://oup.silverchair-cdn.com/article-minimal/6650380 SUPPORT DIRECT PRIMARY RESULT In Vitro

Brain MRI

Imaging may characterize neurological concerns, but six scans in the defining series did not yield a characteristic clinically significant pattern. A normal or nonspecific scan does not exclude the developmental disorder.

Magnetic Resonance Imaging NCIT:C16809

Show evidence (1 reference)

url:https://oup.silverchair-cdn.com/article-minimal/6650380 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Brain MRI was available for six patients, and all the identified anomalies were considered without clinical significance"

Hearing assessment

Audiological assessment characterizes possible hearing problems that can compound language difficulties. The 2026 case had no reported hearing concerns and mild-to-normal measured thresholds, illustrating variable involvement.

Audiometric Test NCIT:C38036

Show evidence (1 reference)

PMID:41859620 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Hearing thresholds were found to be within the mild to normal range under headphones."

Direct case audiological assessment.

Electroencephalography

EEG was abnormal in some reported individuals and normal or unavailable in others. Results should be interpreted with the clinical event history; an EEG abnormality is not a uniform diagnostic feature of CAPRIN1-related disease.

Electroencephalography NCIT:C38054

Show evidence (1 reference)

PMID:41859620 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"| EEG anomalies | NA | + | - | - | - | NA | NA | NA | NA | NA | + | + | NA |"

The clinical comparison table records positive, negative and unavailable EEG observations; this row does not define a characteristic EEG pattern.

📊

Prevalence

Published clinically ascertained cases

Cases In Literature Ultra Rare

The defining clinical series described 12 individuals, including a related father and son. The 2026 ClinGen evaluation included 22 probands from six publications; these overlapping ascertainments must not be added to estimate unique cases. Population prevalence and penetrance remain unquantified.

Show evidence (1 reference)

url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_688d0e25-04f0-4160-a53a-00a6b423cafa-2026-02-02T110000.000Z SUPPORT DIRECT REVIEW SYNTHESIS Other

"Twenty-two PTVs that have been reported in 22 probands in six publications"

Records the scope of the expert evidence review rather than a population prevalence.

🔀

Differential Diagnoses

Conditions with similar clinical presentations that must be differentiated from CAPRIN1 Related Neurodevelopmental Disorder:

CAPRIN1 p.Pro512Leu-associated neurodegeneration Not Yet Curated MONDO:0957985

Overlapping Features The recurrent p.Pro512Leu allele is associated with progressive childhood ataxia, cognitive decline and protein aggregation, rather than the loss-of-function developmental syndrome. Later cases show progressive brain atrophy and axonal neuropathy. Ataxia can also occur with a nonsense allele, so clinical gait findings alone do not separate these entities.

Distinguishing Features

Variant-specific mechanism: p.Pro512Leu aggregation-associated gain of function versus reduced dosage from loss-of-function alleles.
Progressive cognitive and motor decline, brain atrophy and axonal neuropathy favor the neurodegenerative entity.

Show evidence (2 references)

PMID:36136249 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Trio exome sequencing unraveled the identical de novo c.1535C > T (p.Pro512Leu) missense variant in CAPRIN1"

The original neurodegenerative patients shared the recurrent missense allele.

PMID:39878554 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Electroneurography confirmed sensorimotor axonal neuropathy in the lower and upper limbs."

A subsequent patient had objective peripheral neuropathy.

🔬

Clinical Trials

NCT01238250 NOT_APPLICABLE RECRUITING

Simons Searchlight is an international observational program collecting longitudinal clinical information and biospecimens across many rare genetic neurodevelopmental conditions, including CAPRIN1. Its total planned enrollment is not a CAPRIN1-specific sample size.

Show evidence (1 reference)

clinicaltrials:NCT01238250 SUPPORT DIRECT REVIEW SYNTHESIS Other

"Simons Searchlight is an observational, online, international research program for families with rare genetic variants that cause neurodevelopmental disorders and may be associated with autism."

Registry summary identifies the observational purpose.

🧫

Experimental Models

Patient fibroblasts and lymphoblastoid cells PRIMARY_CELL_CULTURE

Patient fibroblasts, PBMCs and lymphoblastoid cells were used for allele-specific RNA, splice and expression assays. Nonsense and splice alleles were examined in different cell preparations; the results are not measurements of patient neurons.

Publication

PMID:35979925

Pathograph links

Aberrant CAPRIN1 Splicing partially recapitulates fidelity: high observes: molecular Exon skipping differs between the two splice variants.

Limitations: Results apply to the tested splice substitutions.

Show evidence (1 reference)

url:https://oup.silverchair-cdn.com/article-minimal/6650380 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Analysis of the cDNA showed skipping of exon 3 ... and of exon 8"

Decay of Premature-Termination CAPRIN1 Transcripts partially recapitulates fidelity: high observes: molecular Cycloheximide partly restores mutant transcript detection.

Limitations: Cycloheximide is an experimental inhibitor, not a treatment tested in affected people.

Show evidence (1 reference)

url:https://oup.silverchair-cdn.com/article-minimal/6650380 SUPPORT DIRECT PRIMARY RESULT In Vitro

Reduced CAPRIN1 Protein Abundance partially recapitulates fidelity: high observes: molecular Patient cells have reduced CAPRIN1 abundance.

Limitations: Protein levels vary by allele and cellular context; peripheral cells do not establish neuronal physiology.

Show evidence (1 reference)

url:https://oup.silverchair-cdn.com/article-minimal/6650380 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Overall, CAPRIN1 protein levels were clearly reduced in all samples analysed, supporting haploinsufficiency as the disease mechanism."

Publisher full text of Pavinato et al., Brain 2023, PMID:35979925: CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD. Direct patient-cell expression studies support reduced protein abundance.

Isogenic CAPRIN1 heterozygous human cortical neurons IPSC_DERIVED_MODEL

A CRISPR-edited heterozygous HUVEC-derived hiPSC line and its isogenic control were differentiated into cortical neurons. Independent differentiations provide repeated cultures, not independent patient genotypes. The model reproduces gene-copy loss but is immature and has limited allelic and genetic-background diversity. Microelectrode analyses excluded wells that never became active.

Publication

PMID:35979925

Pathograph links

Increased Global Neuronal Translation partially recapitulates fidelity: moderate observes: cellular Global translation is increased at day 14, with no significant increase at day 4.

Limitations: Engineered cultured neurons establish a cellular readout; they do not demonstrate its clinical penetrance or a complete causal sequence.

Show evidence (1 reference)

url:https://oup.silverchair-cdn.com/article-minimal/6650380 SUPPORT DIRECT PRIMARY RESULT In Vitro

Reduced Distal Dendritic Translation partially recapitulates fidelity: moderate observes: cellular Distal dendritic puromycin labeling declines more steeply.

Limitations: Engineered cultured neurons establish a cellular readout; they do not demonstrate its clinical penetrance or a complete causal sequence.

Show evidence (1 reference)

url:https://oup.silverchair-cdn.com/article-minimal/6650380 SUPPORT DIRECT PRIMARY RESULT In Vitro

"These data suggest that ... CAPRIN1 ... haploinsufficiency might also affect local protein synthesis."

Impaired Neurite Development partially recapitulates fidelity: moderate observes: cellular Neurite length and organization are impaired.

Limitations: Engineered cultured neurons establish a cellular readout; they do not demonstrate its clinical penetrance or a complete causal sequence.

Show evidence (1 reference)

url:https://oup.silverchair-cdn.com/article-minimal/6650380 SUPPORT DIRECT PRIMARY RESULT In Vitro

"immature neurons showed an alteration of neuronal structure, accompanied by reduced neurites length"

Increased Intracellular Calcium Signals partially recapitulates fidelity: moderate observes: cellular Calcium signals are elevated before overt degeneration.

Limitations: Engineered cultured neurons establish a cellular readout; they do not demonstrate its clinical penetrance or a complete causal sequence.

Show evidence (1 reference)

url:https://oup.silverchair-cdn.com/article-minimal/6650380 SUPPORT DIRECT PRIMARY RESULT In Vitro

"showed an increase in ... signals in ... compared to control neurons, both at 10 and 14 days post-ND"

Increased Neuronal Oxidative Stress partially recapitulates fidelity: moderate observes: cellular Oxidative-stress signal is elevated near degeneration onset.

Limitations: Engineered cultured neurons establish a cellular readout; they do not demonstrate its clinical penetrance or a complete causal sequence.

Show evidence (1 reference)

url:https://oup.silverchair-cdn.com/article-minimal/6650380 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Notably, we observed a significant increase in CellROX signal ... cells compared to controls"

Neuronal Process Degeneration partially recapitulates fidelity: moderate observes: cellular Neuronal processes degenerate around days 17–19.

Limitations: Engineered cultured neurons establish a cellular readout; they do not demonstrate its clinical penetrance or a complete causal sequence.

Show evidence (1 reference)

url:https://oup.silverchair-cdn.com/article-minimal/6650380 SUPPORT DIRECT PRIMARY RESULT In Vitro

Reduced Neuronal Network Activity partially recapitulates fidelity: moderate observes: cellular Spike and burst activity are reduced.

Limitations: Engineered cultured neurons establish a cellular readout; they do not demonstrate its clinical penetrance or a complete causal sequence.

Show evidence (1 reference)

url:https://oup.silverchair-cdn.com/article-minimal/6650380 SUPPORT DIRECT PRIMARY RESULT In Vitro

"The spike rate and spike count were significantly lower in ... neurons versus controls"

Isogenic CAPRIN1 heterozygous neuronal progenitors IPSC_DERIVED_MODEL

Neuronal rosettes and progenitors generated from the same edited human hiPSC background were compared with controls before neuronal maturation.

Publication

PMID:35979925

Pathograph links

Impaired Neurite Development fails to recapitulate fidelity: moderate observes: cellular Early rosette size and progenitor morphology were not detectably altered.

Limitations: Grossly preserved progenitor morphology does not exclude subtle molecular abnormalities or later neuronal defects.

Show evidence (1 reference)

url:https://oup.silverchair-cdn.com/article-minimal/6650380 SUPPORT DIRECT PRIMARY RESULT In Vitro

"No morphological alterations were observed in neural progenitor cells in further passages either"

Publisher full text of Pavinato et al., Brain 2023, PMID:35979925: CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD. Negative morphology result before neuronal maturation.

IGGi006-A patient-derived pluripotent stem cells IPSC_DERIVED_MODEL

An iPSC line was generated from a p.Gln582Ter (c.1744C>T) carrier and validated for pluripotency and three-germ-layer differentiation. This is a patient model resource; the report does not establish a neuronal disease phenotype or therapeutic rescue.

Publication

PMID:40112765

Show evidence (1 reference)

PMID:40112765 SUPPORT DIRECT PRIMARY RESULT In Vitro

"we generated human induced pluripotent stem cells (iPSCs) from a patient carrying the c.1744C>T CAPRIN1 variant."

Documents a patient-derived cellular resource.

Constitutive Caprin1-null primary cortical neurons PRIMARY_CELL_CULTURE

Embryonic mouse null cortical cultures were used for NKA localization/activity, neuronal morphology and AMPA-receptor experiments. The 2010 and 2017 studies measured different readouts in complete-loss preparations.

Publication

PMID:20861386

Pathograph links

Impaired Dendritic mRNA Localisation partially recapitulates fidelity: moderate observes: cellular NKA-related reporter RNA localization and movement are reduced.

Limitations: Complete loss differs from human heterozygosity.

Show evidence (1 reference)

PMID:20861386 SUPPORT DIRECT PRIMARY RESULT In Vitro

"their localization was limited to the cell soma and proximal dendrites and their motility was reduced in Rng105−/− neurons"

Cultured null neurons show altered movement and distribution of NKA-related reporter transcripts.

Reduced Dendritic Sodium-Potassium Pump Activity partially recapitulates fidelity: moderate observes: cellular Dendritic pump activity is reduced while somatic activity is preserved.

Limitations: The sodium-efflux proxy is compartment specific; it is not a human patient measurement.

Show evidence (1 reference)

PMID:20861386 SUPPORT DIRECT PRIMARY RESULT In Vitro

"These results suggest that NKA activity was decreased in dendrites but not in the cell soma of Rng105−/− neurons"

Functional imaging localizes the deficit to dendrites.

Reduced Dendritic AMPA-Receptor Surface Expression partially recapitulates fidelity: moderate observes: cellular Dendritic surface GluR1 is significantly reduced.

Limitations: Receptor effects differ by subunit and dosage.

Show evidence (1 reference)

PMID:26865403 SUPPORT DIRECT PRIMARY RESULT In Vitro

"quantification revealed that the ratio of surface/total GluR1 puncta number in dendrites was significantly reduced in the Rng105−/− neurons"

Complete-loss cultures show a significant surface-receptor deficit.

Impaired Homeostatic AMPA-Receptor Scaling partially recapitulates fidelity: moderate observes: cellular The TTX/APV-induced scaling response is impaired.

Limitations: A null culture does not establish impaired scaling in heterozygous human neurons.

Show evidence (1 reference)

PMID:29157358 SUPPORT DIRECT PRIMARY RESULT In Vitro

"By contrast, the activity deprivation-dependent increase in surface GluR1 expression was not observed in Rng105−/− dendrites"

Direct activity-deprivation experiment in primary null neurons.

Impaired Neurite Development partially recapitulates fidelity: moderate observes: cellular Dendritic length and arborization are reduced.

Limitations: Null primary neurons do not reproduce every aspect of human cortical development.

Show evidence (1 reference)

PMID:20861386 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Sholl analysis revealed that the number of dendrites was significantly reduced in Rng105−/− neurons compared with wild-type neurons"

Direct morphometric result.

Heterozygous Caprin1 primary cortical neurons PRIMARY_CELL_CULTURE

Primary neurons from heterozygous mice were assayed for the ratio of dendritic surface to total GluR1, alongside wild-type and homozygous-null cultures.

Publication

PMID:26865403

Pathograph links

Reduced Dendritic AMPA-Receptor Surface Expression fails to recapitulate fidelity: moderate observes: cellular The heterozygous surface-GluR1 difference was not statistically significant.

Limitations: A nonsignificant trend is not proof of equivalence; power and compensatory protein expression may matter.

Show evidence (1 reference)

PMID:26865403 SUPPORT DIRECT PRIMARY RESULT In Vitro

"GluR1 surface distribution in dendrites tended to be less in Rng105+/− mice than in wild-type mice, though statistically not significant"

Same-copy-number loss did not establish a significant receptor-surface deficit.

CAPRIN1 knockout and missense add-back HeLa cells CELL_LINE

CAPRIN1-null HeLa cells and add-back constructs were examined during arsenite stress. Candidate p.Ile373Lys abolished G3BP1/2 interaction and showed diffuse localization and reduced stress-granule assembly. The study’s main newly described clinical cohort concerns UBAP2L, not CAPRIN1.

Publication

PMID:35977029

Pathograph links

Context-Dependent Impairment of Stress-Granule Assembly perturbs fidelity: moderate observes: cellular CAPRIN1 loss and p.Ile373Lys perturb stress-granule assembly.

Limitations: Non-neuronal knockout/add-back experiments do not establish the effect of all heterozygous loss-of-function alleles; missense pathogenicity requires allele-specific interpretation.

Show evidence (2 references)

PMID:35977029 SUPPORT DIRECT PRIMARY RESULT In Vitro

"We observed a significant reduction of SG numbers in KO cell lines"

CAPRIN1 knockout perturbs granule formation in HeLa cells.

+ 1 more reference

Caprin1 conditional-null cochlear explants OTHER

Postnatal cochlear explants were exposed to 0.5 mM sodium arsenite for one hour. TIA1- and HuR-positive granules formed despite Caprin1 depletion; some cells escaped Cre recombination, but depleted cells also formed granules.

Publication

PMID:35165318

Pathograph links

Context-Dependent Impairment of Stress-Granule Assembly fails to recapitulate fidelity: moderate observes: cellular Granule formation persisted in Caprin1-deficient cochlear cells.

Limitations: Granule counts and marker appearance do not establish normal granule composition, function or recovery kinetics.

Show evidence (1 reference)

PMID:35165318 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Stress granule formation in the cKO and Caprin1-expressing cells in the same explant was indistinguishable"

The within-explant comparison supports preserved granule formation.

🐁

Animal Models

Rng105/Caprin1 heterozygous mouse

Constitutive heterozygous male mice were tested behaviorally. Brain transcript abundance was approximately 50–60% of wild type, whereas protein remained approximately 70–80%. The genotype matches single-copy loss more closely than the null, but protein depletion is less than in some patient fibroblast assays.

Species

Mouse

Genotype

Rng105+/−; heterozygous deletion of the exon containing the translation start site

Publication

PMID:26865403

Rng105/Caprin1 forebrain conditional knockout mouse

Forebrain deletion allowed postnatal behavioral testing. Hippocampal RNA profiling, spine imaging and electrophysiology characterized transport and synaptic phenotypes, alongside severe long-term-memory deficits and occasional provoked seizures.

Species

Mouse

Genotype

Camk2a-Cre;Rng105f/f

Publication

PMID:29157358

Pathograph links

Impaired Dendritic mRNA Localisation partially recapitulates fidelity: moderate observes: cellular Somatodendritic localization of selected regulator mRNAs is reduced.

Limitations: Regional complete loss differs from human systemic heterozygosity.

Show evidence (1 reference)

PMID:29157358 SUPPORT DIRECT PRIMARY RESULT Model Organism

"These results indicated that various mRNAs, encoding AMPAR regulators involved in AMPAR surface expression and retention to postsynapses, were localized to dendrites in an RNG105-dependent manner."

In vivo somatodendritic RNA profiling identifies affected regulator transcripts.

Reduced Excitatory Synaptic Strength partially recapitulates fidelity: moderate observes: cellular Absolute excitatory responses are reduced while relative LTP gain is retained.

Limitations: The neuronal population and dosage differ from human heterozygous cortical cultures.

Show evidence (2 references)

PMID:29157358 SUPPORT DIRECT PRIMARY RESULT Model Organism

"RNG105 deficiency reduced both the amplitude and slope of fEPSP to about half of those of control mice"

Hippocampal physiology measures the lower absolute response.

+ 1 more reference

Rng105/Caprin1 constitutive null mouse

Null neonates failed to breathe and died within approximately 20 minutes. Fetal organs were formed and histologically normal; increased cell death was demonstrated in brain, without establishing a primary pulmonary mechanism.

Species

Mouse

Genotype

Rng105−/−; homozygous deletion of exon 1

Publication

PMID:20861386

Sox10-Cre Caprin1 conditional knockout mouse

Deletion affects inner-ear and craniofacial neural-crest-derived tissues and also reduced brain transcript levels. Hearing thresholds were abnormal by P28 and worsened with age. The C57BL/6 Cdh23ahl background complicates interpretation at older ages.

Species

Mouse

Genotype

Sox10-Cre;Caprin1tm3d/tm3d, deleting floxed exons 5–6

Publication

PMID:35165318

Pathograph links

Abnormal Cochlear Postsynaptic Structure partially recapitulates fidelity: moderate observes: cellular Postsynaptic GluA2 areas are enlarged with reduced auditory-nerve responses.

Limitations: The driver is not specific to a single cochlear cell type. Hair-cell loss and overt synapse loss were not established.

Show evidence (1 reference)

PMID:35165318 SUPPORT DIRECT PRIMARY RESULT Model Organism

"the GluA2-positive post-synaptic densities were almost twofold larger in Caprin1tm3d/tm3d mice compared to wildtypes"

Morphometry identifies altered postsynaptic structure.

Sox10-Cre Caprin1 conditional heterozygous mouse

Conditional heterozygotes were included in the longitudinal hearing study. Early thresholds were comparable to controls, with a small high-frequency elevation later.

Species

Mouse

Genotype

Caprin1+/tm3d in the Sox10-Cre conditional deletion study

Publication

PMID:35165318

{ }

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 associated with heterozygous loss-of-function variants and reduced Caprin-1 dosage. Language impairment, intellectual or learning disability, ADHD and autism dominate the reported spectrum; motor delay, seizures and variable respiratory, skeletal, ocular and auditory findings also occur. Expressivity varies and unaffected variant carriers are documented. ClinGen classified the gene–disease relationship as Moderate in February 2026. Human heterozygous neuronal models show altered global and local translation, calcium signaling, oxidative stress, neurite development and network activity. Dendritic mRNA transport and AMPA-receptor mechanisms are best established in mouse null models and cannot be assumed to operate identically at human heterozygous dosage. The recurrent p.Pro512Leu aggregation-associated neurodegenerative disorder is a distinct allelic condition.
parents:
- Neurodevelopmental Disorder
synonyms:
- CAPRIN1-NDD
- CAPRIN1 haploinsufficiency
- RNG105-related neurodevelopmental disorder
- Neurodevelopmental disorder with language impairment, autism, and attention deficit-hyperactivity disorder
- NEDLAAD
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: Published cohorts are small and clinically ascertained. Frequencies describe the specified series, not penetrance among all CAPRIN1 variant carriers. The defining series includes a father and son and a multigene deletion carrier. Minor anomalies and common comorbidities do not individually establish a CAPRIN1-specific mechanism. Longitudinal outcome data remain limited; early language regression or stagnation has been reported, so a uniformly static course is not established. The publisher full text at https://oup.silverchair-cdn.com/article-minimal/6650380 is Pavinato et al., Brain 2023, PMID:35979925, DOI:10.1093/brain/awac278; both citation forms identify the same paper.
external_assertions:
- name: OMIM NEDLAAD phenotype record
  source: OMIM
  assertion_type: disease_record
  external_id: OMIM:620782
  url: https://omim.org/entry/620782
  description: Phenotype record for the developmental disorder; OMIM:601178 is the CAPRIN1 gene record.
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: Autosomal dominant inheritance with variable expressivity and incomplete penetrance. De novo alleles and transmission from both affected and reportedly unaffected parents are documented. An affected father and son carried p.Arg458Ter, whereas a clinically unaffected mother carried c.279+1G>T. Observed case-series proportions cannot estimate population penetrance.
  evidence:
  - reference: url:https://oup.silverchair-cdn.com/article-minimal/6650380
    reference_title: https://oup.silverchair-cdn.com/article-minimal/6650380
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Case 2 had ... variant inherited from his mother, reported healthy and without history of intellectual disability, speech delay, neurodevelopmental/behavioural concerns or other medical issues; she had a college education.
    explanation: 'Publisher full text of Pavinato et al., Brain 2023, PMID:35979925: CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD. Documents a reportedly unaffected transmitting parent.'
  - reference: url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_688d0e25-04f0-4160-a53a-00a6b423cafa-2026-02-02T110000.000Z
    reference_title: curation results for Gene-Disease Validity
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Twelve PTVs occurred ... de novo ... nine were inherited (including one inherited from an affected father), and one was of unknown inheritance.
    explanation: Expert synthesis of 22 probands distinguishes inheritance from penetrance.
pathophysiology:
- name: Heterozygous Coding Nonsense Substitutions
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: Heterozygous single-nucleotide substitutions introduce premature termination codons, including p.Gln399Ter and p.Gln582Ter. These alleles were functionally investigated in patient fibroblasts.
  evidence:
  - reference: url:https://oup.silverchair-cdn.com/article-minimal/6650380
    reference_title: https://oup.silverchair-cdn.com/article-minimal/6650380
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Sanger sequencing of the cDNA containing the c.1195C... p.Gln399Ter and c.1744C... p.Gln582Ter shows that the mutant allele is probably degraded by NMD
    explanation: 'Publisher full text of Pavinato et al., Brain 2023, PMID:35979925: CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD. The figure identifies the two nonsense alleles and measures their RNA consequence.'
  role: trigger
  genes:
  - &id001
    preferred_term: CAPRIN1
    term:
      id: hgnc:6743
      label: CAPRIN1
  genetic_context:
    gene: *id001
    variant_type: single nucleotide variant
    genomic_contexts:
    - coding sequence
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
  downstream:
  - target: Decay of Premature-Termination CAPRIN1 Transcripts
    description: Tested nonsense alleles produce decay-sensitive transcripts.
    causal_link_type: DIRECT
- name: Intronic CAPRIN1 Splice-Donor Substitution
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: The heterozygous c.279+1G>T substitution affects the intron 3 donor and produces in-frame exon 3 skipping. The variant was transmitted by a reportedly unaffected mother.
  evidence:
  - reference: url:https://oup.silverchair-cdn.com/article-minimal/6650380
    reference_title: https://oup.silverchair-cdn.com/article-minimal/6650380
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The c.279+1G... change causes an in-frame 84 bp exon 3 skipping
    explanation: 'Publisher full text of Pavinato et al., Brain 2023, PMID:35979925: CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD. Allele-specific RNA analysis identifies the consequence of the donor alteration.'
  role: trigger
  genes:
  - *id001
  genetic_context:
    gene: *id001
    variant_type: single nucleotide variant
    genomic_contexts:
    - intron
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
  downstream:
  - target: Aberrant CAPRIN1 Splicing
    description: The two substitutions alter exon inclusion in patient RNA.
    causal_link_type: DIRECT
- name: Exon-Terminal CAPRIN1 Splice-Altering Substitution
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: The heterozygous synonymous c.879G>A substitution affects the final nucleotide of exon 8 and disrupts donor recognition. Patient RNA shows out-of-frame exon 8 skipping.
  evidence:
  - reference: url:https://oup.silverchair-cdn.com/article-minimal/6650380
    reference_title: https://oup.silverchair-cdn.com/article-minimal/6650380
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The c.879G... affects the last base of exon 8 and causes out-of-frame skipping of exon 8 and a degradation by NMD.
    explanation: 'Publisher full text of Pavinato et al., Brain 2023, PMID:35979925: CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD. The figure identifies the exon-terminal alteration and its RNA consequence.'
  role: trigger
  genes:
  - &id002
    preferred_term: CAPRIN1
    term:
      id: hgnc:6743
      label: CAPRIN1
  genetic_context:
    gene: *id002
    variant_type: single nucleotide variant
    genomic_contexts:
    - coding sequence
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
  downstream:
  - target: Aberrant CAPRIN1 Splicing
    description: The two substitutions alter exon inclusion in patient RNA.
    causal_link_type: DIRECT
- name: Heterozygous Small Coding Deletion
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: The c.1493_1496del allele removes four coding nucleotides and predicts p.Ser498AsnfsTer10. Allele-specific RNA decay was not demonstrated for this particular deletion.
  evidence:
  - reference: url:https://oup.silverchair-cdn.com/article-minimal/6650380
    reference_title: https://oup.silverchair-cdn.com/article-minimal/6650380
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Overall, they include two splicing ... and 10 nonsense/frameshift changes.
    explanation: 'Publisher full text of Pavinato et al., Brain 2023, PMID:35979925: CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD. The primary figure legend reports coding frameshift alleles.'
  - reference: url:https://broadinstitute.atlassian.net/wiki/spaces/BCLGC/pages/4871684098/CAPRIN1+Gene+Curation
    reference_title: CAPRIN1 Gene Curation - Broad Clinical Lab Reporting and Interpretation Team - Confluence
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: 'Case 11: c.1493_1496del, p.Ser498AsnfsTer10 ... 3 year old male'
    explanation: The expert case summary names the allele reported in the primary clinical supplement.
  role: trigger
  genes:
  - *id001
  genetic_context:
    gene: *id001
    variant_type: deletion
    genomic_contexts:
    - coding sequence
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
  downstream:
  - target: Decay of Premature-Termination CAPRIN1 Transcripts
    description: Frameshift alleles predict premature termination; their decay was not directly assayed.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Heterozygous Coding Deletion-Insertion
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: The c.1103delinsTATGT allele replaces a coding nucleotide with five bases and predicts p.Gly368ValfsTer5. It is a compound deletion-insertion rather than a simple nucleotide substitution; RNA decay was not directly assayed for this allele.
  evidence:
  - reference: url:https://oup.silverchair-cdn.com/article-minimal/6650380
    reference_title: https://oup.silverchair-cdn.com/article-minimal/6650380
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Overall, they include two splicing ... and 10 nonsense/frameshift changes.
    explanation: 'Publisher full text of Pavinato et al., Brain 2023, PMID:35979925: CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD. The primary figure legend reports coding frameshift alleles.'
  - reference: url:https://broadinstitute.atlassian.net/wiki/spaces/BCLGC/pages/4871684098/CAPRIN1+Gene+Curation
    reference_title: CAPRIN1 Gene Curation - Broad Clinical Lab Reporting and Interpretation Team - Confluence
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: 'Case 7: c.1103delinsTATGT, p.Gly368ValfsTer5 ... 6 year old male'
    explanation: The expert case summary names the allele reported in the primary clinical supplement.
  role: trigger
  genes:
  - &id003
    preferred_term: CAPRIN1
    term:
      id: hgnc:6743
      label: CAPRIN1
  genetic_context:
    gene: *id003
    genomic_contexts:
    - coding sequence
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
    description: Single-base replacement by TATGT at c.1103, creating a frameshift.
  downstream:
  - target: Decay of Premature-Termination CAPRIN1 Transcripts
    description: Frameshift alleles predict premature termination; their decay was not directly assayed.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Heterozygous CAPRIN1 Gene Deletion
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: A de novo 11p13 deletion encompasses CAPRIN1 and seven other genes. It supports a dosage hypothesis but the individual phenotype cannot be attributed solely to CAPRIN1.
  evidence:
  - reference: url:https://oup.silverchair-cdn.com/article-minimal/6650380
    reference_title: https://oup.silverchair-cdn.com/article-minimal/6650380
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The deletion spans eight genes, including ... CAPRIN1
    explanation: 'Publisher full text of Pavinato et al., Brain 2023, PMID:35979925: CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD. Defines the multigene deletion, which is not an isolated CAPRIN1 deletion.'
  role: trigger
  genes:
  - *id001
  genetic_context:
    gene: *id001
    variant_type: deletion
    genomic_contexts:
    - coding sequence
    - intron
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
  downstream:
  - target: Reduced CAPRIN1 Protein Abundance
    description: Deletion removes one CAPRIN1 copy; reduced transcript was measured in the deletion carrier.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Aberrant CAPRIN1 Splicing
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: Patient-derived lymphoblastoid cells showed exon 3 skipping with c.279+1G>T and exon 8 skipping with c.879G>A. The exon 3 event preserves the reading frame and is associated with reduced protein abundance; the exon 8 event introduces a frameshift and a decay-sensitive transcript.
  evidence:
  - reference: url:https://oup.silverchair-cdn.com/article-minimal/6650380
    reference_title: https://oup.silverchair-cdn.com/article-minimal/6650380
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Analysis of the cDNA showed skipping of exon 3 ... and of exon 8
    explanation: 'Publisher full text of Pavinato et al., Brain 2023, PMID:35979925: CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD. RNA analysis distinguishes the two splice outcomes.'
  biological_processes:
  - preferred_term: mRNA splicing, via spliceosome
    term:
      id: GO:0000398
      label: mRNA splicing, via spliceosome
    modifier: ABNORMAL
  downstream:
  - target: Decay of Premature-Termination CAPRIN1 Transcripts
    description: The out-of-frame exon 8 product undergoes decay; this link does not apply to the in-frame exon 3 product.
    causal_link_type: DIRECT
  - target: Reduced CAPRIN1 Protein Abundance
    description: The in-frame splice carrier also has reduced protein; altered stability is proposed.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Decay of Premature-Termination CAPRIN1 Transcripts
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: Mutant transcripts were depleted in tested nonsense and out-of-frame splice carriers. Cycloheximide partly restored their detection, supporting nonsense-mediated decay. This was not demonstrated for every truncating allele and does not describe the in-frame exon 3 product.
  evidence:
  - reference: url:https://oup.silverchair-cdn.com/article-minimal/6650380
    reference_title: https://oup.silverchair-cdn.com/article-minimal/6650380
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: To investigate the occurrence of nonsense-mediated decay (NMD) for premature stop codons, we treated fibroblasts with CHX and showed a partial rescue in the expression of the mutant allele by Sanger sequencing
    explanation: 'Publisher full text of Pavinato et al., Brain 2023, PMID:35979925: CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD. Pharmacological inhibition partially restores the mutant RNA.'
  biological_processes:
  - preferred_term: nuclear-transcribed mRNA catabolic process, nonsense-mediated decay
    term:
      id: GO:0000184
      label: nuclear-transcribed mRNA catabolic process, nonsense-mediated decay
    modifier: INCREASED
  downstream:
  - target: Reduced CAPRIN1 Protein Abundance
    description: Reduced productive RNA accompanies reduced protein in tested patient cells.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Reduced translation of full-length CAPRIN1 from the depleted mutant transcript
- name: Reduced CAPRIN1 Protein Abundance
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: 'Reduced CAPRIN1 abundance was measured in patient cells. Dosage is cell- and allele-dependent: fibroblast immunoblots for p.Gln399Ter and p.Gln582Ter were approximately 26% and 36% of normalized control abundance. The genetic mechanism is loss of function, but a universal precisely 50% protein level is not established.'
  evidence:
  - reference: url:https://oup.silverchair-cdn.com/article-minimal/6650380
    reference_title: https://oup.silverchair-cdn.com/article-minimal/6650380
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Overall, CAPRIN1 protein levels were clearly reduced in all samples analysed, supporting haploinsufficiency as the disease mechanism.
    explanation: 'Publisher full text of Pavinato et al., Brain 2023, PMID:35979925: CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD. Direct patient-cell expression studies support reduced protein abundance.'
  downstream:
  - target: Impaired Dendritic mRNA Localisation
    description: Loss-of-function models support this consequence; cellular intermediates and genotype-dose equivalence remain incompletely defined.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Increased Global Neuronal Translation
    description: Loss-of-function models support this consequence; cellular intermediates and genotype-dose equivalence remain incompletely defined.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Reduced Distal Dendritic Translation
    description: Loss-of-function models support this consequence; cellular intermediates and genotype-dose equivalence remain incompletely defined.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Impaired Neurite Development
    description: Loss-of-function models support this consequence; cellular intermediates and genotype-dose equivalence remain incompletely defined.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Increased Intracellular Calcium Signals
    description: Loss-of-function models support this consequence; cellular intermediates and genotype-dose equivalence remain incompletely defined.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Increased Neuronal Oxidative Stress
    description: Loss-of-function models support this consequence; cellular intermediates and genotype-dose equivalence remain incompletely defined.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Neuronal Process Degeneration
    description: Loss-of-function models support this consequence; cellular intermediates and genotype-dose equivalence remain incompletely defined.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Reduced Neuronal Network Activity
    description: Loss-of-function models support this consequence; cellular intermediates and genotype-dose equivalence remain incompletely defined.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Context-Dependent Impairment of Stress-Granule Assembly
    description: Loss-of-function models support this consequence; cellular intermediates and genotype-dose equivalence remain incompletely defined.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Abnormal Cochlear Postsynaptic Structure
    description: Loss-of-function models support this consequence; cellular intermediates and genotype-dose equivalence remain incompletely defined.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Impaired Dendritic mRNA Localisation
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: Mouse forebrain conditional deletion and constitutive null neurons show reduced dendritic localization of selected transcripts, including AMPA-receptor regulators and Na+/K+-ATPase subunits. AMPA-receptor subunit transcripts themselves were not generally depleted from dendrites. This transport step has not been directly measured in human heterozygous neurons.
  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
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: These results indicated that various mRNAs, encoding AMPAR regulators involved in AMPAR surface expression and retention to postsynapses, were localized to dendrites in an RNG105-dependent manner.
    explanation: In vivo somatodendritic RNA profiling identifies affected regulator transcripts.
  - 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: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: their localization was limited to the cell soma and proximal dendrites and their motility was reduced in Rng105−/− neurons
    explanation: Cultured null neurons show altered movement and distribution of NKA-related reporter transcripts.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: intracellular mRNA localization
    term:
      id: GO:0008298
      label: intracellular mRNA localization
    modifier: DECREASED
  downstream:
  - target: Reduced Dendritic Sodium-Potassium Pump Activity
    description: Mislocalization of NKA-related transcripts accompanies a compartment-specific pump deficit in null neurons.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Reduced Dendritic AMPA-Receptor Surface Expression
    description: Loss of regulator-transcript localization is proposed to alter AMPA-receptor trafficking.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Impaired Homeostatic AMPA-Receptor Scaling
    description: The transport defect and impaired homeostatic scaling coexist in null models; a transcript-specific rescue was not shown.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Increased Global Neuronal Translation
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  description: In CRISPR-edited CAPRIN1+/− human cortical neurons, puromycin incorporation indicated increased global protein synthesis at 14 days after neuronal differentiation. The earlier four-day difference was not significant. The finding contradicts a purely positional defect with preserved global translation in all contexts.
  evidence:
  - reference: url:https://oup.silverchair-cdn.com/article-minimal/6650380
    reference_title: https://oup.silverchair-cdn.com/article-minimal/6650380
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Treatment of hiPSCs-derived neurons with 1 µg/ml puromycin for 30 min resulted in a slightly increased global translation ... neurons 4 days post-ND ... which became significantly higher 14 days post-ND
    explanation: 'Publisher full text of Pavinato et al., Brain 2023, PMID:35979925: CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD. The SUnSET assay distinguishes a nonsignificant early trend from a later significant increase.'
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: translation
    term:
      id: GO:0006412
      label: translation
    modifier: INCREASED
- name: Reduced Distal Dendritic Translation
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  description: The dendritic puromycin signal declined more rapidly with distance from the soma in heterozygous human neurons than in controls, supporting altered local protein synthesis. This readout measures local translation and does not directly establish which mRNAs are mislocalized.
  evidence:
  - reference: url:https://oup.silverchair-cdn.com/article-minimal/6650380
    reference_title: https://oup.silverchair-cdn.com/article-minimal/6650380
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: These data suggest that ... CAPRIN1 ... haploinsufficiency might also affect local protein synthesis.
    explanation: 'Publisher full text of Pavinato et al., Brain 2023, PMID:35979925: CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD. The authors interpret altered dendritic puromycin distribution as a local-translation effect.'
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: translation
    term:
      id: GO:0006412
      label: translation
    modifier: DECREASED
- name: Reduced Dendritic Sodium-Potassium Pump Activity
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: In cultured mouse null neurons, NKA subunit proteins were depleted from dendrites despite similar total abundance. K+-dependent Na+ efflux was reduced in dendrites while somatic activity was preserved. The corresponding pump defect has not been directly measured in human heterozygous neurons.
  evidence:
  - 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: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: These results suggest that NKA activity was decreased in dendrites but not in the cell soma of Rng105−/− neurons
    explanation: Functional imaging localizes the deficit to dendrites.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  molecular_functions:
  - preferred_term: P-type sodium:potassium-exchanging transporter activity
    term:
      id: GO:0005391
      label: P-type sodium:potassium-exchanging transporter activity
    modifier: DECREASED
  downstream:
  - target: Increased Intracellular Calcium Signals
    description: A pump-to-calcium pathway is proposed from mouse and human results; it has not been tested directly in human heterozygous neurons.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Reduced Dendritic AMPA-Receptor Surface Expression
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: Dendritic surface GluR1 was reduced in mouse null neurons. A heterozygous primary-neuron comparison showed a downward trend that was not statistically significant. Reduced surface expression is therefore established for complete loss, with uncertainty at the human genotype dosage.
  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: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: quantification revealed that the ratio of surface/total GluR1 puncta number in dendrites was significantly reduced in the Rng105−/− neurons
    explanation: Complete-loss cultures show a significant surface-receptor deficit.
  - reference: PMID:26865403
    reference_title: 'Comprehensive behavioral analysis of RNG105 (Caprin1) heterozygous mice: Reduced social interaction and attenuated response to novelty.'
    supports: REFUTE
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: GluR1 surface distribution in dendrites tended to be less in Rng105+/− mice than in wild-type mice, though statistically not significant
    explanation: The heterozygous comparison limits claims of a proven same-dose effect.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  downstream:
  - target: Reduced Excitatory Synaptic Strength
    description: Reduced postsynaptic receptor availability is a proposed contributor to lower excitatory responses.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Impaired Homeostatic AMPA-Receptor Scaling
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: Activity deprivation with TTX/APV increased dendritic AMPA-receptor surface puncta in wild-type cortical neurons but failed to induce the corresponding response in Caprin1-null cultures. This experimental scaling defect has not been demonstrated in patient neurons.
  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: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: By contrast, the activity deprivation-dependent increase in surface GluR1 expression was not observed in Rng105−/− dendrites
    explanation: Direct activity-deprivation experiment in primary null neurons.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  downstream:
  - target: Reduced Excitatory Synaptic Strength
    description: Impaired scaling may lower the synaptic set point, but the assays use distinct null preparations.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Reduced Excitatory Synaptic Strength
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: Forebrain conditional knockout mice had reduced absolute hippocampal excitatory postsynaptic responses. Relative potentiation from the lower baseline was preserved, so reduced synaptic strength should not be equated with abolished LTP induction.
  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
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: RNG105 deficiency reduced both the amplitude and slope of fEPSP to about half of those of control mice
    explanation: Hippocampal physiology measures the lower absolute response.
  - 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
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Theta-burst-induced LTP in CA1 neurons revealed that fEPSP was increased from baseline by ~100%, which was comparable between Rng105f/f and Camk2a-Cre;Rng105f/f mice
    explanation: Supports the distinction between reduced absolute synaptic strength and preserved relative LTP gain.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: chemical synaptic transmission
    term:
      id: GO:0007268
      label: chemical synaptic transmission
    modifier: DECREASED
- name: Impaired Neurite Development
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  description: Human heterozygous cortical neurons developed shorter processes and disorganized neuronal architecture. Early neuronal rosettes and progenitor morphology were preserved; the effect emerged during neuronal differentiation rather than gross failure of progenitor formation.
  evidence:
  - reference: url:https://oup.silverchair-cdn.com/article-minimal/6650380
    reference_title: https://oup.silverchair-cdn.com/article-minimal/6650380
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: immature neurons showed an alteration of neuronal structure, accompanied by reduced neurites length
    explanation: 'Publisher full text of Pavinato et al., Brain 2023, PMID:35979925: CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD. The engineered heterozygous human model directly measures neurite morphology.'
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: dendrite development
    term:
      id: GO:0016358
      label: dendrite development
    modifier: DECREASED
  downstream:
  - target: Reduced Neuronal Network Activity
    description: Altered neurite architecture may contribute to reduced network activity.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Increased Intracellular Calcium Signals
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  description: Live imaging of heterozygous human neurons showed elevated intracellular calcium signals at days 10 and 14, before overt degeneration. The assay does not identify the responsible channel or establish that a dendritic NKA defect causes this change.
  evidence:
  - reference: url:https://oup.silverchair-cdn.com/article-minimal/6650380
    reference_title: https://oup.silverchair-cdn.com/article-minimal/6650380
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: showed an increase in ... signals in ... compared to control neurons, both at 10 and 14 days post-ND
    explanation: 'Publisher full text of Pavinato et al., Brain 2023, PMID:35979925: CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD. Calcium imaging precedes overt degeneration. The quoted comparison identifies the two time points of the increased calcium-signal finding.'
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: intracellular calcium ion homeostasis
    term:
      id: GO:0006874
      label: intracellular calcium ion homeostasis
    modifier: ABNORMAL
  downstream:
  - target: Increased Neuronal Oxidative Stress
    description: Calcium elevation precedes oxidative stress; causal direction has not been established.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Increased Neuronal Oxidative Stress
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  description: CellROX signal was increased in human heterozygous neurons at day 18, near the onset of degeneration. The study did not distinguish ROS species or demonstrate that antioxidant treatment rescues the phenotype.
  evidence:
  - reference: url:https://oup.silverchair-cdn.com/article-minimal/6650380
    reference_title: https://oup.silverchair-cdn.com/article-minimal/6650380
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Notably, we observed a significant increase in CellROX signal ... cells compared to controls
    explanation: 'Publisher full text of Pavinato et al., Brain 2023, PMID:35979925: CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD. The cellular assay supports increased oxidative stress without identifying a specific reactive species.'
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  downstream:
  - target: Neuronal Process Degeneration
    description: Oxidative stress accompanies degeneration without a demonstrated rescue experiment.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Neuronal Process Degeneration
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  description: CAPRIN1+/− cortical cultures developed shrinking cell clusters and progressive process degeneration beginning around days 17–19. This in vitro finding does not establish progressive neurodegeneration as the natural history of human loss-of-function disease.
  evidence:
  - reference: url:https://oup.silverchair-cdn.com/article-minimal/6650380
    reference_title: https://oup.silverchair-cdn.com/article-minimal/6650380
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: we observed a progressive degeneration of neuronal processes ... which began with the formation of small clusters of shrinking neuronal cells ... between Days 17 and 19 post-ND in five independent cultures
    explanation: 'Publisher full text of Pavinato et al., Brain 2023, PMID:35979925: CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD. Time-course observations identify the cellular degeneration phenotype.'
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  downstream:
  - target: Reduced Neuronal Network Activity
    description: Degeneration may worsen network function, but reduced activity also precedes overt cell loss.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Reduced Neuronal Network Activity
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  description: Human heterozygous neurons showed reduced spike rates/counts and, at later sampled time points, reduced burst counts on microelectrode arrays. These network readouts are distinct from the AMPA-receptor scaling and hippocampal synaptic assays performed in mouse null models.
  evidence:
  - reference: url:https://oup.silverchair-cdn.com/article-minimal/6650380
    reference_title: https://oup.silverchair-cdn.com/article-minimal/6650380
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The spike rate and spike count were significantly lower in ... neurons versus controls
    explanation: 'Publisher full text of Pavinato et al., Brain 2023, PMID:35979925: CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD. Microelectrode recordings directly demonstrate reduced network activity.'
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: chemical synaptic transmission
    term:
      id: GO:0007268
      label: chemical synaptic transmission
    modifier: DECREASED
- name: Context-Dependent Impairment of Stress-Granule Assembly
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: CAPRIN1 knockout reduced arsenite-induced stress-granule numbers in HeLa cells. Re-expression experiments showed that the candidate p.Ile373Lys variant disrupts G3BP1/2 binding and granule recruitment, but this does not demonstrate the mechanism of all heterozygous truncating alleles. Cochlear null explants still formed TIA1/HuR-positive granules, demonstrating cell-context dependence.
  evidence:
  - reference: PMID:35977029
    reference_title: De novo variants in genes regulating stress granule assembly associate with neurodevelopmental disorders.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: We observed a significant reduction of SG numbers in KO cell lines
    explanation: CAPRIN1 knockout perturbs granule formation in HeLa cells.
  - 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: REFUTE
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: These data suggest that stress granule formation in native cochlear cells is not dependent on Caprin1.
    explanation: Null cochlear explants retain stress-granule formation.
  biological_processes:
  - preferred_term: cytoplasmic stress granule assembly
    term:
      id: GO:0034063
      label: cytoplasmic stress granule assembly
    modifier: DECREASED
- name: Abnormal Cochlear Postsynaptic Structure
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: Sox10-Cre Caprin1 conditional knockout mice showed enlarged postsynaptic GluA2-positive areas at inner-hair-cell–spiral-ganglion synapses, reduced auditory-nerve responses and impaired recovery from noise. Hair cells and their bundles were preserved; synapse loss and hair-cell death were not established explanations. The specific postsynaptic defect has not been shown in human heterozygotes.
  evidence:
  - 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
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: the GluA2-positive post-synaptic densities were almost twofold larger in Caprin1tm3d/tm3d mice compared to wildtypes
    explanation: Morphometry identifies altered postsynaptic structure.
phenotypes:
- name: Delayed Speech and Language Development
  category: Neurologic
  description: Language impairment occurred in all 12 individuals in the defining series. This cohort frequency does not imply full penetrance among variant carriers.
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: url:https://oup.silverchair-cdn.com/article-minimal/6650380
    reference_title: https://oup.silverchair-cdn.com/article-minimal/6650380
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Language impairment was observed in all cases, with most cases speaking very few words at the last evaluations.
    explanation: 'Publisher full text of Pavinato et al., Brain 2023, PMID:35979925: CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD. All 12 clinically ascertained cases had language impairment.'
- name: Intellectual Disability
  category: Neurologic
  description: Intellectual disability ranges from mild to profound. The published 83% combines intellectual and learning disability; individuals with normal-range intellect and specific learning problems were also included, so that percentage is not assigned to intellectual disability alone.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: url:https://oup.silverchair-cdn.com/article-minimal/6650380
    reference_title: https://oup.silverchair-cdn.com/article-minimal/6650380
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Intellectual and/or learning disabilities from mild to very severe were reported for all but Cases 1 and 6
    explanation: 'Publisher full text of Pavinato et al., Brain 2023, PMID:35979925: CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD. The source uses a combined intellectual/learning-disability category.'
- name: Specific Learning Disability
  category: Neurologic
  description: Specific learning problems, including dyslexia and mathematics difficulty, occur in some individuals and are distinct from global intellectual disability.
  phenotype_term:
    preferred_term: Specific learning disability
    term:
      id: HP:0001328
      label: Specific learning disability
  evidence:
  - reference: url:https://broadinstitute.atlassian.net/wiki/spaces/BCLGC/pages/4871684098/CAPRIN1+Gene+Curation
    reference_title: CAPRIN1 Gene Curation - Broad Clinical Lab Reporting and Interpretation Team - Confluence
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: 9 year old female - history of developmental delay (particularly in speech), ADHD, dyslexia
    explanation: Expert case summary corroborates dyslexia in the primary clinical supplement.
- name: Attention Deficit Hyperactivity Disorder
  category: Behavioral
  description: ADHD diagnostic criteria were met by 9 of 11 assessed individuals in the defining series.
  phenotype_term:
    preferred_term: Attention deficit hyperactivity disorder
    term:
      id: HP:0007018
      label: Attention deficit hyperactivity disorder
  evidence:
  - reference: url:https://oup.silverchair-cdn.com/article-minimal/6650380
    reference_title: https://oup.silverchair-cdn.com/article-minimal/6650380
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Nine of eleven patients (82%) met the diagnostic criteria for attention deficit hyperactivity disorder (ADHD).
    explanation: 'Publisher full text of Pavinato et al., Brain 2023, PMID:35979925: CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD. The denominator excludes one unassessed individual.'
  frequency: VERY_FREQUENT
- name: Autism
  category: Behavioral
  description: Autism was diagnosed in 8 of 12 individuals in the defining series.
  phenotype_term:
    preferred_term: Autism
    term:
      id: HP:0000717
      label: Autism
  evidence:
  - reference: url:https://oup.silverchair-cdn.com/article-minimal/6650380
    reference_title: https://oup.silverchair-cdn.com/article-minimal/6650380
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: ASD was diagnosed in eight patients (67%).
    explanation: 'Publisher full text of Pavinato et al., Brain 2023, PMID:35979925: CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD. Reports the cohort-specific autism frequency.'
  frequency: FREQUENT
- name: Global Developmental Delay
  category: Neurologic
  description: Global delay was documented in several cases; language impairment can also occur with near-normal early motor development. The aggregate developmental-delay percentage is not assumed to represent a uniformly global delay.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: url:https://broadinstitute.atlassian.net/wiki/spaces/BCLGC/pages/4871684098/CAPRIN1+Gene+Curation
    reference_title: CAPRIN1 Gene Curation - Broad Clinical Lab Reporting and Interpretation Team - Confluence
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: 'Case 9: 12 year old male - mild ID, global developmental delay, moderate language impairment, ADHD'
    explanation: Case-level evidence explicitly identifies global delay.
- name: Delayed Gross Motor Development
  category: Neurologic
  description: Gross motor delay was reported in the 2026 p.Gln349Ter case, alongside an ataxic gait.
  phenotype_term:
    preferred_term: Delayed gross motor development
    term:
      id: HP:0002194
      label: Delayed gross motor development
  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
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: We present the case of a patient with ASD, gross motor delay, fine motor delay, speech delay, mixed receptive-expressive language disorder, incontinence, and ADHD.
    explanation: Case-level motor development findings.
- name: Delayed Fine Motor Development
  category: Neurologic
  description: Fine motor delay and very poor grasping/visual-motor performance were documented in the 2026 case.
  phenotype_term:
    preferred_term: Delayed fine motor development
    term:
      id: HP:0010862
      label: Delayed fine motor development
  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
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: We present the case of a patient with ASD, gross motor delay, fine motor delay, speech delay, mixed receptive-expressive language disorder, incontinence, and ADHD.
    explanation: Case-level motor development findings.
- name: Developmental Regression
  category: Neurologic
  description: Early stagnation or loss of language skills was reported in a frameshift carrier. This does not establish the progressive childhood dementia characteristic of the distinct p.Pro512Leu disorder.
  phenotype_term:
    preferred_term: Developmental regression
    term:
      id: HP:0002376
      label: Developmental regression
  evidence:
  - reference: url:https://broadinstitute.atlassian.net/wiki/spaces/BCLGC/pages/4871684098/CAPRIN1+Gene+Curation
    reference_title: CAPRIN1 Gene Curation - Broad Clinical Lab Reporting and Interpretation Team - Confluence
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: 6 year old male - ASD, stagnation/decline in development and is now only able to use a few words
    explanation: Case 7 had early loss or stagnation of acquired language.
- name: Speech Apraxia
  category: Neurologic
  description: Speech motor planning difficulties were described in the deletion carrier and the 2026 nonsense-variant case.
  phenotype_term:
    preferred_term: Speech apraxia
    term:
      id: HP:0011098
      label: Speech apraxia
  evidence:
  - reference: url:https://broadinstitute.atlassian.net/wiki/spaces/BCLGC/pages/4871684098/CAPRIN1+Gene+Curation
    reference_title: CAPRIN1 Gene Curation - Broad Clinical Lab Reporting and Interpretation Team - Confluence
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: severe language delay, ASD, severe speech apraxia, fine motor skills deficit
    explanation: Primary cohort deletion case has speech apraxia; the multigene deletion limits gene specificity.
  - 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
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: On the Goldman-Fristoe Test of Articulation-3 (GFTA-3), the patient scored 28%, which is indicative of Apraxia.
    explanation: The later case reports speech apraxia assessment.
- name: Seizures
  category: Neurologic
  description: Seizures include infantile spasms, absences and focal seizures with bilateral spread. The main cohort reports 4/12, but one counted patient had staring spells judged nonepileptic in the detailed supplement. A precise epilepsy frequency is therefore uncertain.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: url:https://oup.silverchair-cdn.com/article-minimal/6650380
    reference_title: https://oup.silverchair-cdn.com/article-minimal/6650380
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Four patients had epileptic seizures with different severity
    explanation: 'Publisher full text of Pavinato et al., Brain 2023, PMID:35979925: CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD. The main report provides a count, interpreted alongside its detailed clinical records.'
- name: Infantile Spasms
  category: Neurologic
  description: One child developed infantile spasms at nine months and later absence epilepsy.
  phenotype_term:
    preferred_term: Infantile spasms
    term:
      id: HP:0012469
      label: Infantile spasms
  evidence:
  - reference: url:https://broadinstitute.atlassian.net/wiki/spaces/BCLGC/pages/4871684098/CAPRIN1+Gene+Curation
    reference_title: CAPRIN1 Gene Curation - Broad Clinical Lab Reporting and Interpretation Team - Confluence
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: 3 year old male - infantile spasms, global developmental delay and speech delay, epilepsy, gait instability, ASD, stereotyped movements, ID, signs of ADHD and aggressivity
    explanation: Case-level evidence for infantile spasms.
- name: Ataxia
  category: Neurologic
  description: A wide-based ataxic gait was documented in the 2026 p.Gln349Ter loss-of-function case. Ataxia alone does not imply the p.Pro512Leu neurodegenerative mechanism.
  phenotype_term:
    preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
  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
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: a wide-based gait with an ataxic quality to movement
    explanation: Direct examination in a nonsense-variant carrier.
- name: Hypotonia
  category: Neurologic
  description: Mild generalized hypotonia was observed in the 2026 case.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  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
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: On neurologic exam, the patient demonstrated mild global hypotonia.
    explanation: Direct neurological examination.
- name: Motor Stereotypy
  category: Behavioral
  description: Stereotyped movements were present in some cohort members.
  phenotype_term:
    preferred_term: Motor stereotypy
    term:
      id: HP:0000733
      label: Motor stereotypy
  evidence:
  - reference: url:https://oup.silverchair-cdn.com/article-minimal/6650380
    reference_title: https://oup.silverchair-cdn.com/article-minimal/6650380
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Stereotyped movements and behaviours were also observed in some of the patients
    explanation: 'Publisher full text of Pavinato et al., Brain 2023, PMID:35979925: CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD. The report directly documents repetitive motor behavior.'
- name: Aggressive Behavior
  category: Behavioral
  description: Aggressive behavior occurs in some affected children; severity and context vary.
  phenotype_term:
    preferred_term: Aggressive behavior
    term:
      id: HP:0000718
      label: Aggressive behavior
  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
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: the school expressed significant concerns regarding aggression, poor focus, self-isolation, and limited interaction with others
    explanation: School observations in the 2026 case.
- name: Self-Injurious Behavior
  category: Behavioral
  description: Self-hitting was reported in the 2026 case.
  phenotype_term:
    preferred_term: Self-injurious behavior
    term:
      id: HP:0100716
      label: Self-injurious behavior
  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
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: including self-injurious behavior such as hitting himself
    explanation: Direct case description.
- name: Anxiety
  category: Behavioral
  description: Anxiety was documented in several loss-of-function carriers, including the affected father and a girl with normal-range intellect.
  phenotype_term:
    preferred_term: Anxiety
    term:
      id: HP:0000739
      label: Anxiety
  evidence:
  - reference: url:https://broadinstitute.atlassian.net/wiki/spaces/BCLGC/pages/4871684098/CAPRIN1+Gene+Curation
    reference_title: CAPRIN1 Gene Curation - Broad Clinical Lab Reporting and Interpretation Team - Confluence
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: generalized anxiety disorder, difficulties with language comprehension
    explanation: Case 4 had generalized anxiety.
- name: Respiratory Distress
  category: Respiratory
  description: Perinatal respiratory concerns included fetal distress and postnatal saturation dips. These observations do not establish a primary lung-development defect.
  phenotype_term:
    preferred_term: Respiratory distress
    term:
      id: HP:0002098
      label: Respiratory distress
  evidence:
  - reference: url:https://oup.silverchair-cdn.com/article-minimal/6650380
    reference_title: https://oup.silverchair-cdn.com/article-minimal/6650380
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Respiratory concerns were reported in six cases, and included foetal respiratory distress, post-natal saturation dips, obstructive sleep apnoea, sudden chocking spells and asthma
    explanation: 'Publisher full text of Pavinato et al., Brain 2023, PMID:35979925: CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD. The source lists a heterogeneous respiratory spectrum; the 6/12 proportion does not apply to distress alone.'
- name: Obstructive Sleep Apnea
  category: Respiratory
  description: Obstructive sleep apnea was reported in the cohort; it is distinct from transient respiratory difficulty at birth.
  phenotype_term:
    preferred_term: Obstructive sleep apnea
    term:
      id: HP:0002870
      label: Obstructive sleep apnea
  evidence:
  - reference: url:https://oup.silverchair-cdn.com/article-minimal/6650380
    reference_title: https://oup.silverchair-cdn.com/article-minimal/6650380
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Respiratory concerns were reported in six cases, and included foetal respiratory distress, post-natal saturation dips, obstructive sleep apnoea, sudden chocking spells and asthma
    explanation: 'Publisher full text of Pavinato et al., Brain 2023, PMID:35979925: CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD. The source lists a heterogeneous respiratory spectrum; the 6/12 proportion does not apply to distress alone.'
- name: Asthma
  category: Respiratory
  description: Asthmatic symptoms occurred in an individual carrier. This common condition is an observed association, not a demonstrated CAPRIN1-specific pulmonary mechanism.
  phenotype_term:
    preferred_term: Asthma
    term:
      id: HP:0002099
      label: Asthma
  evidence:
  - reference: url:https://oup.silverchair-cdn.com/article-minimal/6650380
    reference_title: https://oup.silverchair-cdn.com/article-minimal/6650380
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Respiratory concerns were reported in six cases, and included foetal respiratory distress, post-natal saturation dips, obstructive sleep apnoea, sudden chocking spells and asthma
    explanation: 'Publisher full text of Pavinato et al., Brain 2023, PMID:35979925: CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD. The source lists a heterogeneous respiratory spectrum; the 6/12 proportion does not apply to distress alone.'
- name: Clinodactyly
  category: Musculoskeletal
  description: Mild hand or foot anomalies were reported in six individuals; fifth-digit clinodactyly was a recurrent component rather than a feature present in all six.
  phenotype_term:
    preferred_term: Clinodactyly
    term:
      id: HP:0030084
      label: Clinodactyly
  evidence:
  - reference: url:https://oup.silverchair-cdn.com/article-minimal/6650380
    reference_title: https://oup.silverchair-cdn.com/article-minimal/6650380
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Six patients also showed mild skeletal limb malformations, with fifth digit clinodactyly as the prevalent feature
    explanation: 'Publisher full text of Pavinato et al., Brain 2023, PMID:35979925: CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD. Supports clinodactyly without assigning the aggregate limb-anomaly frequency.'
- name: Scoliosis
  category: Musculoskeletal
  description: Scoliosis or kyphoscoliosis was reported in two cohort members.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: url:https://oup.silverchair-cdn.com/article-minimal/6650380
    reference_title: https://oup.silverchair-cdn.com/article-minimal/6650380
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: two patients had scoliosis and mild kyphoscoliosis.
    explanation: 'Publisher full text of Pavinato et al., Brain 2023, PMID:35979925: CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD. Two of 12 individuals had spinal curvature abnormalities.'
  frequency: OCCASIONAL
- name: Joint Hypermobility
  category: Musculoskeletal
  description: Joint laxity of the hands and feet was reported in a nonsense-variant carrier.
  phenotype_term:
    preferred_term: Joint hypermobility
    term:
      id: HP:0001382
      label: Joint hypermobility
  evidence:
  - reference: url:https://broadinstitute.atlassian.net/wiki/spaces/BCLGC/pages/4871684098/CAPRIN1+Gene+Curation
    reference_title: CAPRIN1 Gene Curation - Broad Clinical Lab Reporting and Interpretation Team - Confluence
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: flexible joints of hands and feet, autism, food selectivity, late/normal motor development milestones, ADHD
    explanation: Case 5 provides joint-laxity evidence.
- name: Feeding Difficulties
  category: Gastrointestinal
  description: The detailed cohort results report feeding difficulties in 2/12 and gastrointestinal issues in a separate 2/12. This distinction is retained instead of assigning the abstract’s aggregate 33% to feeding alone.
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: url:https://oup.silverchair-cdn.com/article-minimal/6650380
    reference_title: https://oup.silverchair-cdn.com/article-minimal/6650380
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Gastrointestinal issues (2/12), feeding difficulties (2/12) and ocular anomalies (4/12) were reported
    explanation: 'Publisher full text of Pavinato et al., Brain 2023, PMID:35979925: CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD. The full results separate feeding from gastrointestinal concerns.'
  frequency: OCCASIONAL
- name: Hearing Impairment
  category: Audiologic
  description: Mild unilateral hearing loss was specifically described in two cohort members. The adult had occupational noise exposure, and the broader table’s third hearing entry concerned ear-tube treatment with otherwise normal hearing. Progressive loss is established in mouse models, not as a universal human course.
  phenotype_term:
    preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  evidence:
  - reference: url:https://oup.silverchair-cdn.com/article-minimal/6650380
    reference_title: https://oup.silverchair-cdn.com/article-minimal/6650380
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Notably, mild hearing loss has been observed in Cases 3 and 10.
    explanation: 'Publisher full text of Pavinato et al., Brain 2023, PMID:35979925: CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD. Two clinically documented hearing-loss cases support the phenotype.'
  frequency: OCCASIONAL
- name: Strabismus
  category: Ophthalmologic
  description: Strabismus was present in the detailed cohort records; its frequency is not inferred from the aggregate 4/12 ocular category.
  phenotype_term:
    preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  evidence:
  - reference: url:https://broadinstitute.atlassian.net/wiki/spaces/BCLGC/pages/4871684098/CAPRIN1+Gene+Curation
    reference_title: CAPRIN1 Gene Curation - Broad Clinical Lab Reporting and Interpretation Team - Confluence
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: 10 year old male - hypermetropic and had strabismus
    explanation: Expert case summary matches the detailed primary clinical supplement.
- name: Astigmatism
  category: Ophthalmologic
  description: Astigmatism was documented among the variable ocular findings.
  phenotype_term:
    preferred_term: Astigmatism
    term:
      id: HP:0000483
      label: Astigmatism
  evidence:
  - reference: url:https://broadinstitute.atlassian.net/wiki/spaces/BCLGC/pages/4871684098/CAPRIN1+Gene+Curation
    reference_title: CAPRIN1 Gene Curation - Broad Clinical Lab Reporting and Interpretation Team - Confluence
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: mild astigmatism and myopia, generalized anxiety disorder, difficulties with language comprehension
    explanation: Expert case summary matches the detailed primary clinical supplement.
- name: Myopia
  category: Ophthalmologic
  description: Myopia was reported in an individual with a truncating allele.
  phenotype_term:
    preferred_term: Myopia
    term:
      id: HP:0000545
      label: Myopia
  evidence:
  - reference: url:https://broadinstitute.atlassian.net/wiki/spaces/BCLGC/pages/4871684098/CAPRIN1+Gene+Curation
    reference_title: CAPRIN1 Gene Curation - Broad Clinical Lab Reporting and Interpretation Team - Confluence
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: mild astigmatism and myopia, generalized anxiety disorder, difficulties with language comprehension
    explanation: Expert case summary matches the detailed primary clinical supplement.
- name: Hypermetropia
  category: Ophthalmologic
  description: Hypermetropia was reported in a nonsense-variant carrier.
  phenotype_term:
    preferred_term: Hypermetropia
    term:
      id: HP:0000540
      label: Hypermetropia
  evidence:
  - reference: url:https://broadinstitute.atlassian.net/wiki/spaces/BCLGC/pages/4871684098/CAPRIN1+Gene+Curation
    reference_title: CAPRIN1 Gene Curation - Broad Clinical Lab Reporting and Interpretation Team - Confluence
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: 10 year old male - hypermetropic and had strabismus
    explanation: Expert case summary matches the detailed primary clinical supplement.
- name: Bulbous Nose
  category: Craniofacial
  description: A broad or bulbous nasal tip recurs, but does not define a recognizable facial gestalt.
  phenotype_term:
    preferred_term: Bulbous nose
    term:
      id: HP:0000414
      label: Bulbous nose
  evidence:
  - reference: url:https://oup.silverchair-cdn.com/article-minimal/6650380
    reference_title: https://oup.silverchair-cdn.com/article-minimal/6650380
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: broad nasal tip, low hanging columella and thin lip recurred in different cases
    explanation: 'Publisher full text of Pavinato et al., Brain 2023, PMID:35979925: CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD. The primary report describes recurrent minor facial features.'
- name: Low Hanging Columella
  category: Craniofacial
  description: Low-hanging columella is a variable minor facial feature.
  phenotype_term:
    preferred_term: Low hanging columella
    term:
      id: HP:0009765
      label: Low hanging columella
  evidence:
  - reference: url:https://oup.silverchair-cdn.com/article-minimal/6650380
    reference_title: https://oup.silverchair-cdn.com/article-minimal/6650380
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: broad nasal tip, low hanging columella and thin lip recurred in different cases
    explanation: 'Publisher full text of Pavinato et al., Brain 2023, PMID:35979925: CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD. The primary report describes recurrent minor facial features.'
- name: Thin Upper Lip Vermilion
  category: Craniofacial
  description: Thin upper-lip vermilion is described in the cohort and its detailed clinical records.
  phenotype_term:
    preferred_term: Thin upper lip vermilion
    term:
      id: HP:0000219
      label: Thin upper lip vermilion
  evidence:
  - reference: url:https://oup.silverchair-cdn.com/article-minimal/6650380
    reference_title: https://oup.silverchair-cdn.com/article-minimal/6650380
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: broad nasal tip, low hanging columella and thin lip recurred in different cases
    explanation: 'Publisher full text of Pavinato et al., Brain 2023, PMID:35979925: CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD. The primary report describes recurrent minor facial features.'
- name: Urinary Incontinence
  category: Genitourinary
  description: Delayed continence was described in the 2026 five-year-old case, who remained in toilet training. This observation does not establish a structural urinary abnormality.
  phenotype_term:
    preferred_term: Urinary incontinence
    term:
      id: HP:0000020
      label: Urinary incontinence
  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
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: He was in the process of toilet training, wearing diapers only at night, and voiding approximately once per hour during the day.
    explanation: The case characterizes delayed continence in its developmental context.
- name: Absence Seizures
  category: Neurologic
  description: Absence-type seizures occurred in the cohort, including following infantile spasms. One separately counted patient’s staring spells were judged nonepileptic in the detailed supplement.
  phenotype_term:
    preferred_term: Generalized non-motor (absence) seizure
    term:
      id: HP:0002121
      label: Generalized non-motor (absence) seizure
  evidence:
  - reference: url:https://oup.silverchair-cdn.com/article-minimal/6650380
    reference_title: https://oup.silverchair-cdn.com/article-minimal/6650380
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Case 11 had infantile spams beginning at 9 months of age, which became absence epilepsy
    explanation: 'Publisher full text of Pavinato et al., Brain 2023, PMID:35979925: CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD. The clinical description identifies the seizure type without supplying a robust population frequency.'
- name: Focal Seizures
  category: Neurologic
  description: A child with p.Gln582Ter had recurrent focal seizures, sometimes evolving into status epilepticus; these were not universal among carriers.
  phenotype_term:
    preferred_term: Focal-onset seizure
    term:
      id: HP:0007359
      label: Focal-onset seizure
  evidence:
  - reference: url:https://broadinstitute.atlassian.net/wiki/spaces/BCLGC/pages/4871684098/CAPRIN1+Gene+Curation
    reference_title: CAPRIN1 Gene Curation - Broad Clinical Lab Reporting and Interpretation Team - Confluence
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: repeated focal seizures evolving into a focal status epilepticus
    explanation: The clinical description identifies the seizure type without supplying a robust population frequency.
genetic:
- name: CAPRIN1
  relationship_type: UNKNOWN
  variant_origin: GERMLINE
  gene_term:
    preferred_term: CAPRIN1
    term:
      id: hgnc:6743
      label: CAPRIN1
  notes: Heterozygous nonsense, frameshift, splice-altering and multigene deletion alleles have been reported. Functional support includes mutant RNA depletion and reduced protein in selected patient cells. Unaffected transmitting parents, siblings and population controls carrying protein-truncating variants limit assumptions of sufficiency or full penetrance. Specific missense alleles require separate interpretation; p.Pro512Leu belongs to a distinct aggregation-associated neurodegenerative disorder. The 2026 p.Gln349Ter case body repeatedly reports maternal inheritance although its abstract also says de novo; trio case details support maternal transmission. No quantified population penetrance or validated modifier is established.
  inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  evidence:
  - reference: url:https://oup.silverchair-cdn.com/article-minimal/6650380
    reference_title: https://oup.silverchair-cdn.com/article-minimal/6650380
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: we identified by exome or genome sequencing 11 additional cases with nonsense or splicing variants affecting donor/acceptor sites
    explanation: 'Publisher full text of Pavinato et al., Brain 2023, PMID:35979925: CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD. The clinical series identified heterozygous coding and splice variants.'
  - reference: url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_688d0e25-04f0-4160-a53a-00a6b423cafa-2026-02-02T110000.000Z
    reference_title: curation results for Gene-Disease Validity
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: The classification was downgraded from strong to moderate due to multiple instances of truncating variants inherited from unaffected parents or present in unaffected siblings and controls.
    explanation: The expert panel explicitly qualifies the strength of the gene–disease relationship.
  - 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
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Trio whole-exome sequencing analysis identified a heterozygous, maternally inherited, likely pathogenic variant in CAPRIN1, c. 1045 C > T/p. Q349*
    explanation: The case body resolves the inheritance used here; the abstract is internally inconsistent.
  association: Loss-of-function gene–disease association with Moderate ClinGen validity and incompletely quantified penetrance.
  gene_disease_validity:
  - validity_classification: MODERATE
    classified_by: CLINGEN
    external_id: CGGV:assertion_688d0e25-04f0-4160-a53a-00a6b423cafa-2026-02-02T110000.000Z
    notes: Intellectual Disability and Autism Gene Curation Expert Panel, 2 February 2026; classification explicitly downgraded from Strong because of unaffected carriers.
    evidence:
    - reference: url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_688d0e25-04f0-4160-a53a-00a6b423cafa-2026-02-02T110000.000Z
      reference_title: curation results for Gene-Disease Validity
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: The classification was downgraded from strong to moderate due to multiple instances of truncating variants inherited from unaffected parents or present in unaffected siblings and controls.
      explanation: The expert panel explicitly qualifies the strength of the gene–disease relationship.
prevalence:
- population: Published clinically ascertained cases
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: The defining clinical series described 12 individuals, including a related father and son. The 2026 ClinGen evaluation included 22 probands from six publications; these overlapping ascertainments must not be added to estimate unique cases. Population prevalence and penetrance remain unquantified.
  evidence:
  - reference: url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_688d0e25-04f0-4160-a53a-00a6b423cafa-2026-02-02T110000.000Z
    reference_title: curation results for Gene-Disease Validity
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Twenty-two PTVs that have been reported in 22 probands in six publications
    explanation: Records the scope of the expert evidence review rather than a population prevalence.
animal_models:
- name: Rng105/Caprin1 heterozygous mouse
  species: Mouse
  genotype: Rng105+/−; heterozygous deletion of the exon containing the translation start site
  description: Constitutive heterozygous male mice were tested behaviorally. Brain transcript abundance was approximately 50–60% of wild type, whereas protein remained approximately 70–80%. The genotype matches single-copy loss more closely than the null, but protein depletion is less than in some patient fibroblast assays.
  publication: PMID:26865403
  modeled_mechanisms:
  - target: Autism
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: Reduced nighttime home-cage social interaction and novelty preference approximate selected behavioral domains.
    limitations: Initial sociability toward an unfamiliar mouse was preserved. Mouse social behavior does not establish the human autism diagnosis.
    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
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Rng105(+/-) mice exhibited a reduced sociality in a home cage and a weak preference for social novelty
      explanation: Behavioral observations at heterozygous genotype.
  - target: Intellectual Disability
    relationship: FAILS_TO_RECAPITULATE
    fidelity: MODERATE
    model_scale: ORGANISM
    description: Reference, working and contextual memory were preserved in the tested tasks.
    limitations: Task performance cannot exclude all cognitive effects; relative reversal-learning difficulty was observed.
    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
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Rng105+/− mice had normal reference memory, working memory and contextual memory.
      explanation: Negative memory findings limit broad cognitive extrapolation.
- name: Rng105/Caprin1 forebrain conditional knockout mouse
  species: Mouse
  genotype: Camk2a-Cre;Rng105f/f
  description: Forebrain deletion allowed postnatal behavioral testing. Hippocampal RNA profiling, spine imaging and electrophysiology characterized transport and synaptic phenotypes, alongside severe long-term-memory deficits and occasional provoked seizures.
  publication: PMID:29157358
  modeled_mechanisms:
  - target: Impaired Dendritic mRNA Localisation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Somatodendritic localization of selected regulator mRNAs is reduced.
    limitations: Regional complete loss differs from human systemic heterozygosity.
    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
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: These results indicated that various mRNAs, encoding AMPAR regulators involved in AMPAR surface expression and retention to postsynapses, were localized to dendrites in an RNG105-dependent manner.
      explanation: In vivo somatodendritic RNA profiling identifies affected regulator transcripts.
  - target: Reduced Excitatory Synaptic Strength
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Absolute excitatory responses are reduced while relative LTP gain is retained.
    limitations: The neuronal population and dosage differ from human heterozygous cortical cultures.
    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
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: RNG105 deficiency reduced both the amplitude and slope of fEPSP to about half of those of control mice
      explanation: Hippocampal physiology measures the lower absolute response.
    - 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
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Theta-burst-induced LTP in CA1 neurons revealed that fEPSP was increased from baseline by ~100%, which was comparable between Rng105f/f and Camk2a-Cre;Rng105f/f mice
      explanation: Supports the distinction between reduced absolute synaptic strength and preserved relative LTP gain.
  - target: Intellectual Disability
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: Spatial and contextual long-term-memory performance is impaired.
    limitations: Memory-task deficits are partial analogues of human cognitive impairment, not an intellectual-disability diagnosis.
    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
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: RNG105-deficient mice displayed unprecedentedly severe defects in long-term memory formation in spatial and contextual learning tasks
      explanation: The reported cognitive readouts are mouse memory tasks.
- name: Rng105/Caprin1 constitutive null mouse
  species: Mouse
  genotype: Rng105−/−; homozygous deletion of exon 1
  description: Null neonates failed to breathe and died within approximately 20 minutes. Fetal organs were formed and histologically normal; increased cell death was demonstrated in brain, without establishing a primary pulmonary mechanism.
  publication: PMID:20861386
  modeled_mechanisms:
  - target: Respiratory Distress
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: ORGANISM
    description: Neonatal failure to breathe provides a severe respiratory phenotype.
    limitations: Complete-loss neonatal lethality is a poor match to the variable respiratory concerns of surviving heterozygous patients; the anatomical cause was not resolved.
    evidence:
    - 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
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Rng105−/− neonates were born normally but failed to breathe, developed cyanosis, and died within 20 min after birth.
      explanation: Direct observation of null neonatal lethality.
- name: Sox10-Cre Caprin1 conditional knockout mouse
  species: Mouse
  genotype: Sox10-Cre;Caprin1tm3d/tm3d, deleting floxed exons 5–6
  description: Deletion affects inner-ear and craniofacial neural-crest-derived tissues and also reduced brain transcript levels. Hearing thresholds were abnormal by P28 and worsened with age. The C57BL/6 Cdh23ahl background complicates interpretation at older ages.
  publication: PMID:35165318
  modeled_mechanisms:
  - target: Abnormal Cochlear Postsynaptic Structure
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Postsynaptic GluA2 areas are enlarged with reduced auditory-nerve responses.
    limitations: The driver is not specific to a single cochlear cell type. Hair-cell loss and overt synapse loss were not established.
    evidence:
    - 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
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: the GluA2-positive post-synaptic densities were almost twofold larger in Caprin1tm3d/tm3d mice compared to wildtypes
      explanation: Morphometry identifies altered postsynaptic structure.
  - target: Hearing Impairment
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: Progressive hearing loss and incomplete recovery from acoustic stress are observed.
    limitations: The model is complete conditional loss; progression and noise susceptibility are not quantified for human heterozygotes.
    evidence:
    - 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
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Subtraction to reveal the threshold shifts confirmed recovery of hearing thresholds in wildtype mice, but not Caprin1tm3d/tm3d mice
      explanation: Auditory testing measures impaired recovery after noise.
- name: Sox10-Cre Caprin1 conditional heterozygous mouse
  species: Mouse
  genotype: Caprin1+/tm3d in the Sox10-Cre conditional deletion study
  description: Conditional heterozygotes were included in the longitudinal hearing study. Early thresholds were comparable to controls, with a small high-frequency elevation later.
  publication: PMID:35165318
  modeled_mechanisms:
  - target: Hearing Impairment
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: A mild later high-frequency threshold effect is detectable at heterozygous dosage.
    limitations: Cdh23ahl-related aging effects and tissue-specific recombination limit extrapolation to systemic human loss of function.
    evidence:
    - 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
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Hearing thresholds in heterozygous mice (Caprin1+/tm3d) did not significantly differ from wildtype at P28
      explanation: Early auditory function was preserved.
    - 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
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: at older ages heterozygotes displayed a small, but significant elevation in the high frequencies compared to wildtype mice
      explanation: Later mild auditory effect in heterozygotes.
diagnosis:
- name: Molecular genetic testing
  description: Exome or genome sequencing can identify coding and splice-region alleles; chromosomal microarray detected the multigene deletion. Interpretation should include segregation and variant-specific functional evidence where available, the Moderate gene–disease classification, and the distinct p.Pro512Leu mechanism.
  diagnosis_term:
    preferred_term: Genetic Testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: url:https://oup.silverchair-cdn.com/article-minimal/6650380
    reference_title: https://oup.silverchair-cdn.com/article-minimal/6650380
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: we identified by exome or genome sequencing 11 additional cases with nonsense or splicing variants affecting donor/acceptor sites
    explanation: 'Publisher full text of Pavinato et al., Brain 2023, PMID:35979925: CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD. The clinical series identified heterozygous coding and splice variants.'
- name: RNA analysis of splice and truncating variants
  description: Patient RNA studies demonstrated exon skipping or decay-sensitive mutant transcripts in selected alleles. These are variant-interpretation assays, not a validated standalone diagnostic biomarker; absence of one particular readout would not exclude every CAPRIN1-associated mechanism.
  diagnosis_term:
    preferred_term: RNA Analysis
    term:
      id: NCIT:C18473
      label: RNA Analysis
  evidence:
  - reference: url:https://oup.silverchair-cdn.com/article-minimal/6650380
    reference_title: https://oup.silverchair-cdn.com/article-minimal/6650380
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Analysis of the cDNA showed skipping of exon 3 ... and of exon 8
    explanation: 'Publisher full text of Pavinato et al., Brain 2023, PMID:35979925: CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD. RNA analysis distinguishes the two splice outcomes.'
  - reference: url:https://oup.silverchair-cdn.com/article-minimal/6650380
    reference_title: https://oup.silverchair-cdn.com/article-minimal/6650380
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: To investigate the occurrence of nonsense-mediated decay (NMD) for premature stop codons, we treated fibroblasts with CHX and showed a partial rescue in the expression of the mutant allele by Sanger sequencing
    explanation: 'Publisher full text of Pavinato et al., Brain 2023, PMID:35979925: CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD. Pharmacological inhibition partially restores the mutant RNA.'
- name: Brain MRI
  description: Imaging may characterize neurological concerns, but six scans in the defining series did not yield a characteristic clinically significant pattern. A normal or nonspecific scan does not exclude the developmental disorder.
  diagnosis_term:
    preferred_term: Magnetic Resonance Imaging
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  evidence:
  - reference: url:https://oup.silverchair-cdn.com/article-minimal/6650380
    reference_title: https://oup.silverchair-cdn.com/article-minimal/6650380
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Brain MRI was available for six patients, and all the identified anomalies were considered without clinical significance
    explanation: 'Publisher full text of Pavinato et al., Brain 2023, PMID:35979925: CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD. The defining cohort does not establish a diagnostic MRI signature.'
- name: Hearing assessment
  description: Audiological assessment characterizes possible hearing problems that can compound language difficulties. The 2026 case had no reported hearing concerns and mild-to-normal measured thresholds, illustrating variable involvement.
  diagnosis_term:
    preferred_term: Audiometric Test
    term:
      id: NCIT:C38036
      label: Audiometric Test
  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
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Hearing thresholds were found to be within the mild to normal range under headphones.
    explanation: Direct case audiological assessment.
- name: Electroencephalography
  description: EEG was abnormal in some reported individuals and normal or unavailable in others. Results should be interpreted with the clinical event history; an EEG abnormality is not a uniform diagnostic feature of CAPRIN1-related disease.
  diagnosis_term:
    preferred_term: Electroencephalography
    term:
      id: NCIT:C38054
      label: Electroencephalography
  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
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: '| EEG anomalies | NA | + | - | - | - | NA | NA | NA | NA | NA | + | + | NA |'
    explanation: The clinical comparison table records positive, negative and unavailable EEG observations; this row does not define a characteristic EEG pattern.
discussions:
- discussion_id: caprin1_dose_gap
  kind: HUMAN_MODEL_MISMATCH
  prompt: Does human heterozygous CAPRIN1 loss reduce dendritic delivery of the same mRNAs affected in mouse null neurons?
  attaches_to:
  - pathophysiology#Impaired Dendritic mRNA Localisation
  - experimental_models#Isogenic CAPRIN1 heterozygous human cortical neurons
  - experimental_models#Heterozygous Caprin1 primary cortical neurons
  rationale: Dendritic transcript mislocalization is directly established in complete-loss mouse models. Human heterozygous neurons have altered local puromycin labeling, which measures translation rather than RNA transport. Heterozygous mouse neurons were assayed for surface GluR1, but the downward trend was not significant; their study was therefore not exclusively behavioral. Testing transcript localization and gene-dosage rescue in the same human background would distinguish a conserved transport defect from other routes to altered translation and network activity.
  evidence:
  - reference: url:https://oup.silverchair-cdn.com/article-minimal/6650380
    reference_title: https://oup.silverchair-cdn.com/article-minimal/6650380
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: These data suggest that ... CAPRIN1 ... haploinsufficiency might also affect local protein synthesis.
    explanation: 'Publisher full text of Pavinato et al., Brain 2023, PMID:35979925: CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD. The authors interpret altered dendritic puromycin distribution as a local-translation effect.'
  - reference: PMID:26865403
    reference_title: 'Comprehensive behavioral analysis of RNG105 (Caprin1) heterozygous mice: Reduced social interaction and attenuated response to novelty.'
    supports: REFUTE
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: GluR1 surface distribution in dendrites tended to be less in Rng105+/− mice than in wild-type mice, though statistically not significant
    explanation: The heterozygous comparison limits claims of a proven same-dose effect.
  proposed_experiments:
  - experiment_id: caprin1_het_localisation_assay
    name: Dendritic RNA localization and dosage rescue in human heterozygous neurons
    description: Measure somatodendritic distributions of AMPA-regulator and NKA-subunit transcripts in heterozygous and isogenic control neurons, with physiological CAPRIN1 restoration. Pair RNA localization with local translation and electrophysiology.
    would_support:
    - pathophysiology#Impaired Dendritic mRNA Localisation
    supporting_outcome:
    - A concordant dendritic RNA deficit reversed by physiological CAPRIN1 restoration.
    refuting_outcome:
    - Preserved RNA distributions despite reproducible local-translation and network abnormalities.
- discussion_id: caprin1_stress_granule_context
  kind: HUMAN_MODEL_MISMATCH
  prompt: Which stress-granule abnormalities occur in human loss-of-function neurons at physiological dosage?
  attaches_to:
  - pathophysiology#Context-Dependent Impairment of Stress-Granule Assembly
  rationale: CAPRIN1-null HeLa cells and an Ile373Lys add-back assay show impaired granule assembly, whereas null cochlear explants retain marker-positive granules. Normal-protein biophysical studies show opposing domain effects and enhanced G3BP1-dependent mRNA recruitment; these establish molecular capabilities, not a proven universal disease mechanism. WDR45-associated granule disassembly and p.Pro512Leu aggregation belong to distinct disease contexts. Physiological-dose neuronal experiments should measure granule composition and recovery, not only granule number.
  evidence:
  - reference: PMID:35977029
    reference_title: De novo variants in genes regulating stress granule assembly associate with neurodevelopmental disorders.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: We observed a significant reduction of SG numbers in KO cell lines
    explanation: CAPRIN1 knockout perturbs granule formation in HeLa cells.
  - 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: REFUTE
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: These data suggest that stress granule formation in native cochlear cells is not dependent on Caprin1.
    explanation: Null cochlear explants retain stress-granule formation.
  - reference: PMID:36279435
    reference_title: Yin and yang regulation of stress granules by Caprin-1.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    directness: INDIRECT
    snippet: The C-terminal domain of Caprin-1 underwent spontaneous LLPS, whereas the N-terminal domain and GIM of Caprin-1 suppressed LLPS of G3BP1.
    explanation: Domain biophysics provides context without establishing the effects of patient loss-of-function alleles.
  - reference: PMID:41131140
    reference_title: mRNA recruitment by G3BP1 condensates is regulated by Caprin1 but requires G3BP1 binding to mRNA.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    directness: INDIRECT
    snippet: However, this function requires intact RNA binding domains of G3BP1.
    explanation: Normal-protein experiments constrain the mechanism of CAPRIN1-assisted recruitment.
- discussion_id: caprin1_penetrance
  kind: OPEN_QUESTION
  prompt: What determines whether a carrier of a CAPRIN1 protein-truncating variant develops neurodevelopmental impairment?
  attaches_to:
  - genetic#CAPRIN1
  rationale: ClinGen downgraded the relationship to Moderate because truncating alleles were also present in reportedly unaffected parents, siblings and controls. Ascertainment, depth of parental phenotyping, allele-specific consequences and additional genetic factors could contribute. Existing series do not support a numerical penetrance estimate or a validated modifier gene.
  evidence:
  - reference: url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_688d0e25-04f0-4160-a53a-00a6b423cafa-2026-02-02T110000.000Z
    reference_title: curation results for Gene-Disease Validity
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: The classification was downgraded from strong to moderate due to multiple instances of truncating variants inherited from unaffected parents or present in unaffected siblings and controls.
    explanation: The expert panel explicitly qualifies the strength of the gene–disease relationship.
experimental_models:
- name: Patient fibroblasts and lymphoblastoid cells
  experimental_model_type: PRIMARY_CELL_CULTURE
  description: Patient fibroblasts, PBMCs and lymphoblastoid cells were used for allele-specific RNA, splice and expression assays. Nonsense and splice alleles were examined in different cell preparations; the results are not measurements of patient neurons.
  publication: PMID:35979925
  modeled_mechanisms:
  - target: Aberrant CAPRIN1 Splicing
    relationship: PARTIALLY_RECAPITULATES
    fidelity: HIGH
    model_scale: MOLECULAR
    description: Exon skipping differs between the two splice variants.
    limitations: Results apply to the tested splice substitutions.
    evidence:
    - reference: url:https://oup.silverchair-cdn.com/article-minimal/6650380
      reference_title: https://oup.silverchair-cdn.com/article-minimal/6650380
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Analysis of the cDNA showed skipping of exon 3 ... and of exon 8
      explanation: 'Publisher full text of Pavinato et al., Brain 2023, PMID:35979925: CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD. RNA analysis distinguishes the two splice outcomes.'
  - target: Decay of Premature-Termination CAPRIN1 Transcripts
    relationship: PARTIALLY_RECAPITULATES
    fidelity: HIGH
    model_scale: MOLECULAR
    description: Cycloheximide partly restores mutant transcript detection.
    limitations: Cycloheximide is an experimental inhibitor, not a treatment tested in affected people.
    evidence:
    - reference: url:https://oup.silverchair-cdn.com/article-minimal/6650380
      reference_title: https://oup.silverchair-cdn.com/article-minimal/6650380
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: To investigate the occurrence of nonsense-mediated decay (NMD) for premature stop codons, we treated fibroblasts with CHX and showed a partial rescue in the expression of the mutant allele by Sanger sequencing
      explanation: 'Publisher full text of Pavinato et al., Brain 2023, PMID:35979925: CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD. Pharmacological inhibition partially restores the mutant RNA.'
  - target: Reduced CAPRIN1 Protein Abundance
    relationship: PARTIALLY_RECAPITULATES
    fidelity: HIGH
    model_scale: MOLECULAR
    description: Patient cells have reduced CAPRIN1 abundance.
    limitations: Protein levels vary by allele and cellular context; peripheral cells do not establish neuronal physiology.
    evidence:
    - reference: url:https://oup.silverchair-cdn.com/article-minimal/6650380
      reference_title: https://oup.silverchair-cdn.com/article-minimal/6650380
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Overall, CAPRIN1 protein levels were clearly reduced in all samples analysed, supporting haploinsufficiency as the disease mechanism.
      explanation: 'Publisher full text of Pavinato et al., Brain 2023, PMID:35979925: CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD. Direct patient-cell expression studies support reduced protein abundance.'
- name: Isogenic CAPRIN1 heterozygous human cortical neurons
  experimental_model_type: IPSC_DERIVED_MODEL
  description: A CRISPR-edited heterozygous HUVEC-derived hiPSC line and its isogenic control were differentiated into cortical neurons. Independent differentiations provide repeated cultures, not independent patient genotypes. The model reproduces gene-copy loss but is immature and has limited allelic and genetic-background diversity. Microelectrode analyses excluded wells that never became active.
  publication: PMID:35979925
  modeled_mechanisms:
  - target: Increased Global Neuronal Translation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Global translation is increased at day 14, with no significant increase at day 4.
    limitations: Engineered cultured neurons establish a cellular readout; they do not demonstrate its clinical penetrance or a complete causal sequence.
    evidence:
    - reference: url:https://oup.silverchair-cdn.com/article-minimal/6650380
      reference_title: https://oup.silverchair-cdn.com/article-minimal/6650380
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Treatment of hiPSCs-derived neurons with 1 µg/ml puromycin for 30 min resulted in a slightly increased global translation ... neurons 4 days post-ND ... which became significantly higher 14 days post-ND
      explanation: 'Publisher full text of Pavinato et al., Brain 2023, PMID:35979925: CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD. The SUnSET assay distinguishes a nonsignificant early trend from a later significant increase.'
  - target: Reduced Distal Dendritic Translation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Distal dendritic puromycin labeling declines more steeply.
    limitations: Engineered cultured neurons establish a cellular readout; they do not demonstrate its clinical penetrance or a complete causal sequence.
    evidence:
    - reference: url:https://oup.silverchair-cdn.com/article-minimal/6650380
      reference_title: https://oup.silverchair-cdn.com/article-minimal/6650380
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: These data suggest that ... CAPRIN1 ... haploinsufficiency might also affect local protein synthesis.
      explanation: 'Publisher full text of Pavinato et al., Brain 2023, PMID:35979925: CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD. The authors interpret altered dendritic puromycin distribution as a local-translation effect.'
  - target: Impaired Neurite Development
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Neurite length and organization are impaired.
    limitations: Engineered cultured neurons establish a cellular readout; they do not demonstrate its clinical penetrance or a complete causal sequence.
    evidence:
    - reference: url:https://oup.silverchair-cdn.com/article-minimal/6650380
      reference_title: https://oup.silverchair-cdn.com/article-minimal/6650380
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: immature neurons showed an alteration of neuronal structure, accompanied by reduced neurites length
      explanation: 'Publisher full text of Pavinato et al., Brain 2023, PMID:35979925: CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD. The engineered heterozygous human model directly measures neurite morphology.'
  - target: Increased Intracellular Calcium Signals
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Calcium signals are elevated before overt degeneration.
    limitations: Engineered cultured neurons establish a cellular readout; they do not demonstrate its clinical penetrance or a complete causal sequence.
    evidence:
    - reference: url:https://oup.silverchair-cdn.com/article-minimal/6650380
      reference_title: https://oup.silverchair-cdn.com/article-minimal/6650380
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: showed an increase in ... signals in ... compared to control neurons, both at 10 and 14 days post-ND
      explanation: 'Publisher full text of Pavinato et al., Brain 2023, PMID:35979925: CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD. Calcium imaging precedes overt degeneration. The quoted comparison identifies the two time points of the increased calcium-signal finding.'
  - target: Increased Neuronal Oxidative Stress
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Oxidative-stress signal is elevated near degeneration onset.
    limitations: Engineered cultured neurons establish a cellular readout; they do not demonstrate its clinical penetrance or a complete causal sequence.
    evidence:
    - reference: url:https://oup.silverchair-cdn.com/article-minimal/6650380
      reference_title: https://oup.silverchair-cdn.com/article-minimal/6650380
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Notably, we observed a significant increase in CellROX signal ... cells compared to controls
      explanation: 'Publisher full text of Pavinato et al., Brain 2023, PMID:35979925: CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD. The cellular assay supports increased oxidative stress without identifying a specific reactive species.'
  - target: Neuronal Process Degeneration
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Neuronal processes degenerate around days 17–19.
    limitations: Engineered cultured neurons establish a cellular readout; they do not demonstrate its clinical penetrance or a complete causal sequence.
    evidence:
    - reference: url:https://oup.silverchair-cdn.com/article-minimal/6650380
      reference_title: https://oup.silverchair-cdn.com/article-minimal/6650380
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: we observed a progressive degeneration of neuronal processes ... which began with the formation of small clusters of shrinking neuronal cells ... between Days 17 and 19 post-ND in five independent cultures
      explanation: 'Publisher full text of Pavinato et al., Brain 2023, PMID:35979925: CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD. Time-course observations identify the cellular degeneration phenotype.'
  - target: Reduced Neuronal Network Activity
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Spike and burst activity are reduced.
    limitations: Engineered cultured neurons establish a cellular readout; they do not demonstrate its clinical penetrance or a complete causal sequence.
    evidence:
    - reference: url:https://oup.silverchair-cdn.com/article-minimal/6650380
      reference_title: https://oup.silverchair-cdn.com/article-minimal/6650380
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: The spike rate and spike count were significantly lower in ... neurons versus controls
      explanation: 'Publisher full text of Pavinato et al., Brain 2023, PMID:35979925: CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD. Microelectrode recordings directly demonstrate reduced network activity.'
- name: Isogenic CAPRIN1 heterozygous neuronal progenitors
  experimental_model_type: IPSC_DERIVED_MODEL
  description: Neuronal rosettes and progenitors generated from the same edited human hiPSC background were compared with controls before neuronal maturation.
  publication: PMID:35979925
  modeled_mechanisms:
  - target: Impaired Neurite Development
    relationship: FAILS_TO_RECAPITULATE
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Early rosette size and progenitor morphology were not detectably altered.
    limitations: Grossly preserved progenitor morphology does not exclude subtle molecular abnormalities or later neuronal defects.
    evidence:
    - reference: url:https://oup.silverchair-cdn.com/article-minimal/6650380
      reference_title: https://oup.silverchair-cdn.com/article-minimal/6650380
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: No morphological alterations were observed in neural progenitor cells in further passages either
      explanation: 'Publisher full text of Pavinato et al., Brain 2023, PMID:35979925: CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD. Negative morphology result before neuronal maturation.'
- name: IGGi006-A patient-derived pluripotent stem cells
  experimental_model_type: IPSC_DERIVED_MODEL
  description: An iPSC line was generated from a p.Gln582Ter (c.1744C>T) carrier and validated for pluripotency and three-germ-layer differentiation. This is a patient model resource; the report does not establish a neuronal disease phenotype or therapeutic rescue.
  publication: PMID:40112765
  evidence:
  - reference: PMID:40112765
    reference_title: Derivation of the IGGi006-A stem cell line from a patient with CAPRIN1 haploinsufficiency.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: we generated human induced pluripotent stem cells (iPSCs) from a patient carrying the c.1744C>T CAPRIN1 variant.
    explanation: Documents a patient-derived cellular resource.
- name: Constitutive Caprin1-null primary cortical neurons
  experimental_model_type: PRIMARY_CELL_CULTURE
  description: Embryonic mouse null cortical cultures were used for NKA localization/activity, neuronal morphology and AMPA-receptor experiments. The 2010 and 2017 studies measured different readouts in complete-loss preparations.
  publication: PMID:20861386
  modeled_mechanisms:
  - target: Impaired Dendritic mRNA Localisation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: NKA-related reporter RNA localization and movement are reduced.
    limitations: Complete loss differs from human heterozygosity.
    evidence:
    - 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: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: their localization was limited to the cell soma and proximal dendrites and their motility was reduced in Rng105−/− neurons
      explanation: Cultured null neurons show altered movement and distribution of NKA-related reporter transcripts.
  - target: Reduced Dendritic Sodium-Potassium Pump Activity
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Dendritic pump activity is reduced while somatic activity is preserved.
    limitations: The sodium-efflux proxy is compartment specific; it is not a human patient measurement.
    evidence:
    - 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: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: These results suggest that NKA activity was decreased in dendrites but not in the cell soma of Rng105−/− neurons
      explanation: Functional imaging localizes the deficit to dendrites.
  - target: Reduced Dendritic AMPA-Receptor Surface Expression
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Dendritic surface GluR1 is significantly reduced.
    limitations: Receptor effects differ by subunit and dosage.
    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: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: quantification revealed that the ratio of surface/total GluR1 puncta number in dendrites was significantly reduced in the Rng105−/− neurons
      explanation: Complete-loss cultures show a significant surface-receptor deficit.
  - target: Impaired Homeostatic AMPA-Receptor Scaling
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: The TTX/APV-induced scaling response is impaired.
    limitations: A null culture does not establish impaired scaling in heterozygous human neurons.
    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: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: By contrast, the activity deprivation-dependent increase in surface GluR1 expression was not observed in Rng105−/− dendrites
      explanation: Direct activity-deprivation experiment in primary null neurons.
  - target: Impaired Neurite Development
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Dendritic length and arborization are reduced.
    limitations: Null primary neurons do not reproduce every aspect of human cortical development.
    evidence:
    - 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: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Sholl analysis revealed that the number of dendrites was significantly reduced in Rng105−/− neurons compared with wild-type neurons
      explanation: Direct morphometric result.
- name: Heterozygous Caprin1 primary cortical neurons
  experimental_model_type: PRIMARY_CELL_CULTURE
  description: Primary neurons from heterozygous mice were assayed for the ratio of dendritic surface to total GluR1, alongside wild-type and homozygous-null cultures.
  publication: PMID:26865403
  modeled_mechanisms:
  - target: Reduced Dendritic AMPA-Receptor Surface Expression
    relationship: FAILS_TO_RECAPITULATE
    fidelity: MODERATE
    model_scale: CELLULAR
    description: The heterozygous surface-GluR1 difference was not statistically significant.
    limitations: A nonsignificant trend is not proof of equivalence; power and compensatory protein expression may matter.
    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: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: GluR1 surface distribution in dendrites tended to be less in Rng105+/− mice than in wild-type mice, though statistically not significant
      explanation: Same-copy-number loss did not establish a significant receptor-surface deficit.
- name: CAPRIN1 knockout and missense add-back HeLa cells
  experimental_model_type: CELL_LINE
  description: CAPRIN1-null HeLa cells and add-back constructs were examined during arsenite stress. Candidate p.Ile373Lys abolished G3BP1/2 interaction and showed diffuse localization and reduced stress-granule assembly. The study’s main newly described clinical cohort concerns UBAP2L, not CAPRIN1.
  publication: PMID:35977029
  modeled_mechanisms:
  - target: Context-Dependent Impairment of Stress-Granule Assembly
    relationship: PERTURBS
    fidelity: MODERATE
    model_scale: CELLULAR
    description: CAPRIN1 loss and p.Ile373Lys perturb stress-granule assembly.
    limitations: Non-neuronal knockout/add-back experiments do not establish the effect of all heterozygous loss-of-function alleles; missense pathogenicity requires allele-specific interpretation.
    evidence:
    - reference: PMID:35977029
      reference_title: De novo variants in genes regulating stress granule assembly associate with neurodevelopmental disorders.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: We observed a significant reduction of SG numbers in KO cell lines
      explanation: CAPRIN1 knockout perturbs granule formation in HeLa cells.
    - reference: PMID:35977029
      reference_title: De novo variants in genes regulating stress granule assembly associate with neurodevelopmental disorders.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: coimmunoprecipitation revealed a complete abolishment of interaction between CAPRIN1 p.I373K mutant proteins and G3BP1/2
      explanation: The binding result is specific to the tested missense variant.
- name: Caprin1 conditional-null cochlear explants
  experimental_model_type: OTHER
  description: Postnatal cochlear explants were exposed to 0.5 mM sodium arsenite for one hour. TIA1- and HuR-positive granules formed despite Caprin1 depletion; some cells escaped Cre recombination, but depleted cells also formed granules.
  publication: PMID:35165318
  modeled_mechanisms:
  - target: Context-Dependent Impairment of Stress-Granule Assembly
    relationship: FAILS_TO_RECAPITULATE
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Granule formation persisted in Caprin1-deficient cochlear cells.
    limitations: Granule counts and marker appearance do not establish normal granule composition, function or recovery kinetics.
    evidence:
    - 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: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Stress granule formation in the cKO and Caprin1-expressing cells in the same explant was indistinguishable
      explanation: The within-explant comparison supports preserved granule formation.
treatments:
- name: Speech and language therapy
  description: Speech-language support was used in affected children. Therapy addresses communication and speech motor difficulties; the reports do not establish a CAPRIN1-specific treatment effect.
  treatment_term:
    preferred_term: Speech Language Therapy
    term:
      id: NCIT:C159273
      label: Speech Language Therapy
  therapeutic_modality: BEHAVIORAL
  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
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: He received physical, occupational, and speech therapy through the school system and used an augmentative and alternative communication device.
    explanation: Documents supportive interventions in the 2026 case; efficacy was not measured in a controlled comparison.
  target_phenotypes:
  - preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  - preferred_term: Speech apraxia
    term:
      id: HP:0011098
      label: Speech apraxia
- name: Augmentative and alternative communication
  description: An augmentative communication device and a personal picture agenda were used in reported cases. Such aids support communication; device type, adherence and comparative outcomes were not systematically evaluated.
  treatment_term:
    preferred_term: Therapeutic Procedure
    term:
      id: NCIT:C49236
      label: Therapeutic Procedure
  therapeutic_modality: DEVICE
  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
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: He received physical, occupational, and speech therapy through the school system and used an augmentative and alternative communication device.
    explanation: Documents supportive interventions in the 2026 case; efficacy was not measured in a controlled comparison.
  - reference: url:https://oup.silverchair-cdn.com/article-minimal/6650380
    reference_title: https://oup.silverchair-cdn.com/article-minimal/6650380
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Case 1, who was helped using a personal picture agenda
    explanation: 'Publisher full text of Pavinato et al., Brain 2023, PMID:35979925: CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD. The defining series documents a communication aid.'
  target_phenotypes:
  - preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
- name: Physical therapy
  description: School-based physical therapy was reported for motor difficulties in the 2026 case. The paper does not quantify improvement attributable to therapy.
  treatment_term:
    preferred_term: Physical Therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  therapeutic_modality: BEHAVIORAL
  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
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: He received physical, occupational, and speech therapy through the school system and used an augmentative and alternative communication device.
    explanation: Documents supportive interventions in the 2026 case; efficacy was not measured in a controlled comparison.
  target_phenotypes:
  - preferred_term: Delayed gross motor development
    term:
      id: HP:0002194
      label: Delayed gross motor development
  - preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
- name: Occupational therapy
  description: School-based occupational therapy addressed functional and fine motor needs. No disorder-specific comparative benefit was measured.
  treatment_term:
    preferred_term: Occupational Therapy
    term:
      id: NCIT:C121351
      label: Occupational Therapy
  therapeutic_modality: BEHAVIORAL
  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
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: He received physical, occupational, and speech therapy through the school system and used an augmentative and alternative communication device.
    explanation: Documents supportive interventions in the 2026 case; efficacy was not measured in a controlled comparison.
  target_phenotypes:
  - preferred_term: Delayed fine motor development
    term:
      id: HP:0010862
      label: Delayed fine motor development
- name: Antiseizure medication
  description: Reported regimens include oxcarbazepine in one child and sodium valproate with carbamazepine in another; valproate provided some control in a child with nocturnal seizures. These are individual treatment histories, not evidence of a preferred regimen for all CAPRIN1-associated seizure types.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Oxcarbazepine
      term:
        id: NCIT:C47643
        label: Oxcarbazepine
    - preferred_term: Valproate Sodium
      term:
        id: NCIT:C48029
        label: Valproate Sodium
    - preferred_term: Carbamazepine
      term:
        id: NCIT:C341
        label: Carbamazepine
  therapeutic_modality: SMALL_MOLECULE
  evidence:
  - reference: url:https://oup.silverchair-cdn.com/article-minimal/6650380
    reference_title: https://oup.silverchair-cdn.com/article-minimal/6650380
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Cases 2 and 4 showed absence type seizures, which resolved after oxcarbazepine and ADHD treatment, respectively.
    explanation: 'Publisher full text of Pavinato et al., Brain 2023, PMID:35979925: CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD. The report documents oxcarbazepine response in Case 2; Case 4’s staring spells were considered nonepileptic in the detailed supplement.'
  - reference: url:https://oup.silverchair-cdn.com/article-minimal/6650380
    reference_title: https://oup.silverchair-cdn.com/article-minimal/6650380
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: was treated with sodium valproate and carbamazepine.
    explanation: 'Publisher full text of Pavinato et al., Brain 2023, PMID:35979925: CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD. Reports the regimen used in the infantile-spasm/absence case.'
  - reference: url:https://oup.silverchair-cdn.com/article-minimal/6650380
    reference_title: https://oup.silverchair-cdn.com/article-minimal/6650380
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Case 12 suffered from secondary generalized epileptic seizures during sleep, and was treated with valproate with discrete control.
    explanation: 'Publisher full text of Pavinato et al., Brain 2023, PMID:35979925: CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD. Individual response description without comparative efficacy data.'
  target_phenotypes:
  - preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  - preferred_term: Infantile spasms
    term:
      id: HP:0012469
      label: Infantile spasms
- name: Genetic counseling
  description: Counseling should distinguish variant transmission from clinical penetrance, address variable expression and consider testing of parents and relatives. A heterozygous carrier can transmit the allele with a 50% probability per pregnancy, but the probability and severity of clinical manifestations are not quantified by the available series.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  therapeutic_modality: OTHER
  evidence:
  - reference: url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_688d0e25-04f0-4160-a53a-00a6b423cafa-2026-02-02T110000.000Z
    reference_title: curation results for Gene-Disease Validity
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
    snippet: More evidence is needed to determine the penetrance and phenotypic spectrum of ... CAPRIN1 ... haploinsufficiency.
    explanation: The expert assessment supports counseling about uncertainty rather than assuming every carrier is affected.
  target_phenotypes: []
- name: ADHD pharmacotherapy
  description: ADHD medication was used in Case 4 of the defining cohort, with resolution of staring spells that the detailed clinical assessment considered nonepileptic. This single treatment history does not establish a CAPRIN1-specific drug response or a preferred regimen.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: url:https://oup.silverchair-cdn.com/article-minimal/6650380
    reference_title: https://oup.silverchair-cdn.com/article-minimal/6650380
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Cases 2 and 4 showed absence type seizures, which resolved after oxcarbazepine and ADHD treatment, respectively.
    explanation: 'Publisher full text of Pavinato et al., Brain 2023, PMID:35979925: CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD. The cohort reports ADHD treatment in Case 4. The detailed supplement considered the staring spells nonepileptic, so their resolution is not evidence of an antiseizure effect. ADHD symptom improvement was not separately quantified, so this records treatment use rather than efficacy for ADHD.'
  target_phenotypes:
  - preferred_term: Attention deficit hyperactivity disorder
    term:
      id: HP:0007018
      label: Attention deficit hyperactivity disorder
clinical_trials:
- name: NCT01238250
  phase: NOT_APPLICABLE
  status: RECRUITING
  description: Simons Searchlight is an international observational program collecting longitudinal clinical information and biospecimens across many rare genetic neurodevelopmental conditions, including CAPRIN1. Its total planned enrollment is not a CAPRIN1-specific sample size.
  notes: Registry checked 2026-10-01. This is observational research, not a treatment trial.
  evidence:
  - reference: clinicaltrials:NCT01238250
    reference_title: 'Online Study of People Who Have Genetic Changes and Features of Autism: Simons Searchlight'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Simons Searchlight is an observational, online, international research program for families with rare genetic variants that cause neurodevelopmental disorders and may be associated with autism.
    explanation: Registry summary identifies the observational purpose.
differential_diagnoses:
- name: CAPRIN1 p.Pro512Leu-associated neurodegeneration
  disease_term:
    preferred_term: neurodegeneration, childhood-onset, with cerebellar ataxia and cognitive decline
    term:
      id: MONDO:0957985
      label: neurodegeneration, childhood-onset, with cerebellar ataxia and cognitive decline
  description: The recurrent p.Pro512Leu allele is associated with progressive childhood ataxia, cognitive decline and protein aggregation, rather than the loss-of-function developmental syndrome. Later cases show progressive brain atrophy and axonal neuropathy. Ataxia can also occur with a nonsense allele, so clinical gait findings alone do not separate these entities.
  distinguishing_features:
  - 'Variant-specific mechanism: p.Pro512Leu aggregation-associated gain of function versus reduced dosage from loss-of-function alleles.'
  - Progressive cognitive and motor decline, brain atrophy and axonal neuropathy favor the neurodegenerative entity.
  evidence:
  - reference: PMID:36136249
    reference_title: CAPRIN1(P512L) causes aberrant protein aggregation and associates with early-onset ataxia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Trio exome sequencing unraveled the identical de novo c.1535C > T (p.Pro512Leu) missense variant in CAPRIN1
    explanation: The original neurodegenerative patients shared the recurrent missense allele.
  - reference: PMID:39878554
    reference_title: CAPRIN1 Pro512Leu Variant Causes Childhood Dementia, Myoclonus-Ataxia, and Sensorimotor Neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Electroneurography confirmed sensorimotor axonal neuropathy in the lower and upper limbs.
    explanation: A subsequent patient had objective peripheral neuropathy.
references:
- reference: PMID:20861386
  title: RNG105 deficiency impairs the dendritic localization of mRNAs for Na+/K+ ATPase subunit isoforms and leads to the degeneration of neuronal networks.
- reference: PMID:26865403
  title: 'Comprehensive behavioral analysis of RNG105 (Caprin1) heterozygous mice: Reduced social interaction and attenuated response to novelty.'
- reference: PMID:29157358
  title: RNG105/caprin1, an RNA granule protein for dendritic mRNA localization, is essential for long-term memory formation.
- reference: PMID:35165318
  title: Targeted deletion of the RNA-binding protein Caprin1 leads to progressive hearing loss and impairs recovery from noise exposure in mice.
- reference: PMID:35977029
  title: De novo variants in genes regulating stress granule assembly associate with neurodevelopmental disorders.
- reference: PMID:35979925
  title: CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD.
- reference: PMID:36136249
  title: CAPRIN1(P512L) causes aberrant protein aggregation and associates with early-onset ataxia.
- reference: PMID:36279435
  title: Yin and yang regulation of stress granules by Caprin-1.
- reference: PMID:39878554
  title: CAPRIN1 Pro512Leu Variant Causes Childhood Dementia, Myoclonus-Ataxia, and Sensorimotor Neuropathy.
- reference: PMID:40112765
  title: Derivation of the IGGi006-A stem cell line from a patient with CAPRIN1 haploinsufficiency.
- reference: PMID:41131140
  title: mRNA recruitment by G3BP1 condensates is regulated by Caprin1 but requires G3BP1 binding to mRNA.
- reference: PMID:41859620
  title: 'CAPRIN1 (Cell Cycle-Associated Protein 1)-Related Neurodevelopmental Disorder: A Novel Mutation With Ataxia.'
- reference: clinicaltrials:NCT01238250
  title: 'Online Study of People Who Have Genetic Changes and Features of Autism: Simons Searchlight'
- reference: url:https://broadinstitute.atlassian.net/wiki/spaces/BCLGC/pages/4871684098/CAPRIN1+Gene+Curation
  title: CAPRIN1 Gene Curation - Broad Clinical Lab Reporting and Interpretation Team - Confluence
- reference: url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_688d0e25-04f0-4160-a53a-00a6b423cafa-2026-02-02T110000.000Z
  title: curation results for Gene-Disease Validity

📚

References & Deep Research

References

PMID:20861386

RNG105 deficiency impairs the dendritic localization of mRNAs for Na+/K+ ATPase subunit isoforms and leads to the degeneration of neuronal networks.

No top-level findings curated for this source.

PMID:26865403

Comprehensive behavioral analysis of RNG105 (Caprin1) heterozygous mice: Reduced social interaction and attenuated response to novelty.

No top-level findings curated for this source.

PMID:29157358

RNG105/caprin1, an RNA granule protein for dendritic mRNA localization, is essential for long-term memory formation.

No top-level findings curated for this source.

PMID:35165318

Targeted deletion of the RNA-binding protein Caprin1 leads to progressive hearing loss and impairs recovery from noise exposure in mice.

No top-level findings curated for this source.

PMID:35977029

De novo variants in genes regulating stress granule assembly associate with neurodevelopmental disorders.

No top-level findings curated for this source.

PMID:35979925

CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD.

No top-level findings curated for this source.

PMID:36136249

CAPRIN1(P512L) causes aberrant protein aggregation and associates with early-onset ataxia.

No top-level findings curated for this source.

PMID:36279435

Yin and yang regulation of stress granules by Caprin-1.

No top-level findings curated for this source.

PMID:39878554

CAPRIN1 Pro512Leu Variant Causes Childhood Dementia, Myoclonus-Ataxia, and Sensorimotor Neuropathy.

No top-level findings curated for this source.

PMID:40112765

Derivation of the IGGi006-A stem cell line from a patient with CAPRIN1 haploinsufficiency.

No top-level findings curated for this source.

PMID:41131140

mRNA recruitment by G3BP1 condensates is regulated by Caprin1 but requires G3BP1 binding to mRNA.

No top-level findings curated for this source.

PMID:41859620

CAPRIN1 (Cell Cycle-Associated Protein 1)-Related Neurodevelopmental Disorder: A Novel Mutation With Ataxia.

No top-level findings curated for this source.

clinicaltrials:NCT01238250

Online Study of People Who Have Genetic Changes and Features of Autism: Simons Searchlight

No top-level findings curated for this source.

url:https://broadinstitute.atlassian.net/wiki/spaces/BCLGC/pages/4871684098/CAPRIN1+Gene+Curation

CAPRIN1 Gene Curation - Broad Clinical Lab Reporting and Interpretation Team - Confluence

No top-level findings curated for this source.

url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_688d0e25-04f0-4160-a53a-00a6b423cafa-2026-02-02T110000.000Z

curation results for Gene-Disease Validity

No top-level findings curated for this source.

Deep Research

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (2)

Review CAPRIN1 clinical evidence, gene validity and experimental mechanisms against cached full text · 2026-10-01T16:01:00Z · View source

Read the founding cohort full text and detailed supplement, subsequent clinical case, ClinGen 2026 assessment, primary neuronal and mouse studies, and matching deep-research report. Represent the Moderate gene–disease association and unaffected carriers; distinguish loss-of-function developmental disease from Pro512Leu neurodegeneration. Correct cohort denominators, feeding and hearing frequencies, ambiguous seizure ascertainment, and the combined intellectual/learning-disability endpoint. Separate variant classes, RNA processing, protein dosage, translation, receptor scaling and synaptic effects. Distinguish heterozygous from null models, preserve negative findings, add documented supportive care and the observational registry, and update the renamed node-class membership. Validate 127 exact evidence excerpts and 143 titles against generated caches, including the full publisher article and current ClinGen page.

Create: CAPRIN1-related neurodevelopmental disorder · 2026-08-28T21:41:24Z · View source

De novo curation from an OpenScientist deep-research report. Gene identifier verified against HGNC and correct: CAPRIN1 is hgnc:6743. This is the one entry in the batch where per-phenotype frequencies are properly citable, and every band is bound to a quote stating that figure for that named phenotype: language impairment 100 percent as OBLIGATE, intellectual disability 83 and ADHD 82 as VERY_FREQUENT, autism 67, respiratory 50, limb and skeletal 50, developmental delay 42, feeding difficulties 33, seizures 33 and ophthalmologic 33 as FREQUENT. That is the discipline the previous batch failed when a frequency was taken from a number describing a neighbouring phenotype in the same sentence. Twelve patients is a coarse denominator and the notes say so. This report was the only one of the five to carry a flagged confabulation. Its own reference validation reported a quote not found in PMID:35979925, beginning The majority of reported pathogenic mutations in the CAPRIN1 gene result in decreased protein levels and haploinsufficiency. That sentence is not in the cached abstract and is not used anywhere in the entry; it is recorded in the top-level notes so it is not re-derived from the report. Pathograph runs from haploinsufficiency through impaired dendritic mRNA localisation to attenuated AMPAR scaling and reduced synaptic strength, then splits into a neuronal arm and an extraneural one. The extraneural node is deliberately a sibling rather than downstream of cortical neuron development, because routing a limb anomaly through neuronal development would be false; its description says the features occur in the disease without claiming each follows from the neuronal mechanism. Respiratory, skeletal and ophthalmologic phenotypes are bound to high-level HP terms because the cohort describes them only as problems or anomalies without naming a specific finding. A HUMAN_MODEL_MISMATCH records the dose problem at the centre of the entry: the mRNA-localisation mechanism is established only in a homozygous mouse deletion while the human disease is haploinsufficiency, and the CRISPR-edited heterozygous iPSC neurons that are at the right dose were characterised for morphology, translation, calcium, oxidative stress and electrical activity but are not reported to have been assayed for dendritic mRNA localisation. A proposed experiment names the assay that would close it. Validation: just validate passes, 24 of 24 snippets verified, entity refs and duplicate keys clean, one root, no dangling targets, every phenotype reached.

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

Medical Actions

Diagnosis

Prevalence

Differential Diagnoses

Clinical Trials

Experimental Models

Animal Models

Source YAML

References & Deep Research

References

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