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Early onset or syndromic epilepsy

Gene: CAPRIN1

Green List (high evidence)

CAPRIN1 (cell cycle associated protein 1)
EnsemblGeneIds (GRCh38): ENSG00000135387
EnsemblGeneIds (GRCh37): ENSG00000135387
OMIM: 601178, Gene2Phenotype
CAPRIN1 is in 5 panels

4 reviews

Eleanor Williams (Genomics England Curator)

This gene currently has no phenotype in OMIM. Check that the publication PMID:35979925 lists this gene name. It does. Gene-checked tag added.
Created: 16 Oct 2023, 4:06 p.m. | Last Modified: 16 Oct 2023, 4:06 p.m.
Panel Version: 4.115

Arina Puzriakova (Genomics England Curator)

Green List (high evidence)

The rating of this gene has been updated to Green following NHS Genomic Medicine Service approval.
Created: 11 Oct 2023, 11:59 a.m. | Last Modified: 11 Oct 2023, 11:59 a.m.
Panel Version: 4.110

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Achchuthan Shanmugasundram (Genomics England Curator)

Green List (high evidence)

Comment on classification: This gene can be rated green as it has been implicated with seizures in 4 unrelated individuals reported with autosomal dominant CAPRIN1-associated neurodevelopmental disorder.

PMID:35979925 reports 12 individuals with a neurodevelopmental disorder characterised by language impairment/speech delay (all 12 individuals), Intellectual Disability (ID; 10 individuals), Attention Deficit Hyperactivity Disorder (ADHD; 10 individuals), and Autism Spectrum Disorder (ASD; 8 individuals). Other features includes seizures (4 individuals), hands and feet malformations (5 individuals), breathing problems (6 individuals), ocular problems (4 individuals) and hearing problems (3 individuals). In addition, functional studies supports pathogenicity.
Created: 7 Feb 2023, 11:30 a.m. | Last Modified: 7 Feb 2023, 11:30 a.m.
Panel Version: 3.32

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Neurodevelopmental disorder, MONDO:0700092; Epilepsy, MONDO:0005027

Publications

Konstantinos Varvagiannis (Other)

Green List (high evidence)

A cohort of 12 individuals harboring pathogenic CAPRIN1 variants is described in a recent report by Pavinato et al (2022 - PMID: 35979925).

DD, impaired speech/language development (100%), ID (83%), ASD (67%) and seizures (33%) are part of the phenotype (details below).

Enrichment for de novo LGD but also missense variants has also been demonstrated upon meta-analysis of different cohorts of 40,853 individuals with ID (N=31,625) or ASD (N=9,228) as discussed by Jia et al (2022 - PMID: 35977029).

Role of the gene:
Evidence supports among others, a role for CAPRIN1 in formation RNA-protein (stress) granules through interaction with other relevant proteins (e.g. G3BP1/2, FMRP) and regulation of gene expression (Pavinato et al - PMID: 35979925, Jia et al - PMID: 35977029).
Jia et al further demonstrated significant reduction of stress granule formation in CAPRIN1 KO HeLa lines.
Following generation of CAPRIN1+/- hiPSC line using CRISPR/Cas9 and differentiation into cortical neurons, Pavinato et al noted, altered neuronal structure, abnormal firing properties as well as increased neuronal degeneration possibly linked to presence of increased Ca+2 signals and increase in reactive oxygen species (ROS). Global de novo protein synthesis in neurons appeared to be impaired.

Variant type and inheritance :
All individuals reported by Paviato et al harbored pLoF (nonsense, frameshift, splicing and a synonymous variant resulting in abnormal splicing) variants. In most cases variants occurred de novo with the exception of 2 subjects having inherited pLoF variants from their affected/unaffected parent. Expressive variability, reduced penetrance and possibility of - a yet to be proven - sex bias are discussed (9M/3F).
Missense variants and enrichment for dn missense SNVs have also been shown in large cohorts. The impact of p.I373K has been studied.

Variant effect:
pLoF : Pavinato et al demonstrated reduced mRNA and protein levels for the truncating variants, and out-of frame exon skipping for a variant affecting splice donor site and a further SNV affecting the last nucleotide of ex8.
Missense SNVs : p.I373K abolished interaction with G3BP1/2 and disrupted stress granule formation in the study by Jia et al demonstrating a role of stress granules in pathogenesis of neurodevelopmental disorders.

Animal model:
As discussed by Pavinato et al abnormal neuronal structure and firing properties are observed in htz mouse models. Htz mice display features of ASD, difficulties in reversal learning (for ID), sporadic occurrence of seizures. Hearing impairment (as in 2-3 individuals described) due to reduced protection from noise exposure was reported in an ear-conditional ko model.

The report by Pavinato et al is summarized below.

For the study by Jia et al a summary can by found under the review of UBAP2L.

Reports of individuals in the context of larger cohorts were not here reviewed (eg. DDD study 2017, PMID: 28135719 || Ruzzo et al 2019, PMID: 31398340 || Fu et al 2021, https://doi.org/10.1101/2021.12.20.21267194).

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Pavinato et al (2022 - PMID: 35979925) describe the phenotype associated with heterozygous CAPRIN1 pathogenic variants.

Overlapping features incl. impaired speech/language development (100%), ID (83%), ASD (67%), ADHD (82%), seizures (33% or 4/12 : absence seizures in 2, infantile spasms with absence epilepsy, secondary generalized epileptic seizures during sleep). Respiratory problems (50%), limb/skeletal anomalies (50%), feeding difficulties (33%), mild hearing hearing impairment (in 2 or 3). There was no evident dysmorphism, despite few recurrent features.

CAPRIN1 encodes cell cycle-associated protein 1. As the authors discuss, the gene is ubiquitously expressed with high expression in brain. The protein is known to interact with other RNA-binding proteins (eg. FMRP, G3BP1) for the formation of ribonucleoparticles / RNA granules. The gene localizes in neuronal RNA granules in dendrites. Previous studies have demonstrated a role in regulation of mRNA translation (acting as translational inhibitor with its overexpression leading to reduced protein synthesis). CAPRIN1 interacts with FMRP and CYFIP1, both also involved in regulation of mRNA translation.

One individual with microdeletion (~1.4 Mb spanning 8 genes with CAPRIN1 the only predicted to be haploinsufficient) as well as 11 additional subjects with nonsense/splicing variants were identified, following CMA, ES or GS. [The gene has a pHaplo of 0.98 and pLI of 0.97 (LOEUF 0.31)].

Variants were mostly de novo, although one individual had inherited a nonsense variant from his affected father while one further from her unaffected mother.

qRT-PCR showed reduced mRNA levels in patient fibroblasts and PBMCs while cycloheximide treatment in fibroblasts resulted in partial rescue in expression of mutant allele. Western blot in fibroblasts confirmed reduced protein levels.

cDNA analysis revealed that c.279+1G>T variant resulted in out-of-frame skipping of ex3, while c.879G>A (last base of ex8) resulted in out-of-frame skipping of ex8 and degradation by NMD, with cycloheximide restoring expression of mutant allele. [ NM_005898.5 ]

The authors generated a CAPRIN1+/- hiPSC line using CRISPR/Cas9 and hiPSCs were differentiated into cortical neurons. Htz immature neurons displayed altered neuronal structure, accompanied by reduced neurite length similar to previous observations in mice.

Increased neuronal degeneration was observed. Ca+2 signals (described in literature to trigger or contribute to neuronal death) were increased compared to controls. Increase in reactive oxygen species (ROS) following Ca+2 overload was also demonstrated, likely contributing to neuronal death.

Given the gene's role in regulation of mRNA translation, the authors assessed global de novo protein synthesis in neurons based on pyromicin incorporation (SUnSET assay) with findings supporting the impact of CAPRIN1 haploinsufficiency.

Heterozygous neurons were shown to display abnormal firing properties similar to a previously reported mouse model.

Mouse model : apart from the findings discussed above (abnormal neuronal structure and firing properties), heterozygous mice displayed similar features to the cohort described eg. reduced sociability and weaker preference for social novelty (as in ASD), difficulties in reversal learning (for ID), sporadic occurrence of seizures upon Morris water maze/contextual fearing tests and epileptic-like fEPSP after LTP. Breathing problems were noted in Carpin1-/- mice. Ear conditional ko was associated with early-onset progressive hearing loss and reduced protection from noise exposure which might be in line with few individuals with hearing impairment.
Sources: Literature
Created: 3 Sep 2022, 10:24 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Global developmental delay; Delayed speech and language development; Intellectual disability; Autistic behavior; Seizures

Publications

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review Green
  • NHS GMS
Phenotypes
  • Global developmental delay
  • Delayed speech and language development
  • Intellectual disability
  • Autistic behavior
  • Seizures
Tags
gene-checked
OMIM
601178
Clinvar variants
Variants in CAPRIN1
Penetrance
Incomplete
Publications
Panels with this gene

History Filter Activity

16 Oct 2023, Gel status: 3

Added Tag

Eleanor Williams (Genomics England Curator)

Tag gene-checked tag was added to gene: CAPRIN1.

11 Oct 2023, Gel status: 3

Removed Tag

Arina Puzriakova (Genomics England Curator)

Tag Q1_23_promote_green was removed from gene: CAPRIN1.

11 Oct 2023, Gel status: 3

Added New Source, Added New Source, Status Update

Arina Puzriakova (Genomics England Curator)

Source NHS GMS was added to CAPRIN1. Source Expert Review Green was added to CAPRIN1. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)

7 Feb 2023, Gel status: 2

Added Tag

Achchuthan Shanmugasundram (Genomics England Curator)

Tag Q1_23_promote_green tag was added to gene: CAPRIN1.

7 Feb 2023, Gel status: 2

Set publications

Achchuthan Shanmugasundram (Genomics England Curator)

Publications for gene: CAPRIN1 were set to 35979925; 35977029; 28135719; 31398340; https://doi.org/10.1101/2021.12.20.21267194

7 Feb 2023, Gel status: 2

Entity classified by Genomics England curator

Achchuthan Shanmugasundram (Genomics England Curator)

Gene: caprin1 has been classified as Amber List (Moderate Evidence).

3 Sep 2022, Gel status: 0

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes, Set penetrance

Konstantinos Varvagiannis (Other)

gene: CAPRIN1 was added gene: CAPRIN1 was added to Genetic epilepsy syndromes. Sources: Literature Mode of inheritance for gene: CAPRIN1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: CAPRIN1 were set to 35979925; 35977029; 28135719; 31398340; https://doi.org/10.1101/2021.12.20.21267194 Phenotypes for gene: CAPRIN1 were set to Global developmental delay; Delayed speech and language development; Intellectual disability; Autistic behavior; Seizures Penetrance for gene: CAPRIN1 were set to Incomplete Review for gene: CAPRIN1 was set to AMBER