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Intellectual disability - microarray and sequencing v5.511 CAPRIN1 Arina Puzriakova Publications for gene: CAPRIN1 were set to 23849776; 35979925; 36136249
Intellectual disability - microarray and sequencing v5.510 CAPRIN1 Arina Puzriakova Added comment: Comment on phenotypes: Gene-checked tag removed as this gene now has a phenotype listed in OMIM (Neurodegeneration, childhood-onset, with cerebellar ataxia and cognitive decline, OMIM:620636)
Intellectual disability - microarray and sequencing v5.510 CAPRIN1 Arina Puzriakova Phenotypes for gene: CAPRIN1 were changed from Global developmental delay; Delayed speech and language development; Intellectual disability; Autistic behaviour; Seizures to Neurodegeneration, childhood-onset, with cerebellar ataxia and cognitive decline, OMIM:620636
Intellectual disability - microarray and sequencing v5.509 CAPRIN1 Arina Puzriakova Tag gene-checked was removed from gene: CAPRIN1.
Intellectual disability - microarray and sequencing v5.308 CAPRIN1 Eleanor Williams Tag gene-checked tag was added to gene: CAPRIN1.
Intellectual disability - microarray and sequencing v5.308 CAPRIN1 Eleanor Williams commented on gene: CAPRIN1
Intellectual disability - microarray and sequencing v5.287 CAPRIN1 Arina Puzriakova Phenotypes for gene: CAPRIN1 were changed from Global developmental delay; Delayed speech and language development; Intellectual disability; Autistic behaviour; Seizures to Global developmental delay; Delayed speech and language development; Intellectual disability; Autistic behaviour; Seizures
Intellectual disability - microarray and sequencing v5.287 CAPRIN1 Arina Puzriakova Phenotypes for gene: CAPRIN1 were changed from AUTISM OR INTELLECTUAL DISABILITY to Global developmental delay; Delayed speech and language development; Intellectual disability; Autistic behaviour; Seizures
Intellectual disability - microarray and sequencing v5.286 CAPRIN1 Arina Puzriakova Tag Q1_23_promote_green was removed from gene: CAPRIN1.
Intellectual disability - microarray and sequencing v5.286 CAPRIN1 Arina Puzriakova reviewed gene: CAPRIN1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v5.286 CAPRIN1 Arina Puzriakova 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)
Intellectual disability - microarray and sequencing v5.9 CAPRIN1 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As indicated by the previous reviewers, there is sufficient evidence (>10 unrelated cases) for this gene to be promoted to GREEN at the next major review.

However, this gene has not yet been associated with relevant phenotypes in OMIM, but it has been reported in Gene2Phenotype with 'moderate' rating.; to: Comment on list classification: As indicated by the previous reviewers, there is sufficient evidence (>10 unrelated cases and supporting functional evidence) for this gene to be promoted to GREEN at the next major review.

However, this gene has not yet been associated with relevant phenotypes in OMIM, but it has been reported in Gene2Phenotype with 'moderate' rating.
Intellectual disability - microarray and sequencing v5.9 CAPRIN1 Achchuthan Shanmugasundram Mode of inheritance for gene: CAPRIN1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v5.9 CAPRIN1 Achchuthan Shanmugasundram Mode of inheritance for gene: CAPRIN1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v5.9 CAPRIN1 Achchuthan Shanmugasundram Mode of inheritance for gene: CAPRIN1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v5.9 CAPRIN1 Achchuthan Shanmugasundram Mode of inheritance for gene: CAPRIN1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v5.9 CAPRIN1 Achchuthan Shanmugasundram Mode of inheritance for gene: CAPRIN1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v5.8 CAPRIN1 Achchuthan Shanmugasundram Publications for gene: CAPRIN1 were set to 23849776; 35979925; 36136249
Intellectual disability - microarray and sequencing v5.8 CAPRIN1 Achchuthan Shanmugasundram Publications for gene: CAPRIN1 were set to 23849776; 35979925; 36136249
Intellectual disability - microarray and sequencing v5.8 CAPRIN1 Achchuthan Shanmugasundram Publications for gene: CAPRIN1 were set to 23849776; 35979925; 36136249
Intellectual disability - microarray and sequencing v5.8 CAPRIN1 Achchuthan Shanmugasundram Deleted their comment
Intellectual disability - microarray and sequencing v5.8 CAPRIN1 Achchuthan Shanmugasundram Deleted their comment
Intellectual disability - microarray and sequencing v5.8 CAPRIN1 Achchuthan Shanmugasundram Publications for gene: CAPRIN1 were set to 23849776; 35979925; 36136249
Intellectual disability - microarray and sequencing v5.7 CAPRIN1 Achchuthan Shanmugasundram Deleted their comment
Intellectual disability - microarray and sequencing v5.7 CAPRIN1 Achchuthan Shanmugasundram Publications for gene: CAPRIN1 were set to 23849776; 35979925; 36136249
Intellectual disability - microarray and sequencing v5.7 CAPRIN1 Achchuthan Shanmugasundram Publications for gene: CAPRIN1 were set to 23849776
Intellectual disability - microarray and sequencing v5.6 CAPRIN1 Achchuthan Shanmugasundram Classified gene: CAPRIN1 as Amber List (moderate evidence)
Intellectual disability - microarray and sequencing v5.6 CAPRIN1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As indicated by the previous reviewers, there is sufficient evidence (>10 unrelated cases) for this gene to be promoted to GREEN at the next major review.

However, this gene has not yet been associated with relevant phenotypes in OMIM, but it has been reported in Gene2Phenotype with 'moderate' rating.
Intellectual disability - microarray and sequencing v5.6 CAPRIN1 Achchuthan Shanmugasundram Gene: caprin1 has been classified as Amber List (Moderate Evidence).
Intellectual disability - microarray and sequencing v5.6 CAPRIN1 Achchuthan Shanmugasundram Classified gene: CAPRIN1 as Amber List (moderate evidence)
Intellectual disability - microarray and sequencing v5.6 CAPRIN1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As indicated by the previous reviewers, there is sufficient evidence (>10 unrelated cases) for this gene to be promoted to GREEN at the next major review.

However, this gene has not yet been associated with relevant phenotypes in OMIM, but it has been reported in Gene2Phenotype with 'moderate' rating.
Intellectual disability - microarray and sequencing v5.6 CAPRIN1 Achchuthan Shanmugasundram Gene: caprin1 has been classified as Amber List (Moderate Evidence).
Intellectual disability - microarray and sequencing v5.6 CAPRIN1 Achchuthan Shanmugasundram Tag Q1_23_promote_green tag was added to gene: CAPRIN1.
Intellectual disability - microarray and sequencing v5.6 CAPRIN1 Achchuthan Shanmugasundram Classified gene: CAPRIN1 as Amber List (moderate evidence)
Intellectual disability - microarray and sequencing v5.6 CAPRIN1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As indicated by the previous reviewers, there is sufficient evidence (>10 unrelated cases) for this gene to be promoted to GREEN at the next major review.

However, this gene has not yet been associated with relevant phenotypes in OMIM, but it has been reported in Gene2Phenotype with 'moderate' rating.
Intellectual disability - microarray and sequencing v5.6 CAPRIN1 Achchuthan Shanmugasundram Gene: caprin1 has been classified as Amber List (Moderate Evidence).
Intellectual disability - microarray and sequencing v5.6 CAPRIN1 Achchuthan Shanmugasundram Classified gene: CAPRIN1 as Amber List (moderate evidence)
Intellectual disability - microarray and sequencing v5.6 CAPRIN1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As indicated by the previous reviewers, there is sufficient evidence (>10 unrelated cases) for this gene to be promoted to GREEN at the next major review.

However, this gene has not yet been associated with relevant phenotypes in OMIM, but it has been reported in Gene2Phenotype with 'moderate' rating.
Intellectual disability - microarray and sequencing v5.6 CAPRIN1 Achchuthan Shanmugasundram Gene: caprin1 has been classified as Amber List (Moderate Evidence).
Intellectual disability - microarray and sequencing v4.13 CAPRIN1 Dmitrijs Rots reviewed gene: CAPRIN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 36136249; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.1701 CAPRIN1 Konstantinos Varvagiannis reviewed gene: CAPRIN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 35979925, 35977029, 28135719, 31398340, https://doi.org/10.1101/2021.12.20.21267194; Phenotypes: Global developmental delay, Delayed speech and language development, Intellectual disability, Autistic behavior, Seizures; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v3.1701 UBAP2L Konstantinos Varvagiannis gene: UBAP2L was added
gene: UBAP2L was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: UBAP2L was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: UBAP2L were set to 35977029
Phenotypes for gene: UBAP2L were set to Delayed speech and language development; Motor delay; Intellectual disability; Autistic behavior; Seizures; Microcephaly; Abnormality of head or neck; Short stature; Abnormality of the skeletal system
Penetrance for gene: UBAP2L were set to unknown
Review for gene: UBAP2L was set to GREEN
Added comment: Based on Jia et al (2022 - PMID: 35977029) speech, motor delay as well as ID are observed in individuals harboring de novo pLoF variants in UBAP2L. The gene encodes a regulator of the stress granule (SG) assembly. Extensive evidence is provided on the effect of variants as well as the role of UBAP2L and other genes for components and/or regulation of SG in pathogenesis of NDDs. Among others a Ubap2l htz deletion mouse model (behavioral and cognitive impairment, abnormal cortical development due to impaired SG assembly, etc). Data from 26 previous studies, aggregating 40,853 probands with NDDs (mostly DD/ID, also ASD) suggest enrichment for DNMs in UBAP2L or other genes previously known and further shown to be important for SG formation (incl. G3BP1/G3BP2, CAPRIN1).

Details provided below.

Not associated with any phenotype in OMIM, G2P or SysNDD.

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Jia et al (2022 - PMID: 35977029) describe 12 affected individuals with heterozygous de novo pLoF variants in UBAP2L.

Phenotype: Features included hypotonia, speech (11/11) and motor delay (8/12), ID (8/10 with formal evaluation), variable behavioral concerns (ADHD 5/11, ASD in 4/10, etc). Seizures were reported in 7/12 with 3/10 having a formal diagnosis of epilepsy. Few had microcephaly (3/10). Facial dysmorphisms were common (9/9) and included abnormal palpebral fissures, deep prominent concha, high broad forehead, hypertelorism, thin upper lip and mild synophrys (each in 4 or less individuals). Short stature or skeletal alterations were described in some (4/10 each).

Role of the gene: UBAP2L encodes an essential regulator of stress granule assembly. Stress granules are membraneless cytoplasmic compartments in eukaryotic cells, induced upon a variety of stressors and playing a role in regulation of gene expression.

Variants identified : 9 nonsense/frameshift UBAP2L variants and 3 splicing ones were reported, in all cases as de novo events, upon trio/quad exome sequencing. All were absent from gnomAD. There were no other causative variants.

Variant effect/studies (NM_014847.4 / NP_055662.3) :
- Minigene assays revealed that the 3 splice variants all resulted in out-of-frame exon skipping.
- In patient fibroblasts one of these splice variants was demonstrated to result to reduced protein levels.
- 8 of the 9 nonsense/frameshift variants were predicted to result to NMD.
- 1 nonsense variant (c.88C>T/p.Q30*) was shown to result to decreased protein expression in patient fibroblasts, with detection of the protein using an antibody for the C terminus but not the N terminus. Protein N-terminal sequencing confirmed that the protein lacked the N terminus, with utilization of an alternative start site (11 codons downstream).
- Generation of HeLa UBAP2L KO cell lines resulted in significant reduction of SG numbers which was also the case for 4 variants studied, under stress conditions.
- The protein has a DUF domain (aa 495-526) known to mediate interaction of UBAP2L with G3BP1 (a stress granule marker) with deletions of this domain leading to shuttling of UBAP2L from the cytoplasm to the nucleus. Truncating variants upstream of the DUF domain were shown to result in nuclear localization.

Mouse model :
- The authors generated Ubap2l KO model with hmz deletion of Ubap2l resulting in a lethal phenotype (2.6% survived) and htz deletion leading to behavioral issues (low preference for social novelty, anxious-like behaviors) and cognitive impairment.
- Ubap2l haploinsufficiency resulted in abnormal cortical development and lamination with reduction of neural progenitor proliferation.
- Ubap2l deficiency was shown to impair SG assembly during cortical development both under physiological stress conditions or upon utilization of an oxidative stress inducer.

Additional evidence of UBAP2L and SG overall in pathogenesis of NDDs:
- Based on DNMs from 40,853 individuals with NDDs from 26 studies (9,228 with ASD, 31,625 with DD/ID) the authors demonstrate significant excess of DNM in 31 genes encoding SG components, regulators or both, the latter being the case for UBAP2L and 2 further genes (G3BP1 and G3BP2 - both with crucial roles in SG assembly).
- Excess dn splice-site (N=3) and missense (N=5) variants in G3BP1 were observed in the above cohort [c.95+1G>A, c.353+1G>T, c.539+1G>A / p.S208C, R320C, V366M].
- Excess dn missense (N=7) variants in G3BP2 were observed in the above cohort [p.R13W, D151N, E158K, L209P, E399D, K408E, R438C].
- Generation of G3BP1 or G3BP2 KO HeLa cell lines and immunofluorescence upon use of oxidative stress inducer revealed significant reduction of stress granules.
- Generation of HeLa cell lines for 5 G3BP1 mutants (R78C*, R132I*, S208C*, R320C*, V366M) and 7 G3BP2 mutants (p.R13W*, D151N*, E158K, L209P*, E399D, K408E, R438C) revealed that several (those in asterisk) resulted in significantly fewer SG formation under oxidative stress compared to WT while the subcellular distribution of the proteins under stress was identical to WT.
- Among the identified genes for SG enriched for DNMs, CAPRIN1 was implicated in previous publications as a NDD risk gene with 3 dn missense SNVs reported (p.I373K, p.Q446H, p.L484P). CAPRIN1 binding to G3BP1/2 has been shown to promote SG formation. Significant reduction of SG was observed in CAPRIN1 KO HeLa lines. p.I373K abolished interaction with G3BP1/2 and disrupted SG formation.
Sources: Literature