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Intellectual disability

Gene: CTNND2

Amber List (moderate evidence)
CTNND2 (catenin delta 2)
EnsemblGeneIds (GRCh38): ENSG00000169862
EnsemblGeneIds (GRCh37): ENSG00000169862
OMIM: 604275, Gene2Phenotype
CTNND2 is in 3 panels

1 review

Arina Puzriakova (Genomics England Curator)

Comment on list classification: Upgraded from Red to Amber following discussion with the Genomics England clinical team.

There are multiple papers and cases in decipher of patients with intragenic deletions in CTNND2; however, almost all have mild or borderline ID (often isolated). Some variants are inherited from parents with mildly low/normal IQ. Deletion size is thought to correlate with severity of mental impairment.

Rationale for upgrading to Amber, is that smaller intragenic deletions in CTNND2 would not be picked up the region that encompasses this gene (ISCA-37390-Loss) as they fall below the 60% overlap threshold. However, mild ID is not within the scope of the panel and the only cases with SNVs have a slightly different phenotype (myoclonus, but they were missense and could be acting in a different mechanism).

This gene has recently been signed off for GMS use via the DDG2P panel (v4.8) meaning it will be applied to any patients referred under the R27 Paediatric disorders super panel.
Created: 6 Sep 2024, 9:34 a.m. | Last Modified: 6 Sep 2024, 9:34 a.m.
Panel Version: 7.23
This gene is not associated with any phenotype in OMIM but is linked to 'CTNND2-related neurodevelopmental disorder' in Gene2Phenotype with a 'strong' disease confidence category.

CTNND2 maps to a critical region on chromosome 5p15.2 that is deleted in cri-du-chat syndrome. Both structural and single nucleotide variants have also been associated with various other neurodevelopmental phenotypes including ASD, ADHD, depression, cerebral palsy, anxiety, epilepsy, and schizophrenia.
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Specifically relating to ID:

PMID:10673328 (2000), PMID: 24677774 (2014) - breakpoints in patients with 5p terminal deletions have been characterised with respect to symptom severity and the deletion size/location. This revealed a correlation between hemizygous loss of CTNND2, in particular, and severe mental impairment.

PMID: 25839933 (2015) - Two unrelated individuals with intragenic CTNND2 deletions and isolated mild intellectual disability. In one case the variant was maternally inherited, where the mother also had delayed psychomotor development milestones, but otherwise no ID.

PMID: 29127138 (2017) - Three patients in one family with familial cortical myoclonic tremor and epilepsy were found to harbour with a missense variant (p.Glu1044Lys) in the CTNND2 gene that co-segregated with the phenotype.

PMID: 25473103 (2015) - Intragenic deletion affecting exons 12–18 of the CTNND2 gene identified in a patient with pronounced learning disabilities, dysmorphic features, joint laxity in the fingers and a marfanoid habitus.

PMID: 25106414 (2014) - Patient with a de novo 113 kb out-of-frame deletion encompassing exons 4–7 of CTNND2, presenting clinically with borderline ID and mild facial dysmorphic features.
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Mouse studies:

PMID: 15380068 (2004) - CTNND2 null mice display severe deficits in learning, memory, and synaptic plasticity.

PMID:19914181 (2009) - CTNND2 null mice show normal neuronal development and synaptic ultrastructure. However, after 5-weeks of age mutant mice experience progressive dendritic retraction, a reduction in spine density and stability, and concomitant reductions in cortical responsiveness, indicating that CTNND2 is required to maintain dendrites and dendritic spines in mature cortex, but not to establish these structures during development.
Created: 26 Feb 2024, 4:37 p.m. | Last Modified: 26 Feb 2024, 4:37 p.m.
Panel Version: 5.465
Created: 26 Feb 2024, 4:37 p.m.
Last Modified: 26 Feb 2024, 4:37 p.m.
Panel version: 5.465

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review Amber
  • Victorian Clinical Genetics Services
Phenotypes
  • CTNND2-related neurodevelopmental disorder
OMIM
604275
Clinvar variants
Variants in CTNND2
Penetrance
None
Panels with this gene

History Filter Activity

6 Sep 2024, Gel status: 2

Entity classified by Genomics England curator

Arina Puzriakova (Genomics England Curator)

Gene: ctnnd2 has been classified as Amber List (Moderate Evidence).

26 Feb 2024, Gel status: 1

Set Phenotypes

Arina Puzriakova (Genomics England Curator)

Phenotypes for gene: CTNND2 were changed from to CTNND2-related neurodevelopmental disorder

26 Feb 2024, Gel status: 1

Set mode of inheritance

Arina Puzriakova (Genomics England Curator)

Mode of inheritance for gene: CTNND2 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

28 Sep 2018, Gel status: 1

Created, Added New Source, Set mode of inheritance

Louise Daugherty (Genomics England Curator)

gene: CTNND2 was added gene: CTNND2 was added to Intellectual disability. Sources: Victorian Clinical Genetics Services Mode of inheritance for gene: CTNND2 was set to