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Intellectual disability

Gene: CTNNA2

Green List (high evidence)

CTNNA2 (catenin alpha 2)
EnsemblGeneIds (GRCh38): ENSG00000066032
EnsemblGeneIds (GRCh37): ENSG00000066032
OMIM: 114025, Gene2Phenotype
CTNNA2 is in 3 panels

2 reviews

Louise Daugherty (Genomics England Curator)

Comment on list classification: New gene added by external expert and reviewed by curation team: appropriate phenotype, sufficient cases and external expert review all support gene-disease association and relevance to this panel to rate gene to Green.
Created: 25 Feb 2019, 4:57 p.m.
from Schaffer et al. (2018) PMID:(PMID: 30013181 reported 13 children from 3 unrelated consanguineous Middle Eastern families with CDCBM9. The patients presented at birth or in early infancy with profoundly delayed global development, hypotonia, and intractable seizures. Brain imaging showed pachygyria with dramatic cortical thickening up to 3 to 4 cm without an obvious posterior-anterior gradient or focal dysplasia.
Created: 25 Feb 2019, 4:56 p.m.

Konstantinos Varvagiannis (Other)

I don't know

Biallelic loss-of-function mutations in CTNNA2 cause cortical dysplasia, complex, with other brain malformations 9 (MIM 618174).
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Schaffer et al. (PMID: 30013181) report on 7 individuals from 3 unrelated consanguineous families. All individuals presented with profoundly impaired motor and cognitive development (severe ID in 6/7 for whom this information was available, all 6 from 2 families - a further individual from the 3rd family was non-ambulatory with absent speech at the age of 28 months), with acquired microcephaly and intractable seizures (7/7 - onset: 6m-3y - atonic/myoclonic/infantile spasms). Pachygyria without posterior-anterior gradient or focal dysplasias was common to all.

All affected individuals were homozygous for nonsense mutations, private to each family (3 different variants).

CTNNA2 encodes αN-catenin. It is expressed in human fetal brain, mainly in regions expressing migration markers DCX and TUJ1. Reduced migration was shown for iPSC-derived neural progenitor cells from an affected individual, compared to controls. The protein contains a putative actin-binding domain (ABD) at its C terminus. Several lines of evidence are provided that this domain is critical for the process of neuronal migration.
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CTNNA2 is included in the DD panel of G2P associated with disordered cortical neuronal migration (Disease confidence: probable / ID and seizures among the phenotypes assigned to this entry).

This gene is not commonly included in gene panels for intellectual disability.
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As a result CTNNA2 could be considered for inclusion in this panel as amber or possibly green.
Sources: Literature
Created: 26 Dec 2018, 9:56 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Cortical dysplasia, complex, with other brain malformations 9 (MIM 618174)

Publications

Details

Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
Phenotypes
  • Cortical dysplasia, complex, with other brain malformations 9, 618174
  • intellectual disability
  • global developmental delay
OMIM
114025
Clinvar variants
Variants in CTNNA2
Penetrance
Complete
Publications
Panels with this gene

History Filter Activity

25 Feb 2019, Gel status: 3

Entity classified by Genomics England curator

Louise Daugherty (Genomics England Curator)

Gene: ctnna2 has been classified as Green List (High Evidence).

25 Feb 2019, Gel status: 0

Set Phenotypes

Louise Daugherty (Genomics England Curator)

Phenotypes for gene: CTNNA2 were changed from Cortical dysplasia, complex, with other brain malformations 9, 618174 to Cortical dysplasia, complex, with other brain malformations 9, 618174; intellectual disability; global developmental delay

25 Feb 2019, Gel status: 0

Set Phenotypes

Louise Daugherty (Genomics England Curator)

Phenotypes for gene: CTNNA2 were changed from Cortical dysplasia, complex, with other brain malformations 9 (MIM 618174) to Cortical dysplasia, complex, with other brain malformations 9, 618174

26 Dec 2018, Gel status: 0

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

Konstantinos Varvagiannis (Other)

gene: CTNNA2 was added gene: CTNNA2 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: CTNNA2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CTNNA2 were set to 30013181 Phenotypes for gene: CTNNA2 were set to Cortical dysplasia, complex, with other brain malformations 9 (MIM 618174) Penetrance for gene: CTNNA2 were set to Complete Review for gene: CTNNA2 was set to AMBER