Early onset or syndromic epilepsy

Gene: CTNNA2

I don't know

Kept rating as Green based on Green post-Webex review from Helen Lord.

Created: 9 Sep 2019, 10:18 a.m. | Last Modified: 9 Sep 2019, 10:18 a.m.

Panel Version: 1.314

Review and rating collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene was added to the Genetic epilepsy syndromes panel after the initial panel was reviewed by West Midlands, Oxford and Wessex GLH: this gene was therefore reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy.

Created: 5 Sep 2019, 2:26 p.m. | Last Modified: 5 Sep 2019, 2:26 p.m.

Panel Version: 1.262

Green List (high evidence)

AR CDCBM9. Schaffer et al, 2018 (30013181) - 13 children from 3 unrelated consang middle Eastern families. Clinical details only available for 7 of them (5 deceased) - all 7 had intractable sezures. Each of the 3 families had a hom nonsense variant and segregated with disease in all 3 families. In vitro studies of patient-dervied nerve cells showed decreased neurite length and impaired neuronal migration compared to controls.

Created: 5 Sep 2019, 2:22 p.m. | Last Modified: 5 Sep 2019, 2:22 p.m.

Panel Version: 1.261

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

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, 5:02 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. The seizures tended to be myoclonic or atonic, and all patients had an abnormal EEG.

Created: 25 Feb 2019, 5 p.m.

Green List (high evidence)

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 green (or amber).
Sources: Literature

Created: 26 Dec 2018, 9:58 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Cortical dysplasia, complex, with other brain malformations 4, 618174

Publications

• 30013181