Early onset or syndromic epilepsy

Gene: MAGI2

Red List (low evidence)

The rating of this gene has been updated to Red following NHS Genomic Medicine Service approval.

Created: 11 Oct 2023, noon | Last Modified: 11 Oct 2023, noon

Panel Version: 4.110

Red List (low evidence)

In addition, note the gene-disease relationship to epilepsy has been assessed as DISPUTED by ClinGen.

Created: 24 Aug 2023, 6:33 a.m. | Last Modified: 24 Aug 2023, 6:33 a.m.

Panel Version: 4.87

Bi-allelic variants in this gene are associated with nephrotic syndrome. I cannot see seizures reported in these patients, and the Magi2-null mice have a renal phenotype.

The link to seizures as far as I can tell comes from the report of a recurrent heterozygous intragenic deletion in 2008 by Marshall et al 18565486 (as well as bigger deletions but these contain multiple genes). I am concerned there have been no reports since. This recent paper refers to the evidence re MAGI2 as contradictory and reports no increased variants in this gene in cases v controls. All pathogenic variants in ClinVar seem to relate to the nephrotic phenotype.

Created: 24 Jan 2020, 7:26 a.m. | Last Modified: 24 Jan 2020, 7:26 a.m.

Panel Version: 2.0

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Epilepsy

Publications

• 31056551

Green List (high evidence)

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

I don't know

Comment on mode of inheritance: Updated Mode of Inheritance from 'BOTH monoallelic and biallelic' to 'BIALLELIC' based on Post-Webex review by Helen Lord (AD inheritance was based on deletions including the MAGI2 gene).

Created: 7 Sep 2019, 11:36 a.m. | Last Modified: 7 Sep 2019, 11:36 a.m.

Panel Version: 1.281

Mode of inheritance 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 is part of a subset where the mode of inheritance was re-reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy. No rating was included in the review, so I have uploaded a Green rating to match the original West Midlands, Oxford and Wessex GLH rating.

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

Panel Version: 1.262

Comment on mode of inheritance: OMIM lists AR inheritance for 'Nephrotic syndrome, type 15' (MIM:617609). Gene2Phenotype lists 'monoallelic' inheritance for EARLY ONSET EPILEPTIC ENCEPHALOPATHY based on PMID:18565486 which examines deletions spanning MAGI2.

Created: 13 Aug 2019, 1:04 p.m. | Last Modified: 7 Sep 2019, 11:35 a.m.

Panel Version: 1.280

Review and rating collated by Tracy Lester (Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust, 2019_02_06) on behalf of Wessex and West Midlands GLH for GMS Neurology specialist test group, for Clinical Indication R59 'Early onset or syndromic epilepsy'. Review contributors: John Taylor and Helen Lord. Suggested gene rating: Green.

Created: 6 Aug 2019, 8:38 p.m. | Last Modified: 6 Aug 2019, 8:38 p.m.

Panel Version: 1.189

Green List (high evidence)

Seizures can be part of a larger 7q11.23-q21.11 deletion and may be part of Nephrotic syndrome. AR nephrotic syndrome type 15 (NPHS15) - on pubmed. In OMIM Marshall et al 2008 - infantile spasms (IS) most severe and common form of epilepsy in early life - found 7q11.23-q21.1 interstital deletions locus for IS. The breakpoints delineate a 500kb interval within the MAG12 gene (1.4Mb in size) that is hemizygously disrupted in 15/16 participants with IS or childhood epilepsy but remains intact in 11 of 12 patients with no seizure history.

Created: 6 Aug 2019, 8:31 p.m. | Last Modified: 6 Aug 2019, 8:31 p.m.

Panel Version: 1.188

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Nephrotic syndrome, type 15, 617609

Publications

• 27932480
• 18565486

Red List (low evidence)

Sarah Leigh commented on gene: MAGI2: Clingen refuted association with epilepsy https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7d622b88-9c77-47f8-93b1-808517da0cff-2023-10-17T190000.000Z?page=1&size=25&search=

Created: 28 Nov 2023, 2:37 p.m. | Last Modified: 28 Nov 2023, 2:37 p.m.

Panel Version: 4.133

Comment on list classification: There is not enough evidence for this gene to be rated GREEN on this panel.

Created: 23 Feb 2023, 4:28 p.m. | Last Modified: 23 Feb 2023, 4:29 p.m.

Panel Version: 3.70

The association of MAGI2 deletions with epilepsy is disputed according to the ClinGen Epilepsy Gene Curation Expert Panel report (https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7d622b88-9c77-47f8-93b1-808517da0cff-2018-06-19T160000.000Z?page=1&size=25&search= ). This expert panel outlines that although some of the deletions seen in epilepsy patients encompases MAGI2, other do not, suggesting the presence of another locus responsible for the epilepsy. Furthermore, no single-gene deletions or single nucleotide variants have been reported in MAGI2 in individuals with epilepsy.

Created: 23 Feb 2023, 4:27 p.m. | Last Modified: 23 Feb 2023, 4:27 p.m.

Panel Version: 3.69

Comment on mode of inheritance:
OMIM reports homozygous and compound heterozygous variants in Nephrotic syndrome, type 15 617609 (PMID 27932480), whereas Gen2Phen reports hemizygous microdeletions of a 1.5 Mb region of chromosome 7q11.23 encompassing the MAGI2 gene (PMID 18565486).

Created: 7 Nov 2018, 3:29 p.m.

Comment on phenotypes: Biallelic frame shifting truncating variants associated with Nephrotic syndrome, type 15 617609

Created: 26 Sep 2018, 3:42 p.m.

Green List (high evidence)

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

Phenotypes
Infantile Spasms

Publications

• Marshall et al (2008) Am J Hum Genet 83: 106_111,

Variants in this GENE are reported as part of current diagnostic practice

Green List (high evidence)

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

Phenotypes
Infantile Spasms

Publications

• Marshall et al (2008) Am J Hum Genet 83: 106_111,

Variants in this GENE are reported as part of current diagnostic practice

Green List (high evidence)

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

Phenotypes
Infantile Spasms

Publications

• Marshall et al (2008) Am J Hum Genet 83: 106_111,

Variants in this GENE are reported as part of current diagnostic practice

Green List (high evidence)

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

Phenotypes
Infantile Spasms

Publications

• Marshall et al (2008) Am J Hum Genet 83: 106 111,

Variants in this GENE are reported as part of current diagnostic practice

Red List (low evidence)

Insufficient evidence for diagnostic use to date - only large deletions reported

Created: 4 Feb 2016, 10:49 p.m.

Publications

• 18565486

Comment on list classification: Reviews later agreed by email that the gene should be red due to lack of evidence beyond multigenic deletions. It is a possible DD gene, and so not strong evidence.

Created: 29 Jan 2016, 11:36 a.m.

The 4 reviewers decided that this gene should actually be rated red, due to lack of evidence beyond multigenic deletions.

Created: 23 Nov 2015, 5:40 p.m.