Early onset or syndromic epilepsy

Gene: MAST1

Red List (low evidence)

Very few disease-associated variants have been reported.

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

Panel Version: 1.188

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Mega-corpus-callosum syndrome with cerebellar hypoplasia and cortical malformations, 618273

Comment when marking as ready: Based on reviewers' comments.

Created: 11 Dec 2018, 1:24 p.m.

I don't know

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: Alison Callaway and John Taylor. Suggested gene rating: Red.

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

Panel Version: 1.189

Added 'watchlist' tag.

Created: 11 Dec 2018, 11:10 a.m.

Comment on list classification: Updated rating from Grey to Amber. 6 individuals in PMID:30449657 with MAST1 variants, and seizures in 2/6 patients. DDD participant DDD4K.02310 has a synonymous variant in RXRG and a missense variant in MAST (Supplementary material of PMID:28135719). 1 individual in PMID:23934111 (Epi4K encephalopathies) had seizures- listed as benign variant from Polyphen in the paper tables. The phenotype appears complex, and MAST1 is not yet linked to epilepsy in OMIM, and is not yet on the DD-G2P list. Therefore rated as Amber awaiting further confirmed cases from the literature or clinic.

Created: 11 Dec 2018, 11:10 a.m.

Green List (high evidence)

PMID: 30449657 reports on 6 unrelated individuals with de novo mutations in MAST1. All these 6 individuals were investigated for a strikingly similar phenotype of enlarged corpus callosum (CC), cerebellar hypoplasia, cortical malformation with associated DD/ID. Seizures were a feature in 2/6 (one further had EEG anomalies without clinical seizures).

Three of them harbored an in-frame deletion of 1 amino-acid (3 different indels reported - all in a specific domain) while 3 others had a missense variant (NM_014975.2:c.1549G>A or p.Gly517Ser).

Mast1 has embryonic expression in murine models with postnatal decrease. Similarly qPCR of human fetal brain cDNA demonstrated expression at 13 and 22 gestational weeks. A murine model for L278del recapitulated the brain (incl. CC) and cerebellar phenotype while Mast1 knockout mice do not present similar morphological defects. While Western blot in murine brain lysates demonstrated absence of Mast1 in knockout and reduction in the L278del, Mast1 transcript levels for L278del were similar to wildtype. Other Mast proteins (Mast1 & Mast2) were significantly reduced upon western blot while this was not reflected in their mRNA levels, suggesting a dominant-negative effect, at least for the L278del.

4 additional individuals with somewhat different phenotype consisting DD/ID and microcephaly/autism are described in the supplement. All 4 had de novo missense variants but did not display the CC-cerebral and cerebellar anomalies. Four different (additional to Gly517Ser) missense SNVs were observed.

Several additional individuals exist in the denovo-db (among others DDD participant DDD4K.02310 published in 28135719, 25666757 - McMichael et al. commented in the article, 27479843, etc.). [http://denovo-db.gs.washington.edu/denovo-db/QueryVariantServlet?searchBy=Gene&target=Mast1]

Epilepsy was a feature in 4/10 individuals (with an additional one with EEG anomalies without clinical seizures). One further individual from PMID:23934111 (in denovo-db) had seizures.

As the authors comment (and as evident from the 6+4 reported patients) the related neurodevelopmental phenotype may be more complex.

MAST1 is not related to any phenotype in G2P, nor in OMIM.

As a result, this gene can be considered for inclusion in this panel as green (or amber).
Sources: Literature

Created: 9 Dec 2018, 11:34 a.m.

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

Phenotypes
Global developmental delay, Intellectual disability, Abnormality of the corpus callosum, Cerebellar hypoplasia, Abnormality of the cerebral cortex, Seizures; Global developmental delay, Intellectual disability, Microcephaly, Autism, Seizures

Publications

• 30449657
• 23934111