Early onset or syndromic epilepsy

Gene: SIX3

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: Amber.

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

Panel Version: 1.189

I don't know

Some evidence. This gene appears to be associated with holoprosencephaly where seizures can ben a feature.

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
Holoprosencephaly 2, 157170; Schizencephaly, 269160

Publications

• 15523651
• 21940735

Comment on publications: PMID 18791198 discusses incomplete penetrance.

Created: 11 Dec 2018, 10:09 a.m.

Comment when marking as ready: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene, however, seizures have only been reported in two cases of SIX3 variant carriers. In PMID: 20157829, patient 4 had a seizure but certain epilepsy characteristic activity in the subsequent electroencephalogram (EEG) was not met. The variants (c.618C>A + c.621G>A; p.Gly206Gly + p.Glu207Glu) were found in this case. The synonymous variant c.621G>A, was not predicted to effect splicing, although it was was predicted to create a consensus sequence motif for an additional SF2/ASF (score 2.71378; threshold 1.956) as well as SRp40 (score 2.98263; threshold 2.67) splice enhancer. Both consensus sequences are recognized by the human proteins SF2/ASF or SRp40, respectively, and are important for the recognition and utilization of regular as well as alternative splice sites (Wang et al. 2005), and these may be considered to be pathogenic.
In PMID 28670735 a deletion of SIX3 gene was reported in a case with seizures, but incomplete penetrance has been suggested. The publication PMID 19346217 mentions seizures as a clinical feature, however, precise details about cases cannot be found as the supplementary material tables 1a & b are no longer available (the authors have been contacted, December 2018).

Created: 11 Dec 2018, 10 a.m.

Comment on publications: Variants reported in following articles in either Holoprosencephaly 2 157170 or Schizencephaly 269160 however, seizures are not mentioned in the patients being reported PMID: 19353631, 17001667, 10369266, 15523651.

Created: 4 Dec 2018, 5:09 p.m.

Comment on phenotypes: Schizencephaly 269160

Created: 4 Dec 2018, 12:14 p.m.

Green List (high evidence)

Seizures are part of the phenotype of this brain development disorder.

Created: 21 Aug 2018, 9:30 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Holoprosencephaly 2, MIM#157170

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