Early onset or syndromic epilepsy

Gene: SRPX2

Red List (low evidence)

I agree with the previous assessments that this is a refuted gene: variant in this gene originally identified in a 3-generation family. However, GRIN2A variant subsequently reported in same family plus original SRPX2 variant found to be at high pop frequency, now reclassified as benign; therefore no evidence currently for gene-disease association.

Created: 29 Feb 2020, 12:27 a.m. | Last Modified: 29 Feb 2020, 12:27 a.m.

Panel Version: 2.3

Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females

Phenotypes
Rolandic epilepsy, mental retardation, and speech dyspraxia, MIM# 300643

Publications

• 16497722
• 23933820
• 23871722

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

Red List (low evidence)

Contradictory evidence: One family has been reported- PMID 16497722 reported variation in the SRPX2 gene (N327S) as being responsible for rolandic seizures associated with oral and speech dyspraxia and mental retardation in a 3-generation French family. This was questioned by PMID 24995671.

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

Panel Version: 1.188

Mode of inheritance
Unknown

Phenotypes
?Rolandic epilepsy mental retardation and speech dyspraxia, 300643

Publications

• 23933820
• 23831613

Comment on list classification: Based evidence that the gene / disease associate has been refuted (PMID 24995671).

Created: 3 Jun 2020, 11:30 a.m. | Last Modified: 3 Jun 2020, 11:30 a.m.

Panel Version: 2.89

Comment when marking as ready: Associated with relevant phenotype in OMIM and as possible Gen2Phen gene.

Created: 27 Sep 2018, 3:33 p.m.

Comment on list classification: Copied from Louise Daugherty (Genomics England Curator) review of SRPX2 in the Intellectual disability panel https://panelapp.genomicsengland.co.uk/panels/285/gene/SRPX2/.
Two variants reported PMID:16497722, the involvement of variant rs121918363 has been refuted (PMID 24995671), however rs121918364 remains pathogenic in ClinVar, but has been reported in only one family (1 affected). In view of recent external review noting presence of previously reported pathogenic missense variants have since been found in the Exome Variant Server database and in high frequency in gnomAD and ExAC reference databases, this gene should be rated as Red, until further evidence to support gene-disease association to ID.

Created: 24 Jul 2018, 10:17 a.m.

Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 3 variants reported in at least 3 cases, although the evidence for the association for rs121918363 has been refuted (PMID 24995671). PMID 18718938 comments that previous studies have shown that uPAR(-/-) knock-out mice exhibited enhanced susceptibility to epileptic seizures and had brain cortical anomalies consistent with altered neuronal migration and maturation, all features that are reminiscent to the phenotypes associated with SRPX2 variants. PMID 18718938 goes on to shows that SRPX2 is a ligand for urokinase-type plasminogen activator (uPA) receptor. The reported variant p.Y72S led to a 5.8-fold gain-of-affinity of SRPX2 with uPAR. Two additional SRPX2 partners were identified: cysteine protease cathepsin B (CTSB) and metalloproteinase ADAMTS4, which are also components of the extracellular proteolysis machinery and CTSB is a well-known activator of uPA and therefore could be potentially relevant for these phenotypes. PMID 29663392 demonstrate expression of SRPX2 in hypothalamo-pituitary axis with SRPX2 protein also in the plasma and CSF.

Created: 15 May 2018, 12:58 p.m.

Red List (low evidence)

Red List (low evidence)

Red List (low evidence)

Red List (low evidence)