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Intellectual disability

Gene: SRPX2

Red List (low evidence)

SRPX2 (sushi repeat containing protein, X-linked 2)
EnsemblGeneIds (GRCh38): ENSG00000102359
EnsemblGeneIds (GRCh37): ENSG00000102359
OMIM: 300642, Gene2Phenotype
SRPX2 is in 4 panels

5 reviews

Louise Daugherty (Genomics England Curator)

Red List (low evidence)

Comment on list classification: demoted from Amber to Red.
Created: 18 Jul 2018, 4:33 p.m.
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: 18 Jul 2018, 4:23 p.m.
Comment on publications: added missing publications suggested by external and internal reviews.

Created: 18 Jul 2018, 4:06 p.m.

Andrew Douglas (University of Southampton / Wessex Clinical Genetics Service)

I don't know

The pathogenicity of SRPX2 variants in X-linked intellectual disability has been challenged due the relatively high frequency of such variants in databases such as EVS (see PMID 23871722). Missense variants previously reported as pathogenic have since been found in the EVS database. A large number of missense variants are present in ExAC and gnomAD. In ExAC, 124 missense variants are observed compared with 123.1 expected, leading to a missense constraint score of z = -0.04. Additionally, a number of loss-of-function mutations are present in gnomAD, including one homozygous frameshift mutation.
Created: 15 Jun 2018, 12:47 p.m.

Mode of inheritance
Unknown

Publications

Mode of pathogenicity
Other

Sarah Leigh (Genomics England Curator)

I don't know

Comment on list classification: Demoted to amber after consultation with Helen Britain (Clinical Fellow, Genomics England), based on the evidence for involvement of variant rs121918363 has been refuted (PMID 24995671).
Created: 7 Jun 2018, 9:35 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, 12:11 p.m.

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

Phenotypes
?Rolandic epilepsy, mental retardation, and speech dyspraxia 300643

Publications

Caroline Wright (Sanger)

Green List (high evidence)

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

Phenotypes
ROLANDIC EPILEPSY WITH SPEECH DYSPRAXIA AND MENTAL RETARDATION X-LINKED (RESDX)

Publications

Lu Raymond (university of cambridge )

Green List (high evidence)

Details

Mode of Inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females
Sources
  • Victorian Clinical Genetics Services
  • Expert Review Red
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Rolandic epilepsy, mental retardation, and speech dyspraxia, 300643 -3
  • ROLANDIC EPILEPSY WITH SPEECH DYSPRAXIA AND MENTAL RETARDATION X-LINKED (RESDX)
OMIM
300642
Clinvar variants
Variants in SRPX2
Penetrance
Complete
Publications
Panels with this gene

History Filter Activity

29 Sep 2018, Gel status: 1

Added New Source

Louise Daugherty (Genomics England Curator)

Source Victorian Clinical Genetics Services was added to SRPX2.

18 Jul 2018, Gel status: 1

Entity classified by Genomics England curator

Louise Daugherty (Genomics England Curator)

Gene: srpx2 has been classified as Red List (Low Evidence).

18 Jul 2018, Gel status: 2

Set publications

Louise Daugherty (Genomics England Curator)

Publications for gene: SRPX2 were set to 24179158; 18718938; 29663392; 24995671; 16497722; 23871722; 26350204

18 Jul 2018, Gel status: 2

Set publications

Louise Daugherty (Genomics England Curator)

Publications for gene: SRPX2 were set to 24179158; 18718938; 29663392; 24995671; 16497722; 23871722

7 Jun 2018, Gel status: 2

Entity classified by Genomics England curator

Sarah Leigh (Genomics England Curator)

Gene: srpx2 has been classified as Amber List (Moderate Evidence).

7 Jun 2018, Gel status: 2

Entity classified by Genomics England curator

Sarah Leigh (Genomics England Curator)

Gene: srpx2 has been classified as Amber List (Moderate Evidence).

7 Jun 2018, Gel status: 2

Entity classified by Genomics England curator

Sarah Leigh (Genomics England Curator)

Gene: srpx2 has been classified as Amber List (Moderate Evidence).

12 Mar 2018, Gel status: 3

Panel promoted to version 2.0

Ellen McDonagh (Genomics England Curator)

12.03.2018: Due to major updates completed (Phase 1, 2 and 3), this panel was promoted to Version 2 in order to reflect the major updates since November 2017 which have resulted in reviews for 836 genes added by Genomics England Curators and the Clinical Team, 130 new Green genes added to the interpretation pipeline (from 751 to 881 Green genes), and the gene total has increased from 1879 to 1927.

13 Nov 2015, Gel status: 4

gel status update

GEL ()

The Gel status was updated for this whole panel

13 Nov 2015, Gel status: 4

gel status update

GEL ()

The Gel status was updated for this whole panel

13 Nov 2015, Gel status: 1

Set Mode of Inheritance, Added New Source

Ellen McDonagh (Genomics England Curator)

SRPX2 was added to Intellectual disabilitypanel. Source: Expert Review Green Model of inheritance for gene SRPX2 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females

24 Jun 2015, Gel status: 1

Added New Source

Ellen McDonagh (Genomics England Curator)

SRPX2 was added to Intellectual disabilitypanel. Sources: Radboud University Medical Center, Nijmegen