Intellectual disability - microarray and sequencing
Gene: SRPX2 Red List (low evidence)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.
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
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
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
Green List (high evidence)
Phenotypes for gene: SRPX2 were changed from Rolandic epilepsy, mental retardation, and speech dyspraxia, 300643 -3; ROLANDIC EPILEPSY WITH SPEECH DYSPRAXIA AND MENTAL RETARDATION X-LINKED (RESDX) to ?Rolandic epilepsy, impaired intellectual development, and speech dyspraxia, OMIM:300643
Source Victorian Clinical Genetics Services was added to SRPX2.
Gene: srpx2 has been classified as Red List (Low Evidence).
Publications for gene: SRPX2 were set to 24179158; 18718938; 29663392; 24995671; 16497722; 23871722; 26350204
Publications for gene: SRPX2 were set to 24179158; 18718938; 29663392; 24995671; 16497722; 23871722
Gene: srpx2 has been classified as Amber List (Moderate Evidence).
Gene: srpx2 has been classified as Amber List (Moderate Evidence).
Gene: srpx2 has been classified as Amber List (Moderate Evidence).
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.
The Gel status was updated for this whole panel
The Gel status was updated for this whole panel
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
SRPX2 was added to Intellectual disabilitypanel. Sources: Radboud University Medical Center, Nijmegen
If promoting or demoting a gene, please provide comments to justify a decision to move it.
Genes included in a Genomics England gene panel for a rare disease category (green list) should fit the criteria A-E outlined below.
These guidelines were developed as a combination of the ClinGen DEFINITIVE evidence for a causal role of the gene in the disease(a), and the Developmental Disorder Genotype-Phenotype (DDG2P) CONFIRMED DD Gene evidence level(b) (please see the original references provided below for full details). These help provide a guideline for expert reviewers when assessing whether a gene should be on the green or the red list of a panel.
A. There are plausible disease-causing mutations(i) within, affecting or encompassing an interpretable functional region(ii) of this gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
B. There are plausible disease-causing mutations(i) within, affecting or encompassing cis-regulatory elements convincingly affecting the expression of a single gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
C. As definitions A or B but in 2 or 3 unrelated cases/families with the phenotype, with the addition of convincing bioinformatic or functional evidence of causation e.g. known inborn error of metabolism with mutation in orthologous gene which is known to have the relevant deficient enzymatic activity in other species; existence of an animal model which recapitulates the human phenotype.
AND
D. Evidence indicates that disease-causing mutations follow a Mendelian pattern of causation appropriate for reporting in a diagnostic setting(iv).
AND
E. No convincing evidence exists or has emerged that contradicts the role of the gene in the specified phenotype.
(i)Plausible disease-causing mutations: Recurrent de novo mutations convincingly affecting gene function. Rare, fully-penetrant mutations - relevant genotype never, or very rarely, seen in controls. (ii) Interpretable functional region: ORF in protein coding genes miRNA stem or loop. (iii) Phenotype: the rare disease category, as described in the eligibility statement. (iv) Intermediate penetrance genes should not be included.
It’s assumed that loss-of-function variants in this gene can cause the disease/phenotype unless an exception to this rule is known. We would like to collect information regarding exceptions. An example exception is the PCSK9 gene, where loss-of-function variants are not relevant for a hypercholesterolemia phenotype as they are associated with increased LDL-cholesterol uptake via LDLR (PMID: 25911073).
If a curated set of known-pathogenic variants is available for this gene-phenotype, please contact us at [email protected]
We classify loss-of-function variants as those with the following Sequence Ontology (SO) terms:
Term descriptions can be found on the PanelApp homepage and Ensembl.
If you are submitting this evaluation on behalf of a clinical laboratory please indicate whether you report variants in this gene as part of your current diagnostic practice by checking the box
Standardised terms were used to represent the gene-disease mode of inheritance, and were mapped to commonly used terms from the different sources. Below each of the terms is described, along with the equivalent commonly-used terms.
A variant on one allele of this gene can cause the disease, and imprinting has not been implicated.
A variant on the paternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on the maternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on one allele of this gene can cause the disease. This is the default used for autosomal dominant mode of inheritance where no knowledge of the imprinting status of the gene required to cause the disease is known. Mapped to the following commonly used terms from different sources: autosomal dominant, dominant, AD, DOMINANT.
A variant on both alleles of this gene is required to cause the disease. Mapped to the following commonly used terms from different sources: autosomal recessive, recessive, AR, RECESSIVE.
The disease can be caused by a variant on one or both alleles of this gene. Mapped to the following commonly used terms from different sources: autosomal recessive or autosomal dominant, recessive or dominant, AR/AD, AD/AR, DOMINANT/RECESSIVE, RECESSIVE/DOMINANT.
A variant on one allele of this gene can cause the disease, however a variant on both alleles of this gene can result in a more severe form of the disease/phenotype.
A variant in this gene can cause the disease in males as they have one X-chromosome allele, whereas a variant on both X-chromosome alleles is required to cause the disease in females. Mapped to the following commonly used term from different sources: X-linked recessive.
A variant in this gene can cause the disease in males as they have one X-chromosome allele. A variant on one allele of this gene may also cause the disease in females, though the disease/phenotype may be less severe and may have a later-onset than is seen in males. X-linked inactivation and mosaicism in different tissues complicate whether a female presents with the disease, and can change over their lifetime. This term is the default setting used for X-linked genes, where it is not known definitately whether females require a variant on each allele of this gene in order to be affected. Mapped to the following commonly used terms from different sources: X-linked dominant, x-linked, X-LINKED, X-linked.
The gene is in the mitochondrial genome and variants within this can cause this disease, maternally inherited. Mapped to the following commonly used term from different sources: Mitochondrial.
Mapped to the following commonly used terms from different sources: Unknown, NA, information not provided.
For example, if the mode of inheritance is digenic, please indicate this in the comments and which other gene is involved.