SRPX2

protein-coding

sushi repeat containing protein X-linked 2, the group of Sushi domain containing

Gene summary

This gene encodes a secreted protein that contains three sushi repeat motifs. The encoded protein may play a role in the development of speech and language centers in the brain. This protein may also be involved in angiogenesis. Mutations in this gene are the cause of bilateral perisylvian polymicrogyria, rolandic epilepsy, speech dyspraxia and cognitive disability. [provided by RefSeq, May 2010]

MANE transcript

NM_014467.3

Inheritance

XL, AD

ClinVar variants

P:2U:152B:54

Top phenotype

Rolandic epilepsy, intellectual developmental disorder, and speech dyspraxia, X-linked

gnomAD constraint

pLI —, LoF o/e 0.29

Max pathogenic AF

—

Genomic locus

chrX:100,644,195-100,675,788

External References & Databases

Ensembl (ENSG00000102359)

Transcript & Mutation Effects

hg38 • Region Span ~31.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

rolandic epilepsy, impaired intellectual development, and speech dyspraxia, X-linkedLIMITED

Inheritance Pattern: XL

Disease ID:MONDO:0010388

Submitter: Labcorp Genetics (formerly Invitae)

rolandic epilepsy-speech dyspraxia syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015587

Submitter: Orphanet

rolandic epilepsy, impaired intellectual development, and speech dyspraxia, X-linkedLIMITED

Inheritance Pattern: XL

Disease ID:MONDO:0010388

Submitter: PanelApp Australia

rolandic epilepsy, impaired intellectual development, and speech dyspraxia, X-linkedNO_KNOWN

Inheritance Pattern: XL

Disease ID:MONDO:0010388

Submitter: Ambry Genetics

epilepsyNO_KNOWN

Inheritance Pattern: XL

Disease ID:MONDO:0005027

Submitter: ClinGen

*SRPX2* was first reported in relation to epilepsy (primarily characterized as Rolandic epilepsy-speech dyspraxia syndrome but changed to epilepsy by the ClinGen Epilepsy GCEP, in 2021) in 2006 when 2 multiplex families were described in a single paper (PMID:16497722). This remained the sole *SRPX2* gene-disease relationship report until 2017 (PMID:28440294). Overall, three missense variants have been reported in humans to date (with one additional variant reported through a mouse model (PMID:24179158)). However, these variants do not have supportive functional evidence. *SRPX2* is not constrained for missense variants and at least one of the variants is present at a high frequency in the general population. While initial evidence (such as segregation and initial experiments) seemed to support pathogenicity in respect to epilepsy, subsequent evidence including mean allele frequency in gnomAD, a high dN/dS ratio, variable clinical presentations and the detection of another putative cause in one of the families (GRIN2A) (PMID:23933820) brings this gene disease relationship into question. Without significant supportive genetic evidence, a correlation to epilepsy and/or neurodevelopmental disorders is not supported. This gene-disease pair was originally evaluated by the ClinGen Epilepsy GCEP on July 8, 2018. It was reevaluated in October 2023. As a result of this reevaluation, the classification was changed from disputed to refuted due to lack of any additional supportive evidence. This updated classification was approved by the ClinGen Epilepsy GCEP on October 17th, 2023.

polymicrogyria, bilateral perisylvian, X-linkedLIMITED

Inheritance Pattern: XL

Disease ID:MONDO:0010314

Submitter: G2P

Clinical Genomic Database (CGD)

Rolandic epilepsy, intellectual developmental disorder, and speech dyspraxia, X-linkedXL

Manifestation: Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Comments: The evidence of variants as being related to disease causation has been questioned due to subsequent population-based studies

Refs: 16497722; 23871722; 24995671

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SRPX2 variants in ClinVar

8 Conditions Cataloged

Rolandic epilepsy, intellectual disability, and speech dyspraxia, X-linkedTotal: 90

not specifiedTotal: 85

not providedTotal: 74

SRPX2-related disorderTotal: 10

History of neurodevelopmental disorderTotal: 2

Genetic developmental and epileptic encephalopathyTotal: 1

EpilepsyTotal: 1

See casesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_014467.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			11 clinvar	30 clinvar	1 clinvar	42
missense		1 clinvar	120 clinvar	23 clinvar		144
nonsense	1 clinvar		4 clinvar			5
start loss						0
frameshift			3 clinvar			3
splice donor/acceptor (+/-2bp)			14 clinvar			14
Total	1	1	152	53	1	208

Highest pathogenic variant AF is 0.0000018211636

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 5 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_014467.3	RefSeq	NP_055282.1	10	MANE Select
ENST00000373004.5	Ensembl	ENSP00000362095.3	10	MANE Select
ENST00000638458.1	Ensembl	ENSP00000492168.1	7	Standard
ENST00000640282.1	Ensembl	ENSP00000491188.1	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Pregnane X Receptor pathway
Nuclear Receptors Meta-Pathway
Liver steatosis AOP

Biological Process

angiogenesis
regulation of phosphorylation
cell motility
positive regulation of synapse assembly
vocalization behavior

Molecular Function

signaling receptor binding
protein binding
hepatocyte growth factor binding
identical protein binding

Cellular Component

extracellular space
cytoplasm
cell surface
cell junction
excitatory synapse

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000373004
Coding exons: 10
Length: 27082
Individuals with no LoFs: 125735
Homozygous LoFs: 4
Heterozygous LoFs: 4
Defined: 125743
p: 0.0000318

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.226	204	213	0.956	0.0000187	2996
Missense (PolyPhen)		78	88.715	0.87922		1156
Synonymous	1.21	62	75.3	0.823	0.00000618	918
Loss of Function	3.27	7	24.4	0.286	0.00000235	300

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000076	0.000062	rare
Latino/Admixed American	0.000036	0.000029	rare
Ashkenazi Jewish	0.00013	0.000099	rare
East Asian	0.000074	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000026	0.000018	rare
South Asian	0.00016	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Acts as a ligand for the urokinase plasminogen activator surface receptor. Plays a role in angiogenesis by inducing endothelial cell migration and the formation of vascular network (cords). Involved in cellular migration and adhesion. Increases the phosphorylation levels of FAK. Interacts with and increases the mitogenic activity of HGF. Promotes synapse formation. May have a role in the perisylvian region, critical for language and cognitive development. {ECO:0000269|PubMed:16497722, ECO:0000269|PubMed:18718938, ECO:0000269|PubMed:19065654, ECO:0000269|PubMed:24179158}.;
Disease: DISEASE: Rolandic epilepsy with speech dyspraxia and mental retardation X-linked (RESDX) [MIM:300643]: A condition characterized by the association of rolandic seizures with oral and speech dyspraxia, and mental retardation. Rolandic seizures occur during a period of significant brain maturation. During this time, dysfunction of neural network activities such as focal discharges may be associated with specific developmental disabilities resulting in specific cognitive impairments of language, visuo-spatial abilities or attention. {ECO:0000269|PubMed:16497722}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.138

Intolerance Scores

LoFtool: 0.464
RVIS EVS: 0.17
RVIS percentile EVS: 65.96

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.0211

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium