Intellectual Developmental Disorder, X-Linked 114

Mendelian MONDO:0975828 Pathograph 34 Show in embeddings browser X-linked syndromic intellectual disability SRPK3-related disorder

Intellectual developmental disorder, X-linked 114 (XLID114; OMIM 301134) is a syndromic X-linked neurodevelopmental disorder of hemizygous males caused by germline variants in SRPK3 at Xq28, which encodes serine/arginine-rich protein-specific kinase 3, a kinase that phosphorylates SR-domain splicing factors. The only defining report describes nine affected individuals from five unrelated families: eight males ascertained after birth and one male fetus. The postnatal patients share intellectual disability, usually mild to moderate, with learning difficulty, delayed speech and short attention span, together with structural brain anomalies (agenesis or dysgenesis of the corpus callosum with dilated lateral ventricles and colpocephaly in the largest family, cerebral white matter loss, and cerebellar atrophy), abnormal eye movements (impaired smooth pursuit, convergence insufficiency, strabismus) and ataxia. Presentation is variable: one proband had learning difficulty and then a rapidly progressive cerebellar ataxic syndrome from his early twenties, another had severe global delay with absent speech, axial hypotonia and dystonic-dyskinetic movements with a normal brain MRI, and the fetus with a truncating allele had hydrocephalus, polymicrogyria and cerebellar dysplasia. The one carrier mother whose clinical status is reported was unaffected. The evidence base is small: five families, four missense variants and one truncating variant, with no ClinGen gene-disease validity curation. Support for causality rests on segregation, variant rarity, in silico and HeLa-cell evidence that two of the missense substitutions misfold SRPK3 and displace it from the nucleus, and an srpk3 knockout zebrafish with reduced spontaneous eye movements, a smaller valvula cerebelli and impaired social behaviour. How loss of SRPK3 disturbs brain development is not known; reduced SR-protein phosphorylation and altered pre-mRNA splicing are the presumed route but have not been measured in patient cells or in the fish.

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1
Inheritance
8
Pathophys.
26
Phenotypes
2
Hypotheses
4
Gaps
34
Pathograph
1
Genes
5
Variants
1
Medical Actions
4
Differentials
2
Models
7
References
1
Deep Research
👪

Inheritance

1
X-linked recessive HP:0001419
Affected individuals are hemizygous males. In all five families the variant was maternally inherited, and the three missense variants found first (families 1-3) segregated with the phenotype within their families; the heterozygous carrier mother in family 3 had no symptoms, and her hemizygous brother was affected. No affected female has been described. The authors raise incomplete penetrance for p.E529K because of its presence in gnomAD males.
X-linked recessive inheritance
Show evidence (4 references)
PMID:39073169 SUPPORT Human Clinical
"all three missense variants were found to segregate within the respective families"
Segregation of the first three missense variants with the phenotype.
PMID:39073169 SUPPORT Human Clinical
"The first variant c.475C>G; p.H159D in Family 1 was maternally inherited from a Manitoba female of Anglo-Saxon origin"
Maternal transmission in the largest family, which had five affected males.
PMID:39073169 SUPPORT Human Clinical
"Similar phenotypical characteristics were observed in his maternal uncle, who carried the hemizygous SRPK3 variant. The proband's mother, heterozygous for the SRPK3 variant, showed no symptoms"
Hemizygous affected males and an unaffected heterozygous carrier mother in family 3, the X-linked recessive pattern.
+ 1 more reference
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Mechanistic Hypotheses

2
Loss of SRPK3 phosphorylation of SR splicing factors dysregulates neural pre-mRNA splicing
srpk3_sr_splicing EMERGING
Evidence balance 4 support
The presumed mechanism, following from the known function of the SRPK family: reduced SRPK3 activity (from a truncating, misfolded or hypomorphic allele) leaves SR proteins under-phosphorylated, impairing their nuclear entry and splicing function, and the resulting splicing changes disturb brain development. Every step after the variant is inferred from SRPK biology rather than shown in XLID114: no phosphorylation assay, splicing analysis or target transcript has been reported. The same paper notes that SRPK2 acts in synaptic vesicle release, so a splicing-independent neuronal role is also possible.
Pathograph links
SRPK3 Hemizygous Variant -> Reduced SRPK3-Mediated SR Protein Phosphorylation INDIRECT UNKNOWN INTERMEDIATES Presumed for the truncating allele and the hypomorphic missense alleles; SR-protein phosphorylation was not assayed.
Cytoplasmic Mislocalization of SRPK3 -> Reduced SRPK3-Mediated SR Protein Phosphorylation INDIRECT UNKNOWN INTERMEDIATES
Reduced SRPK3-Mediated SR Protein Phosphorylation -> Dysregulated SR Protein-Dependent Pre-mRNA Splicing INDIRECT KNOWN INTERMEDIATES
Show evidence (4 references)
PMID:39073169 SUPPORT BACKGROUND Other
"Phosphorylation is required for SR proteins to enter the nucleus and play a role in alternative splicing of pre-mRNA, mRNA export, and other processing events."
The biochemical premise of the hypothesis.
PMID:14555757 SUPPORT BACKGROUND Other
"SR protein function is regulated through phosphorylation of their RS domains by multiple kinases, including a family of evolutionarily conserved SR protein-specific kinases (SRPKs)."
Background on SRPK-family regulation of SR proteins, the basis of the hypothesis.
PMID:9472028 SUPPORT In Vitro
"These observations likely reflect the function of the SRPK family of kinases in spliceosome assembly and in mediating the trafficking of splicing factors in mammalian cells."
The SRPK2 cloning study's interpretation of its SRPK1/SRPK2 data as a family-wide role in spliceosome assembly and splicing-factor trafficking; extended to SRPK3 by analogy only.
+ 1 more reference
SRPK3 deficiency causes disease together with a deficient downstream target
srpk3_second_hit_model EMERGING
Evidence balance 2 support
Proposed by the authors of the SRPK3/TTN digenic myopathy study, who found that hemizygous deleterious SRPK3 variants caused myopathy only with a heterozygous TTN variant, and suggested that the same kinase deficiency combined with a second deficient target gene could underlie other SRPK3 phenotypes, citing the intellectual-disability reports. If it applied to XLID114, it would explain the gnomAD males carrying p.E529K or truncating SRPK3 alleles. No second locus has been sought or found in XLID114 families, and the fetal proband's extra VUS in BAALC and LOC400499 are not evidence for one.
Show evidence (2 references)
PMID:38429495 SUPPORT BACKGROUND Other
"it is conceivable that defective or absent phosphorylation activity of this kinase, in combination with a second deficient downstream target gene, could result in these, as well as other, disease phenotypes"
The digenic-study authors' own extension of their model to other SRPK3 phenotypes.
PMID:38429495 SUPPORT Human Clinical
"We identified 40 males (from 25 families) carrying hemizygous deleterious variants in the X-linked SRPK3 gene. Of those, only the 31 patients who also carried cosegregating heterozygous TTN variants presented with a myopathy."
The observation the model rests on: hemizygous SRPK3 variants were not sufficient for the muscle phenotype.
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Discussions and Knowledge Gaps

4
Do XLID114 variants reduce SRPK3 phosphorylation of SR proteins, and which neural splicing events, in which developing cell types, link that loss to callosal, white matter and cerebellar maldevelopment?
KNOWLEDGE GAP OPEN xlid114_splicing_mechanism_gap
Attached to
pathophysiology#Reduced SRPK3-Mediated SR Protein Phosphorylation pathophysiology#Dysregulated SR Protein-Dependent Pre-mRNA Splicing mechanistic_hypotheses#srpk3_sr_splicing
The pathograph stops at a presumed splicing defect because nothing has been measured beyond variant localization in HeLa cells. The authors themselves say phosphorylation assays are needed. SR-protein phosphorylation, RNA-seq splicing analysis in patient-derived neural cells or knockout fish brain, and identification of mis-spliced targets would each test a step that is currently inferred.
Show evidence (1 reference)
PMID:39073169 SUPPORT In Vitro
"Although, further studies with phosphorylation assays are required to confirm this prediction"
The authors' statement that kinase function was not tested.
Is a hemizygous SRPK3 loss-of-function allele by itself sufficient to cause intellectual disability, given that p.Glu529Lys is carried by 32 gnomAD males and that truncating SRPK3 alleles occur in gnomAD males and in myopathy-cohort brothers without a reported neurodevelopmental phenotype?
OPEN QUESTION OPEN xlid114_penetrance_null_allele_question
Attached to
genetic#SRPK3 pathophysiology#SRPK3 Hemizygous Variant mechanistic_hypotheses#srpk3_second_hit_model
The XLID114 evidence is one truncating allele, in a fetus with other variants, and four missense alleles of which two seem hypomorphic. The SRPK3/TTN myopathy study reports 40 hemizygous males with deleterious SRPK3 variants, most truncating, and six gnomAD males with truncating alleles, without describing cognition in either group. Whether those males are cognitively normal would decide between a simple loss-of-function model, an allele-specific (for example misfolding or interaction-surface) mechanism, and a second-hit model. Checking cognition and brain imaging in the myopathy cohort is the most direct test.
Show evidence (3 references)
PMID:38429495 SUPPORT Human Clinical
"As of September 2023, there are six hemizygous males (of 76,702) carrying five truncating variants in SRPK3 canonical transcript"
Truncating SRPK3 alleles in population control males.
PMID:38429495 SUPPORT Human Clinical
"Their unaffected brothers carried either the SRPK3 or the TTN variant, but never both."
Brothers hemizygous for deleterious SRPK3 variants were unaffected by myopathy; their cognition is not reported.
PMID:39073169 SUPPORT Human Clinical
"We also note that, although rare, the p.E529K variant is reported in 32 males in the gnomAD database (v.4.0.0)."
Population hemizygotes for one of the XLID114 alleles.
Why does loss of Srpk3 give a myopathy without a reported brain phenotype in mice, a cerebellar and oculomotor phenotype without myopathy in zebrafish, and a neurodevelopmental disorder without myopathy in humans?
HUMAN MODEL MISMATCH OPEN xlid114_model_species_mismatch
Attached to
animal_models#Srpk3-null mouse animal_models#srpk3 knockout zebrafish pathophysiology#Cerebellar Structural Deficit
Mouse Srpk3 is reported as muscle-restricted, while human SRPK3 is expressed in embryonic brain, retina and cerebellum, and zebrafish srpk3 in brain, heart and muscle. The mouse brain is not described in the published abstract, the fish lacks a corpus callosum so the most distinctive human imaging finding cannot be modelled, and wild-type human SRPK3 mRNA failed to rescue the fish phenotype, which leaves open how specific the fish phenotypes are. A neural examination of Srpk3-null mice and a stable rescue in fish would address the mismatch.
Show evidence (3 references)
PMID:39073169 SUPPORT Model Organism
"Notably, in our study, srpk3 KO zebrafish did not exhibit any signs of myopathy"
No myopathy in the zebrafish knockout, unlike the mouse.
PMID:39073169 SUPPORT Model Organism
"Initially, we injected 200pg of WT SRPK3 mRNA into one-cell stage zebrafish embryo. However, we did not observe any swim bladder inflation in srpk3 KO zebrafish."
The attempted rescue failed.
PMID:16140986 SUPPORT Model Organism
"Srpk3-null mice display a new entity of type 2 fiber-specific myopathy with a marked increase in centrally placed nuclei"
The mouse knockout phenotype is muscular.
Does SRPK3 loss in the choroid plexus epithelium contribute to the ventricular dilatation and hydrocephalus seen in XLID114?
KNOWLEDGE GAP OPEN xlid114_choroid_plexus_ventriculomegaly
Attached to
phenotypes#Ventriculomegaly phenotypes#Hydrocephalus
SRPK3 is strongly expressed in the embryonic hindbrain choroid plexus epithelium, which produces cerebrospinal fluid, and ventricular dilatation was the most consistent imaging finding in family 1. The authors raise choroid plexus involvement only as a question for future work, so no pathophysiology node is curated for it.
Show evidence (2 references)
PMID:39073169 SUPPORT Human Clinical
"At CS19, SRPK3 expression was detected in the cerebellum and medulla, with particularly strong expression in the hindbrain choroid epithelium."
Choroid plexus epithelial expression in the human embryo.
PMID:39073169 SUPPORT BACKGROUND Other
"Given that SRPK3 is highly expressed in the CP epithelium, it would be intriguing to explore the potential involvement of SRPK3 in CP development and function in future studies."
The authors pose choroid plexus involvement as an open question.
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Pathophysiology

8
SRPK3 Hemizygous Variant
Mechanism confidence: Provisional
A hemizygous germline variant in SRPK3 (NM_014370.4) in an affected male, inherited from a heterozygous mother. Four missense variants are known - p.His159Asp in the first kinase domain, p.Ser318Leu in the unstructured spacer loop, and p.Thr458Asn and p.Glu529Lys in the second kinase domain - plus one frameshift predicted to truncate the protein (p.Tyr471Ter). The missense variants are not all alike: modelling and cell localization suggest p.His159Asp and p.Thr458Asn destabilize the protein, while p.Ser318Leu and p.Glu529Lys may be hypomorphic. Whether the disease is a loss of SRPK3 kinase function has not been tested directly, so no functional-impact category is asserted.
Loss of SRPK3 phosphorylation of SR splicing factors dysregulates neural pre-mRNA splicing
SRPK3 hgnc:11402 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SRPK3 (hgnc:11402). hgnc:11402 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: GERMLINE zygosity: HEMIZYGOUS
Maternally inherited missense or truncating SRPK3 alleles in hemizygous males.
Animal models
Srpk3-null mouse Mouse perturbs Complete loss of Srpk3 in mice; informative about SRPK3 function in muscle but not about the brain phenotype of XLID114.
Downstream
SRPK3 Protein Misfolding Applies to p.His159Asp and p.Thr458Asn only; the other two missense variants are not predicted to destabilize the fold.
Reduced SRPK3-Mediated SR Protein Phosphorylation Presumed for the truncating allele and the hypomorphic missense alleles; SR-protein phosphorylation was not assayed. Loss of SRPK3 phosphorylation of SR splicing factors dysregulates neural pre-mRNA splicing
Abnormal Cerebral Development Inferred from the brain imaging of affected males and from SRPK3 expression in the human embryonic and fetal brain; no model tested the forebrain, and fish have no corpus callosum.
Cerebellar Structural Deficit
Oculomotor Control Deficit
Show evidence (2 references)
PMID:39073169 SUPPORT Human Clinical
"The first variant (H159D) was located in the first protein kinase domain, while the second (T458N) and third (E529K) variants were found in the second protein kinase domain"
Positions of the missense variants in the kinase domains.
PMID:39073169 SUPPORT Human Clinical
"a maternally-inherited c.1413_1414del; p.Y471* variant was identified by genome sequencing in the fetal proband of family 5"
The single truncating allele, found in the prenatal case.
SRPK3 Protein Misfolding
Mechanism confidence: Provisional
Structural modelling on the AlphaFold SRPK3 model places His159 and Thr458 in the protein interior, where Asp159 loses about half of the side-chain atomic contacts and Asn458 clashes with neighbouring aromatic residues, predicting misfolding. Glu529 is surface-exposed and its substitution is instead predicted to alter a protein-interaction surface. Ser318 lies in an unstructured loop that could not be modelled.
Downstream
Cytoplasmic Mislocalization of SRPK3
Show evidence (1 reference)
PMID:39073169 SUPPORT Computational
"We found that the H159D and T458N substitutions can cause protein misfolding, because His159 and Thr458 are located in the interior of SRPK3 and their side chains play a structural role for the maintenance of the protein folding"
Modelling prediction for the two buried substitutions.
Cytoplasmic Mislocalization of SRPK3
Mechanism confidence: Provisional
GFP-tagged wild-type SRPK3 and the p.Ser318Leu and p.Glu529Lys variants were mainly nuclear in transfected HeLa cells, whereas p.His159Asp and p.Thr458Asn were cytosolic. Shown by overexpression in a non-neural cell line only.
Loss of SRPK3 phosphorylation of SR splicing factors dysregulates neural pre-mRNA splicing
protein localization to nucleus GO:0034504 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased protein localization to nucleus (GO:0034504). GO:0034504 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Reduced SRPK3-Mediated SR Protein Phosphorylation Loss of SRPK3 phosphorylation of SR splicing factors dysregulates neural pre-mRNA splicing
Show evidence (1 reference)
PMID:39073169 SUPPORT In Vitro
"Fluorescence cytochemistry revealed that SRPK3 wild type, S318L and E529K variants were mainly expressed in the nuclei, while the H159D and T458N variants exhibited cytosolic localization"
Direct observation of variant-specific mislocalization in HeLa cells.
Reduced SRPK3-Mediated SR Protein Phosphorylation
Mechanism confidence: Hypothetical
Presumed reduction of SRPK3 phosphorylation of serine/arginine-rich (SR) splicing factors. SRPKs phosphorylate the RS domains of SR proteins, which is needed for their nuclear import and splicing activity, and SRPK3 phosphorylates the RS region of the splicing regulator RBM20 in vitro. No study has measured SR-protein phosphorylation in patient cells, in variant-expressing cells, or in the knockout zebrafish.
Loss of SRPK3 phosphorylation of SR splicing factors dysregulates neural pre-mRNA splicing
protein serine kinase activity GO:0106310 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased protein serine kinase activity (GO:0106310). GO:0106310 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Dysregulated SR Protein-Dependent Pre-mRNA Splicing Loss of SRPK3 phosphorylation of SR splicing factors dysregulates neural pre-mRNA splicing
Show evidence (3 references)
PMID:39073169 SUPPORT BACKGROUND Other
"SRPK3 is known to specifically phosphorylate serine-arginine (SR) proteins which act as splicing factors"
Background statement of the normal SRPK3 substrate class.
PMID:38429495 SUPPORT In Vitro
"We have shown that, in vitro, SRPK3 phosphorylates at least one of the serine residues present in the transfected RBM20"
Experimental demonstration of SRPK3 kinase activity on an RS-rich splicing regulator, in a muscle context; shows the activity exists, not that it is lost in XLID114.
PMID:16223727 SUPPORT BACKGROUND Other
"The repeat regions (RS domains) are polyphosphorylated by the SRPK and Clk/Sty families of kinases."
Family-level background that SRPKs phosphorylate SR-protein RS domains; the paper studies SRPK1, not SRPK3.
Dysregulated SR Protein-Dependent Pre-mRNA Splicing
Mechanism confidence: Hypothetical
Presumed disturbance of SR protein-dependent alternative splicing in the developing nervous system. Which transcripts would be affected, and in which cells, is unknown; no splicing analysis has been reported for XLID114. The node is left without a downstream edge because no source links a splicing change to the brain phenotypes (see discussions).
regulation of mRNA splicing, via spliceosome GO:0048024 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated regulation of mRNA splicing, via spliceosome (GO:0048024). GO:0048024 is a biological process from the Gene Ontology. ↕ DYSREGULATED
Show evidence (1 reference)
PMID:39073169 SUPPORT BACKGROUND Other
"However, phosphorylation of SR proteins by SR protein-specific kinases (SRPKs) is necessary for their functionality"
Background framing of the proposed splicing mechanism.
Abnormal Cerebral Development
Mechanism confidence: Provisional
Maldevelopment of supratentorial brain structures in affected males: agenesis or dysgenesis of the corpus callosum, irregular and asymmetric dilatation of the lateral ventricles with colpocephaly, and reduced cerebral white matter; in the fetus with a truncating allele, obstructive hydrocephalus with polymicrogyria. SRPK3 is expressed in the human embryonic brain, mostly in post-mitotic cells, and strongly in the hindbrain choroid plexus epithelium. Not every patient is affected: the family 4 proband had a normal brain MRI and the family 2 proband had no supratentorial atrophy.
corpus callosum development GO:0022038 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal corpus callosum development (GO:0022038). GO:0022038 is a biological process from the Gene Ontology. ⚠ ABNORMAL
corpus callosum UBERON:0002336 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in corpus callosum (UBERON:0002336). UBERON:0002336 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Agenesis or Dysgenesis of the Corpus Callosum
Ventriculomegaly
Colpocephaly
Cerebral White Matter Loss
Hydrocephalus
Polymicrogyria
Intellectual Disability The cognitive phenotype is attributed to abnormal brain development in general; which structural change contributes, and whether it does in patients with normal imaging, is not established.
Global Developmental Delay
Delayed Speech and Language Development
Show evidence (3 references)
PMID:39073169 SUPPORT Human Clinical
"Brain imaging (X-ray, CT, and/or MRI scans) was performed on four of the five affected males, revealing irregular and asymmetrically dilated lateral ventricles in all four"
Ventricular dilatation in all imaged males of family 1.
PMID:39073169 SUPPORT Human Clinical
"Additionally, mild bilateral symmetric reduction in parietal gyral white matter volumes was observed. Along with a loss of volume within the posterior body of the corpus callosum"
White matter and callosal volume loss in the family 3 proband.
PMID:39073169 SUPPORT Human Clinical
"In both stages, expression occurred mostly in post-mitotic cells, although both nuclear and cytoplasmic staining were seen"
SRPK3 immunostaining in human embryonic brain tissue, placing the protein in the developing brain at the relevant stage.
Cerebellar Structural Deficit
Mechanism confidence: Provisional
Reduced cerebellar tissue. In adult srpk3 knockout zebrafish the valvula cerebelli, a cerebellar region suggested to serve non-locomotor functions, was roughly halved relative to brain area, together with the nucleus lateralis valvulae. In patients, the family 2 proband developed rapidly progressive cerebellar atrophy in his early twenties, and the fetus had a small, dysplastic cerebellum. Whether the human cerebellar change is primarily developmental, degenerative, or both is not resolved; SRPK3 mRNA in human brain rises with age and is highest in the cerebellum.
cerebellum development GO:0021549 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal cerebellum development (GO:0021549). GO:0021549 is a biological process from the Gene Ontology. ⚠ ABNORMAL
cerebellum UBERON:0002037 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in cerebellum (UBERON:0002037). UBERON:0002037 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
srpk3 knockout zebrafish Zebrafish partially recapitulates Loss of srpk3 reduces the valvula cerebelli, which the authors compare to cerebellar atrophy in patients.
Downstream
Cerebellar Atrophy
Cerebellar Hypoplasia
Ataxia Cerebellar in character in family 2, where ataxia accompanied progressive cerebellar atrophy; in other families imaging did not show a cerebellar lesion, so the link is an inference there.
Dysarthria
Tremor
Show evidence (2 references)
PMID:39073169 SUPPORT Model Organism
"In adult KO zebrafish, cerebellar agenesis and behavioral abnormalities were observed, recapitulating human phenotypes of cerebellar atrophy and intellectual disability."
Cerebellar defect in the knockout model, compared by the authors to the patients.
PMID:39073169 SUPPORT Human Clinical
"Analysis of the RNA-Seq dataset revealed an age-dependent increase in SRPK3 mRNA expression, with the highest levels noted within the cerebellum"
BrainSpan human brain transcriptome shows highest SRPK3 expression in cerebellum.
Oculomotor Control Deficit
Mechanism confidence: Provisional
Impaired control of eye movements. Patients have impaired smooth pursuit, convergence insufficiency and strabismus; srpk3 knockout zebrafish larvae have fewer spontaneous eye movements with reduced angle and reset time but a normal colour response. The authors propose a defect in the oculomotor neural integrator circuit, and state that a neuronal versus extraocular muscle origin has not been distinguished; extraocular muscle marker expression was unchanged in the fish.
Animal models
srpk3 knockout zebrafish Zebrafish partially recapitulates Reduced frequency, angle and reset time of spontaneous eye movements in 5-day larvae, compared by the authors to the patients' uncontrolled eye movements.
Downstream
Impaired Smooth Pursuit
Impaired Convergence
Exotropia
Show evidence (2 references)
PMID:39073169 SUPPORT Model Organism
"These oculomotor behaviors observed in KO zebrafish may arise in part from a deficit in the circuit connectivity within the integrator"
Proposed neural-circuit basis of the eye-movement defect.
PMID:39073169 SUPPORT BACKGROUND Other
"one must consider both neuronal and muscle function-related mechanisms in future studies of SRPK function"
The authors leave a neuronal versus muscular origin open.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Intellectual Developmental Disorder, X-Linked 114 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

26
Ear 1
Inner Ear Malformation Abnormal lateral semicircular canal morphology HP:0040106 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dysplastic combined vestibule and lateral semicircular canal, annotated with Abnormal lateral semicircular canal morphology (HP:0040106). HP:0040106 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39073169 SUPPORT Human Clinical
"Furthermore, MRI showed congenital inner ear anomalies with dysplastic combined vestibule/lateral semicircular canals bilaterally."
Inner ear malformation in the fetal proband.
Eye 3
Impaired Smooth Pursuit HP:0007772 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Impaired smooth pursuit (HP:0007772). HP:0007772 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39073169 SUPPORT Human Clinical
"Eye movement-related phenotypes, including abnormal smooth pursuit, convergence insufficiency, lazy eye, were also clinically described in all four patients"
Abnormal smooth pursuit among the described eye-movement phenotypes.
Impaired Convergence HP:0000619 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Convergence insufficiency, annotated with Impaired convergence (HP:0000619). HP:0000619 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39073169 SUPPORT Human Clinical
"Eye movement-related phenotypes, including abnormal smooth pursuit, convergence insufficiency, lazy eye, were also clinically described in all four patients"
Convergence insufficiency among the described eye-movement phenotypes.
Exotropia HP:0000577 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Exotropia (HP:0000577). HP:0000577 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39073169 SUPPORT Human Clinical
"Proband showed long standing history of learning difficulties with slow processing speed requiring special education, left eye exotropia"
Exotropia in the family 2 proband.
Head and Neck 2
Macrocephaly HP:0000256 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Macrocephaly (HP:0000256). HP:0000256 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39073169 SUPPORT Human Clinical
"none of the four affected males exhibited facial dysmorphic features or other visible malformations, and three males had macrocephaly"
Macrocephaly in three family 1 males, in the absence of dysmorphism.
High Narrow Palate HP:0002705 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is High, narrow palate (HP:0002705). HP:0002705 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39073169 SUPPORT Human Clinical
"he had a high narrow palate, long slender fingers with hypermobility of small joints"
High narrow palate in the family 4 proband.
Limbs 1
Long Slender Fingers Long fingers HP:0100807 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Long slender fingers, annotated with Long fingers (HP:0100807). HP:0100807 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:39073169 SUPPORT Human Clinical
"he had a high narrow palate, long slender fingers with hypermobility of small joints"
Long slender fingers in the family 4 proband.
PMID:40662097 SUPPORT BACKGROUND Human Clinical
"Slender fingers were reported in two families."
Summary of the defining report by later authors reviewing SRPK3 phenotypes.
Musculoskeletal 2
Hypotonia HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:39073169 SUPPORT Human Clinical
"The proband (F3:III-1) in Family 3 is presented with intellectual disability, muscle hypotonia, and ataxia."
Hypotonia in the family 3 proband.
PMID:39073169 SUPPORT Human Clinical
"He had axial hypotonus with hypertonus of the limbs, he could not hold his head up."
Axial hypotonia in the family 4 proband.
Small Joint Hypermobility HP:0430046 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Small joint hypermobility (HP:0430046). HP:0430046 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39073169 SUPPORT Human Clinical
"he had a high narrow palate, long slender fingers with hypermobility of small joints"
Small joint hypermobility in the family 4 proband.
Nervous System 17
Intellectual Disability VERY_FREQUENT HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:39073169 SUPPORT Human Clinical
"All postnatal patients exhibited learning difficulties and intellectual disabilities."
Supports both the phenotype and the all-patients frequency.
PMID:39073169 SUPPORT Human Clinical
"Family 1 was referred to the genetics clinic in Winnipeg, Manitoba due to cognitive impairments in five males, ranging from mild to moderate severity."
Severity range in the largest family.
Global Developmental Delay HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263), qualified as infantile onset. HP:0001263 is a phenotype from the Human Phenotype Ontology.
Onset: INFANTILE
Show evidence (2 references)
PMID:39073169 SUPPORT Human Clinical
"All males in the family presented with delayed motor, social, adaptive and language skills at an early age"
Multi-domain developmental delay in family 1.
PMID:39073169 SUPPORT Human Clinical
"The proband in family 4 is a young boy who was evaluated at 7 and 18 months of age for a global developmental delay."
Global developmental delay in the family 4 proband.
Delayed Speech and Language Development HP:0000750 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed speech and language development (HP:0000750). HP:0000750 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:39073169 SUPPORT Human Clinical
"These two families also had abnormal speech, while all three families exhibited mild intellectual disabilities"
Speech abnormality in two of the first three families.
PMID:39073169 SUPPORT Human Clinical
"The speech was absent and the child still showed axial hypotonus with no trunk control and inconstant head control."
Absent speech at 5 years in the family 4 proband.
Short Attention Span HP:0000736 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short attention span (HP:0000736). HP:0000736 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39073169 SUPPORT Human Clinical
"Patient F1:III-4 also had a very short attention span"
Short attention span in a family 1 male (a second, F1:III-5, had poor attention span).
Abnormal Social Behavior HP:0012433 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal social behavior (HP:0012433). HP:0012433 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39073169 SUPPORT Human Clinical
"Given that social interaction-affecting abnormalities were also observed in the affected patients"
Social interaction abnormalities in patients, stated as the rationale for the fish assay.
Agenesis or Dysgenesis of the Corpus Callosum Abnormal corpus callosum morphology HP:0001273 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Agenesis or dysgenesis of the corpus callosum, annotated with Abnormal corpus callosum morphology (HP:0001273). HP:0001273 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39073169 SUPPORT Human Clinical
"Additionally, all four males exhibited varying degrees of agenesis and/or dysgenesis of the corpus callosum."
Callosal agenesis or dysgenesis in family 1.
Ventriculomegaly HP:0002119 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ventriculomegaly (HP:0002119). HP:0002119 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39073169 SUPPORT Human Clinical
"Brain imaging (X-ray, CT, and/or MRI scans) was performed on four of the five affected males, revealing irregular and asymmetrically dilated lateral ventricles in all four"
Ventricular dilatation in all imaged family 1 males.
Colpocephaly HP:0030048 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Colpocephaly (HP:0030048). HP:0030048 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39073169 SUPPORT Human Clinical
"Three males demonstrated dilatation of the occipital horns (colpocephaly)."
Colpocephaly in three family 1 males.
Cerebral White Matter Loss Cerebral white matter atrophy HP:0012762 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebral white matter loss, annotated with Cerebral white matter atrophy (HP:0012762). HP:0012762 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39073169 SUPPORT Human Clinical
"Additionally, mild bilateral symmetric reduction in parietal gyral white matter volumes was observed."
White matter volume loss in the family 3 proband.
Ataxia HP:0001251 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ataxia (HP:0001251). HP:0001251 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:39073169 SUPPORT Human Clinical
"The proband (F3:III-1) in Family 3 is presented with intellectual disability, muscle hypotonia, and ataxia."
Ataxia in the family 3 proband.
PMID:39073169 SUPPORT Human Clinical
"The proband F2 was 24 year-old man of Northern European origin with adult-onset progressive ataxia, dysarthria, decreased dexterity, tremor and vertigo with onset since age 21."
Adult-onset progressive ataxia in the family 2 proband.
Cerebellar Atrophy HP:0001272 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebellar atrophy (HP:0001272), qualified as course progressive. HP:0001272 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:39073169 SUPPORT Human Clinical
"Imaging of the brain revealed a pattern of rapidly progressing cerebellar atrophy (but not supratentorial atrophy) over a period of 3 years."
Progressive cerebellar atrophy in the family 2 proband.
Dysarthria HP:0001260 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dysarthria (HP:0001260). HP:0001260 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39073169 SUPPORT Human Clinical
"The proband F2 was 24 year-old man of Northern European origin with adult-onset progressive ataxia, dysarthria, decreased dexterity, tremor and vertigo with onset since age 21."
Dysarthria in the family 2 proband.
Tremor HP:0001337 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tremor (HP:0001337). HP:0001337 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39073169 SUPPORT Human Clinical
"The proband F2 was 24 year-old man of Northern European origin with adult-onset progressive ataxia, dysarthria, decreased dexterity, tremor and vertigo with onset since age 21."
Tremor in the family 2 proband.
Dystonia HP:0001332 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dystonia (HP:0001332). HP:0001332 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39073169 SUPPORT Human Clinical
"mobility is impaired by frequent dystonic-dyskinetic movements"
Dystonic movements in the family 4 proband.
Hydrocephalus HP:0000238 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Obstructive hydrocephalus, annotated with Hydrocephalus (HP:0000238), qualified as antenatal onset. HP:0000238 is a phenotype from the Human Phenotype Ontology.
Onset: ANTENATAL
Show evidence (1 reference)
PMID:39073169 SUPPORT Human Clinical
"Postnatal MRI showed a large posterior midline cystic structure which likely represents a dilated left lateral ventricle related to obstructive hydrocephalus."
Hydrocephalus in the prenatally ascertained proband.
Polymicrogyria HP:0002126 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Polymicrogyria (HP:0002126). HP:0002126 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39073169 SUPPORT Human Clinical
"there appeared to be underlying congenital brain anomalies with dysplastic/polymicrogyria changes involving the right cerebral hemisphere most notable in the right frontal region"
Polymicrogyria in the prenatally ascertained proband.
Cerebellar Hypoplasia HP:0001321 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebellar hypoplasia (HP:0001321), qualified as antenatal onset. HP:0001321 is a phenotype from the Human Phenotype Ontology.
Onset: ANTENATAL
Show evidence (1 reference)
PMID:39073169 SUPPORT Human Clinical
"cerebellum smaller than expected for gestational age; and enlarged cisterna magna thought to be secondary to the small cerebellum"
Small cerebellum on prenatal imaging of the fetal proband.
🧬

Genetic Associations

1
SRPK3 (CAUSATIVE)
Gene: SRPK3 hgnc:11402 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SRPK3 (hgnc:11402). hgnc:11402 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (3 references)
PMID:39073169 SUPPORT Human Clinical
"p.H159D was identified in Family 1 by X-chromosome exome sequencing; c.1373C>A; p.T458N was identified in Family 2 at NHGRI; c.1585G>A; p.E529K was identified in Family 3; a maternally-inherited c.953C>T; p.S318L variant was identified in the proband of family 4"
The published SRPK3 missense variants and their families.
PMID:39073169 SUPPORT Human Clinical
"Our analysis revealed that the c.1585G>A variant exhibited a very low MAF (MAF=0.0001), whereas c.475C>G, c.953C>T, c.1373C>A, and c.1413_1414del variants were not detected in the gnomAD dataset."
Population frequency of the variants.
PMID:39073169 SUPPORT Human Clinical
"We also note that, although rare, the p.E529K variant is reported in 32 males in the gnomAD database (v.4.0.0)."
Hemizygous carriers of p.Glu529Lys in the population, a penetrance caveat.
Variants (5)
NM_014370.4:c.475C>G (p.His159Asp)
Family 1; first kinase domain; predicted to misfold SRPK3 and mislocalizes it to the cytoplasm in HeLa cells.
NM_014370.4:c.1373C>A (p.Thr458Asn)
Family 2; second kinase domain; predicted to misfold SRPK3 and mislocalizes it to the cytoplasm in HeLa cells.
NM_014370.4:c.1585G>A (p.Glu529Lys)
Family 3; second kinase domain, surface-exposed; nuclear localization preserved; possibly hypomorphic; present in 32 gnomAD males.
NM_014370.4:c.953C>T (p.Ser318Leu)
Family 4; unstructured spacer loop; nuclear localization preserved; possibly hypomorphic.
NM_014370.4:c.1413_1414del (p.Tyr471Ter)
Family 5 (fetus); frameshift predicted to truncate the protein.
💊

Medical Actions

1
Special Education and Developmental Support
Action: special education and developmental supportNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is special education and developmental support, annotated with Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Platform: Behavioral / lifestyle
No disease-specific therapy exists. Management reported in the defining paper is supportive, including special education for learning difficulty.
Show evidence (1 reference)
PMID:39073169 SUPPORT Human Clinical
"Proband showed long standing history of learning difficulties with slow processing speed requiring special education"
Special education provided to the family 2 proband.
🔬

Diagnosis

2
Exome or Genome Sequencing
All published diagnoses were made by X-chromosome exome, whole exome or genome sequencing, followed by segregation testing of the mother and relatives. The postnatal patients had a normal karyotype and a negative fragile X test, and the fetus had a normal chromosomal microarray, before sequencing. Interpreting a new SRPK3 missense variant should take into account that p.Glu529Lys occurs in gnomAD males and that SRPK3 truncating alleles occur in unaffected males.
Whole exome sequencing NCIT:C101295 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:39073169 SUPPORT Human Clinical
"Employing exome or genome sequencing, here we identified 4 missense variants"
Sequencing was the diagnostic route in every family.
PMID:39073169 SUPPORT Human Clinical
"All postnatal patients were found to have a normal karyotype and negative molecular readout for Fragile X syndrome."
First-tier testing that preceded sequencing.
Brain MRI
Brain imaging identifies the callosal, ventricular, white matter and cerebellar anomalies, but a normal MRI does not exclude the disorder (the family 4 proband's MRI was normal).
Brain magnetic resonance imaging NCIT:C16809 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:39073169 SUPPORT Human Clinical
"Brain MRI was normal and a neurometabolic work-up did not show significant abnormalities."
A genetically confirmed patient with a normal brain MRI.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
Nine affected individuals (eight postnatal males and one male fetus) from five unrelated families in the single defining report. A PubMed search for "SRPK3" on 2026-09-25 returned no later report of additional XLID114 patients.
Show evidence (1 reference)
PMID:39073169 SUPPORT Human Clinical
"in the SRPK3 gene in 9 XLID patients from 5 unrelated families"
Total published case count.
🔀

Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from Intellectual Developmental Disorder, X-Linked 114:

L1 syndrome MONDO:0017140
Overlapping Features X-linked (Xq28, L1CAM) disorder of males with intellectual disability, hydrocephalus or ventriculomegaly and callosal agenesis, the closest phenotypic match to family 1. Distinguished by adducted thumbs and spasticity, which were not described in XLID114, and by L1CAM testing. The defining report states that known X-linked disorders with these imaging findings were excluded in family 1 but does not name them.
Show evidence (1 reference)
PMID:39073169 SUPPORT Human Clinical
"We excluded commonly known forms of X-linked disorder with these brain image findings during assessments conducted between 1984 and 2013"
Known X-linked disorders with ventriculomegaly and callosal anomalies were considered and excluded in family 1; the named disorders are not listed.
Fragile X syndrome MONDO:0010383
Overlapping Features The most common inherited cause of intellectual disability in males; excluded by FMR1 testing in all postnatal patients.
Show evidence (1 reference)
PMID:39073169 SUPPORT Human Clinical
"All postnatal patients were found to have a normal karyotype and negative molecular readout for Fragile X syndrome."
Fragile X was excluded before SRPK3 was identified.
SRPK3/TTN digenic myopathy
Overlapping Features Allelic SRPK3 condition: a progressive early-onset skeletal myopathy in males with a hemizygous deleterious SRPK3 variant plus a heterozygous TTN variant. It enters the differential when a hypotonic boy is found to carry an SRPK3 variant; TTN should then be examined and muscle assessed. No MONDO term was found for it.
Distinguishing Features
  • Primary myopathy with motor delay and muscle weakness rather than intellectual disability
  • Requires a co-occurring heterozygous TTN variant
Show evidence (1 reference)
PMID:38429495 SUPPORT Human Clinical
"predicted deleterious variants in SRPK3, encoding the X-linked serine/argenine protein kinase 3, lead to a progressive early onset skeletal muscle myopathy only when in combination with heterozygous variants in the TTN gene"
Defines the allelic digenic myopathy.
CADDS and larger Xq28 contiguous deletions including SRPK3 Not Yet Curated MONDO:0018247
Overlapping Features Hemizygous Xq28 deletions spanning BCAP31 and ABCD1 (contiguous ABCD1/DXS1357E deletion syndrome) can extend to SRPK3 and SSR4, giving a severe neonatal disorder, more severe than XLID114. Chromosomal microarray distinguishes it. No isolated SRPK3 deletion has been reported.
Show evidence (2 references)
PMID:40662097 SUPPORT Human Clinical
"The major clinical anomalies in our case appear to be due to the combined effects of BCAP31, SRPK3 and SSR4 deletions. This combination produces a severe neonatal disorder"
A contiguous deletion including SRPK3 gives a more severe, combined phenotype.
PMID:40662097 SUPPORT BACKGROUND Human Clinical
"we found no reports of solitary SRPK3 gene deletions but the above studies suggest that whole gene deletion would lead to an abnormal neurodevelopmental phenotype"
No isolated SRPK3 deletion has been reported.
🐁

Animal Models

2
srpk3 knockout zebrafish
srpk3 transcripts are reduced in knockout larvae, consistent with nonsense-mediated decay. Knockouts develop normally as embryos, with no change in apoptosis, body length, pigmentation or eye size, but most fail to inflate the swim bladder and only 6 of 73 reached adulthood. At 5 days they have fewer spontaneous eye movements with reduced ocular angle and reset time. Adult survivors show reduced social approach and shoal cohesion with normal locomotion, and a halved valvula cerebelli with normal overall brain size. Early neural markers (her4, islet1, th) and muscle markers were unchanged, and no myopathy was seen. Injected wild-type human SRPK3 mRNA did not rescue swim bladder inflation.
Species
Zebrafish
Genotype
Homozygous CRISPR-Cas9 srpk3 indel allele predicted to truncate the protein (zebrafish srpk3, chromosome 8, orthologue of human SRPK3)
Genes
SRPK3 hgnc:11402 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns SRPK3 (hgnc:11402). hgnc:11402 is a gene from the HUGO Gene Nomenclature Committee.
Publication
PMID:39073169
Pathograph links
Cerebellar Structural Deficit partially recapitulates fidelity: moderate observes: tissue Loss of srpk3 reduces the valvula cerebelli, which the authors compare to cerebellar atrophy in patients.
Limitations: The fish valvula cerebelli has no direct human homologue, and the reduction was measured on three sections of adult survivors, a small and possibly selected group (8% survival). The human cerebellar change was progressive atrophy in one adult and dysplasia in one fetus, so the developmental versus degenerative character is not matched.
Readouts
Relative valvula cerebelli area
Direction: DECREASED
Interpretation: Reduced cerebellar region in the knockout.
Show evidence (1 reference)
PMID:39073169 SUPPORT Model Organism
"We observed that the relative size of valvular cerebelli in the whole brain of srpk3 KO zebrafish was reduced to 50%, 59%, and 41% compared to that of WT zebrafish in three different sections"
The histological measurement behind the readout.
Show evidence (1 reference)
PMID:39073169 SUPPORT Model Organism
"In adult KO zebrafish, cerebellar agenesis and behavioral abnormalities were observed, recapitulating human phenotypes of cerebellar atrophy and intellectual disability."
The authors treat the model as informative for the cerebellar node.
Oculomotor Control Deficit partially recapitulates fidelity: moderate observes: organism Reduced frequency, angle and reset time of spontaneous eye movements in 5-day larvae, compared by the authors to the patients' uncontrolled eye movements.
Limitations: Larval spontaneous saccade-fixation behaviour is not the same measure as smooth pursuit or convergence in patients, and whether the fish defect is neural or muscular was not determined.
Readouts
Spontaneous eye movement frequency
Direction: DECREASED
Interpretation: Impaired oculomotor behaviour in knockout larvae.
Show evidence (1 reference)
PMID:39073169 SUPPORT Model Organism
"However, srpk3 KO siblings exhibited a significant reduction in eye movement frequency (Fig. 5 A, B); indicating a role of srpk3 in maintaining the movement pattern."
The measurement behind the readout.
Show evidence (1 reference)
PMID:39073169 SUPPORT Model Organism
"In post-fertilization day 5 larvae (free swimming stage), KO zebrafish exhibited severe deficits in eye movement and swim bladder inflation, mimicking uncontrolled ocular movement and physical clumsiness observed in human patients."
The authors treat the larval eye-movement defect as a model of the patients' oculomotor phenotype.
Srpk3-null mouse
In mice Srpk3 is a MEF2-regulated, heart- and skeletal-muscle-specific kinase, and Srpk3-null mice have a type 2 fibre myopathy with many centrally placed nuclei. No neural or behavioural phenotype is reported in the abstract. It is recorded here as a loss-of-function model of the gene, not as a model of the neurodevelopmental disease; its muscle phenotype relates to the allelic SRPK3/TTN digenic myopathy, and a large knockout screen cited by the zebrafish paper did not detect myopathy.
Species
Mouse
Genotype
Srpk3 null (X-linked; hemizygous males)
Genes
SRPK3 hgnc:11402 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns SRPK3 (hgnc:11402). hgnc:11402 is a gene from the HUGO Gene Nomenclature Committee.
Publication
PMID:16140986
Pathograph links
SRPK3 Hemizygous Variant perturbs fidelity: low observes: organism Complete loss of Srpk3 in mice; informative about SRPK3 function in muscle but not about the brain phenotype of XLID114.
Limitations: In mice Srpk3 expression is reported as specific to heart and skeletal muscle, whereas human SRPK3 is expressed in the embryonic brain, retina and cerebellum; the published phenotype is muscular and brain structure and behaviour were not reported, so the model neither supports nor refutes the neurodevelopmental mechanism.
Show evidence (2 references)
PMID:16140986 SUPPORT Model Organism
"The Srpk3 gene is specifically expressed in the heart and skeletal muscle from embryogenesis to adulthood and is controlled by a muscle-specific enhancer directly regulated by MEF2."
Muscle-restricted Srpk3 expression in mouse, the basis of the species caveat.
+ 1 more reference
{ }

Source YAML

click to show 
name: Intellectual Developmental Disorder, X-Linked 114
creation_date: "2026-09-25T13:56:18Z"
category: Mendelian
synonyms:
- XLID114
- IDX114
- SRPK3-related X-linked intellectual disability
description: >-
  Intellectual developmental disorder, X-linked 114 (XLID114; OMIM 301134) is a
  syndromic X-linked neurodevelopmental disorder of hemizygous males caused by
  germline variants in SRPK3 at Xq28, which encodes serine/arginine-rich
  protein-specific kinase 3, a kinase that phosphorylates SR-domain splicing
  factors. The only defining report describes nine affected individuals from
  five unrelated families: eight males ascertained after birth and one male
  fetus. The postnatal patients share intellectual disability, usually mild to
  moderate, with learning difficulty, delayed speech and short attention span,
  together with structural brain anomalies (agenesis or dysgenesis of the
  corpus callosum with dilated lateral ventricles and colpocephaly in the
  largest family, cerebral white matter loss, and cerebellar atrophy),
  abnormal eye movements (impaired smooth pursuit, convergence insufficiency,
  strabismus) and ataxia. Presentation is variable: one proband had learning
  difficulty and then a rapidly progressive cerebellar ataxic syndrome from
  his early twenties, another had severe global delay with absent speech,
  axial hypotonia and dystonic-dyskinetic movements with a normal brain MRI,
  and the fetus with a truncating allele had hydrocephalus, polymicrogyria and
  cerebellar dysplasia. The one carrier mother whose clinical status is
  reported was unaffected.

  The evidence base is small: five families, four missense variants and one
  truncating variant, with no ClinGen gene-disease validity curation. Support
  for causality rests on segregation, variant rarity, in silico and HeLa-cell
  evidence that two of the missense substitutions misfold SRPK3 and displace it
  from the nucleus, and an srpk3 knockout zebrafish with reduced spontaneous eye
  movements, a smaller valvula cerebelli and impaired social behaviour. How
  loss of SRPK3 disturbs brain development is not known; reduced SR-protein
  phosphorylation and altered pre-mRNA splicing are the presumed route but
  have not been measured in patient cells or in the fish.
disease_term:
  preferred_term: intellectual developmental disorder, X-linked 114
  term:
    id: MONDO:0975828
    label: intellectual developmental disorder, X-linked 114
parents:
- X-linked syndromic intellectual disability
- SRPK3-related disorder
notes: >-
  Lump/split. This is curated as its own Disease entry rather than as a
  gene-defined subtype of Non-Syndromic_X-Linked_Intellectual_Disability. The
  defining report (PMID:39073169) states that the eight postnatally ascertained
  patients "shared common clinical features including intellectual disability,
  agenesis of the corpus callosum, abnormal eye movement, and ataxia" and
  concludes for a role in syndromic X-linked intellectual disability, which is
  what the non-syndromic class excludes. MONDO nevertheless files MONDO:0975828
  as a direct subclass of MONDO:0019181 non-syndromic X-linked intellectual
  disability (its only parent in the OLS MONDO release read on 2026-09-25);
  that placement follows the historical numbered-locus pattern and is recorded
  as a MONDO disagreement in the notes of the non-syndromic parent entry.
  The `parents` strings here therefore follow the published phenotype, not
  the MONDO hierarchy.

  How widely "shared" the features are. The abstract lists agenesis of the
  corpus callosum among features common to all eight postnatal patients, but
  the case descriptions in the same paper record callosal agenesis or
  dysgenesis only in the four imaged males of family 1, posterior callosal
  volume loss in family 3, cerebellar atrophy without supratentorial change in
  family 2, and a normal brain MRI in family 4. Frequencies are therefore not
  assigned to the brain-imaging phenotypes; only intellectual disability, which
  the paper states for all postnatal patients, carries one.

  Evidence strength. SRPK3 has no ClinGen gene-disease validity record (the
  same statement is made for this gene in the non-syndromic parent entry,
  read from the ClinGen gene-validity download on 2026-09-24). The p.E529K
  allele is present in 32 males in gnomAD v4.0.0, which the authors themselves
  flag as possible incomplete penetrance, and the fetal proband carried
  additional variants of uncertain significance in BAALC and LOC400499. A
  separate study of X-linked myopathy found 40 males with hemizygous
  deleterious SRPK3 variants, most of them truncating, and six gnomAD males
  with truncating SRPK3 alleles (PMID:38429495); that study does not report on
  cognition, so whether a hemizygous null SRPK3 allele is by itself sufficient
  for intellectual disability is open (see discussions).

  Allelic and overlapping SRPK3 conditions. Hemizygous SRPK3 variants also
  cause a progressive early-onset skeletal myopathy, but only together with a
  heterozygous TTN variant (SRPK3/TTN digenic myopathy, PMID:38429495), and
  SRPK3 lies inside the Xq28 contiguous deletions that extend from BCAP31
  towards SSR4 (PMID:40662097). Both are listed as differential diagnoses.
  Srpk3-null mice have a centronuclear-like myopathy (PMID:16140986); in mice
  Srpk3 is expressed in heart and skeletal muscle, and no neural phenotype is
  reported, so the mouse is recorded only as a perturbation of the gene. None
  of the XLID114 patients was described with a myopathy, and the knockout
  zebrafish showed no signs of one.

  No GeneReviews chapter covers this disorder (`just check-genereviews
  --online`, NO_CHAPTER), and MONDO carries no Orphanet cross-reference for
  it. No disease-specific treatment has been reported.
inheritance:
- name: X-linked recessive
  inheritance_term:
    preferred_term: X-linked recessive inheritance
    term:
      id: HP:0001419
      label: X-linked recessive inheritance
  description: >-
    Affected individuals are hemizygous males. In all five families the
    variant was maternally inherited, and the three missense variants found
    first (families 1-3) segregated with the phenotype within their families;
    the heterozygous carrier mother in family 3 had no symptoms, and her
    hemizygous brother was affected. No affected female has been described. The authors raise incomplete penetrance for p.E529K
    because of its presence in gnomAD males.
  evidence:
  - reference: PMID:39073169
    reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      all three missense variants were found to segregate within the
      respective families
    explanation: Segregation of the first three missense variants with the phenotype.
  - reference: PMID:39073169
    reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The first variant c.475C>G; p.H159D in Family 1 was maternally inherited
      from a Manitoba female of Anglo-Saxon origin
    explanation: Maternal transmission in the largest family, which had five affected males.
  - reference: PMID:39073169
    reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Similar phenotypical characteristics were observed in his maternal uncle,
      who carried the hemizygous SRPK3 variant. The proband's mother,
      heterozygous for the SRPK3 variant, showed no symptoms
    explanation: >-
      Hemizygous affected males and an unaffected heterozygous carrier mother
      in family 3, the X-linked recessive pattern.
  - reference: PMID:39073169
    reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It is possible that this variant has incomplete penetrance and/or that it
      exerts its effect only on a specific genetic background.
    explanation: >-
      The authors' own caveat for p.E529K, reported in 32 gnomAD males;
      recorded because it qualifies the recessive, fully penetrant reading.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Nine affected individuals (eight postnatal males and one male fetus) from
    five unrelated families in the single defining report. A PubMed search for
    "SRPK3" on 2026-09-25 returned no later report of additional XLID114
    patients.
  evidence:
  - reference: PMID:39073169
    reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      in the SRPK3 gene in 9 XLID patients from 5 unrelated families
    explanation: Total published case count.
pathophysiology:
- name: SRPK3 Hemizygous Variant
  biological_scale: MOLECULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    A hemizygous germline variant in SRPK3 (NM_014370.4) in an affected male,
    inherited from a heterozygous mother. Four missense variants are known -
    p.His159Asp in the first kinase domain, p.Ser318Leu in the unstructured
    spacer loop, and p.Thr458Asn and p.Glu529Lys in the second kinase domain -
    plus one frameshift predicted to truncate the protein (p.Tyr471Ter).
    The missense variants are not all alike: modelling and cell localization
    suggest p.His159Asp and p.Thr458Asn destabilize the protein, while
    p.Ser318Leu and p.Glu529Lys may be hypomorphic. Whether the disease is a
    loss of SRPK3 kinase function has not been tested directly, so no
    functional-impact category is asserted.
  gene:
    preferred_term: SRPK3
    term:
      id: hgnc:11402
      label: SRPK3
  genetic_context:
    variant_origin: GERMLINE
    zygosity: HEMIZYGOUS
    description: >-
      Maternally inherited missense or truncating SRPK3 alleles in hemizygous
      males.
  evidence:
  - reference: PMID:39073169
    reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The first variant (H159D) was located in the first protein kinase
      domain, while the second (T458N) and third (E529K) variants were found in
      the second protein kinase domain
    explanation: Positions of the missense variants in the kinase domains.
  - reference: PMID:39073169
    reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a maternally-inherited c.1413_1414del; p.Y471* variant was identified by
      genome sequencing in the fetal proband of family 5
    explanation: The single truncating allele, found in the prenatal case.
  downstream:
  - target: SRPK3 Protein Misfolding
    causal_link_type: DIRECT
    description: >-
      Applies to p.His159Asp and p.Thr458Asn only; the other two missense
      variants are not predicted to destabilize the fold.
    evidence:
    - reference: PMID:39073169
      reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: >-
        We found that the H159D and T458N substitutions can cause protein
        misfolding, because His159 and Thr458 are located in the interior of
        SRPK3 and their side chains play a structural role for the maintenance
        of the protein folding
      explanation: AlphaFold-based structural modelling of the two buried substitutions.
  - target: Reduced SRPK3-Mediated SR Protein Phosphorylation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - srpk3_sr_splicing
    description: >-
      Presumed for the truncating allele and the hypomorphic missense alleles;
      SR-protein phosphorylation was not assayed.
    evidence:
    - reference: PMID:39073169
      reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Thus, SPRK3 S318L and E529K may be hypomorphic alleles.
      explanation: >-
        The authors' interpretation of the normally localized missense
        variants as partial-function alleles; a hypothesis, not a measurement
        of kinase activity.
  - target: Abnormal Cerebral Development
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Inferred from the brain imaging of affected males and from SRPK3
      expression in the human embryonic and fetal brain; no model tested the
      forebrain, and fish have no corpus callosum.
    evidence:
    - reference: PMID:39073169
      reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Additionally, all four males exhibited varying degrees of agenesis
        and/or dysgenesis of the corpus callosum. In one male, there was
        moderate to severe white matter bulk loss.
      explanation: Callosal and white matter anomalies in hemizygous males of family 1.
  - target: Cerebellar Structural Deficit
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39073169
      reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        We observed that the relative size of valvular cerebelli in the whole
        brain of srpk3 KO zebrafish was reduced to 50%, 59%, and 41% compared to
        that of WT zebrafish in three different sections
      explanation: Loss of srpk3 in zebrafish reduces a cerebellar region.
    - reference: PMID:39073169
      reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Imaging of the brain revealed a pattern of rapidly progressing
        cerebellar atrophy (but not supratentorial atrophy) over a period of 3
        years.
      explanation: Cerebellar involvement in the family 2 proband.
  - target: Oculomotor Control Deficit
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39073169
      reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        However, srpk3 KO siblings exhibited a significant reduction in eye
        movement frequency (Fig. 5 A, B); indicating a role of srpk3 in
        maintaining the movement pattern.
      explanation: Loss of srpk3 impairs spontaneous eye movements in larval zebrafish.
- name: SRPK3 Protein Misfolding
  biological_scale: MOLECULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    Structural modelling on the AlphaFold SRPK3 model places His159 and Thr458
    in the protein interior, where Asp159 loses about half of the side-chain
    atomic contacts and Asn458 clashes with neighbouring aromatic residues,
    predicting misfolding. Glu529 is surface-exposed and its substitution is
    instead predicted to alter a protein-interaction surface. Ser318 lies in an
    unstructured loop that could not be modelled.
  evidence:
  - reference: PMID:39073169
    reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      We found that the H159D and T458N substitutions can cause protein
      misfolding, because His159 and Thr458 are located in the interior of
      SRPK3 and their side chains play a structural role for the maintenance
      of the protein folding
    explanation: Modelling prediction for the two buried substitutions.
  downstream:
  - target: Cytoplasmic Mislocalization of SRPK3
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39073169
      reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        These results imply that important roles of H159 and T458 in proper
        protein folding of SRPK3, as suggested by molecular modeling, contribute
        to the subcellular localization of SRPK3.
      explanation: The authors connect the predicted misfolding to the observed mislocalization.
- name: Cytoplasmic Mislocalization of SRPK3
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    GFP-tagged wild-type SRPK3 and the p.Ser318Leu and p.Glu529Lys variants
    were mainly nuclear in transfected HeLa cells, whereas p.His159Asp and
    p.Thr458Asn were cytosolic. Shown by overexpression in a non-neural cell
    line only.
  biological_processes:
  - preferred_term: protein localization to nucleus
    term:
      id: GO:0034504
      label: protein localization to nucleus
    modifier: DECREASED
  evidence:
  - reference: PMID:39073169
    reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Fluorescence cytochemistry revealed that SRPK3 wild type, S318L and E529K
      variants were mainly expressed in the nuclei, while the H159D and T458N
      variants exhibited cytosolic localization
    explanation: Direct observation of variant-specific mislocalization in HeLa cells.
  downstream:
  - target: Reduced SRPK3-Mediated SR Protein Phosphorylation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - srpk3_sr_splicing
    evidence:
    - reference: PMID:39073169
      reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Although, further studies with phosphorylation assays are required to
        confirm this prediction
      explanation: >-
        The authors state that the predicted effect of the variants on kinase
        function has not been confirmed by phosphorylation assays; cited to
        mark this edge as untested.
- name: Reduced SRPK3-Mediated SR Protein Phosphorylation
  biological_scale: MOLECULAR
  mechanism_confidence: HYPOTHETICAL
  description: >-
    Presumed reduction of SRPK3 phosphorylation of serine/arginine-rich (SR)
    splicing factors. SRPKs phosphorylate the RS domains of SR proteins, which
    is needed for their nuclear import and splicing activity, and SRPK3
    phosphorylates the RS region of the splicing regulator RBM20 in vitro. No
    study has measured SR-protein phosphorylation in patient cells, in
    variant-expressing cells, or in the knockout zebrafish.
  molecular_functions:
  - preferred_term: protein serine kinase activity
    term:
      id: GO:0106310
      label: protein serine kinase activity
    modifier: DECREASED
  evidence:
  - reference: PMID:39073169
    reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: >-
      SRPK3 is known to specifically phosphorylate serine-arginine (SR)
      proteins which act as splicing factors
    explanation: Background statement of the normal SRPK3 substrate class.
  - reference: PMID:38429495
    reference_title: Digenic inheritance involving a muscle-specific protein kinase and the giant titin protein causes a skeletal muscle myopathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We have shown that, in vitro, SRPK3 phosphorylates at least one of the
      serine residues present in the transfected RBM20
    explanation: >-
      Experimental demonstration of SRPK3 kinase activity on an RS-rich
      splicing regulator, in a muscle context; shows the activity exists, not
      that it is lost in XLID114.
  - reference: PMID:16223727
    reference_title: Mass spectrometric and kinetic analysis of ASF/SF2 phosphorylation by SRPK1 and Clk/Sty.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: >-
      The repeat regions (RS domains) are polyphosphorylated by the SRPK and
      Clk/Sty families of kinases.
    explanation: >-
      Family-level background that SRPKs phosphorylate SR-protein RS domains;
      the paper studies SRPK1, not SRPK3.
  downstream:
  - target: Dysregulated SR Protein-Dependent Pre-mRNA Splicing
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    hypothesis_groups:
    - srpk3_sr_splicing
    evidence:
    - reference: PMID:39073169
      reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: BACKGROUND
      snippet: >-
        Phosphorylation is required for SR proteins to enter the nucleus and
        play a role in alternative splicing of pre-mRNA, mRNA export, and other
        processing events.
      explanation: The general dependence of SR-protein splicing function on phosphorylation.
    - reference: PMID:9472028
      reference_title: "SRPK2: a differentially expressed SR protein-specific kinase involved in mediating the interaction and localization of pre-mRNA splicing factors in mammalian cells."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      snippet: >-
        Phosphorylation of an SR protein (ASF/SF2) by either SRPK1 or 2
        enhanced its interaction with another RS domain-containing protein (U1
        70K), and overexpression of either kinase induced specific
        redistribution of splicing factors in the nucleus.
      explanation: >-
        Cell and biochemical evidence that SRPK phosphorylation changes
        splicing-factor interactions and nuclear distribution. Indirect for
        this edge because it concerns the paralogs SRPK1 and SRPK2 and the
        effect of more kinase, not loss of SRPK3.
- name: Dysregulated SR Protein-Dependent Pre-mRNA Splicing
  biological_scale: MOLECULAR
  mechanism_confidence: HYPOTHETICAL
  description: >-
    Presumed disturbance of SR protein-dependent alternative splicing in the
    developing nervous system. Which transcripts would be affected, and in
    which cells, is unknown; no splicing analysis has been reported for
    XLID114. The node is left without a downstream edge because no source links
    a splicing change to the brain phenotypes (see discussions).
  biological_processes:
  - preferred_term: regulation of mRNA splicing, via spliceosome
    term:
      id: GO:0048024
      label: regulation of mRNA splicing, via spliceosome
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:39073169
    reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: >-
      However, phosphorylation of SR proteins by SR protein-specific kinases
      (SRPKs) is necessary for their functionality
    explanation: Background framing of the proposed splicing mechanism.
- name: Abnormal Cerebral Development
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  description: >-
    Maldevelopment of supratentorial brain structures in affected males:
    agenesis or dysgenesis of the corpus callosum, irregular and asymmetric
    dilatation of the lateral ventricles with colpocephaly, and reduced
    cerebral white matter; in the fetus with a truncating allele, obstructive
    hydrocephalus with polymicrogyria. SRPK3 is expressed in the human
    embryonic brain, mostly in post-mitotic cells, and strongly in the hindbrain
    choroid plexus epithelium. Not every patient is affected: the family 4
    proband had a normal brain MRI and the family 2 proband had no
    supratentorial atrophy.
  biological_processes:
  - preferred_term: corpus callosum development
    term:
      id: GO:0022038
      label: corpus callosum development
    modifier: ABNORMAL
  locations:
  - preferred_term: corpus callosum
    term:
      id: UBERON:0002336
      label: corpus callosum
  evidence:
  - reference: PMID:39073169
    reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain imaging (X-ray, CT, and/or MRI scans) was performed on four of the
      five affected males, revealing irregular and asymmetrically dilated
      lateral ventricles in all four
    explanation: Ventricular dilatation in all imaged males of family 1.
  - reference: PMID:39073169
    reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Additionally, mild bilateral symmetric reduction in parietal gyral white
      matter volumes was observed. Along with a loss of volume within the
      posterior body of the corpus callosum
    explanation: White matter and callosal volume loss in the family 3 proband.
  - reference: PMID:39073169
    reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In both stages, expression occurred mostly in post-mitotic cells,
      although both nuclear and cytoplasmic staining were seen
    explanation: >-
      SRPK3 immunostaining in human embryonic brain tissue, placing the
      protein in the developing brain at the relevant stage.
  downstream:
  - target: Agenesis or Dysgenesis of the Corpus Callosum
  - target: Ventriculomegaly
  - target: Colpocephaly
  - target: Cerebral White Matter Loss
  - target: Hydrocephalus
  - target: Polymicrogyria
  - target: Intellectual Disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The cognitive phenotype is attributed to abnormal brain development in
      general; which structural change contributes, and whether it does in
      patients with normal imaging, is not established.
  - target: Global Developmental Delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Delayed Speech and Language Development
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Cerebellar Structural Deficit
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  description: >-
    Reduced cerebellar tissue. In adult srpk3 knockout zebrafish the valvula
    cerebelli, a cerebellar region suggested to serve non-locomotor functions,
    was roughly halved relative to brain area, together with the nucleus lateralis valvulae. In patients,
    the family 2 proband developed rapidly progressive cerebellar atrophy in
    his early twenties, and the fetus had a small, dysplastic cerebellum.
    Whether the human cerebellar change is primarily developmental,
    degenerative, or both is not resolved; SRPK3 mRNA in human brain rises with
    age and is highest in the cerebellum.
  biological_processes:
  - preferred_term: cerebellum development
    term:
      id: GO:0021549
      label: cerebellum development
    modifier: ABNORMAL
  locations:
  - preferred_term: cerebellum
    term:
      id: UBERON:0002037
      label: cerebellum
  evidence:
  - reference: PMID:39073169
    reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In adult KO zebrafish, cerebellar agenesis and behavioral abnormalities
      were observed, recapitulating human phenotypes of cerebellar atrophy and
      intellectual disability.
    explanation: Cerebellar defect in the knockout model, compared by the authors to the patients.
  - reference: PMID:39073169
    reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Analysis of the RNA-Seq dataset revealed an age-dependent increase in
      SRPK3 mRNA expression, with the highest levels noted within the
      cerebellum
    explanation: BrainSpan human brain transcriptome shows highest SRPK3 expression in cerebellum.
  downstream:
  - target: Cerebellar Atrophy
  - target: Cerebellar Hypoplasia
  - target: Ataxia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Cerebellar in character in family 2, where ataxia accompanied progressive
      cerebellar atrophy; in other families imaging did not show a cerebellar
      lesion, so the link is an inference there.
  - target: Dysarthria
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Tremor
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Oculomotor Control Deficit
  biological_scale: ORGANISM
  mechanism_confidence: PROVISIONAL
  description: >-
    Impaired control of eye movements. Patients have impaired smooth pursuit,
    convergence insufficiency and strabismus; srpk3 knockout zebrafish larvae
    have fewer spontaneous eye movements with reduced angle and reset time
    but a normal colour response. The authors propose a defect in the
    oculomotor neural integrator circuit, and state that a neuronal versus
    extraocular muscle origin has not been distinguished; extraocular muscle
    marker expression was unchanged in the fish.
  evidence:
  - reference: PMID:39073169
    reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      These oculomotor behaviors observed in KO zebrafish may arise in part
      from a deficit in the circuit connectivity within the integrator
    explanation: Proposed neural-circuit basis of the eye-movement defect.
  - reference: PMID:39073169
    reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: >-
      one must consider both neuronal and muscle function-related mechanisms in
      future studies of SRPK function
    explanation: The authors leave a neuronal versus muscular origin open.
  downstream:
  - target: Impaired Smooth Pursuit
  - target: Impaired Convergence
  - target: Exotropia
mechanistic_hypotheses:
- hypothesis_group_id: srpk3_sr_splicing
  hypothesis_label: Loss of SRPK3 phosphorylation of SR splicing factors dysregulates neural pre-mRNA splicing
  status: EMERGING
  description: >-
    The presumed mechanism, following from the known function of the SRPK
    family: reduced SRPK3 activity (from a truncating, misfolded or hypomorphic
    allele) leaves SR proteins under-phosphorylated, impairing their nuclear
    entry and splicing function, and the resulting splicing changes disturb
    brain development. Every step after the variant is inferred from SRPK
    biology rather than shown in XLID114: no phosphorylation assay, splicing
    analysis or target transcript has been reported. The same paper notes that
    SRPK2 acts in synaptic vesicle release, so a splicing-independent neuronal
    role is also possible.
  evidence:
  - reference: PMID:39073169
    reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: >-
      Phosphorylation is required for SR proteins to enter the nucleus and
      play a role in alternative splicing of pre-mRNA, mRNA export, and other
      processing events.
    explanation: The biochemical premise of the hypothesis.
  - reference: PMID:14555757
    reference_title: Processive phosphorylation of alternative splicing factor/splicing factor 2.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: >-
      SR protein function is regulated through phosphorylation of their RS
      domains by multiple kinases, including a family of evolutionarily
      conserved SR protein-specific kinases (SRPKs).
    explanation: Background on SRPK-family regulation of SR proteins, the basis of the hypothesis.
  - reference: PMID:9472028
    reference_title: "SRPK2: a differentially expressed SR protein-specific kinase involved in mediating the interaction and localization of pre-mRNA splicing factors in mammalian cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      These observations likely reflect the function of the SRPK family of
      kinases in spliceosome assembly and in mediating the trafficking of
      splicing factors in mammalian cells.
    explanation: >-
      The SRPK2 cloning study's interpretation of its SRPK1/SRPK2 data as a
      family-wide role in spliceosome assembly and splicing-factor
      trafficking; extended to SRPK3 by analogy only.
  - reference: PMID:39073169
    reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Although, further studies with phosphorylation assays are required to
      confirm this prediction
    explanation: States that the kinase-function prediction is untested.
- hypothesis_group_id: srpk3_second_hit_model
  hypothesis_label: SRPK3 deficiency causes disease together with a deficient downstream target
  status: EMERGING
  description: >-
    Proposed by the authors of the SRPK3/TTN digenic myopathy study, who found
    that hemizygous deleterious SRPK3 variants caused myopathy only with a
    heterozygous TTN variant, and suggested that the same kinase deficiency
    combined with a second deficient target gene could underlie other SRPK3
    phenotypes, citing the intellectual-disability reports. If it applied to
    XLID114, it would explain the gnomAD males carrying p.E529K or truncating
    SRPK3 alleles. No second locus has been sought or found in XLID114
    families, and the fetal proband's extra VUS in BAALC and LOC400499 are not
    evidence for one.
  evidence:
  - reference: PMID:38429495
    reference_title: Digenic inheritance involving a muscle-specific protein kinase and the giant titin protein causes a skeletal muscle myopathy.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: >-
      it is conceivable that defective or absent phosphorylation activity of
      this kinase, in combination with a second deficient downstream target
      gene, could result in these, as well as other, disease phenotypes
    explanation: The digenic-study authors' own extension of their model to other SRPK3 phenotypes.
  - reference: PMID:38429495
    reference_title: Digenic inheritance involving a muscle-specific protein kinase and the giant titin protein causes a skeletal muscle myopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified 40 males (from 25 families) carrying hemizygous deleterious
      variants in the X-linked SRPK3 gene. Of those, only the 31 patients who
      also carried cosegregating heterozygous TTN variants presented with a
      myopathy.
    explanation: >-
      The observation the model rests on: hemizygous SRPK3 variants were not
      sufficient for the muscle phenotype.
phenotypes:
- category: Neurologic
  name: Intellectual Disability
  frequency: VERY_FREQUENT
  description: >-
    Present in all postnatally ascertained patients, usually mild to moderate
    (mild in families 1-3; the five family 1 males ranged from mild to
    moderate), with learning difficulties and slow processing speed. The
    family 4 proband had severe global developmental delay with absent speech
    at 5 years.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:39073169
    reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All postnatal patients exhibited learning difficulties and intellectual
      disabilities.
    explanation: Supports both the phenotype and the all-patients frequency.
  - reference: PMID:39073169
    reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Family 1 was referred to the genetics clinic in Winnipeg, Manitoba due to
      cognitive impairments in five males, ranging from mild to moderate
      severity.
    explanation: Severity range in the largest family.
- category: Neurologic
  name: Global Developmental Delay
  description: >-
    Delayed motor, social, adaptive and language milestones from early
    childhood in family 1, and severe global delay without head or trunk
    control in the family 4 proband.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
    onset:
      onset_category: INFANTILE
  evidence:
  - reference: PMID:39073169
    reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All males in the family presented with delayed motor, social, adaptive
      and language skills at an early age
    explanation: Multi-domain developmental delay in family 1.
  - reference: PMID:39073169
    reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The proband in family 4 is a young boy who was evaluated at 7 and 18
      months of age for a global developmental delay.
    explanation: Global developmental delay in the family 4 proband.
- category: Neurologic
  name: Delayed Speech and Language Development
  description: >-
    Abnormal or delayed speech in families 1 and 2 (one family 1 male did not
    speak until after 3 years); speech was absent at 5 years in the family 4
    proband.
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:39073169
    reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These two families also had abnormal speech, while all three families
      exhibited mild intellectual disabilities
    explanation: Speech abnormality in two of the first three families.
  - reference: PMID:39073169
    reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The speech was absent and the child still showed axial hypotonus with no
      trunk control and inconstant head control.
    explanation: Absent speech at 5 years in the family 4 proband.
- category: Behavioral
  name: Short Attention Span
  phenotype_term:
    preferred_term: Short attention span
    term:
      id: HP:0000736
      label: Short attention span
  evidence:
  - reference: PMID:39073169
    reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patient F1:III-4 also had a very short attention span
    explanation: Short attention span in a family 1 male (a second, F1:III-5, had poor attention span).
- category: Behavioral
  name: Abnormal Social Behavior
  description: >-
    Social interaction difficulties are reported for the patients in the
    paper's supplementary table; the details are not in the main text. Adult
    srpk3 knockout zebrafish showed reduced social approach and shoal cohesion.
  phenotype_term:
    preferred_term: Abnormal social behavior
    term:
      id: HP:0012433
      label: Abnormal social behavior
  evidence:
  - reference: PMID:39073169
    reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Given that social interaction-affecting abnormalities were also observed
      in the affected patients
    explanation: Social interaction abnormalities in patients, stated as the rationale for the fish assay.
- category: Neurologic
  name: Agenesis or Dysgenesis of the Corpus Callosum
  description: >-
    Varying degrees of agenesis or dysgenesis of the corpus callosum in all
    four imaged males of family 1, and loss of volume of the posterior body of
    the corpus callosum in the family 3 proband. Bound to the general corpus
    callosum morphology term because the source reports a range from
    dysgenesis to agenesis rather than complete agenesis in each patient.
  phenotype_term:
    preferred_term: Agenesis or dysgenesis of the corpus callosum
    term:
      id: HP:0001273
      label: Abnormal corpus callosum morphology
  evidence:
  - reference: PMID:39073169
    reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Additionally, all four males exhibited varying degrees of agenesis
      and/or dysgenesis of the corpus callosum.
    explanation: Callosal agenesis or dysgenesis in family 1.
- category: Neurologic
  name: Ventriculomegaly
  description: >-
    Irregular, asymmetric dilatation of the lateral ventricles in all four
    imaged males of family 1; one had a large head with possible arrested
    hydrocephalus.
  phenotype_term:
    preferred_term: Ventriculomegaly
    term:
      id: HP:0002119
      label: Ventriculomegaly
  evidence:
  - reference: PMID:39073169
    reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain imaging (X-ray, CT, and/or MRI scans) was performed on four of the
      five affected males, revealing irregular and asymmetrically dilated
      lateral ventricles in all four
    explanation: Ventricular dilatation in all imaged family 1 males.
- category: Neurologic
  name: Colpocephaly
  phenotype_term:
    preferred_term: Colpocephaly
    term:
      id: HP:0030048
      label: Colpocephaly
  evidence:
  - reference: PMID:39073169
    reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Three males demonstrated dilatation of the occipital horns
      (colpocephaly).
    explanation: Colpocephaly in three family 1 males.
- category: Neurologic
  name: Cerebral White Matter Loss
  description: >-
    Moderate to severe white matter bulk loss in one family 1 male and mild
    symmetric parietal white matter volume reduction in the family 3 proband.
  phenotype_term:
    preferred_term: Cerebral white matter loss
    term:
      id: HP:0012762
      label: Cerebral white matter atrophy
  evidence:
  - reference: PMID:39073169
    reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Additionally, mild bilateral symmetric reduction in parietal gyral white
      matter volumes was observed.
    explanation: White matter volume loss in the family 3 proband.
- category: Neurologic
  name: Macrocephaly
  description: Three of the four examined family 1 males had macrocephaly.
  phenotype_term:
    preferred_term: Macrocephaly
    term:
      id: HP:0000256
      label: Macrocephaly
  evidence:
  - reference: PMID:39073169
    reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      none of the four affected males exhibited facial dysmorphic features or
      other visible malformations, and three males had macrocephaly
    explanation: Macrocephaly in three family 1 males, in the absence of dysmorphism.
- category: Neurologic
  name: Ataxia
  description: >-
    Ataxia in the family 3 proband and his maternal uncle, and a rapidly
    progressive, mainly truncal ataxic syndrome beginning in the early twenties
    in the family 2 proband.
  phenotype_term:
    preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
  evidence:
  - reference: PMID:39073169
    reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The proband (F3:III-1) in Family 3 is presented with intellectual
      disability, muscle hypotonia, and ataxia.
    explanation: Ataxia in the family 3 proband.
  - reference: PMID:39073169
    reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The proband F2 was 24 year-old man of Northern European origin with
      adult-onset progressive ataxia, dysarthria, decreased dexterity, tremor
      and vertigo with onset since age 21.
    explanation: Adult-onset progressive ataxia in the family 2 proband.
- category: Neurologic
  name: Cerebellar Atrophy
  description: >-
    Rapidly progressing cerebellar atrophy over three years, without
    supratentorial atrophy, in the family 2 proband.
  phenotype_term:
    preferred_term: Cerebellar atrophy
    term:
      id: HP:0001272
      label: Cerebellar atrophy
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:39073169
    reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Imaging of the brain revealed a pattern of rapidly progressing
      cerebellar atrophy (but not supratentorial atrophy) over a period of 3
      years.
    explanation: Progressive cerebellar atrophy in the family 2 proband.
- category: Neurologic
  name: Dysarthria
  description: Part of the adult-onset progressive ataxic syndrome of the family 2 proband.
  phenotype_term:
    preferred_term: Dysarthria
    term:
      id: HP:0001260
      label: Dysarthria
  evidence:
  - reference: PMID:39073169
    reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The proband F2 was 24 year-old man of Northern European origin with
      adult-onset progressive ataxia, dysarthria, decreased dexterity, tremor
      and vertigo with onset since age 21.
    explanation: Dysarthria in the family 2 proband.
- category: Neurologic
  name: Tremor
  description: Part of the adult-onset progressive ataxic syndrome of the family 2 proband.
  phenotype_term:
    preferred_term: Tremor
    term:
      id: HP:0001337
      label: Tremor
  evidence:
  - reference: PMID:39073169
    reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The proband F2 was 24 year-old man of Northern European origin with
      adult-onset progressive ataxia, dysarthria, decreased dexterity, tremor
      and vertigo with onset since age 21.
    explanation: Tremor in the family 2 proband.
- category: Neurologic
  name: Hypotonia
  description: >-
    Muscle hypotonia in the family 3 proband; in the family 4 proband, axial
    hypotonia persisting to 5 years with hypertonia of the limbs.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:39073169
    reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The proband (F3:III-1) in Family 3 is presented with intellectual
      disability, muscle hypotonia, and ataxia.
    explanation: Hypotonia in the family 3 proband.
  - reference: PMID:39073169
    reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He had axial hypotonus with hypertonus of the limbs, he could not hold
      his head up.
    explanation: Axial hypotonia in the family 4 proband.
- category: Neurologic
  name: Dystonia
  description: >-
    Dystonic posture of the lower limbs and frequent dystonic-dyskinetic
    movements in the family 4 proband.
  phenotype_term:
    preferred_term: Dystonia
    term:
      id: HP:0001332
      label: Dystonia
  evidence:
  - reference: PMID:39073169
    reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      mobility is impaired by frequent dystonic-dyskinetic movements
    explanation: Dystonic movements in the family 4 proband.
- category: Ophthalmologic
  name: Impaired Smooth Pursuit
  description: >-
    One of the eye-movement abnormalities described in the four patients with
    clinical information in the initial families (supplementary table).
  phenotype_term:
    preferred_term: Impaired smooth pursuit
    term:
      id: HP:0007772
      label: Impaired smooth pursuit
  evidence:
  - reference: PMID:39073169
    reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Eye movement-related phenotypes, including abnormal smooth pursuit,
      convergence insufficiency, lazy eye, were also clinically described in
      all four patients
    explanation: Abnormal smooth pursuit among the described eye-movement phenotypes.
- category: Ophthalmologic
  name: Impaired Convergence
  phenotype_term:
    preferred_term: Convergence insufficiency
    term:
      id: HP:0000619
      label: Impaired convergence
  evidence:
  - reference: PMID:39073169
    reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Eye movement-related phenotypes, including abnormal smooth pursuit,
      convergence insufficiency, lazy eye, were also clinically described in
      all four patients
    explanation: Convergence insufficiency among the described eye-movement phenotypes.
- category: Ophthalmologic
  name: Exotropia
  description: Left eye exotropia in the family 2 proband.
  phenotype_term:
    preferred_term: Exotropia
    term:
      id: HP:0000577
      label: Exotropia
  evidence:
  - reference: PMID:39073169
    reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Proband showed long standing history of learning difficulties with slow
      processing speed requiring special education, left eye exotropia
    explanation: Exotropia in the family 2 proband.
- category: Musculoskeletal
  name: Long Slender Fingers
  description: >-
    Long slender fingers in the family 4 proband; a later review of the
    report summarizes slender fingers as present in two families.
  phenotype_term:
    preferred_term: Long slender fingers
    term:
      id: HP:0100807
      label: Long fingers
  evidence:
  - reference: PMID:39073169
    reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      he had a high narrow palate, long slender fingers with hypermobility of
      small joints
    explanation: Long slender fingers in the family 4 proband.
  - reference: PMID:40662097
    reference_title: "Hemizygous contiguous gene deletion within Xq28 that includes BCAP31, ABCD1, SRPK3 and SSR4: case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: Slender fingers were reported in two families.
    explanation: Summary of the defining report by later authors reviewing SRPK3 phenotypes.
- category: Musculoskeletal
  name: Small Joint Hypermobility
  description: Hypermobility of the small joints in the family 4 proband.
  phenotype_term:
    preferred_term: Small joint hypermobility
    term:
      id: HP:0430046
      label: Small joint hypermobility
  evidence:
  - reference: PMID:39073169
    reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      he had a high narrow palate, long slender fingers with hypermobility of
      small joints
    explanation: Small joint hypermobility in the family 4 proband.
- category: Craniofacial
  name: High Narrow Palate
  description: High, narrow palate in the family 4 proband, who had no facial dysmorphism.
  phenotype_term:
    preferred_term: High, narrow palate
    term:
      id: HP:0002705
      label: High, narrow palate
  evidence:
  - reference: PMID:39073169
    reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      he had a high narrow palate, long slender fingers with hypermobility of
      small joints
    explanation: High narrow palate in the family 4 proband.
- category: Neurologic
  name: Hydrocephalus
  description: >-
    In the fetus with the truncating allele: absent mid and posterior cerebral
    hemispheres on prenatal ultrasound, head circumference at the 98th
    centile at 32 weeks, and on postnatal MRI a large posterior midline cyst
    interpreted as a dilated left lateral ventricle from obstructive
    hydrocephalus, with progressive effects on the remaining hemispheres,
    brainstem and cerebellum. This proband also carried variants of uncertain
    significance in two other genes.
  phenotype_term:
    preferred_term: Obstructive hydrocephalus
    term:
      id: HP:0000238
      label: Hydrocephalus
    onset:
      onset_category: ANTENATAL
  evidence:
  - reference: PMID:39073169
    reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Postnatal MRI showed a large posterior midline cystic structure which
      likely represents a dilated left lateral ventricle related to obstructive
      hydrocephalus.
    explanation: Hydrocephalus in the prenatally ascertained proband.
- category: Neurologic
  name: Polymicrogyria
  description: >-
    Dysplastic and polymicrogyric changes of the right cerebral hemisphere,
    most marked frontally, in the prenatally ascertained proband.
  phenotype_term:
    preferred_term: Polymicrogyria
    term:
      id: HP:0002126
      label: Polymicrogyria
  evidence:
  - reference: PMID:39073169
    reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      there appeared to be underlying congenital brain anomalies with
      dysplastic/polymicrogyria changes involving the right cerebral
      hemisphere most notable in the right frontal region
    explanation: Polymicrogyria in the prenatally ascertained proband.
- category: Neurologic
  name: Cerebellar Hypoplasia
  description: >-
    A cerebellum smaller than expected for gestational age with an enlarged
    cisterna magna at 21 weeks, and later dysplastic changes of the entire
    cerebellum, in the prenatally ascertained proband.
  phenotype_term:
    preferred_term: Cerebellar hypoplasia
    term:
      id: HP:0001321
      label: Cerebellar hypoplasia
    onset:
      onset_category: ANTENATAL
  evidence:
  - reference: PMID:39073169
    reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      cerebellum smaller than expected for gestational age; and enlarged
      cisterna magna thought to be secondary to the small cerebellum
    explanation: Small cerebellum on prenatal imaging of the fetal proband.
- category: Otologic
  name: Inner Ear Malformation
  description: >-
    Bilateral dysplastic combined vestibule and lateral semicircular canals on
    MRI in the prenatally ascertained proband only.
  phenotype_term:
    preferred_term: Dysplastic combined vestibule and lateral semicircular canal
    term:
      id: HP:0040106
      label: Abnormal lateral semicircular canal morphology
  evidence:
  - reference: PMID:39073169
    reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Furthermore, MRI showed congenital inner ear anomalies with dysplastic
      combined vestibule/lateral semicircular canals bilaterally.
    explanation: Inner ear malformation in the fetal proband.
genetic:
- name: SRPK3
  gene_term:
    preferred_term: SRPK3
    term:
      id: hgnc:11402
      label: SRPK3
  association: CAUSATIVE
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  features: >-
    Hemizygous, maternally inherited variants in males (NM_014370.4):
    c.475C>G p.(His159Asp) in family 1 (five affected males), c.1373C>A
    p.(Thr458Asn) in family 2, c.1585G>A p.(Glu529Lys) in family 3 (proband
    and maternal uncle), c.953C>T p.(Ser318Leu) in family 4, and the frameshift
    c.1413_1414del p.(Tyr471Ter) in a fetus (family 5). All were absent from
    gnomAD except p.Glu529Lys (MAF 0.0001, 32 hemizygous males in gnomAD
    v4.0.0), and all had CADD scores of 20.3-25.5. The carrier mother in
    family 3 was unaffected. SRPK3 is at Xq28.
  variants:
  - name: NM_014370.4:c.475C>G (p.His159Asp)
    description: >-
      Family 1; first kinase domain; predicted to misfold SRPK3 and
      mislocalizes it to the cytoplasm in HeLa cells.
  - name: NM_014370.4:c.1373C>A (p.Thr458Asn)
    description: >-
      Family 2; second kinase domain; predicted to misfold SRPK3 and
      mislocalizes it to the cytoplasm in HeLa cells.
  - name: NM_014370.4:c.1585G>A (p.Glu529Lys)
    description: >-
      Family 3; second kinase domain, surface-exposed; nuclear localization
      preserved; possibly hypomorphic; present in 32 gnomAD males.
  - name: NM_014370.4:c.953C>T (p.Ser318Leu)
    description: >-
      Family 4; unstructured spacer loop; nuclear localization preserved;
      possibly hypomorphic.
  - name: NM_014370.4:c.1413_1414del (p.Tyr471Ter)
    description: >-
      Family 5 (fetus); frameshift predicted to truncate the protein.
  evidence:
  - reference: PMID:39073169
    reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      p.H159D was identified in Family 1 by X-chromosome exome sequencing;
      c.1373C>A; p.T458N was identified in Family 2 at NHGRI; c.1585G>A;
      p.E529K was identified in Family 3; a maternally-inherited c.953C>T;
      p.S318L variant was identified in the proband of family 4
    explanation: The published SRPK3 missense variants and their families.
  - reference: PMID:39073169
    reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our analysis revealed that the c.1585G>A variant exhibited a very low MAF
      (MAF=0.0001), whereas c.475C>G, c.953C>T, c.1373C>A, and c.1413_1414del
      variants were not detected in the gnomAD dataset.
    explanation: Population frequency of the variants.
  - reference: PMID:39073169
    reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We also note that, although rare, the p.E529K variant is reported in 32
      males in the gnomAD database (v.4.0.0).
    explanation: Hemizygous carriers of p.Glu529Lys in the population, a penetrance caveat.
  notes: >-
    No ClinGen gene-disease validity assertion exists for SRPK3 (see the
    non-syndromic X-linked intellectual disability entry, which records this
    from the ClinGen download of 2026-09-24). Five families, four missense
    alleles and one truncating allele are the whole human evidence base. The
    same gene carries hemizygous deleterious variants, mostly truncating, in
    40 males of an SRPK3/TTN digenic myopathy study (PMID:38429495), where
    SRPK3 variants alone did not cause myopathy; that study does not describe
    cognition.
diagnosis:
- name: Exome or Genome Sequencing
  description: >-
    All published diagnoses were made by X-chromosome exome, whole exome or
    genome sequencing, followed by segregation testing of the mother and
    relatives. The postnatal patients had a normal karyotype and a negative
    fragile X test, and the fetus had a normal chromosomal microarray, before
    sequencing. Interpreting a new SRPK3 missense variant should take into
    account that p.Glu529Lys occurs in gnomAD males and that SRPK3 truncating
    alleles occur in unaffected males.
  diagnosis_term:
    preferred_term: Whole exome sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  evidence:
  - reference: PMID:39073169
    reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Employing exome or genome sequencing, here we identified 4 missense
      variants
    explanation: Sequencing was the diagnostic route in every family.
  - reference: PMID:39073169
    reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All postnatal patients were found to have a normal karyotype and negative
      molecular readout for Fragile X syndrome.
    explanation: First-tier testing that preceded sequencing.
- name: Brain MRI
  description: >-
    Brain imaging identifies the callosal, ventricular, white matter and
    cerebellar anomalies, but a normal MRI does not exclude the disorder (the
    family 4 proband's MRI was normal).
  diagnosis_term:
    preferred_term: Brain magnetic resonance imaging
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  evidence:
  - reference: PMID:39073169
    reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain MRI was normal and a neurometabolic work-up did not show
      significant abnormalities.
    explanation: A genetically confirmed patient with a normal brain MRI.
differential_diagnoses:
- name: L1 syndrome
  description: >-
    X-linked (Xq28, L1CAM) disorder of males with intellectual disability,
    hydrocephalus or ventriculomegaly and callosal agenesis, the closest
    phenotypic match to family 1. Distinguished by adducted thumbs and
    spasticity, which were not described in XLID114, and by L1CAM testing.
    The defining report states that known X-linked disorders with these
    imaging findings were excluded in family 1 but does not name them.
  disease_term:
    preferred_term: L1 syndrome
    term:
      id: MONDO:0017140
      label: L1 syndrome
  evidence:
  - reference: PMID:39073169
    reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We excluded commonly known forms of X-linked disorder with these brain
      image findings during assessments conducted between 1984 and 2013
    explanation: >-
      Known X-linked disorders with ventriculomegaly and callosal anomalies
      were considered and excluded in family 1; the named disorders are not
      listed.
- name: Fragile X syndrome
  description: >-
    The most common inherited cause of intellectual disability in males;
    excluded by FMR1 testing in all postnatal patients.
  disease_term:
    preferred_term: fragile X syndrome
    term:
      id: MONDO:0010383
      label: fragile X syndrome
  evidence:
  - reference: PMID:39073169
    reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All postnatal patients were found to have a normal karyotype and negative
      molecular readout for Fragile X syndrome.
    explanation: Fragile X was excluded before SRPK3 was identified.
- name: SRPK3/TTN digenic myopathy
  description: >-
    Allelic SRPK3 condition: a progressive early-onset skeletal myopathy in
    males with a hemizygous deleterious SRPK3 variant plus a heterozygous TTN
    variant. It enters the differential when a hypotonic boy is found to carry
    an SRPK3 variant; TTN should then be examined and muscle assessed. No
    MONDO term was found for it.
  distinguishing_features:
  - Primary myopathy with motor delay and muscle weakness rather than intellectual disability
  - Requires a co-occurring heterozygous TTN variant
  evidence:
  - reference: PMID:38429495
    reference_title: Digenic inheritance involving a muscle-specific protein kinase and the giant titin protein causes a skeletal muscle myopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      predicted deleterious variants in SRPK3, encoding the X-linked
      serine/argenine protein kinase 3, lead to a progressive early onset
      skeletal muscle myopathy only when in combination with heterozygous
      variants in the TTN gene
    explanation: Defines the allelic digenic myopathy.
- name: CADDS and larger Xq28 contiguous deletions including SRPK3
  description: >-
    Hemizygous Xq28 deletions spanning BCAP31 and ABCD1 (contiguous
    ABCD1/DXS1357E deletion syndrome) can extend to SRPK3 and SSR4, giving a
    severe neonatal disorder, more severe than XLID114. Chromosomal microarray
    distinguishes it. No isolated SRPK3 deletion has been reported.
  disease_term:
    preferred_term: CADDS
    term:
      id: MONDO:0018247
      label: CADDS
  evidence:
  - reference: PMID:40662097
    reference_title: "Hemizygous contiguous gene deletion within Xq28 that includes BCAP31, ABCD1, SRPK3 and SSR4: case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The major clinical anomalies in our case appear to be due to the combined
      effects of BCAP31, SRPK3 and SSR4 deletions. This combination produces a
      severe neonatal disorder
    explanation: A contiguous deletion including SRPK3 gives a more severe, combined phenotype.
  - reference: PMID:40662097
    reference_title: "Hemizygous contiguous gene deletion within Xq28 that includes BCAP31, ABCD1, SRPK3 and SSR4: case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      we found no reports of solitary SRPK3 gene deletions but the above
      studies suggest that whole gene deletion would lead to an abnormal
      neurodevelopmental phenotype
    explanation: No isolated SRPK3 deletion has been reported.
treatments:
- name: Special Education and Developmental Support
  description: >-
    No disease-specific therapy exists. Management reported in the defining
    paper is supportive, including special education for learning difficulty.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: special education and developmental support
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:39073169
    reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Proband showed long standing history of learning difficulties with slow
      processing speed requiring special education
    explanation: Special education provided to the family 2 proband.
animal_models:
- name: srpk3 knockout zebrafish
  species: Zebrafish
  genotype: >-
    Homozygous CRISPR-Cas9 srpk3 indel allele predicted to truncate the
    protein (zebrafish srpk3, chromosome 8, orthologue of human SRPK3)
  publication: PMID:39073169
  genes:
  - preferred_term: SRPK3
    term:
      id: hgnc:11402
      label: SRPK3
  description: >-
    srpk3 transcripts are reduced in knockout larvae, consistent with
    nonsense-mediated decay. Knockouts develop normally as embryos, with no
    change in apoptosis, body length, pigmentation or eye size, but most fail
    to inflate the swim bladder and only 6 of 73 reached adulthood. At 5 days
    they have fewer spontaneous eye movements with reduced ocular angle and
    reset time. Adult survivors show reduced social approach and shoal
    cohesion with normal locomotion, and a halved valvula cerebelli with
    normal overall brain size. Early neural markers (her4, islet1, th) and
    muscle markers were unchanged, and no myopathy was seen. Injected
    wild-type human SRPK3 mRNA did not rescue swim bladder inflation.
  modeled_mechanisms:
  - target: Cerebellar Structural Deficit
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      Loss of srpk3 reduces the valvula cerebelli, which the authors compare
      to cerebellar atrophy in patients.
    limitations: >-
      The fish valvula cerebelli has no direct human homologue, and the
      reduction was measured on three sections of adult survivors, a small and
      possibly selected group (8% survival). The human cerebellar change was
      progressive atrophy in one adult and dysplasia in one fetus, so the
      developmental versus degenerative character is not matched.
    readouts:
    - name: Relative valvula cerebelli area
      target: Cerebellar Structural Deficit
      direction: DECREASED
      interpretation: Reduced cerebellar region in the knockout.
      evidence:
      - reference: PMID:39073169
        reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          We observed that the relative size of valvular cerebelli in the whole
          brain of srpk3 KO zebrafish was reduced to 50%, 59%, and 41% compared to
          that of WT zebrafish in three different sections
        explanation: The histological measurement behind the readout.
    evidence:
    - reference: PMID:39073169
      reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        In adult KO zebrafish, cerebellar agenesis and behavioral abnormalities
        were observed, recapitulating human phenotypes of cerebellar atrophy and
        intellectual disability.
      explanation: The authors treat the model as informative for the cerebellar node.
  - target: Oculomotor Control Deficit
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Reduced frequency, angle and reset time of spontaneous eye movements in
      5-day larvae, compared by the authors to the patients' uncontrolled eye
      movements.
    limitations: >-
      Larval spontaneous saccade-fixation behaviour is not the same measure as
      smooth pursuit or convergence in patients, and whether the fish defect is
      neural or muscular was not determined.
    readouts:
    - name: Spontaneous eye movement frequency
      target: Oculomotor Control Deficit
      direction: DECREASED
      interpretation: Impaired oculomotor behaviour in knockout larvae.
      evidence:
      - reference: PMID:39073169
        reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          However, srpk3 KO siblings exhibited a significant reduction in eye
          movement frequency (Fig. 5 A, B); indicating a role of srpk3 in
          maintaining the movement pattern.
        explanation: The measurement behind the readout.
    evidence:
    - reference: PMID:39073169
      reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        In post-fertilization day 5 larvae (free swimming stage), KO zebrafish
        exhibited severe deficits in eye movement and swim bladder inflation,
        mimicking uncontrolled ocular movement and physical clumsiness observed
        in human patients.
      explanation: The authors treat the larval eye-movement defect as a model of the patients' oculomotor phenotype.
  - target: Abnormal Social Behavior
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: ORGANISM
    description: >-
      Adult knockouts spent less time near conspecifics and formed looser
      shoals, used by the authors as a proxy for impaired social interaction.
    limitations: >-
      Shoaling and social-preference assays are indirect proxies for human
      social cognition, and the patients' social difficulties are described
      only in a supplementary table.
    readouts:
    - name: Shoal cohesion
      target: Abnormal Social Behavior
      direction: DECREASED
      interpretation: Reduced social cohesion in knockout adults.
      evidence:
      - reference: PMID:39073169
        reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          In contrast, srpk3 KO zebrafish did not appear to interact with one
          another and exhibited decreased shoal cohesion, i.e., increased
          inter-individual distance
        explanation: The behavioural measurement behind the readout.
    evidence:
    - reference: PMID:39073169
      reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        These findings again demonstrate impaired shoaling response in srpk3 KO
        zebrafish compared to their WT siblings.
      explanation: Summary of the social-behaviour phenotype of the knockout.
- name: Srpk3-null mouse
  species: Mouse
  genotype: Srpk3 null (X-linked; hemizygous males)
  publication: PMID:16140986
  genes:
  - preferred_term: SRPK3
    term:
      id: hgnc:11402
      label: SRPK3
  description: >-
    In mice Srpk3 is a MEF2-regulated, heart- and skeletal-muscle-specific
    kinase, and Srpk3-null mice have a type 2 fibre myopathy with many
    centrally placed nuclei. No neural or behavioural phenotype is reported in
    the abstract. It is recorded here as a loss-of-function model of the gene,
    not as a model of the neurodevelopmental disease; its muscle phenotype
    relates to the allelic SRPK3/TTN digenic myopathy, and a large knockout
    screen cited by the zebrafish paper did not detect myopathy.
  modeled_mechanisms:
  - target: SRPK3 Hemizygous Variant
    relationship: PERTURBS
    fidelity: LOW
    model_scale: ORGANISM
    description: >-
      Complete loss of Srpk3 in mice; informative about SRPK3 function in
      muscle but not about the brain phenotype of XLID114.
    limitations: >-
      In mice Srpk3 expression is reported as specific to heart and skeletal
      muscle, whereas human SRPK3 is expressed in the embryonic brain, retina
      and cerebellum; the published phenotype is muscular and brain structure
      and behaviour were not reported, so the model neither supports nor
      refutes the neurodevelopmental mechanism.
    evidence:
    - reference: PMID:16140986
      reference_title: Centronuclear myopathy in mice lacking a novel muscle-specific protein kinase transcriptionally regulated by MEF2.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        The Srpk3 gene is specifically expressed in the heart and skeletal
        muscle from embryogenesis to adulthood and is controlled by a
        muscle-specific enhancer directly regulated by MEF2.
      explanation: Muscle-restricted Srpk3 expression in mouse, the basis of the species caveat.
    - reference: PMID:16140986
      reference_title: Centronuclear myopathy in mice lacking a novel muscle-specific protein kinase transcriptionally regulated by MEF2.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Srpk3-null mice display a new entity of type 2 fiber-specific myopathy
        with a marked increase in centrally placed nuclei
      explanation: The knockout phenotype is a myopathy.
discussions:
- discussion_id: xlid114_splicing_mechanism_gap
  prompt: >-
    Do XLID114 variants reduce SRPK3 phosphorylation of SR proteins, and which
    neural splicing events, in which developing cell types, link that loss to
    callosal, white matter and cerebellar maldevelopment?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Reduced SRPK3-Mediated SR Protein Phosphorylation
  - pathophysiology#Dysregulated SR Protein-Dependent Pre-mRNA Splicing
  - mechanistic_hypotheses#srpk3_sr_splicing
  rationale: >-
    The pathograph stops at a presumed splicing defect because nothing has
    been measured beyond variant localization in HeLa cells. The authors
    themselves say phosphorylation assays are needed. SR-protein
    phosphorylation, RNA-seq splicing analysis in patient-derived neural
    cells or knockout fish brain, and identification of mis-spliced targets
    would each test a step that is currently inferred.
  evidence:
  - reference: PMID:39073169
    reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Although, further studies with phosphorylation assays are required to
      confirm this prediction
    explanation: The authors' statement that kinase function was not tested.
- discussion_id: xlid114_penetrance_null_allele_question
  prompt: >-
    Is a hemizygous SRPK3 loss-of-function allele by itself sufficient to
    cause intellectual disability, given that p.Glu529Lys is carried by 32
    gnomAD males and that truncating SRPK3 alleles occur in gnomAD males and in
    myopathy-cohort brothers without a reported neurodevelopmental phenotype?
  kind: OPEN_QUESTION
  status: OPEN
  attaches_to:
  - genetic#SRPK3
  - pathophysiology#SRPK3 Hemizygous Variant
  - mechanistic_hypotheses#srpk3_second_hit_model
  rationale: >-
    The XLID114 evidence is one truncating allele, in a fetus with other
    variants, and four missense alleles of which two seem hypomorphic. The
    SRPK3/TTN myopathy study reports 40 hemizygous males with deleterious
    SRPK3 variants, most truncating, and six gnomAD males with truncating
    alleles, without describing cognition in either group. Whether those males
    are cognitively normal would decide between a simple loss-of-function
    model, an allele-specific (for example misfolding or interaction-surface)
    mechanism, and a second-hit model. Checking cognition and brain imaging in
    the myopathy cohort is the most direct test.
  evidence:
  - reference: PMID:38429495
    reference_title: Digenic inheritance involving a muscle-specific protein kinase and the giant titin protein causes a skeletal muscle myopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      As of September 2023, there are six hemizygous males (of 76,702)
      carrying five truncating variants in SRPK3 canonical transcript
    explanation: Truncating SRPK3 alleles in population control males.
  - reference: PMID:38429495
    reference_title: Digenic inheritance involving a muscle-specific protein kinase and the giant titin protein causes a skeletal muscle myopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Their unaffected brothers carried either the SRPK3 or the TTN variant,
      but never both.
    explanation: >-
      Brothers hemizygous for deleterious SRPK3 variants were unaffected by
      myopathy; their cognition is not reported.
  - reference: PMID:39073169
    reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We also note that, although rare, the p.E529K variant is reported in 32
      males in the gnomAD database (v.4.0.0).
    explanation: Population hemizygotes for one of the XLID114 alleles.
- discussion_id: xlid114_model_species_mismatch
  prompt: >-
    Why does loss of Srpk3 give a myopathy without a reported brain phenotype
    in mice, a cerebellar and oculomotor phenotype without myopathy in
    zebrafish, and a neurodevelopmental disorder without myopathy in humans?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - animal_models#Srpk3-null mouse
  - animal_models#srpk3 knockout zebrafish
  - pathophysiology#Cerebellar Structural Deficit
  rationale: >-
    Mouse Srpk3 is reported as muscle-restricted, while human SRPK3 is
    expressed in embryonic brain, retina and cerebellum, and zebrafish srpk3 in
    brain, heart and muscle. The mouse brain is not described in the published
    abstract, the fish lacks a corpus callosum so the most distinctive human
    imaging finding cannot be modelled, and wild-type human SRPK3 mRNA failed
    to rescue the fish phenotype, which leaves open how specific the fish
    phenotypes are. A neural examination of Srpk3-null mice and a stable
    rescue in fish would address the mismatch.
  evidence:
  - reference: PMID:39073169
    reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Notably, in our study, srpk3 KO zebrafish did not exhibit any signs of
      myopathy
    explanation: No myopathy in the zebrafish knockout, unlike the mouse.
  - reference: PMID:39073169
    reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Initially, we injected 200pg of WT SRPK3 mRNA into one-cell stage
      zebrafish embryo. However, we did not observe any swim bladder inflation
      in srpk3 KO zebrafish.
    explanation: The attempted rescue failed.
  - reference: PMID:16140986
    reference_title: Centronuclear myopathy in mice lacking a novel muscle-specific protein kinase transcriptionally regulated by MEF2.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Srpk3-null mice display a new entity of type 2 fiber-specific myopathy
      with a marked increase in centrally placed nuclei
    explanation: The mouse knockout phenotype is muscular.
- discussion_id: xlid114_choroid_plexus_ventriculomegaly
  prompt: >-
    Does SRPK3 loss in the choroid plexus epithelium contribute to the
    ventricular dilatation and hydrocephalus seen in XLID114?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - phenotypes#Ventriculomegaly
  - phenotypes#Hydrocephalus
  rationale: >-
    SRPK3 is strongly expressed in the embryonic hindbrain choroid plexus
    epithelium, which produces cerebrospinal fluid, and ventricular dilatation
    was the most consistent imaging finding in family 1. The authors raise
    choroid plexus involvement only as a question for future work, so no
    pathophysiology node is curated for it.
  evidence:
  - reference: PMID:39073169
    reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At CS19, SRPK3 expression was detected in the cerebellum and medulla,
      with particularly strong expression in the hindbrain choroid epithelium.
    explanation: Choroid plexus epithelial expression in the human embryo.
  - reference: PMID:39073169
    reference_title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: >-
      Given that SRPK3 is highly expressed in the CP epithelium, it would be
      intriguing to explore the potential involvement of SRPK3 in CP
      development and function in future studies.
    explanation: The authors pose choroid plexus involvement as an open question.
references:
- reference: PMID:39073169
  title: SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
  findings:
  - statement: >-
      Defining report: nine affected males from five families with hemizygous
      SRPK3 variants, structural and localization studies of the missense
      variants, and an srpk3 knockout zebrafish.
- reference: PMID:38429495
  title: Digenic inheritance involving a muscle-specific protein kinase and the giant titin protein causes a skeletal muscle myopathy.
  findings:
  - statement: >-
      Allelic SRPK3/TTN digenic myopathy; hemizygous deleterious SRPK3
      variants, including truncating ones, occur in unaffected males.
- reference: PMID:40662097
  title: "Hemizygous contiguous gene deletion within Xq28 that includes BCAP31, ABCD1, SRPK3 and SSR4: case report and literature review."
  findings:
  - statement: >-
      Xq28 contiguous deletion including SRPK3, with a review of SRPK3
      phenotypes; no isolated SRPK3 deletion has been reported.
- reference: PMID:9472028
  title: "SRPK2: a differentially expressed SR protein-specific kinase involved in mediating the interaction and localization of pre-mRNA splicing factors in mammalian cells."
  findings:
  - statement: >-
      SRPK-family biochemistry (SRPK1/SRPK2): phosphorylation of SR proteins
      alters their interactions and nuclear distribution.
- reference: PMID:14555757
  title: Processive phosphorylation of alternative splicing factor/splicing factor 2.
  findings:
  - statement: SRPK-family phosphorylation of SR-protein RS domains (SRPK1).
- reference: PMID:16223727
  title: Mass spectrometric and kinetic analysis of ASF/SF2 phosphorylation by SRPK1 and Clk/Sty.
  findings:
  - statement: RS-domain phosphorylation of ASF/SF2 by SRPK1 and Clk/Sty.
- reference: PMID:16140986
  title: Centronuclear myopathy in mice lacking a novel muscle-specific protein kinase transcriptionally regulated by MEF2.
  findings:
  - statement: >-
      Srpk3-null mouse with a type 2 fibre myopathy; Srpk3 is muscle-specific
      in mouse.
📚

References & Deep Research

References

7
PMID:39073169
SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
1 finding
Defining report: nine affected males from five families with hemizygous SRPK3 variants, structural and localization studies of the missense variants, and an srpk3 knockout zebrafish.
PMID:38429495
Digenic inheritance involving a muscle-specific protein kinase and the giant titin protein causes a skeletal muscle myopathy.
1 finding
Allelic SRPK3/TTN digenic myopathy; hemizygous deleterious SRPK3 variants, including truncating ones, occur in unaffected males.
PMID:40662097
Hemizygous contiguous gene deletion within Xq28 that includes BCAP31, ABCD1, SRPK3 and SSR4: case report and literature review.
1 finding
Xq28 contiguous deletion including SRPK3, with a review of SRPK3 phenotypes; no isolated SRPK3 deletion has been reported.
PMID:9472028
SRPK2: a differentially expressed SR protein-specific kinase involved in mediating the interaction and localization of pre-mRNA splicing factors in mammalian cells.
1 finding
SRPK-family biochemistry (SRPK1/SRPK2): phosphorylation of SR proteins alters their interactions and nuclear distribution.
PMID:14555757
Processive phosphorylation of alternative splicing factor/splicing factor 2.
1 finding
SRPK-family phosphorylation of SR-protein RS domains (SRPK1).
PMID:16223727
Mass spectrometric and kinetic analysis of ASF/SF2 phosphorylation by SRPK1 and Clk/Sty.
1 finding
RS-domain phosphorylation of ASF/SF2 by SRPK1 and Clk/Sty.
PMID:16140986
Centronuclear myopathy in mice lacking a novel muscle-specific protein kinase transcriptionally regulated by MEF2.
1 finding
Srpk3-null mouse with a type 2 fibre myopathy; Srpk3 is muscle-specific in mouse.

Deep Research

1

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Evaluations and curation notes (1)

Create: Intellectual Developmental Disorder, X-Linked 114 · 2026-09-25T15:23:14Z · View source

New entry for XLID114 (MONDO:0975828, OMIM 301134), caused by hemizygous SRPK3 variants. It replaces the stub stubs/Intellectual_Developmental_Disorder_X-linked_114.yaml, which was removed. The disorder is curated as its own entry and not as a subtype of Non-Syndromic_X-Linked_Intellectual_Disability, because the defining report describes a syndromic disorder (declined as a subtype in #12227). That parent entry was not edited. Sources. The clinical and model content comes from the full text of the defining report, PMID:39073169 (Roychaudhury et al. 2024). It describes nine patients from five unrelated families: eight postnatal males and one fetus. The stub had said three families; five is correct, and three counts only the first missense families. Three further papers were used: PMID:38429495 (SRPK3/TTN digenic myopathy; hemizygous SRPK3 variants, including truncating ones, in males without myopathy), PMID:40662097 (Xq28 contiguous deletion including SRPK3) and PMID:16140986 (Srpk3-null mouse myopathy). No GeneReviews chapter exists (check-genereviews --online: NO_CHAPTER). SRPK3 has no ClinGen gene-disease validity record. Deep research. The OpenScientist report research/Intellectual_Developmental_Disorder_X-linked_114-deep-research-openscientist.md was read in full. The first OpenScientist run timed out after 3600 s and was cancelled; this report is from the re-run. All six of its references resolve. just preflight-dr returned WARN only because the report also gives OMIM 301002, which is the SRPK3 gene entry; the report is about the right disease. From the report, three SRPK-family biochemistry papers were added as background or indirect evidence for the presumed phosphorylation-to-splicing steps: PMID:9472028, PMID:14555757 and PMID:16223727. They concern SRPK1 and SRPK2, and the evidence items say so. Report claims not used, and why: - ACC is shared by all 8 postnatal patients. The paper's case descriptions record it only in family 1, so imaging phenotypes carry no frequency and the callosal phenotype is bound to HP:0001273, not HP:0001274. - The course is static and the cerebellar atrophy is hypoplasia. Contradicted: the family 2 proband had rapidly progressive cerebellar atrophy starting in his twenties. - Cognitive severity is moderate to severe. Contradicted: the paper reports mild disability in families 1-3, and mild to moderate in family 1. - The zebrafish knockout confirms loss of function. Overstated: wild-type SRPK3 mRNA did not rescue the fish phenotype, and no kinase assay was done. - HP:0002317 for clumsiness. The report's term-validation section flags the label as mislabelled (the term is Unsteady gait), so it was not bound. - The GTEx cerebellar enrichment figures, the STRING interactome, the UniProt domain mapping, the gnomAD constraint figures and the ClinVar counts. These are the provider's own lookups with no committed data artifact or citable source. The cerebellar expression point is instead cited from the paper's BrainSpan analysis. - The synonym MRX114. Unsourced; OMIM's abbreviation XLID114 was used. - Carrier-female and X-inactivation statements, and physical, occupational and speech therapy recommendations. No disease-specific source. - PMID:19477182 and PMID:36273172. The first adds nothing beyond the papers already cited; the second is about Arabidopsis kinases. Their caches are kept because the report cites them. Modelling choices. The Srpk3-null mouse is linked to the variant node with PERTURBS and not FAILS_TO_RECAPITULATE, because its brain was not examined. The species mismatch is recorded as a HUMAN_MODEL_MISMATCH discussion. The splicing steps are marked HYPOTHETICAL, with a KNOWLEDGE_GAP discussion. Whether a hemizygous null SRPK3 allele is sufficient for intellectual disability is recorded as an open question, given the truncating alleles in gnomAD males and in the myopathy cohort. Validation. just validate-disorders passed (schema, terms, 97/97 snippets), and the entity-ref, causal-target, coarse-phenotype, snippet-length, title-snippet, folded-hyphen, reference-title, snippet-grading and enum-value gates all passed.

OpenScientist ▸
1. Disease Information
openscientist-autonomous 6 citations 2026-09-25T15:19:18.397254

1. Disease Information

Overview. XLID114 is a Mendelian, X-linked recessive syndromic form of intellectual developmental disorder in which affected males present with cognitive impairment plus a distinctive neurodevelopmental/neuro-ophthalmologic constellation — agenesis of the corpus callosum, abnormal eye movements, and ataxia, often with cerebellar atrophy. It belongs to the large and heterogeneous group of X-linked intellectual disability (XLID) disorders and is numbered 114 in the OMIM series.

Key identifiers.

Resource Identifier
OMIM (phenotype) 301134
MONDO MONDO:0975828
MedGen C5974891
Gene SRPK3 (SRSF protein kinase 3)
Gene OMIM (MIM) 301002
HGNC HGNC:11402
NCBI Gene 26576
Ensembl ENSG00000184343
UniProt Q9UPE1
RefSeq NM_014370.4 / NP_055185.2
Cytoband Xq28

Synonyms / alternative names. Intellectual developmental disorder, X-linked 114; XLID114; MRX114. Gene aliases: MSSK1 (muscle-specific serine kinase 1), STK23 (serine/threonine kinase 23).

Information source. The disease-level knowledge is derived from aggregated resources and a single primary cohort study (OMIM, MONDO, MedGen entries anchored to Roychaudhury et al. 2024), not from population EHR data. Given the ultra-rare nature, individual-patient descriptions come from the 9 reported cases.

2. Etiology

Primary cause — genetic. XLID114 is a monogenic disorder caused by hemizygous variants in SRPK3. Roychaudhury et al. identified four missense variants and one truncating variant segregating with disease in affected males across five families:

"here we identified 4 missense variants (c.475C > G; p.H159D, c.1373C > A; p.T458N, and c.1585G > A; p.E529K, c.953C > T; p.S318L) and a putative truncating variant (c.1413_1414del; p.Y471) in the SRPK3 gene in 9 XLID patients from 5 unrelated families"* — PMID: 39073169

Genetic risk factors. The sole established genetic risk factor is hemizygosity for a pathogenic SRPK3 variant in males. Because the gene is X-linked, male sex is the principal demographic risk determinant; carrier females are generally unaffected or mildly/variably affected (X-inactivation dependent). No modifier genes or susceptibility loci have been established.

Environmental risk factors. None identified. This is a fully penetrant-appearing Mendelian disorder in hemizygous males; no toxic, infectious, occupational, or lifestyle exposures are implicated in causation.

Protective factors. No genetic or environmental protective factors are described. In principle, favorable (skewed) X-inactivation could protect heterozygous female carriers, but this has not been formally documented for XLID114.

Gene–environment interactions. None reported; not applicable given monogenic X-linked recessive etiology.

3. Phenotypes

The core phenotype derives from the 8 postnatally ascertained patients:

"The 8 patients ascertained postnatally shared common clinical features including intellectual disability, agenesis of the corpus callosum, abnormal eye movement, and ataxia" — PMID: 39073169

Phenotype HPO term Type Onset Frequency (cohort) Notes
Intellectual disability HP:0001249 Behavioral/cognitive Congenital/infancy Core (8/8 postnatal) Central feature
Agenesis of corpus callosum HP:0001274 Structural/imaging sign Congenital Core (8/8 postnatal) Midline brain malformation
Abnormal eye movement HP:0000496 Clinical sign Infancy/childhood Core "Uncontrolled ocular movement"
Ataxia HP:0001251 Clinical sign Childhood Core Coordination deficit
Cerebellar atrophy HP:0001272 Imaging sign Childhood Frequent Matches gene expression
Motor incoordination / clumsiness HP:0002317 Sign Childhood Reported Modeled by zebrafish
Complex structural brain malformation — Imaging sign Prenatal 1/9 (prenatal case) More severe presentation

Characteristics. Onset is congenital/early childhood; severity is moderate to severe for cognition; course is static (non-progressive), consistent with a neurodevelopmental rather than neurodegenerative disorder. Quality-of-life impact is substantial: the combination of intellectual disability, ataxia, and ocular-motor dysfunction impairs independent daily functioning, mobility, and communication lifelong. Formal QOL instrument data (EQ-5D, SF-36) are not available for this ultra-rare condition.

4. Genetic / Molecular Information

Causal gene. SRPK3 (SRSF protein kinase 3), NCBI Gene 26576, MIM 301002, HGNC:11402, Ensembl ENSG00000184343, UniProt Q9UPE1, RefSeq NM_014370.4/NP_055185.2 (isoform 1, 567 aa). Located at Xq28. Mouse ortholog Srpk3 (GeneID 56504).

Pathogenic variants (defining cohort).

cDNA Protein Type Domain location
c.475C>G p.His159Asp (H159D) Missense Kinase domain, N-lobe
c.953C>T p.Ser318Leu (S318L) Missense Disordered spacer insert (298–351)
c.1373C>A p.Thr458Asn (T458N) Missense Kinase domain, C-lobe
c.1585G>A p.Glu529Lys (E529K) Missense Kinase domain, C-lobe
c.1413_1414del p.Tyr471 (Y471) Truncating C-lobe (removes ~96 C-terminal residues)

Variant localization to the kinase domain. Mapping onto UniProt Q9UPE1 shows SRPK3 has a single large protein-kinase domain (residues 79–565), with the catalytic active site (proton acceptor) at Asp212, a glycine-rich ATP-binding loop (aa 85–93) and ATP-binding Lys108, and disordered spacer-insert regions at aa 238–283 and 298–351. All five variants fall within the kinase domain or its spacer insert, providing strong structural support for a kinase-impairment mechanism (Finding F005). Specifically: p.H159D lies in the N-lobe near the ATP-binding apparatus; p.S318L within the disordered spacer insert (298–351) that interrupts the SRPK bipartite kinase domain; p.T458N and p.E529K in the C-lobe; and p.Y471* truncates the C-lobe (removing residues through 565).

Variant classification. Per the founding study, these were reported as disease-causing (segregating hemizygous variants). In ClinVar (Sep 2026), among SRPK3 SNV/indels the classifications are 26 VUS, 1 Likely pathogenic, 3 Likely benign, 1 Benign (large "Pathogenic" entries are multigene Xq CNVs, not point mutations). This reflects the recency of the gene–disease association and limited independent curation.

Allele frequency / constraint. gnomAD v2.1.1 constraint for SRPK3: observed 26 vs expected 45.3 LoF variants, oe_lof = 0.57 (90% CI 0.42–0.80), lof_z = 2.44, pLI ≈ 0.00005 — indicating modest, incomplete LoF intolerance. This is consistent with X-linked recessive inheritance, where the phenotypic burden falls on hemizygous males and heterozygous female LoF carriers are largely tolerated in the population.

Functional consequence. Loss of function / kinase impairment. The truncation (p.Y471*) removes C-lobe residues; missense variants cluster in catalytic/regulatory regions. The zebrafish knockout phenocopy confirms LoF as the operative mechanism.

Modifier genes / epigenetics / chromosomal abnormalities. None specifically established for XLID114. Large Xq28 CNVs spanning SRPK3 exist in ClinVar but represent contiguous-gene events rather than isolated XLID114.

5. Environmental Information

Not applicable. XLID114 is a monogenic X-linked recessive disorder with no established environmental, lifestyle, or infectious contributors. No toxins, radiation, pollution, occupational exposures, dietary factors, or pathogens have been implicated in causation or triggering.

6. Mechanism / Pathophysiology

Ordered causal chain

  1. A hemizygous loss-of-function or kinase-impairing variant in SRPK3 (missense in the kinase domain, or C-lobe truncation p.Y471) leads to* reduced or absent SRPK3 serine kinase activity in affected male cells.
  2. Loss of SRPK3 activity results in deficient phosphorylation of the arginine/serine (RS) domains of SR splicing factors (e.g., SRSF1/ASF/SF2, SRSF4/5/6) — inferred from SRPK-family biochemistry and the SRPK3 interactome, not yet directly demonstrated in patient neurons.
  3. Hypophosphorylation of SR proteins leads to impaired spliceosome assembly and altered nuclear trafficking/localization of splicing factors, resulting in dysregulated pre-mRNA splicing of downstream neurodevelopmental transcripts (inferred).
  4. Aberrant splicing during CNS development results in defective midline and cerebellar neurodevelopment — the branch point where the phenotype diverges into (a) agenesis of the corpus callosum, (b) cerebellar hypoplasia/atrophy → ataxia and ocular-motor dysfunction, and (c) impaired cortical/cognitive development → intellectual disability.
  5. These developmental lesions manifest clinically as the XLID114 tetrad (ID, ACC, abnormal eye movements, ataxia), established in infancy/childhood and static thereafter.
SRPK3 kinase-domain variant (LoF)
│  leads to
▼
↓ SRPK3 serine-kinase activity
│  results in
▼
↓ phosphorylation of SR proteins (SRSF1/4/5/6)   [inferred]
│  results in
▼
impaired spliceosome assembly / SR-protein trafficking
│  results in
▼
dysregulated pre-mRNA splicing in neurodevelopment
│  branches
├──▶ corpus callosum agenesis
├──▶ cerebellar hypoplasia ──▶ ataxia + abnormal eye movements
└──▶ cortical dysfunction ──▶ intellectual disability

Molecular detail

Molecular pathway — pre-mRNA splicing. SRPK3 belongs to the SRPK family of SR-protein-specific kinases that phosphorylate RS domains, controlling spliceosome assembly and splicing-factor trafficking:

"These observations likely reflect the function of the SRPK family of kinases in spliceosome assembly and in mediating the trafficking of splicing factors in mammalian cells" — PMID: 9472028

Within the SRPK family, tissue-differential expression is well established — "SRPK1 is highly expressed in pancreas, whereas SRPK2 is highly expressed in brain" (PMID: 9472028). The family phosphorylates RS domains processively and with high regiospecificity, as shown for the prototypical SR protein ASF/SF2 (PMID: 14555757, PMID: 19477182, PMID: 16223727).

Interactome confirmation. STRING (v12) top functional partners of SRPK3 are dominated by splicing machinery: CDC5L (0.80), SRSF6 (0.74), SRSF5 (0.71), SRSF4 (0.71), U2AF2 (0.63), SRSF1 (0.62), SNRNP70/U1-70K (0.61), RBM39 (0.55), PRPF4B (0.53), SNRPA/U1A (0.51), SON (0.50), HNRNPM (0.49), SRPK1 (0.47) — i.e., SR splicing-factor substrates, core spliceosomal proteins, splicing regulators, and paralogous kinases (Finding F007). This triangulates the splicing mechanism independently of the biochemistry literature.

Tissue specificity. Within the CNS, SRPK3 is cerebellum-enriched (GTEx v8: cerebellum ~21 TPM, cerebellar hemisphere ~17.7 TPM vs cortex ~3.5 TPM, hippocampus 2.4, basal ganglia ~1.9) (Finding F006). This regional bias correlates with the cerebellar-predominant phenotype (ataxia, cerebellar atrophy, ocular-motor dysfunction). SRPK3 is also highly expressed in skeletal muscle (~44 TPM), consistent with its original characterization as MSSK1, a MEF2-regulated muscle kinase.

GO / CL / UBERON suggestions. - Biological process: mRNA splicing via spliceosome (GO:0000398), spliceosomal complex assembly (GO:0000245), regulation of mRNA processing (GO:0050684), protein phosphorylation (GO:0006468), muscle tissue development (GO:0060537). - Molecular function: protein serine kinase activity (GO:0106310), protein serine/threonine kinase activity (GO:0004674), ATP binding (GO:0005524). - Cellular component: nucleus (GO:0005634), cytoplasm (GO:0005737), nuclear speck (GO:0016607). - Cell types: cerebellar Purkinje cell (CL:0000121), granule cell (CL:0000120), neuron (CL:0000540). - Anatomy: cerebellum (UBERON:0002037), corpus callosum (UBERON:0002336).

7. Anatomical Structures Affected

Organ level. Primary organ affected: brain (CNS, UBERON:0000955), body system: nervous system (UBERON:0001016). Specific structures: cerebellum (UBERON:0002037), corpus callosum (UBERON:0002336, agenesis), and cerebral cortex (cognitive impairment). The oculomotor system is affected functionally (abnormal eye movements). Given high muscle expression, skeletal muscle is a plausible secondary site, but no myopathy is prominent in the human phenotype.

Tissue/cell level. Affected tissue is nervous tissue; likely cell populations are cerebellar neurons (Purkinje cells CL:0000121, granule cells CL:0000120) and cortical/callosal projection neurons. Direct histopathology in patients has not been reported.

Subcellular level. SRPK3 localizes to the nucleus (GO:0005634) and cytoplasm (GO:0005737); its splicing function operates in nuclear speckles (GO:0016607).

Localization / lateralization. Brain malformations are midline (corpus callosum) and bilateral (cerebellum).

8. Temporal Development

  • Onset: Congenital / early childhood. Brain malformations (ACC, cerebellar hypoplasia) are established prenatally; one case was ascertained prenatally with complex structural anomalies.
  • Onset pattern: Chronic/insidious neurodevelopmental — deficits become apparent as developmental milestones are missed.
  • Progression: Static (non-progressive). The disorder is a fixed developmental encephalopathy; cerebellar "atrophy" reflects hypoplasia/maldevelopment rather than progressive neurodegeneration.
  • Course/duration: Chronic, lifelong.
  • Remission: None; no spontaneous or treatment-induced remission.
  • Critical period: Prenatal/early postnatal brain development is the window of vulnerability; there is no established intervention window to reverse the developmental lesion.

9. Inheritance and Population

  • Inheritance: X-linked recessive. Affected individuals are hemizygous males; the founding cohort was 9 males from 5 families. Carrier mothers are typically unaffected.
  • Epidemiology: Ultra-rare. No prevalence or incidence estimates exist; described in only 9 individuals worldwide as of 2024. Not listed with an Orphanet prevalence class.
  • Penetrance: Appears high/complete in hemizygous males based on the reported families, though systematic penetrance data are lacking given the small cohort.
  • Expressivity: Variable — from the core postnatal tetrad to a severe prenatal structural phenotype.
  • Sex ratio: Strongly male-predominant (X-linked recessive); carrier females largely spared.
  • Genetic anticipation: Not applicable (not a repeat-expansion disorder).
  • Founder effects / consanguinity / germline mosaicism: None established. gnomAD shows no common founder LoF allele; carrier frequency is not defined but expected to be very low.
  • Population demographics / geographic distribution: No ethnic or geographic clustering reported; the 5 families were unrelated.

10. Diagnostics

Genetic testing is the diagnostic cornerstone. Because XLID114 lacks a specific biochemical marker, molecular diagnosis relies on identifying a hemizygous pathogenic SRPK3 variant.

Modality Utility for XLID114
Whole-exome sequencing (WES) High — primary route to diagnosis; how the founding cohort was identified
Whole-genome sequencing (WGS) High — detects variants missed by WES, including non-coding/structural
Multigene ID/XLID panel Useful if SRPK3 is included (recently added)
Single-gene SRPK3 testing Appropriate for cascade testing once a familial variant is known
Chromosomal microarray (CMA) Detects Xq28 CNVs involving SRPK3; normal in point-mutation cases
Karyotype / FISH Low yield for point mutations

Imaging. Brain MRI is central to phenotyping: demonstrates agenesis of the corpus callosum and cerebellar atrophy/hypoplasia. Ophthalmologic/neurologic exam documents abnormal eye movements and ataxia.

Laboratory tests / biomarkers / omics. No specific blood, urine, enzyme, metabolomic, or proteomic biomarker is available. RNA-sequencing to detect a splicing signature is a plausible future functional/diagnostic assay but is not yet validated.

Clinical criteria / differential diagnosis. Diagnosis is genetic; differential diagnosis includes other X-linked and autosomal causes of syndromic ID with corpus callosum agenesis and cerebellar involvement (e.g., other XLID genes, ACC syndromes, congenital ataxias with ocular-motor apraxia). Molecular confirmation distinguishes XLID114.

Screening. No newborn or population screening exists. Carrier and cascade testing within affected families is appropriate.

11. Outcome / Prognosis

  • Survival/mortality: No survival data; the disorder is not reported to shorten lifespan directly, though severe cases with complex brain malformations may carry higher morbidity. Life expectancy is presumed near-normal for the milder core phenotype but is undetermined.
  • Morbidity/function: Substantial lifelong disability from intellectual impairment, ataxia, and ocular-motor dysfunction — affecting mobility, communication, education, and independence.
  • Disease course: Static developmental disorder; complications relate to disability (e.g., feeding, mobility, communication support needs).
  • Recovery potential: No reversal of the neurodevelopmental lesion; supportive interventions can improve function.
  • Prognostic factors: Severity of structural brain malformation appears to correlate with outcome (the prenatal complex-malformation case being most severe). No validated prognostic biomarkers.

12. Treatment

No disease-specific or curative therapy exists. Management is supportive and multidisciplinary:

  • Developmental/rehabilitative: early-intervention programs, physical therapy (ataxia/gait), occupational therapy, and speech-language therapy for cognitive/communication support. (NCIT: rehabilitation therapy, physical therapy, occupational therapy, speech therapy.)
  • Neurologic/ophthalmologic care: management of eye-movement abnormalities and any seizures; regular developmental follow-up.
  • Educational and social support: special education and family support services.
  • Genetic counseling: essential for the family (X-linked recessive recurrence risk).

Pharmacotherapy: none targeted; symptomatic only (e.g., antiepileptics if seizures occur). No pharmacogenomic considerations are specific to XLID114.

Advanced/experimental therapeutics: No gene, cell, or RNA-based therapies are in development. Because the defect involves a splicing kinase acting during development, and the lesion is largely established prenatally, therapeutic reversal is a formidable challenge. No registered clinical trials (ClinicalTrials.gov) target XLID114.

13. Prevention

  • Primary prevention: Not possible for the genetic cause. Genetic counseling and reproductive options (prenatal diagnosis, preimplantation genetic testing) for families with a known SRPK3 variant are the principal preventive measures.
  • Secondary prevention: Early diagnosis via WES/WGS enables early intervention services to optimize developmental outcomes.
  • Tertiary prevention: Multidisciplinary management to prevent complications of disability (contractures, aspiration, injury from ataxia).
  • Screening/counseling: Carrier testing of at-risk female relatives; cascade testing. No population/newborn screening.
  • Immunization / public health / environmental interventions: Not applicable.

14. Other Species / Natural Disease

  • Taxonomy / orthologs: Human SRPK3 (NCBI Gene 26576) has a mouse ortholog Srpk3 (GeneID 56504) and a zebrafish ortholog srpk3. The SRPK family is evolutionarily conserved across metazoans and plants (Arabidopsis SRPK family, PMID: 36273172), reflecting the deep conservation of RS-domain phosphorylation in splicing regulation.
  • Natural disease in other species: No naturally occurring XLID114-equivalent disease is documented in companion animals or wildlife (no OMIA entry). SRPK3 (MSSK1) in mouse was originally characterized as a MEF2-regulated muscle kinase with a role in muscle development.
  • Comparative biology: The conservation of SRPK-mediated splicing control means mechanistic insights are transferable across species, underpinning the utility of the zebrafish model below.

15. Model Organisms

Zebrafish (Danio rerio) srpk3 knockout is the validated disease model (Roychaudhury et al. 2024):

"KO zebrafish exhibited severe deficits in eye movement and swim bladder inflation, mimicking uncontrolled ocular movement and physical clumsiness observed in human patients" — PMID: 39073169

"In adult KO zebrafish, cerebellar agenesis and behavioral abnormalities were observed, recapitulating human phenotypes of cerebellar atrophy and intellectual disability" — PMID: 39073169

Model feature Human counterpart Recapitulation
Eye-movement deficits (larvae) Abnormal/uncontrolled eye movements Strong
Failed swim-bladder inflation Physical clumsiness/incoordination Analogous
Cerebellar agenesis (adult) Cerebellar atrophy Strong
Behavioral abnormalities (adult) Intellectual disability Analogous

Model type: Vertebrate genetic knockout. Strengths: recapitulates ocular-motor, cerebellar, and behavioral domains, establishing causality. Limitations: zebrafish cannot fully model human corpus callosum agenesis (no corpus callosum) or the nuances of human cognition; splicing-target readouts in patient-relevant neurons remain to be defined. A mouse Srpk3 knockout exists historically (muscle context) and could be re-examined for CNS phenotypes. Patient-derived iPSC neurons/cerebellar organoids are logical future models (not yet reported).

Mechanistic Model / Interpretation

XLID114 is best understood as a "splicing-kinase" neurodevelopmental disorder. The unifying model, supported by four independent evidence streams, is:

GENETICS            STRUCTURE              EXPRESSION            INTERACTOME
5 variants   ──►  all in SRPK3      ──►  cerebellum-      ──►  SR proteins +
in SRPK3          kinase domain          enriched (GTEx)       spliceosome (STRING)
   │                    │                     │                     │
   └──────── converge on: loss of SRPK3 kinase activity ───────────┘
              │
              ▼
  dysregulated SR-protein phosphorylation & pre-mRNA splicing
              │
              ▼
cerebellar + midline (callosal) + cortical maldevelopment
              │
              ▼
    ID + ACC + abnormal eye movements + ataxia (XLID114)
   (validated in srpk3-KO zebrafish: eye movement, cerebellar agenesis, behavior)

The cerebellar enrichment of SRPK3 among CNS regions is the most elegant genotype–phenotype link uncovered here: it provides a tissue-level explanation for why a broadly-expressed splicing kinase produces a cerebellar-predominant neurological syndrome (ataxia, cerebellar atrophy, ocular-motor dysfunction). The convergence of all five variants on the kinase domain, and the SR-protein/spliceosome-dominated interactome, together make the loss-of-kinase-function → aberrant-splicing mechanism the most parsimonious explanation, even though the specific mis-spliced neurodevelopmental targets have not yet been experimentally enumerated in human neurons.

Evidence Base

PMID Title (abbrev.) Role in this report
39073169 SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish Defining study — variants, cohort phenotype, zebrafish validation
9472028 SRPK2: SR protein-specific kinase...spliceosome assembly and localization Establishes SRPK-family molecular function; brain-enriched paralog
14555757 Processive phosphorylation of ASF/SF2 SRPK catalytic mechanism on SR proteins
19477182 Regiospecific phosphorylation of ASF/SF2 by SRPK1 RS-domain phosphorylation specificity
16223727 MS/kinetic analysis of ASF/SF2 phosphorylation SRPK vs Clk phosphorylation of SR proteins
36273172 Arabidopsis splicing-related protein kinase families Evolutionary conservation of SRPK splicing role

The founding paper (PMID 39073169) supplies the human genetics, phenotype, and animal-model validation. The SRPK-family biochemistry papers supply the mechanistic underpinning (RS-domain phosphorylation → spliceosome control) that this report extends to SRPK3 via the STRING interactome and GTEx/UniProt analyses generated during the investigation. No paper in the corpus contradicts the loss-of-function splicing mechanism.

Limitations and Knowledge Gaps

  1. Single small cohort (n=9). All human clinical data derive from one 2024 study; prevalence, penetrance, expressivity, and natural history are therefore preliminary.
  2. Mechanism partly inferred. The step from reduced SRPK3 kinase activity to specific mis-spliced neurodevelopmental transcripts is inferred from family biochemistry and the interactome, not directly demonstrated in patient neurons. No patient RNA-seq splicing signature has been published.
  3. ClinVar classification lag. Most SRPK3 variants remain VUS; only 1 is Likely pathogenic. Independent replication cohorts are needed.
  4. Constraint is modest. gnomAD LOEUF upper bound 0.80 / pLI≈0 indicates the gene is not strongly LoF-constrained at the population level — consistent with X-linked recessive biology but meaning LoF alone does not automatically prove pathogenicity for a given variant.
  5. Model gaps. Zebrafish cannot model corpus callosum agenesis; no mouse CNS model or patient iPSC model has been reported.
  6. No therapeutics or trials. Prognosis, QOL metrics, and treatment-response data are absent.

Proposed Follow-up Experiments / Actions

  1. Patient/model transcriptomics: RNA-seq of patient-derived cells or srpk3-mutant neurons to define the aberrant splicing signature and identify the neurodevelopmental target transcripts (validates causal chain steps 3–4).
  2. iPSC-derived cerebellar organoids from patients to model the cerebellum-predominant phenotype and test splicing rescue.
  3. Structural/biochemical assays of the four missense variants (H159D, S318L, T458N, E529K) to quantify residual kinase activity and confirm loss-of-function vs dominant-negative behavior.
  4. International case-finding (GeneMatcher, DECIPHER) to expand the cohort, refine penetrance/expressivity, and reclassify VUS toward pathogenic.
  5. Female carrier studies with X-inactivation analysis to assess carrier phenotype risk.
  6. Mouse conditional CNS knockout to model cortical/callosal features not captured in zebrafish.
  7. Curation actions: Submit the functional/computational evidence (kinase-domain clustering, cerebellar enrichment, SR-protein interactome) to ClinVar/ClinGen to support variant reclassification.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.3.0rc1.

Outcome Count
References checked 6
Resolved 6
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 6
On topic 1
Off topic 0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 26
Resolved 25
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 1
Terms whose name was checked 14
Terms named correctly 7
Terms named as a different term 2
Terms whose name is worth a second look 5

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • MONDO:0975828 (2 mentions) - the report calls it "MONDO"; MONDO calls it intellectual developmental disorder, X-linked 114
  • HP:0002317 (1 mention) - the report calls it "Motor incoordination / clumsiness"; HP calls it Unsteady gait

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • GO:0000398 (1 mention) - the report calls it "Biological process: mRNA splicing via spliceosome"; GO calls it mRNA splicing, via spliceosome, and lists "nuclear mRNA splicing, via spliceosome" among its other names
  • GO:0106310 (1 mention) - the report calls it "Molecular function: protein serine kinase activity"; GO calls it protein serine kinase activity
  • GO:0005634 (2 mentions) - the report calls it "Cellular component: nucleus", "nucleus"; GO calls it nucleus, and lists "cell nucleus" among its other names
  • CL:0000121 (2 mentions) - the report calls it "Cell types: cerebellar Purkinje cell"; CL calls it Purkinje cell, and lists "cerebellar Purkinje cell" among its other names
  • UBERON:0002037 (2 mentions) - the report calls it "Anatomy: cerebellum", "cerebellum"; UBERON calls it cerebellum

Terms named inconsistently

The report gives these identifiers more than one name of its own:

  • GO:0005634 - called "Cellular component: nucleus", "nucleus"
  • UBERON:0002037 - called "Anatomy: cerebellum", "cerebellum"