Intellectual Developmental Disorder, X-Linked 114

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.

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

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).

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.

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 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

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

• OpenScientist final report
• OpenScientist final report

Reference Validation

Checked with linkml-reference-validator 0.3.0rc1.

All extracted references resolved successfully.

Term Validation

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

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"