| domain | disease-specific finding | quantitative evidence / frequency | suggested ontology terms | evidence level and source date |
|---|---|---|---|---|
| Nosology | Syndromic X-linked intellectual disability, Shashi type; causal gene RBMX | MONDO MONDO:0010277; disease-target association to RBMX supported by literature and ClinVar-linked evidence | MONDO:0010277; Gene: RBMX | Curated disease ontology and genetics evidence; Open Targets context citing PMIDs 10677307 and 25256757; accessed in current tool session (pqac-00000000) |
| Disease definition | RBMX-associated X-linked intellectual disability syndrome originally described in a pedigree with affected males | Original pedigree reported 7 affected males; aggregated disease-level knowledge remains sparse | MONDO:0010277; HPO: Intellectual disability HP:0001249 | Human clinical genetics and pedigree-level evidence; 2015 genetic association summarized in 2021 Cell Reports intro (pqac-00000007) |
| Inheritance | X-linked inheritance | Male-limited affected pedigree; exact penetrance not reported | MONDO:0010277; inheritance ontology not specified here | Human pedigree evidence; original family summarized 2021 (pqac-00000007) |
| Core phenotype | Intellectual disability is the defining clinical feature | Frequency in original pedigree not fully enumerated in retrieved text; syndrome-level feature established | HPO: HP:0001249 | Human clinical and pedigree evidence; 2000 and 2015 source lineage via curated association and 2021 summary (pqac-00000000, pqac-00000007) |
| Core phenotype | Short stature reported in original syndrome descriptions | Frequency not reported in retrieved evidence | HPO: Short stature HP:0004322 | Human clinical report lineage; evidence indirect in retrieved corpus and sparsely quantified (pqac-00000000) |
| Core phenotype | Obesity reported in original syndrome descriptions | Frequency not reported in retrieved evidence | HPO: Obesity HP:0001513 | Human clinical report lineage; evidence indirect in retrieved corpus and sparsely quantified (pqac-00000000) |
| Core phenotype | Hypogonadism or genital phenotype reported in original syndrome descriptions | Frequency not reported in retrieved evidence | HPO: Hypogonadism HP:0000135; genital abnormality term uncertain or not specified from retrieved text | Human clinical report lineage; evidence indirect in retrieved corpus and sparsely quantified (pqac-00000000) |
| Molecular lesion | 23-bp deletion in the last exon of RBMX predicted to cause frameshift and premature stop, deleting the C-terminal RGG or RG motif | Size 23 bp; truncates last 38 aa encompassing RGG or RG motif | Gene: RBMX; GO: RNA binding GO:0003723; protein region: C-terminal RGG or RG motif | Human genetic evidence and disease-model recapitulation; 2021 peer-reviewed mechanistic study summarizing 2015 family variant (pqac-00000005, pqac-00000007) |
| Protein and mechanism | RBMX C-terminal RGG or RG motif is methylated by PRMT5 | In vivo methylated arginines identified at R369 and R373; minimal PRMT5-methylated region aa 366-391 | GO: protein arginine methylation GO:0018216; GO: mRNA splicing via spliceosome GO:0000398 | In vitro and cellular mechanistic evidence; 2021 (pqac-00000005) |
| Mechanism | PRMT5-RBMX methylation promotes RBMX-SRSF1 higher-order complexes that support MDM4 exon 6 inclusion | 1,6-hexanediol reduced RBMX foci size by 43.8 percent, intensity by 62.48 percent, RBMX-SRSF1 colocalization by 25 percent, and SRSF1 binding to MDM4 RNA by 50 percent | GO: regulation of mRNA splicing GO:0048024; GO: nuclear speck GO:0016607; CL: neural progenitor cell CL:0011115 | Cellular mechanistic evidence in U2OS and neuronal systems; 2021 (pqac-00000006) |
| Mechanism | Loss of RBMX RGG or RG function causes MDM4 missplicing, reduced MDM4 protein, p53 pathway activation, and apoptosis | In patient-modeled iPSCs, nuclear p53-positive cells: 8.67 percent control vs 19.74 percent DRGG1 vs 19.93 percent DRGG2; cleaved caspase-3 area: 2.9 percent control vs 4.8 percent DRGG1 vs 6.06 percent DRGG2 | GO: apoptotic process GO:0006915; GO: regulation of transcription by p53 class mediator GO:1901796; GO: alternative mRNA splicing via spliceosome GO:0000380 | Human iPSC disease model; 2021 (pqac-00000005, pqac-00000007) |
| Transcriptomics | Shashi-XLID iPSCs show broad transcriptional dysregulation with p53 signature enrichment | 847 upregulated and 1067 downregulated genes in DRGG1 iPSCs with fold change threshold greater than 1.5 | GO: intrinsic apoptotic signaling pathway by p53 class mediator GO:0072332; GO: neuron differentiation GO:0030182 | Human CRISPR-engineered iPSC model; 2021 (pqac-00000005) |
| NPC phenotype | Neural progenitor cells differentiate efficiently but show developmental transcriptional defects | NPC induction efficiency greater than 90 percent SOX1 positive, SOX2 positive, and PAX6 positive; 258 downregulated and 15 upregulated genes in DRGG1 NPCs; 111 significant splicing events in DRGG NPCs | CL: neural progenitor cell CL:0011115; GO: central nervous system development GO:0007417; GO: neuron differentiation GO:0030182 | Human iPSC-derived NPC model; 2021 (pqac-00000006, pqac-00000015) |
| Neuronal phenotype | Impaired glutamatergic neurogenesis in cortical-neuron differentiation | 3 percent VGLUT1 positive neurons in RBMX-DRGG cultures vs 15 percent in controls; GABAergic difference not significant in reported experiment | GO: glutamatergic synaptic transmission GO:0035249; CL: glutamatergic neuron CL:0000679; UBERON: cerebral cortex UBERON:0000956; HPO neurodevelopmental term broad or unspecified | Human iPSC-derived cortical neuron model; 2021 (pqac-00000006, pqac-00000015) |
| Additional neuronal readouts | Neurogenesis regulators are reduced and apoptosis rises after neuronal differentiation | Downregulated FOXG1, TBR1, and SLC17A7; increased CDKN1A and BAX in 14-day neurons; increased cleaved caspase-3 or 7 activity | GO: forebrain development GO:0030900; GO: neuron fate commitment GO:0048663; CL: cortical neuron term uncertain or not specified | Human iPSC-derived neuronal model; 2021 (pqac-00000006) |
| Affected anatomy | Primary system is central nervous system and cerebral cortex; subcellular involvement includes nucleus and splicing-related compartments | Quantitative anatomy not available for Shashi patients in retrieved evidence | UBERON: brain UBERON:0000955; UBERON: cerebral cortex UBERON:0000956; GO cellular component nucleus GO:0005634; GO cellular component nuclear speck GO:0016607 | Mechanistic and model-based inference anchored to disease models; 2021 (pqac-00000006, pqac-00000007) |
| Comparative RBMX disorders | Gustavson syndrome is also RBMX-related but clinically more severe and mechanistically distinct, so it should not be conflated with Shashi syndrome | Comparative statement only; not a Shashi frequency estimate | Differential diagnosis note; MONDO term not specified here | Human comparative genetics; 2024 peer-reviewed study (pqac-00000008) |
| Diagnostics | Most direct diagnostic approach is molecular testing of RBMX, especially sequencing methods capable of detecting small coding deletions; phenotype alone is insufficiently specific | No validated biomarker beyond genetic diagnosis found; no disease-specific biochemical assay found | MAXO: genetic testing term uncertain or not specified; HPO-guided neurodevelopmental gene panel or exome sequencing concept | Clinical genetics practice inference from causal variant architecture and mechanistic confirmation (pqac-00000000, pqac-00000007) |
| Genetic testing modalities | Single-gene RBMX analysis, XLID or neurodevelopmental gene panels, WES, and WGS are reasonable; CMA and karyotype may miss small exon-level indels unless rearrangement is suspected | No performance statistics reported for Shashi specifically in retrieved evidence | MAXO: molecular genetic testing term uncertain or not specified | Evidence-informed inference based on lesion type and published disease-model recapitulation; no disease-specific guideline located (pqac-00000005, pqac-00000007) |
| Treatment and management | No disease-specific molecular therapy established; management is supportive and multidisciplinary | No disease-specific response-rate data found | MAXO: supportive care term uncertain or not specified; speech therapy, occupational therapy, and physical therapy terms uncertain or not specified | Evidence gap plus standard rare neurodevelopmental care inference; no relevant disease-specific trials found in tool search (pqac-00000000) |
| Prevention and counseling | Genetic counseling, cascade testing in families, and reproductive counseling are relevant because of X-linked inheritance | No carrier-frequency or founder-effect data found | MAXO: genetic counseling term uncertain or not specified | Human genetics implication from pedigree structure; disease-specific epidemiology sparse (pqac-00000000, pqac-00000007) |
| Clinical trials | No Shashi syndrome-specific interventional trials identified | 0 relevant disease-specific trials found in current search | MAXO not applicable | Clinical trials search in current session; no relevant registered study returned (pqac-00000000) |
| Epidemiology | Ultra-rare Mendelian disorder with evidence based on a small number of reported families and patients | Prevalence, incidence, sex ratio beyond X-linked expectation, and life expectancy not reported in retrieved evidence | MONDO:0010277 | Evidence gap; current knowledge largely from individual patients, pedigrees, and disease-level curation (pqac-00000000, pqac-00000007) |


*Table: This table compacts the key disease-specific evidence and ontology suggestions for RBMX-related Shashi X-linked intellectual disability syndrome. It highlights what is directly supported by available evidence, where quantitative model data exist, and where frequencies or ontology IDs remain uncertain.*