| Domain | Best-supported finding | Evidence level/limitations |
|---|---|---|
| Disease entity | **Myelofibrosis, congenital, with anemia, neutropenia, developmental delay, and ocular abnormalities**; **MONDO:0975797**. | Curated disease-level entity; Open Targets maps the exact MONDO disease to a single target, **RBSN**. No disease-specific ICD-10/11 or MeSH identifier was established (pqac-00000000, pqac-00000005). |
| Causal gene | **RBSN** (rabenosyn, RAB effector); **Ensembl ENSG00000131381**; **MIM 609511**. RBSN regulates sorting of internalized cargo through early endosomes (pqac-00000005, pqac-00000013, pqac-00000015). | Strong human genetic and patient-cell evidence, but only one family defines this exact syndrome. |
| Disease-defining variant | Homozygous **NM_022340.3:c.289G>C**—originally described at protein level as p.Gly97Arg—causes **exon 5 skipping and absence of detectable RBSN protein**, making it an apparent protein-null allele (pqac-00000003, pqac-00000012, pqac-00000015). | Variant-to-splicing and protein consequences were demonstrated in patient-derived EBV-transformed lymphoblastoid cells. Population frequency and a formal ACMG/AMP classification were not supplied in the accessible evidence. |
| Inheritance | **Autosomal recessive/biallelic**; all three reported siblings were homozygous. Current Genomics England/Open Targets evidence specifies a biallelic autosomal or pseudoautosomal requirement (pqac-00000005, pqac-00000015). | Based on one sibship; penetrance, carrier frequency, germline-mosaicism risk, and founder effect are unknown. |
| Reported population | **Three affected siblings** in the original 2018 report; they remain the only individuals clearly assigned to the exact c.289G>C/protein-null syndrome in the retrieved literature (pqac-00000003, pqac-00000012). | No prevalence, incidence, geographic distribution, ethnicity-specific rate, or reliable sex ratio can be calculated from one family. |
| Hematologic phenotype | Congenital/severe **myelofibrosis 3/3**, anemia **3/3**, acute neutropenia **3/3**, hepatomegaly **3/3**, and marked extramedullary hematopoiesis **3/3**; thrombocytopenia occurred in **2/3**, reticulin fibrosis was present, and foamy macrophages were not reported (pqac-00000016). | Frequencies are descriptive fractions from three siblings, not population estimates. Exact blood counts, serial marrow measurements, and standardized severity grades were unavailable. |
| Neurodevelopmental phenotype | Developmental delay **3/3**, intellectual disability **3/3**, inability to talk **3/3**, severe hypotonia/muscle weakness **3/3**, and inability to sit, stand, or walk **3/3**; delayed bone growth and delayed myelination each occurred in **1/3–2/3** as tabulated (pqac-00000015, pqac-00000012). | Severe and apparently early-onset in the reported family; formal developmental scores and longitudinal trajectories are unavailable. |
| Ocular phenotype | **Microphthalmia 3/3**, optic-nerve hypoplasia **3/3**, and poor visual response **3/3** (pqac-00000016). | Detailed ophthalmic imaging, visual-acuity data, and lateralization were not available; these findings should not be generalized to every RBSN genotype. |
| Other manifestations | Thin corpus callosum, cerebral atrophy, gastrostomy dependence, XY sex reversal, and hyperlipidemia were reported; tracheomalacia occurred in **2/3**, hearing impairment in **1/3**, and osteopenia and thrombocytopenia in **2/3** (pqac-00000016). | Findings may be allele- or family-specific. Causality for every associated anomaly cannot be resolved from three related patients. |
| Cellular mechanism | The c.289G>C allele produces exon-5-skipped transcript and no detectable RBSN protein, with **reduced/slower endosomal recycling** in patient cells. Loss of RBSN-mediated early-endosomal cargo handling is therefore demonstrated upstream; how this causes marrow fibrosis, cytopenias, ocular maldevelopment, and neurologic injury remains **inferred**, and lysosomal degradation was not tested in these patients (pqac-00000012, pqac-00000017, pqac-00000019). | Human patient-cell evidence supports RBSN loss of function, but no disease-specific hematopoietic or ocular model establishes the complete tissue-level causal chain. |
| Diagnosis | Suspect from congenital marrow fibrosis/cytopenias plus severe developmental and ocular abnormalities; evaluate CBC with differential, reticulocytes, marrow biopsy/reticulin staining, ophthalmology, neurodevelopment, brain MRI, hearing, feeding/airway, liver/spleen, and bone health. Confirm by detecting **biallelic RBSN variants**, then use RNA analysis to demonstrate exon 5 skipping when c.289G>C is found; absent protein can provide functional support (pqac-00000012, pqac-00000015, pqac-00000016). | No consensus diagnostic criteria or validated biomarker exists. WES/WGS or a marrow-failure/neutropenia panel containing RBSN is more appropriate than karyotype, repeat-expansion, or mitochondrial testing unless other findings indicate them. |
| Management | No disease-modifying therapy is established. Care is phenotype-directed: pediatric hematology monitoring and transfusion/infection support as indicated; ophthalmologic and low-vision care; nutrition/gastrostomy support; airway and hearing assessment; physical, occupational, speech and developmental therapies; and surveillance of hepatomegaly, extramedullary hematopoiesis, thrombocytopenia and osteopenia. | Recommendations are extrapolated supportive care, not tested disease-specific protocols. Evidence was insufficient to establish efficacy or safety of hematopoietic stem-cell transplantation, antifibrotic/JAK therapy, gene therapy, or pharmacogenomic strategies. |
| Epidemiology and prognosis | Ultra-rare: the exact molecular syndrome is documented in one family with three siblings. Severe lifelong motor, communication, visual, feeding and hematologic morbidity is evident, but survival, mortality, life expectancy, remission probability and prognostic biomarkers are unknown (pqac-00000012, pqac-00000016). | No registry, natural-history cohort, quality-of-life study, incidence estimate, or survival analysis was identified. |
| Trials and models | No registered disease-specific interventional trial, validated natural animal disease, or dedicated organismal model was identified in the searches. Patient lymphoblastoid cells are the principal direct model for c.289G>C; patient fibroblasts have been used for other RBSN alleles (pqac-00000004, pqac-00000012). | Negative search finding, not proof that no unpublished model or broadly eligible marrow-failure study exists. |
| Allelic-disorder boundary | Do **not** merge this exact protein-null syndrome with other RBSN disorders: homozygous **c.1273G>A (p.Gly425Arg)** alters transferrin recycling and causes a partially overlapping encephalopathic/hematologic phenotype, whereas FYVE-domain **c.538C>G (p.Arg180Gly)** and **c.547G>A (p.Gly183Arg)** impair PI3P binding and endosomal maturation but generally lack myelofibrosis, anemia and neutropenia (pqac-00000015, pqac-00000016, pqac-00000017, pqac-00000020). | RBSN shows marked allele/domain-specific, non-overlapping phenotypes; mechanistic or frequency data from another allele should not automatically populate MONDO:0975797. |


*Table: Compact knowledge-base summary of the exact homozygous RBSN c.289G>C protein-null syndrome, including phenotype frequencies, mechanism, diagnosis, management, and evidence gaps. The final row separates it from mechanistically distinct RBSN allelic disorders.*