| Gene (HGNC symbol) | Protein/complex | Inheritance pattern reported | Variant types (general) | Key clinical notes/complications | Key supporting recent sources with publication year and URL |
|---|---|---|---|---|---|
| **WASHC5** | Strumpellin; core **WASH** complex subunit functionally linked to Commander-mediated recycling | **Autosomal recessive** for RSS/3C in retrieved evidence; biallelic loss-of-function reported | General **loss-of-function**; splice/disruptive variants reported in RSS literature summaries | Classic RSS/3C phenotype with developmental delay, cerebellar hypoplasia, cardiac abnormalities; 2024 summary table notes developmental delay in 11/11 and cardiac abnormalities in 7/11 WASHC5-associated cases; mechanism tied to reduced recycling of surface cargo proteins (pqac-00000000, pqac-00000005, pqac-00000027) | Kato et al., 2024, medRxiv, https://doi.org/10.1101/2024.08.17.24311658; Otsuji et al., 2023, J Med Genet, https://doi.org/10.1136/jmg-2022-108602 (pqac-00000000, pqac-00000005, pqac-00000027) |
| **CCDC22** | **CCC** complex subunit within Commander | **X-linked / hemizygous** form reported; gene-specific RSS/3C overlap with XLID | Missense and other variants that disrupt CCC assembly/COMMD binding; loss-of-function/functional impairment reported | RSS/3C with craniofacial, cerebellar, cardiac, and neurodevelopmental involvement; some attenuated phenotypes may lack major cardiac/neuroanatomical abnormalities; CCDC22 dysfunction perturbs CCC assembly and Commander function (pqac-00000001, pqac-00000003, pqac-00000016) | Healy et al., 2023, Cell, https://doi.org/10.1016/j.cell.2023.04.003; Singla et al., 2025, BMC Med Genomics, https://doi.org/10.1186/s12920-025-02168-7; Otsuji et al., 2023, J Med Genet, https://doi.org/10.1136/jmg-2022-108602 (pqac-00000001, pqac-00000003, pqac-00000016) |
| **VPS35L** | **Retriever** subunit (with VPS26C and VPS29) within Commander | **Autosomal recessive / biallelic** | Biallelic pathogenic variants including truncating, splice-altering, in-frame deletion, and missense alleles with reduced protein stability/function | Distinct VPS35L-associated RSS spectrum with variable severity; novel 2023 complications include **hypercholesterolaemia, hypogammaglobulinaemia, intestinal lymphangiectasia, and proteinuria**; mechanism includes reduced cell-surface LRP1/LDLR and reduced LDL uptake (pqac-00000004, pqac-00000006, pqac-00000021, pqac-00000026) | Otsuji et al., 2023, J Med Genet, https://doi.org/10.1136/jmg-2022-108602; Healy et al., 2023, Cell, https://doi.org/10.1016/j.cell.2023.04.003 (pqac-00000004, pqac-00000006, pqac-00000021, pqac-00000020, pqac-00000026) |
| **COMMD4** | **CCC** complex subunit; Commander-associated | **Autosomal recessive / biallelic** in 2024 preprint cohort | Biallelic pathogenic variants; severe **COMMD4-L41R** genotype highlighted | Newly proposed RSS gene; associated with severe multisystem disease and **early childhood death (ages 0–5)** in reported family; functional studies suggest major Commander cargo-recycling defects (pqac-00000002, pqac-00000025) | Kato et al., 2024, medRxiv, https://doi.org/10.1101/2024.08.17.24311658 (pqac-00000002, pqac-00000025) |
| **COMMD9** | **CCC** complex subunit; Commander-associated | **Autosomal recessive / biallelic** in 2024 preprint cohort | Biallelic pathogenic/truncating variants reported in candidate-gene expansion study | Newly proposed RSS gene; functional data indicate milder cargo-trafficking defects than COMMD4 or CCDC93 loss, suggesting residual pathway activity may moderate severity (pqac-00000002, pqac-00000025) | Kato et al., 2024, medRxiv, https://doi.org/10.1101/2024.08.17.24311658 (pqac-00000002, pqac-00000025) |
| **CCDC93** | **CCC** complex scaffold subunit within Commander | **Autosomal recessive / biallelic** in 2024 preprint cohort | Biallelic pathogenic variants causing loss of CCC/Commander function | Newly proposed RSS gene; linked to dysgenic corpus callosum, cerebellar abnormalities, limb/nail anomalies, and broader multisystem RSS manifestations; knockout/cell studies support defective endosomal recycling (pqac-00000002, pqac-00000025) | Kato et al., 2024, medRxiv, https://doi.org/10.1101/2024.08.17.24311658 (pqac-00000002, pqac-00000025) |
| **Pathway-level note** | **Commander = Retriever + CCC**, acting with the **WASH** complex in SNX17-dependent endosomal recycling | Not applicable | Not applicable | Retrieved evidence supports RSS as an **endosomal recyclinopathy** caused by impaired retrieval/recycling of membrane cargoes including integrins and lipoprotein receptors; this provides a unifying mechanism across WASHC5, CCDC22, VPS35L, and newly proposed CCC-gene cases (pqac-00000005, pqac-00000007, pqac-00000020, pqac-00000024, pqac-00000025) | Healy et al., 2023, Cell, https://doi.org/10.1016/j.cell.2023.04.003; Kato et al., 2024, medRxiv, https://doi.org/10.1101/2024.08.17.24311658; Otsuji et al., 2023, J Med Genet, https://doi.org/10.1136/jmg-2022-108602 (pqac-00000005, pqac-00000007, pqac-00000020, pqac-00000024, pqac-00000025) |


*Table: This table summarizes the currently supported and newly proposed genetic causes of Ritscher-Schinzel syndrome/3C syndrome, emphasizing the shared Commander-Retriever-CCC-WASH endosomal recycling mechanism. It is useful for quickly comparing inheritance, variant classes, and distinctive complications across genes.*