| domain | high-confidence finding | quantitative/detail | evidence type | suggested ontology terms |
|---|---|---|---|---|
| Disease identity | RFT1-congenital disorder of glycosylation is a rare congenital disorder of N-linked glycosylation caused by RFT1 deficiency | Supported IDs: MONDO:0012783; OMIM disease 612015; historical nomenclature proposed as CDG-In in 2008 literature (pqac-00000000, pqac-00000014, pqac-00000015) | Disease ontology/resource linkage + human primary literature | Suggested: MONDO:0012783 |
| Causal gene / inheritance | Causal gene is RFT1; inheritance is autosomal recessive | RFT1 gene OMIM 611908; biallelic pathogenic variants reported in affected individuals; homozygous and compound heterozygous missense alleles documented (pqac-00000001, pqac-00000002, pqac-00000008) | Human clinical genetics + functional complementation | Suggested: HGNC RFT1; GENO autosomal recessive inheritance |
| Pathogenic variants | Recurrently reported disease-associated missense variants include p.R67C, p.K152E, p.E298K, p.I296K, p.I296R; additional variants were examined functionally in 2024 molecular work | c.199C>T (p.R67C), c.454A>G (p.K152E), c.892G>A (p.E298K), c.887T>A (p.I296K), c.887T>G (p.I296R); most reported variants are missense and map to conserved regions (pqac-00000001, pqac-00000007, pqac-00000010, pqac-00000011) | Human case reports/series + yeast functional assays | Suggested: SO:0001583 missense_variant |
| Core phenotype | Severe neurodevelopmental disease is the dominant presentation | Common findings across early reported patients: severe developmental delay/intellectual disability, hypotonia, seizures/epilepsy, feeding problems/failure to thrive, visual impairment, microcephaly, and sensorineural hearing loss (pqac-00000006, pqac-00000007, pqac-00000008) | Human case series | Suggested HPO: HP:0001263 developmental delay; HP:0001252 hypotonia; HP:0001250 seizures; HP:0001508 failure to thrive; HP:0000252 microcephaly; HP:0000407 sensorineural hearing impairment; HP:0000505 visual impairment |
| Distinguishing phenotype | Sensorineural deafness is a notable and repeatedly emphasized feature | Early literature reported deafness in all 4 initially compared patients and later described RFT1-CDG as the first CDG firmly associated with deafness; by 2021 review, 11 patients had been described in the literature (pqac-00000006, pqac-00000007, pqac-00000008) | Human case series + review summary | Suggested HPO: HP:0000407 sensorineural hearing impairment |
| Additional/variable phenotypes | Other features are variable rather than universal | Respiratory insufficiency, pulmonary infections, coagulopathy, hepatomegaly, nystagmus, stroke-like episodes, venous thrombosis, brisk reflexes, dysmorphy, and gastrointestinal problems reported in subsets of patients (pqac-00000001, pqac-00000002, pqac-00000007, pqac-00000008) | Human case reports | Suggested HPO: HP:0002093 respiratory insufficiency; HP:0003256 thrombosis; HP:0012379 abnormal coagulation; HP:0000622 nystagmus |
| Onset / course | Typical onset is congenital or infantile, with severe early course but some longer-term survival | One reported patient died at 8 months; severe infantile presentations are common, but adult survivors with milder intellectual disability have been noted in cohort/review literature (pqac-00000001, pqac-00000006) | Human longitudinal case observation + cohort review | Suggested HPO: HP:0003577 congenital onset; HP:0011463 childhood onset |
| Diagnostic screening biomarker | Serum transferrin testing shows a type I hypoglycosylation pattern | Capillary zone electrophoresis / serum sialotransferrin type 1 pattern reported; generalized CDG guidance still considers transferrin IEF a first-line test for many N-glycosylation disorders (pqac-00000003, pqac-00000008) | Human biochemical diagnostics + CDG practice review | Suggested LOINC class: transferrin glycoform analysis; Suggested HPO: HP:0012345 abnormal glycosylation test |
| Disease-specific biochemical hallmark | Cells accumulate incomplete dolichol-linked oligosaccharide intermediate M5-DLO / DolPP-GlcNAc2Man5 | Patient fibroblasts showed accumulation of DolPP-GlcNAc2Man5 / Man5GlcNAc2-PP-dolichol with reduced full-length Glc3Man9GlcNAc2-PP-dolichol and hypoglycosylation (pqac-00000001, pqac-00000014, pqac-00000015) | Human cellular biochemistry | Suggested CHEBI: dolichol-linked oligosaccharide terms; Suggested GO: protein N-linked glycosylation |
| Functional confirmation | Wild-type RFT1 rescues the cellular defect | Lentiviral expression of normal RFT1 cDNA in patient fibroblasts restored synthesis of complete LLO and normalized secretion/glycosylation readouts; mutant p.R67C failed in yeast complementation (pqac-00000005, pqac-00000014, pqac-00000015) | Human patient fibroblasts + yeast complementation | Suggested ECO: functional complementation evidence |
| Mechanism / pathway | RFT1 is an ER membrane protein required for normal assembly of the N-glycosylation donor used in protein N-glycosylation | Upstream defect: impaired handling of M5-DLO in ER membrane biogenesis pathway; downstream effect: depletion of mature donor and protein hypoglycosylation, despite intact downstream glycosyltransferases/OST (pqac-00000010, pqac-00000014, pqac-00000015) | Human cellular biochemistry + mechanistic primary literature | Suggested GO: GO:0006487 protein N-linked glycosylation; GO:0005783 endoplasmic reticulum |
| Mechanistic uncertainty | Whether RFT1 is itself the M5-DLO flippase/scramblase remains unresolved | 2013 Trypanosoma work found Rft1-null cells retained significant N-glycosylation and normal steady-state mature DLO; 2024 work found Rft1-depleted proteoliposomes had undiminished M5-DLO scramblase activity and concluded any such activity by Rft1 would be minor/redundant (pqac-00000009, pqac-00000010, pqac-00000017) | Model-organism and reconstitution studies | Suggested GO: lipid translocation; GO: endoplasmic reticulum membrane |
| Protein features | Human Rft1 is a multispanning ER membrane protein with cytoplasmic N- and C-termini and is not N-glycosylated | 2024 molecular characterization predicted 14 transmembrane spans; Nin/Cin topology supported experimentally; N227 sequon is in a cytoplasmic loop and not glycosylated (pqac-00000009, pqac-00000010) | Yeast reporter system + structural prediction + topology assays | Suggested GO: GO:0016021 integral component of membrane; GO:0005789 endoplasmic reticulum membrane |
| Anatomical systems affected | Nervous system involvement is primary; multisystem involvement occurs secondarily/variably | Brain/neurodevelopmental, auditory, visual, respiratory, coagulation/vascular, and possibly hepatic systems affected in reported patients (pqac-00000001, pqac-00000006, pqac-00000007) | Human phenotype aggregation | Suggested UBERON: brain, inner ear, eye, liver; Suggested CL: neuron |
| Models | Useful models include yeast complementation systems, patient fibroblasts, and Rft1-null Trypanosoma brucei | Yeast shows essentiality and supports human RFT1 rescue assays; patient fibroblasts recapitulate M5-DLO accumulation; Trypanosoma null model challenges simple flippase assignment (pqac-00000005, pqac-00000014, pqac-00000017) | In vitro cellular + model organism | Suggested NCBITaxon: Saccharomyces cerevisiae, Trypanosoma brucei; Suggested CL: fibroblast |
| Diagnostics in practice | Best-supported diagnostic approach is biochemical screening followed by molecular confirmation of biallelic RFT1 variants | Real-world implementation: transferrin glycoform testing, LLO analysis in specialized settings, and exome/genome/panel-based confirmation; hearing evaluation such as brainstem audiometry has been informative clinically (pqac-00000003, pqac-00000008) | Clinical diagnostic workflow | Suggested NCIT: Genetic Testing; Suggested HPO: HP:0000407 sensorineural hearing impairment |
| Treatment status | No disease-specific approved therapy identified; management is supportive/symptomatic | Symptomatic seizure management reported (e.g., valproic acid in one case); no RFT1-specific interventional trials identified in the trial search performed here (pqac-00000008) | Human case management + trial search negative finding | Suggested NCIT: Supportive Care; Anticonvulsant Therapy |
| Prevention / counseling | Prevention is genetic rather than environmental | Autosomal recessive inheritance supports carrier testing, reproductive counseling, prenatal or preimplantation testing when familial variants are known; no environmental protective factors established (pqac-00000002, pqac-00000008) | Genetic counseling inference from Mendelian etiology | Suggested NCIT: Genetic Counseling |
| Epidemiology | Extremely rare; precise prevalence/incidence are not established from direct patient registries | Literature review noted only 11 described patients by 2021 review context; broader 2021 prevalence study emphasizes that most non-PMM2 N-linked CDGs are expected to be rarer than 1 in 100,000 and that estimates for specific rare CDGs are uncertain (pqac-00000012, pqac-00000016) | Review summary + population-allele-frequency modeling context | Suggested MONDO rare disease classification |
| Evidence gaps | Major gaps remain in prevalence, genotype-phenotype correlations, natural history, prognosis, and molecular mechanism | No robust disease-specific incidence data, no established modifier/protective factors, no validated prognostic biomarkers, no RFT1-specific treatment trials, and no definitive proof that RFT1 is the M5-DLO flippase (pqac-00000009, pqac-00000010, pqac-00000016, pqac-00000017) | Evidence-gap synthesis | Suggested: none; ontology mapping not applicable |
| Source provenance | Evidence comes primarily from aggregated disease-level resources and small patient series rather than EHR-scale datasets | High-confidence claims rely on a handful of primary human case reports/series and mechanistic model studies; not from large observational databases (pqac-00000001, pqac-00000007, pqac-00000010) | Evidence characterization | Suggested ECO: case report evidence; experimental evidence |


*Table: This compact table summarizes high-confidence disease knowledge for RFT1-CDG across identifiers, genetics, phenotype, mechanism, diagnostics, models, treatment status, and evidence gaps. It is structured for direct knowledge-base ingestion and labels ontology mappings as suggested rather than asserted.*