RFT1-congenital disorder of glycosylation (RFT1-CDG, CDG-In) is an ultra-rare autosomal recessive type I congenital disorder of glycosylation caused by biallelic pathogenic variants in RFT1, which encodes a multispanning endoplasmic-reticulum membrane protein. Assembly of the lipid-linked oligosaccharide donor for N-glycosylation begins on the cytosolic face of the ER and is completed in the lumen, and the two compartments are bridged by transbilayer movement of the heptasaccharide intermediate Man5GlcNAc2-PP-dolichol. RFT1 deficiency blocks the pathway at exactly this step: patient cells accumulate the truncated Man5 intermediate and fail to build the mature GlcNAc2Man9Glc3 donor, so nascent glycoproteins are hypoglycosylated and serum transferrin shows a CDG type I pattern. Clinically RFT1-CDG is a severe multisystem neurological disease — early-onset drug-resistant epilepsy, profound developmental impairment, visual failure, feeding difficulty and coagulopathy — distinguished among the CDG by consistent sensorineural deafness, which led to its description as the first "deafness-CDG". Whether RFT1 is itself the flippase that translocates the intermediate, or is instead required for that step by some other means, remains genuinely unsettled and is curated here as two competing hypotheses.
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name: RFT1-congenital disorder of glycosylation
creation_date: "2026-08-22T00:00:00Z"
description: >-
RFT1-congenital disorder of glycosylation (RFT1-CDG, CDG-In) is an ultra-rare
autosomal recessive type I congenital disorder of glycosylation caused by
biallelic pathogenic variants in RFT1, which encodes a multispanning
endoplasmic-reticulum membrane protein. Assembly of the lipid-linked
oligosaccharide donor for N-glycosylation begins on the cytosolic face of the
ER and is completed in the lumen, and the two compartments are bridged by
transbilayer movement of the heptasaccharide intermediate
Man5GlcNAc2-PP-dolichol. RFT1 deficiency blocks the pathway at exactly this
step: patient cells accumulate the truncated Man5 intermediate and fail to
build the mature GlcNAc2Man9Glc3 donor, so nascent glycoproteins are
hypoglycosylated and serum transferrin shows a CDG type I pattern. Clinically
RFT1-CDG is a severe multisystem neurological disease — early-onset
drug-resistant epilepsy, profound developmental impairment, visual failure,
feeding difficulty and coagulopathy — distinguished among the CDG by
consistent sensorineural deafness, which led to its description as the first
"deafness-CDG". Whether RFT1 is itself the flippase that translocates the
intermediate, or is instead required for that step by some other means,
remains genuinely unsettled and is curated here as two competing hypotheses.
category: Mendelian
parents:
- hereditary disease
synonyms:
- RFT1-CDG
- CDG-In
- CDG1N
- congenital disorder of glycosylation type In
- congenital disorder of glycosylation type 1n
- RFT1 deficiency
disease_term:
preferred_term: RFT1-congenital disorder of glycosylation
term:
id: MONDO:0012783
label: RFT1-congenital disorder of glycosylation
classifications:
harrisons_chapter:
- classification_value: ENDOCRINOLOGY_METABOLISM
evidence:
- reference: PMID:19862844
reference_title: "Congenital disorders of glycosylation: an update on defects affecting the biosynthesis of dolichol-linked oligosaccharides."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Defects in the biosynthesis of the oligosaccharide precursor for
N-glycosylation lead to decreased occupancy of glycosylation sites and
thereby to diseases known as congenital disorders of glycosylation (CDG).
explanation: >-
Frames the dolichol-linked oligosaccharide CDG, RFT1 among them, as
inherited metabolic disease.
- classification_value: GENETICS_ENVIRONMENT_DISEASE
evidence:
- reference: PMID:26892341
reference_title: "RFT1-congenital disorder of glycosylation (CDG) syndrome: a cause of early-onset severe epilepsy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
RFT1-congenital disorder of glycosylation (CDG) syndrome, a recessive
N-glycosylation disorder caused by mutation in the RFT1 gene, is a very
rare subtype of CDG syndrome associated with deafness, developmental
delay, and non-specific epilepsy.
explanation: >-
Establishes RFT1-CDG as a single-gene recessive Mendelian disorder.
references:
- reference: PMID:18313027
title: "Human RFT1 deficiency leads to a disorder of N-linked glycosylation."
- reference: PMID:19267216
title: "Comprehensive description of the phenotype of the first case of congenital disorder of glycosylation due to RFT1 deficiency (CDG In)."
- reference: PMID:19856127
title: "RFT1-CDG: deafness as a novel feature of congenital disorders of glycosylation."
- reference: PMID:26892341
title: "RFT1-congenital disorder of glycosylation (CDG) syndrome: a cause of early-onset severe epilepsy."
- reference: PMID:39025454
title: "Molecular characterization of Rft1, an ER membrane protein associated with congenital disorder of glycosylation RFT1-CDG."
- reference: PMID:19862844
title: "Congenital disorders of glycosylation: an update on defects affecting the biosynthesis of dolichol-linked oligosaccharides."
- reference: PMID:19701946
title: "RFT1 deficiency in three novel CDG patients."
- reference: PMID:23111317
title: "RFT1-CDG in adult siblings with novel mutations."
- reference: PMID:29923091
title: "RFT1-CDG: Absence of Epilepsy and Deafness in Two Patients with Novel Pathogenic Variants."
- reference: PMID:30071302
title: "A family with floppy neonates with severe respiratory insufficiency: A lethal phenotype of RFT1-CDG due to a novel mutation."
inheritance:
- name: Autosomal recessive inheritance
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
description: >-
RFT1-CDG requires biallelic RFT1 variants. The index patient was homozygous
for a missense allele, and subsequent reports have described further
homozygous and compound heterozygous genotypes. Causality for the index
allele was established functionally rather than by segregation alone:
expressing wild-type RFT1 cDNA in patient fibroblasts restored the normal
glycosylation profile.
evidence:
- reference: PMID:18313027
reference_title: "Human RFT1 deficiency leads to a disorder of N-linked glycosylation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
A young patient diagnosed with a congenital disorder of glycosylation
characterized by an intracellular accumulation of DolPP-GlcNAc(2)Man(5) was
found to carry a homozygous point mutation in the RFT1 gene.
explanation: >-
A homozygous RFT1 point mutation in the index patient establishes recessive
inheritance.
- reference: PMID:18313027
reference_title: "Human RFT1 deficiency leads to a disorder of N-linked glycosylation."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
The causality of the RFT1 p.R67C mutation was further established by
restoration of normal glycosylation profiles in patient-derived fibroblasts
after lentiviral expression of a normal RFT1 cDNA.
explanation: >-
Functional complementation in patient cells confirms the biallelic RFT1
genotype is causal rather than incidental.
pathophysiology:
- name: RFT1 Loss of Function
biological_scale: MOLECULAR
role: trigger
mechanism_confidence: ESTABLISHED
description: >-
Biallelic pathogenic RFT1 variants reduce or abolish the function of RFT1, a
multispanning ER membrane protein whose N and C termini both face the
cytoplasm. The index allele, c.199C>T (p.Arg67Cys), was shown to be
functionally deleterious by complementation assay in RFT1-null yeast, and
most RFT1-CDG alleles reported since fall in regions of the protein that are
highly conserved across eukaryotes.
genes:
- preferred_term: RFT1
term:
id: hgnc:30220
label: RFT1
genetic_context:
functional_impact_category: LOSS_OF_FUNCTION
variant_origin: GERMLINE
description: >-
Reported genotypes are biallelic germline RFT1 variants, homozygous in the
index case. Loss of function is established functionally: the index allele
failed to complement RFT1-null yeast, and wild-type RFT1 cDNA restored
normal glycosylation in patient fibroblasts.
locations:
- preferred_term: endoplasmic reticulum membrane
term:
id: GO:0005789
label: endoplasmic reticulum membrane
cell_types:
- preferred_term: Fibroblast
term:
id: CL:0000057
label: fibroblast
evidence:
- reference: PMID:18313027
reference_title: "Human RFT1 deficiency leads to a disorder of N-linked glycosylation."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Despite the low sequence similarity between the yeast and the human RFT1
proteins, we demonstrated both their functional orthology and the pathologic
effect of the human p.R67C mutation by complementation assay in Deltarft1
yeast cells.
explanation: >-
Establishes that the patient allele is loss-of-function and that human RFT1
is the functional orthologue of yeast Rft1.
- reference: PMID:39025454
reference_title: "Molecular characterization of Rft1, an ER membrane protein associated with congenital disorder of glycosylation RFT1-CDG."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
We show that it is a multispanning membrane protein located in the ER, with
its N and C termini facing the cytoplasm.
explanation: >-
Defines the topology and subcellular location of the affected protein.
- reference: PMID:39025454
reference_title: "Molecular characterization of Rft1, an ER membrane protein associated with congenital disorder of glycosylation RFT1-CDG."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
The majority of RFT1-CDG mutations map to highly conserved regions of the
protein.
explanation: >-
Supports treating the reported patient alleles as damaging to a conserved
functional core.
downstream:
- target: Block in Transbilayer Completion of the Lipid-Linked Oligosaccharide
- name: Block in Transbilayer Completion of the Lipid-Linked Oligosaccharide
biological_scale: MOLECULAR
role: central_effector
mechanism_confidence: ESTABLISHED
description: >-
Assembly of the N-glycosylation donor is a two-compartment process: the
Man5GlcNAc2-PP-dolichol intermediate is built on the cytosolic face of the ER
and must reach the lumen for the remaining mannose and glucose residues to be
added. In RFT1 deficiency this transition fails, and the pathway stalls at
the Man5 intermediate. The step itself is not in doubt; what RFT1 actually
does at this step is, and the two readings are curated as competing
hypotheses below.
biological_processes:
- preferred_term: dolichol-linked oligosaccharide biosynthetic process
modifier: DECREASED
term:
id: GO:0006488
label: dolichol-linked oligosaccharide biosynthetic process
locations:
- preferred_term: endoplasmic reticulum membrane
term:
id: GO:0005789
label: endoplasmic reticulum membrane
evidence:
- reference: PMID:18313027
reference_title: "Human RFT1 deficiency leads to a disorder of N-linked glycosylation."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
The substrate of N-linked glycosylation, dolichol pyrophosphate
(DolPP)-GlcNAc(2)Man(9)Glc(3), is assembled through a complex series of
ordered reactions requiring the translocation of the intermediate
DolPP-GlcNAc(2)Man(5) structure across the endoplasmic-reticulum membrane.
explanation: >-
States the transbilayer step at which the RFT1 block occurs.
- reference: PMID:19856127
reference_title: "RFT1-CDG: deafness as a novel feature of congenital disorders of glycosylation."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
RFT1 is involved in the transfer of Man(5)GlcNAc(2)-PP-Dol from the
cytoplasmic to the luminal side of the endoplasmic reticulum.
explanation: >-
Places RFT1 at the cytosolic-to-luminal transfer of the Man5 intermediate.
downstream:
- target: Accumulation of the Truncated Man5 Intermediate
- name: Accumulation of the Truncated Man5 Intermediate
biological_scale: MOLECULAR
role: consequence
mechanism_confidence: ESTABLISHED
description: >-
Because the pathway stalls, the truncated species Dol-PP-GlcNAc2Man5
accumulates intracellularly while the cytosolic free oligosaccharide
GlcNAc2Man5 is absent. This paired pattern is the biochemical signature that
first identified the defect and mirrors the profile of RFT1-null yeast.
biological_processes:
- preferred_term: dolichol-linked oligosaccharide biosynthetic process
modifier: DECREASED
term:
id: GO:0006488
label: dolichol-linked oligosaccharide biosynthetic process
cell_types:
- preferred_term: Fibroblast
term:
id: CL:0000057
label: fibroblast
evidence:
- reference: PMID:18313027
reference_title: "Human RFT1 deficiency leads to a disorder of N-linked glycosylation."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
RFT1 deficiency in both yeast and human cells leads to the accumulation of
incomplete DolPP-GlcNAc(2)Man(5) and to a profound glycosylation disorder in
humans.
explanation: >-
Direct demonstration of the accumulating intermediate in human cells.
- reference: PMID:19267216
reference_title: "Comprehensive description of the phenotype of the first case of congenital disorder of glycosylation due to RFT1 deficiency (CDG In)."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Accumulation of intracellular DolPP-GlcNAc(2)Man(5) with absence of
cytosolic GlcNAc(2)Man(5) resembled the profile of a yeast mutant deficient
in RFT1, a protein that is thought to have a role as a flippase.
explanation: >-
Records both halves of the signature — the accumulating lipid-linked
species and the absent cytosolic free oligosaccharide.
downstream:
- target: Protein N-Hypoglycosylation
- name: Protein N-Hypoglycosylation
biological_scale: CELLULAR
role: central_effector
mechanism_confidence: ESTABLISHED
description: >-
With the mature donor unavailable, the oligosaccharyltransferase reaction
proceeds at reduced efficiency and sequons on nascent glycoproteins are left
unoccupied. Site occupancy, rather than glycan structure, is what falls —
which is why the defect presents biochemically as a CDG type I pattern on
serum transferrin isoelectric focusing.
biological_processes:
- preferred_term: protein N-linked glycosylation
modifier: DECREASED
term:
id: GO:0006487
label: protein N-linked glycosylation
locations:
- preferred_term: endoplasmic reticulum
term:
id: GO:0005783
label: endoplasmic reticulum
evidence:
- reference: PMID:19701946
reference_title: "RFT1 deficiency in three novel CDG patients."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
The pathogenic character of the novel mutations was illustrated by the
accumulation of Man(5)GlcNAc(2)-PP-dolichol and by reduced recombinant
DNase 1 secretion.
explanation: >-
A functional readout of hypoglycosylation at the level of a single reporter
glycoprotein, which is what makes it more than a transferrin pattern: the
novel alleles impair secretion of a heterologous N-glycoprotein in patient
fibroblasts.
- reference: PMID:19701946
reference_title: "RFT1 deficiency in three novel CDG patients."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Both the glycosylation pattern and recombinant DNase 1 secretion could be
normalized by expression of normal RFT1 cDNA in the patients' fibroblasts.
explanation: >-
The rescue arm, and the strongest single piece of evidence that the
hypoglycosylation is caused by the RFT1 alleles rather than merely
correlated with them.
- reference: PMID:19862844
reference_title: "Congenital disorders of glycosylation: an update on defects affecting the biosynthesis of dolichol-linked oligosaccharides."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Defects in the biosynthesis of the oligosaccharide precursor for
N-glycosylation lead to decreased occupancy of glycosylation sites and
thereby to diseases known as congenital disorders of glycosylation (CDG).
explanation: >-
States the mechanistic link between a precursor-assembly block and reduced
glycosylation-site occupancy.
- reference: PMID:18313027
reference_title: "Human RFT1 deficiency leads to a disorder of N-linked glycosylation."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
RFT1 deficiency in both yeast and human cells leads to the accumulation of
incomplete DolPP-GlcNAc(2)Man(5) and to a profound glycosylation disorder in
humans.
explanation: >-
Links the precursor block to a global glycosylation defect in human cells.
downstream:
- target: Multisystem Neurological and Sensory Disease
- name: Multisystem Neurological and Sensory Disease
biological_scale: ORGANISM
role: consequence
mechanism_confidence: ESTABLISHED
description: >-
Because N-glycosylation is required by a very large and functionally diverse
set of secreted and membrane proteins, hypoglycosylation produces disease in
many organs at once. In RFT1-CDG the burden falls most heavily on the nervous
system and the ear: drug-resistant early-onset epilepsy, profound
developmental impairment and visual failure, together with the sensorineural
deafness that distinguishes this CDG from the others. Coagulation-factor
hypoglycosylation adds a bleeding-and-thrombosis diathesis that proved fatal
in the index case.
evidence:
- reference: PMID:19856127
reference_title: "RFT1-CDG: deafness as a novel feature of congenital disorders of glycosylation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Remarkably, all six patients with RFT1-CDG show sensorineural deafness as
part of a severe neurological syndrome.
explanation: >-
Establishes the consistent pairing of sensorineural deafness with severe
neurological disease across the reported cohort.
- reference: PMID:19267216
reference_title: "Comprehensive description of the phenotype of the first case of congenital disorder of glycosylation due to RFT1 deficiency (CDG In)."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The patient showed very little development and no vision and suffered from
drug-resistant epilepsy.
explanation: >-
Documents the neurological and visual burden in the index patient.
mechanistic_hypotheses:
- hypothesis_group_id: rft1_flippase_model
hypothesis_label: RFT1-as-Flippase Model
status: CANONICAL
description: >-
The original and still most widely cited reading is that RFT1 is itself the
transporter that flips Man5GlcNAc2-PP-dolichol from the cytosolic to the
luminal leaflet of the ER membrane. On this model the accumulating Man5
intermediate in patient cells is the direct substrate of a missing transport
activity, and RFT1-CDG is a transporter deficiency.
evidence:
- reference: PMID:18313027
reference_title: "Human RFT1 deficiency leads to a disorder of N-linked glycosylation."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
The human RFT1 protein shares 22% identity with its yeast ortholog, which is
involved in the translocation of DolPP-GlcNAc(2)Man(5) from the cytosolic
into the lumenal side of the endoplasmic reticulum.
explanation: >-
States the translocation role attributed to the yeast orthologue and carried
over to human RFT1.
- reference: PMID:18313027
reference_title: "Human RFT1 deficiency leads to a disorder of N-linked glycosylation."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
The definition of the RFT1 defect establishes the functional conservation of
the DolPP-GlcNAc(2)Man(5) translocation process in eukaryotes.
explanation: >-
The authors' own framing of the defect as one of a conserved translocation
process.
- hypothesis_group_id: rft1_non_flippase_essential_role
hypothesis_label: RFT1-Essential-But-Not-The-Flippase Model
status: ALTERNATIVE
description: >-
Reconstitution work argues against RFT1 being the flippase itself:
heptasaccharide lipid flipping proceeds in microsomes and in proteoliposomes
reconstituted from ER membrane proteins without a requirement for RFT1, and
at least one eukaryote does not need RFT1 for viability. On this reading RFT1
is genuinely essential for N-glycosylation in yeast and mammalian cells, and
RFT1-CDG alleles are genuinely damaging, but the molecular activity being
lost is something other than direct transbilayer transport — and has not yet
been identified.
evidence:
- reference: PMID:39025454
reference_title: "Molecular characterization of Rft1, an ER membrane protein associated with congenital disorder of glycosylation RFT1-CDG."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
However, other studies indicated that Rft1 is not required for
heptasaccharide lipid flipping in microsomes or unilamellar vesicles
reconstituted with ER membrane proteins, nor is it required for the
viability of at least one eukaryote.
explanation: >-
The direct experimental challenge to the flippase attribution.
- reference: PMID:39025454
reference_title: "Molecular characterization of Rft1, an ER membrane protein associated with congenital disorder of glycosylation RFT1-CDG."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
It is therefore not known what essential role Rft1 plays in N-glycosylation.
explanation: >-
States plainly that the molecular function remains unresolved, which is why
this entry curates two hypotheses rather than one mechanism.
- reference: PMID:19701946
reference_title: "RFT1 deficiency in three novel CDG patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
However, recent evidence suggests that the RFT1 protein would not be the
flippase enzyme itself, but would play a critical accessory role in
translocating Man5GlcNAc2PP-dolichol to the ER lumen
explanation: >-
Worth recording because of its date: this 2009 clinical series already
stated the accessory-role reading, fifteen years before the 2024
reconstitution work that is the primary support for this hypothesis. The
alternative is therefore long-standing rather than a recent
reinterpretation.
phenotypes:
- category: Neurologic
name: Early-Onset Drug-Resistant Epilepsy
description: >-
Seizures begin early and are characteristically refractory to
anticonvulsants. Epilepsy is one of the two features, with deafness, that
define the recognizable RFT1-CDG presentation.
phenotype_term:
preferred_term: Seizure
term:
id: HP:0001250
label: Seizure
evidence:
- reference: PMID:19267216
reference_title: "Comprehensive description of the phenotype of the first case of congenital disorder of glycosylation due to RFT1 deficiency (CDG In)."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The patient showed very little development and no vision and suffered from
drug-resistant epilepsy.
explanation: >-
Documents drug-resistant epilepsy in the index patient.
- reference: PMID:26892341
reference_title: "RFT1-congenital disorder of glycosylation (CDG) syndrome: a cause of early-onset severe epilepsy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
RFT1-congenital disorder of glycosylation (CDG) syndrome, a recessive
N-glycosylation disorder caused by mutation in the RFT1 gene, is a very rare
subtype of CDG syndrome associated with deafness, developmental delay, and
non-specific epilepsy.
explanation: >-
Lists epilepsy among the defining clinical associations of RFT1-CDG.
- reference: PMID:29923091
reference_title: "RFT1-CDG: Absence of Epilepsy and Deafness in Two Patients with Novel Pathogenic Variants."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Neither of them shows signs of epilepsy, which was observed in all RFT1-CDG
patients reported to date (n = 14).
explanation: >-
Two patients without epilepsy, against 14 previously reported with it;
marked PARTIAL because it bounds rather than supports the phenotype.
- category: Auditory
name: Sensorineural Deafness
description: >-
Sensorineural hearing loss is the most discriminating feature of RFT1-CDG and
is rarely reported across the CDG generally, which is why RFT1-CDG was
designated the first "deafness-CDG" and why CDG entered the differential for
syndromic congenital hearing loss. It is not, however, universal. It was
present in all six patients in the report that established it, but later
cases include two patients in whom deafness was absent, and adult siblings in
whom hearing impairment affected only one of the pair. Treat it as the
strongest single pointer to this diagnosis, not as a required feature.
phenotype_term:
preferred_term: Sensorineural hearing impairment
term:
id: HP:0000407
label: Sensorineural hearing impairment
evidence:
- reference: PMID:19856127
reference_title: "RFT1-CDG: deafness as a novel feature of congenital disorders of glycosylation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Remarkably, all six patients with RFT1-CDG show sensorineural deafness as
part of a severe neurological syndrome.
explanation: >-
Direct observation of sensorineural deafness in every reported patient at
the time.
- reference: PMID:19856127
reference_title: "RFT1-CDG: deafness as a novel feature of congenital disorders of glycosylation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We conclude that RFT1-CDG is the first 'deafness-CDG'.
explanation: >-
The authors' framing of deafness as the distinguishing feature of this CDG.
- reference: PMID:29923091
reference_title: "RFT1-CDG: Absence of Epilepsy and Deafness in Two Patients with Novel Pathogenic Variants."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Also, deafness, which is often associated with this condition, was not
observed in our patients.
explanation: >-
Establishes that deafness is not universal in RFT1-CDG; marked PARTIAL
because it qualifies rather than supports the phenotype.
- reference: PMID:23111317
reference_title: "RFT1-CDG in adult siblings with novel mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In addition, visual acuity is normal in both patients and hearing impairment
is present only in one.
explanation: >-
Adult siblings in whom hearing impairment affected only one of two, further
qualifying universality.
- category: Neurologic
name: Profound Developmental Impairment
description: >-
Psychomotor development is severely limited from infancy, with little
acquisition of milestones in the most severely affected patients.
phenotype_term:
preferred_term: Global developmental delay
term:
id: HP:0001263
label: Global developmental delay
evidence:
- reference: PMID:19267216
reference_title: "Comprehensive description of the phenotype of the first case of congenital disorder of glycosylation due to RFT1 deficiency (CDG In)."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The patient showed very little development and no vision and suffered from
drug-resistant epilepsy.
explanation: >-
Documents near-absent developmental progress.
- reference: PMID:26892341
reference_title: "RFT1-congenital disorder of glycosylation (CDG) syndrome: a cause of early-onset severe epilepsy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
RFT1-congenital disorder of glycosylation (CDG) syndrome, a recessive
N-glycosylation disorder caused by mutation in the RFT1 gene, is a very rare
subtype of CDG syndrome associated with deafness, developmental delay, and
non-specific epilepsy.
explanation: >-
Lists developmental delay among the defining clinical associations.
- category: Ophthalmologic
name: Visual Failure
description: >-
Vision is severely impaired or absent in severely affected patients.
phenotype_term:
preferred_term: Visual impairment
term:
id: HP:0000505
label: Visual impairment
evidence:
- reference: PMID:19267216
reference_title: "Comprehensive description of the phenotype of the first case of congenital disorder of glycosylation due to RFT1 deficiency (CDG In)."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The patient showed very little development and no vision and suffered from
drug-resistant epilepsy.
explanation: >-
Records absent vision in the index patient.
- category: Prenatal
name: Intrauterine Growth Restriction
description: >-
The disorder affects intrauterine development and fetal movement, producing
growth restriction before birth.
phenotype_term:
preferred_term: Intrauterine growth retardation
term:
id: HP:0001511
label: Intrauterine growth retardation
evidence:
- reference: PMID:19267216
reference_title: "Comprehensive description of the phenotype of the first case of congenital disorder of glycosylation due to RFT1 deficiency (CDG In)."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
It was a severe disorder affecting intrauterine development and movement,
and leading to intrauterine growth retardation.
explanation: >-
Direct statement of intrauterine growth restriction.
- category: Musculoskeletal
name: Arthrogryposis
description: >-
Reduced fetal movement in utero results in multiple congenital joint
contractures, present at birth in the index patient.
phenotype_term:
preferred_term: Arthrogryposis multiplex congenita
term:
id: HP:0002804
label: Arthrogryposis multiplex congenita
evidence:
- reference: PMID:19267216
reference_title: "Comprehensive description of the phenotype of the first case of congenital disorder of glycosylation due to RFT1 deficiency (CDG In)."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The child was born with several musculoskeletal abnormalities including
arthrogryposis.
explanation: >-
Documents arthrogryposis at birth.
- category: Gastrointestinal
name: Failure to Thrive
description: >-
Severe gastro-oesophageal reflux and disordered bowel motility contribute to
poor postnatal growth.
phenotype_term:
preferred_term: Failure to thrive
term:
id: HP:0001508
label: Failure to thrive
evidence:
- reference: PMID:19267216
reference_title: "Comprehensive description of the phenotype of the first case of congenital disorder of glycosylation due to RFT1 deficiency (CDG In)."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Postnatally, severe reflux and irregular bowl movements contributed to
failure to thrive.
explanation: >-
Names the gastrointestinal contributors to failure to thrive.
- category: Hematologic
name: Coagulopathy
description: >-
Several coagulation factors and their regulators are N-glycoproteins, so
hypoglycosylation disturbs haemostasis. In the index patient the disturbance
was prothrombotic and ultimately fatal, causing thrombosis and death from
pulmonary embolism at four years of age.
phenotype_term:
preferred_term: Abnormality of the coagulation cascade
term:
id: HP:0003256
label: Abnormality of the coagulation cascade
evidence:
- reference: PMID:19267216
reference_title: "Comprehensive description of the phenotype of the first case of congenital disorder of glycosylation due to RFT1 deficiency (CDG In)."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Abnormal coagulation resulted in thrombosis and the patient died at the age
of 4 years from a pulmonary embolus.
explanation: >-
Documents the coagulation abnormality and its fatal thrombotic outcome.
- category: Neurologic
name: Ataxia
description: >-
Reported at the milder end of the spectrum, alongside behavioural problems
and only mild psychomotor disability, in patients who lacked both epilepsy
and deafness.
phenotype_term:
preferred_term: Ataxia
term:
id: HP:0001251
label: Ataxia
evidence:
- reference: PMID:29923091
reference_title: "RFT1-CDG: Absence of Epilepsy and Deafness in Two Patients with Novel Pathogenic Variants."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Their phenotype is characterized by mild psychomotor disability, behavioral
problems, ataxia, and mild dysmorphism.
explanation: >-
Documents ataxia in the milder RFT1-CDG presentation.
- category: Neurologic
name: Hypoplastic Pons and Cerebellum
description: >-
Posterior fossa hypoplasia, reported in the lethal neonatal presentation.
Cerebellar involvement is a recurring theme across the CDG and appears here
both structurally in the severe case and functionally as ataxia in milder
patients.
phenotype_term:
preferred_term: Cerebellar hypoplasia
term:
id: HP:0001321
label: Cerebellar hypoplasia
evidence:
- reference: PMID:30071302
reference_title: "A family with floppy neonates with severe respiratory insufficiency: A lethal phenotype of RFT1-CDG due to a novel mutation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
He had fetal growth restriction, facial dysmorphism, high arched palate,
bilateral cryptorchidism, hypoplastic pons and cerebellum and probable
hearing impairment.
explanation: >-
Documents pontocerebellar hypoplasia in the severe neonatal phenotype.
- category: Respiratory
name: Neonatal Respiratory Insufficiency
description: >-
The lethal end of the spectrum: a floppy neonate with severe respiratory
insufficiency and ventilator dependence from birth, dying on day 24. Two
previous siblings died in the early neonatal period from respiratory
insufficiency, and the extended family had multiple neonatal and infant
deaths, so this presentation appears to breed true for the causative allele.
phenotype_term:
preferred_term: Respiratory insufficiency
term:
id: HP:0002093
label: Respiratory insufficiency
evidence:
- reference: PMID:30071302
reference_title: "A family with floppy neonates with severe respiratory insufficiency: A lethal phenotype of RFT1-CDG due to a novel mutation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Our patient presented as a floppy neonate with severe respiratory
insufficiency and ventilator dependence in the newborn period.
explanation: >-
Documents the lethal neonatal respiratory presentation.
- category: Craniofacial
name: Facial Dysmorphism
description: >-
Reported at both ends of the severity range — mild dysmorphism in the
ataxic, epilepsy-free patients and facial dysmorphism with a high arched
palate in the lethal neonatal case.
phenotype_term:
preferred_term: Abnormal facial shape
term:
id: HP:0001999
label: Abnormal facial shape
evidence:
- reference: PMID:30071302
reference_title: "A family with floppy neonates with severe respiratory insufficiency: A lethal phenotype of RFT1-CDG due to a novel mutation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
He had fetal growth restriction, facial dysmorphism, high arched palate,
bilateral cryptorchidism, hypoplastic pons and cerebellum and probable
hearing impairment.
explanation: >-
Documents facial dysmorphism and high arched palate.
- reference: PMID:29923091
reference_title: "RFT1-CDG: Absence of Epilepsy and Deafness in Two Patients with Novel Pathogenic Variants."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Their phenotype is characterized by mild psychomotor disability, behavioral
problems, ataxia, and mild dysmorphism.
explanation: >-
Documents mild dysmorphism at the milder end of the spectrum.
- category: Genitourinary
name: Cryptorchidism
description: >-
Bilateral undescended testes in the lethal neonatal case.
phenotype_term:
preferred_term: Cryptorchidism
term:
id: HP:0000028
label: Cryptorchidism
evidence:
- reference: PMID:30071302
reference_title: "A family with floppy neonates with severe respiratory insufficiency: A lethal phenotype of RFT1-CDG due to a novel mutation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
He had fetal growth restriction, facial dysmorphism, high arched palate,
bilateral cryptorchidism, hypoplastic pons and cerebellum and probable
hearing impairment.
explanation: >-
Documents bilateral cryptorchidism.
- category: Neurologic
name: Generalized Hypotonia
description: >-
Generalized hypotonia is present in every RFT1-CDG patient reported to date
and is typically the presenting sign, alongside feeding difficulty, in the
neonatal period — one family's report is titled around floppy neonates. It
is part of the core neurological picture rather than a variable feature.
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Generalized hypotonia
term:
id: HP:0001290
label: Generalized hypotonia
evidence:
- reference: PMID:23111317
reference_title: "RFT1-CDG in adult siblings with novel mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Only 6 children with RFT1-CDG have been described, all with failure to
thrive, feeding problems, hypotonia, developmental delay, epilepsy,
decreased vision, deafness and thrombotic complications.
explanation: >-
States hypotonia as present in all six reported children, which is what
licenses the VERY_FREQUENT band rather than a bare association.
- reference: PMID:19701946
reference_title: "RFT1 deficiency in three novel CDG patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
All four known RFT1-deficient patients showed very similar characteristics
including severe mental retardation, hypotonia, epilepsy, myoclonic jerks,
decreased visual acuity, sensorineural deafness, and feeding problems
explanation: >-
Independent confirmation across the four patients known at the time of this
series.
- category: Gastrointestinal
name: Feeding Difficulties
description: >-
Feeding problems are reported in every described patient and are severe
enough to require gastrostomy in some; they are a separate clinical problem
from the failure to thrive they contribute to, and are among the earliest
presenting features.
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Feeding difficulties
term:
id: HP:0011968
label: Feeding difficulties
evidence:
- reference: PMID:23111317
reference_title: "RFT1-CDG in adult siblings with novel mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Only 6 children with RFT1-CDG have been described, all with failure to
thrive, feeding problems, hypotonia, developmental delay, epilepsy,
decreased vision, deafness and thrombotic complications.
explanation: >-
Establishes feeding problems as universal in the reported cohort.
- category: Neurologic
name: Microcephaly
description: >-
Microcephaly is reported in a subset of patients rather than universally,
which distinguishes it from hypotonia and feeding difficulty.
phenotype_term:
preferred_term: Microcephaly
term:
id: HP:0000252
label: Microcephaly
evidence:
- reference: PMID:19701946
reference_title: "RFT1 deficiency in three novel CDG patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Patient 1 was the first child of healthy, unrelated North Americans of
Scottish-English origin and presented with respiratory insufficiency, severe
generalized epilepsy with intractable seizures, infantile spasms,
microcephaly, failure to thrive, hypotonia, sensorineural deafness, and
decreased visual acuity.
explanation: >-
Documents microcephaly in the first of the three novel patients.
- reference: PMID:19701946
reference_title: "RFT1 deficiency in three novel CDG patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
During the first year of life, he presented with severe developmental
delay, microcephaly, nystagmus, sensorineural deafness, relapsing
aspiration pneumonia, a generalized hypotonia, and inverted nipples.
explanation: >-
A second patient with microcephaly in the same series.
- category: Neurologic
name: Progressive Cerebral Atrophy
description: >-
Serial imaging shows progressive loss of cortical and subcortical volume.
Note the contrast with the pontocerebellar hypoplasia curated separately:
the supratentorial change is progressive and acquired on serial MRI, whereas
the infratentorial finding is a hypoplasia, and in the patient followed with
serial scans the cerebellum was explicitly spared.
phenotype_term:
preferred_term: Cerebral atrophy
clinical_course: PROGRESSIVE
term:
id: HP:0002059
label: Cerebral atrophy
evidence:
- reference: PMID:19701946
reference_title: "RFT1 deficiency in three novel CDG patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Serial brain MRI examinations showed progressive cortical and subcortical
atrophy with no cerebellar involvement.
explanation: >-
Direct serial-imaging evidence for progression, and for the absence of
cerebellar involvement in this patient.
- category: Vascular
name: Venous Thrombosis
description: >-
The prothrombotic consequence of the coagulopathy, curated as its own
phenotype because the thrombotic event is what is clinically actionable and
what is listed among the universal features of the disorder. Reported events
span recurrent deep venous thrombosis, a stroke-like episode, and a fatal
pulmonary embolism.
phenotype_term:
preferred_term: Deep venous thrombosis
term:
id: HP:0002625
label: Deep venous thrombosis
evidence:
- reference: PMID:19701946
reference_title: "RFT1 deficiency in three novel CDG patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
At the age of 4 years, computer tomography scan of the brain revealed a
stroke-like episode affecting the left frontal lobe, and the following year
he started to suffer from recurrent deep venous thrombosis of the left leg.
explanation: >-
Documents both a cerebrovascular event and recurrent deep venous
thrombosis in one patient.
- reference: PMID:23111317
reference_title: "RFT1-CDG in adult siblings with novel mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Only 6 children with RFT1-CDG have been described, all with failure to
thrive, feeding problems, hypotonia, developmental delay, epilepsy,
decreased vision, deafness and thrombotic complications.
explanation: >-
Lists thrombotic complications among the universal features.
- category: Gastrointestinal
name: Hepatomegaly
description: >-
Hepatomegaly is reported in a subset of patients. It is a recognised feature
across the CDG group generally, and in RFT1-CDG it is variable rather than a
core feature.
phenotype_term:
preferred_term: Hepatomegaly
term:
id: HP:0002240
label: Hepatomegaly
evidence:
- reference: PMID:19701946
reference_title: "RFT1 deficiency in three novel CDG patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Haeuptle and coworkers described a young girl presenting with marked
psychomotor retardation, hypotonia, seizures, hepatomegaly, and
coagulopathy.
explanation: >-
Documents hepatomegaly in the index patient as summarised by this series.
biochemical:
- name: Transferrin Isoelectric Focusing Type I Pattern
presence: PRESENT
notes: >-
RFT1-CDG is a defect of lipid-linked oligosaccharide assembly, so serum
transferrin isoelectric focusing shows a CDG type I pattern (loss of whole
N-glycans, and hence of glycosylation-site occupancy, rather than altered
glycan processing). This is the standard first-line CDG screen and is what
places a patient in the type I group before the gene is known.
evidence:
- reference: PMID:19862844
reference_title: "Congenital disorders of glycosylation: an update on defects affecting the biosynthesis of dolichol-linked oligosaccharides."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Defects in the biosynthesis of the oligosaccharide precursor for
N-glycosylation lead to decreased occupancy of glycosylation sites and
thereby to diseases known as congenital disorders of glycosylation (CDG).
explanation: >-
Explains why a precursor-assembly defect such as RFT1-CDG produces reduced
site occupancy, the basis of the type I pattern.
- reference: PMID:30071302
reference_title: "A family with floppy neonates with severe respiratory insufficiency: A lethal phenotype of RFT1-CDG due to a novel mutation."
supports: REFUTE
evidence_source: HUMAN_CLINICAL
snippet: "Transferrin iso-electric focusing was normal."
explanation: >-
A genetically confirmed RFT1-CDG patient with a normal transferrin screen,
showing the first-line test can miss the diagnosis.
- name: Lipid-Linked Oligosaccharide Profile with Man5 Accumulation
presence: PRESENT
notes: >-
The discriminating assay. Metabolic labelling of patient fibroblasts shows
accumulation of Dol-PP-GlcNAc2Man5 together with absence of the cytosolic
free oligosaccharide GlcNAc2Man5. This paired result localizes the block to
the transbilayer step and is what originally pointed to RFT1 by analogy with
the RFT1-null yeast profile.
evidence:
- reference: PMID:19267216
reference_title: "Comprehensive description of the phenotype of the first case of congenital disorder of glycosylation due to RFT1 deficiency (CDG In)."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Accumulation of intracellular DolPP-GlcNAc(2)Man(5) with absence of
cytosolic GlcNAc(2)Man(5) resembled the profile of a yeast mutant deficient
in RFT1, a protein that is thought to have a role as a flippase.
explanation: >-
Describes both components of the discriminating biochemical profile.
- reference: PMID:18313027
reference_title: "Human RFT1 deficiency leads to a disorder of N-linked glycosylation."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
RFT1 deficiency in both yeast and human cells leads to the accumulation of
incomplete DolPP-GlcNAc(2)Man(5) and to a profound glycosylation disorder in
humans.
explanation: >-
Confirms the accumulating species in human cells.
genetic:
- name: RFT1
gene_term:
preferred_term: RFT1
term:
id: hgnc:30220
label: RFT1
relationship_type: CAUSATIVE
variant_origin: GERMLINE
presence: PRESENT
frequency: All reported patients (biallelic in every case)
notes: >-
RFT1 (3p21.1) encodes a multispanning ER membrane protein with cytoplasmic N
and C termini. The index allele is the homozygous missense c.199C>T
(p.Arg67Cys); most RFT1-CDG alleles reported since map to regions of the
protein conserved across eukaryotes, consistent with damage to a shared
functional core. Note that human and yeast RFT1 share only about 22% sequence
identity, so functional orthology had to be demonstrated experimentally by
complementation rather than assumed from sequence.
Variant class and spectrum. Every RFT1-CDG allele reported is missense and
biallelic; no null allele has been described, which is consistent with
complete loss of RFT1 being incompatible with life. Alleles reported across
the series include p.R67C (the index and recurrent allele), p.K152E and
p.E298K (PMID:19701946), p.M408V and p.R442Q (PMID:23111317), and p.G276D,
p.R25W and p.C70R (PMID:29923091), plus p.G340S (PMID:30071302).
Where the alleles fall. The three earliest-characterised alleles all sit in
hydrophilic loops predicted to face the ER lumen, which is the structural
observation behind reading these as damaging a shared translocation-relevant
surface rather than being scattered. Later work identified p.G340S in a
transmembrane helix instead, so luminal-loop localisation is a strong
tendency and not a rule — a variant outside the loops is not thereby benign.
The same structural point is used diagnostically and is curated in the
`diagnosis` section as well.
Recurrence. p.R67C has been found homozygously in unrelated patients of
British origin with no known relationship, which the reporting authors read
as a possible founder effect rather than a mutational hotspot.
evidence:
- reference: PMID:18313027
reference_title: "Human RFT1 deficiency leads to a disorder of N-linked glycosylation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The c.199C-->T mutation introduced the amino acid substitution p.R67C.
explanation: >-
Identifies the index pathogenic allele at nucleotide and protein level.
- reference: PMID:39025454
reference_title: "Molecular characterization of Rft1, an ER membrane protein associated with congenital disorder of glycosylation RFT1-CDG."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
The majority of RFT1-CDG mutations map to highly conserved regions of the
protein.
explanation: >-
Characterizes the distribution of pathogenic alleles across the protein.
- reference: PMID:19701946
reference_title: "RFT1 deficiency in three novel CDG patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The first patient was homozygous for the earlier reported RFT1 missense
mutation (c.199C>T; p.R67C), whereas the two other patients were homozygous
for the missense mutation c.454A>G (p.K152E) and c.892G>A (p.E298 K),
respectively.
explanation: >-
Adds two novel alleles beyond the index p.R67C and establishes that all
three are homozygous missense.
- reference: PMID:19701946
reference_title: "RFT1 deficiency in three novel CDG patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
All three RFT1 mutations identified so far are located in one of the
hydrophilic loops predicted to be within the ER lumen.
explanation: >-
The structural localisation of the early allele set. Read as a tendency
rather than a rule: a later transmembrane-helix allele (p.G340S) does not
fit it.
- reference: PMID:19701946
reference_title: "RFT1 deficiency in three novel CDG patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
This could thus point to a founder effect of the p.R67C mutation.
explanation: >-
The authors' own reading of p.R67C recurrence in unrelated British
patients, curated as their hypothesis rather than as an established
founder haplotype.
diagnosis:
- name: Serum Transferrin Isoelectric Focusing
description: >-
First-line screening test. A type I pattern places the patient in the
lipid-linked-oligosaccharide-assembly group of CDG but does not identify the
gene. Important caveat: it was normal in a genetically confirmed, lethally
affected neonate, so a normal result does not exclude RFT1-CDG and should not
stop a sequencing work-up when the clinical picture fits.
evidence:
- reference: PMID:19862844
reference_title: "Congenital disorders of glycosylation: an update on defects affecting the biosynthesis of dolichol-linked oligosaccharides."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Defects in the biosynthesis of the oligosaccharide precursor for
N-glycosylation lead to decreased occupancy of glycosylation sites and
thereby to diseases known as congenital disorders of glycosylation (CDG).
explanation: >-
Grounds the screening logic: reduced site occupancy is what the type I
pattern detects.
- name: Exome Sequencing when the Transferrin Screen is Normal
description: >-
The diagnostic route that worked where the biochemical screen failed.
Clinical exome sequencing identified the causative RFT1 variant in the
neonate whose transferrin isoelectric focusing was normal. That case also
broadened the variant spectrum: previously reported pathogenic variants all
affected luminal loops, whereas this one lay in a transmembrane helical
domain.
evidence:
- reference: PMID:30071302
reference_title: "A family with floppy neonates with severe respiratory insufficiency: A lethal phenotype of RFT1-CDG due to a novel mutation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Transferrin iso-electric focusing was normal."
explanation: >-
Establishes the circumstance in which sequencing rather than biochemistry
makes the diagnosis.
- reference: PMID:30071302
reference_title: "A family with floppy neonates with severe respiratory insufficiency: A lethal phenotype of RFT1-CDG due to a novel mutation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The pathogenic variants so far reported are all missense variants affecting
the luminal loops; whereas the variant in our case is in the trans-membrane
helical domain.
explanation: >-
Documents the extension of the variant spectrum beyond the luminal loops.
- name: CDG Screening in Syndromic Congenital Hearing Loss
description: >-
Because sensorineural deafness is consistent in RFT1-CDG and unusual among
the CDG generally, the RFT1-CDG cohort report argued for adding CDG screening
to the diagnostic work-up of congenital syndromic hearing loss. This is a
diagnostic-pathway recommendation rather than a specific assay.
evidence:
- reference: PMID:19856127
reference_title: "RFT1-CDG: deafness as a novel feature of congenital disorders of glycosylation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
CDG should be included in the work-up of congenital, particularly syndromic,
hearing loss.
explanation: >-
The authors' explicit diagnostic recommendation arising from this disorder.
discussions:
- discussion_id: rft1_molecular_function_unresolved
kind: KNOWLEDGE_GAP
status: OPEN
prompt: >-
What is the essential molecular activity of RFT1 in N-glycosylation, given
that reconstitution experiments argue it is not itself the flippase for the
Man5 lipid intermediate?
attaches_to:
- "pathophysiology#Block in Transbilayer Completion of the Lipid-Linked Oligosaccharide"
rationale: >-
This is the central unresolved question of the disease and the reason this
entry curates two mechanistic hypotheses rather than one chain. The flippase
attribution is inherited from yeast genetics and from the shape of the
patient biochemistry: the Man5 intermediate accumulates and the cytosolic
free oligosaccharide is absent, exactly as a transport block would predict.
But flipping proceeds without RFT1 in microsomes and in reconstituted
proteoliposomes, and at least one eukaryote does not require RFT1 for
viability. Both observations can be true — RFT1 may be a regulator,
assembly factor, or accessory subunit whose loss disables a transport step
catalysed by something else. The gap matters for curation because it sets
how strongly a downstream causal edge may be stated, and it matters
clinically because a transporter deficiency and a regulatory-factor
deficiency imply different therapeutic entry points.
proposed_experiments:
- experiment_id: exp_rft1_reconstitution_with_patient_alleles
name: Reconstitution of flipping activity with RFT1-CDG patient alleles
description: >-
Reconstitute ER membrane protein fractions from cells expressing wild-type
versus RFT1-CDG alleles into unilamellar vesicles and assay Man5 lipid
flipping directly, to test whether patient alleles impair transport in a
defined system rather than only in intact cells.
- experiment_id: exp_rft1_interactome
name: Proximity labelling of the RFT1 interactome in the ER membrane
description: >-
Use proximity-dependent biotinylation from tagged RFT1 to identify partners
in the ER membrane, testing the hypothesis that RFT1 acts as an accessory
or regulatory subunit of a transport machine rather than as the transporter.
- discussion_id: rft1_genotype_phenotype_severity
kind: KNOWLEDGE_GAP
status: OPEN
prompt: >-
Does the position or class of an RFT1 allele predict clinical severity, and
is there a milder end of the RFT1-CDG spectrum that is currently
under-ascertained?
attaches_to:
- "pathophysiology#RFT1 Loss of Function"
rationale: >-
The published RFT1-CDG cohort is very small and was ascertained through
severe presentations — early-onset drug-resistant epilepsy with deafness. In
several other CDG (DPM2-CDG among them) an initially uniformly severe
phenotype broadened once milder, later-diagnosed patients were found,
sometimes surviving to adulthood. Whether RFT1-CDG has a comparable mild tail
is unknown, and ascertainment through epileptic encephalopathy would
systematically miss it. Deafness may be the more sensitive handle: it is the
feature that is consistent across the cohort, and screening syndromic
congenital hearing loss for CDG is the route by which a milder tail would
most plausibly be found.
notes: >-
Scope and boundaries. This entry covers the RFT1-CDG disease entity
(MONDO:0012783, CDG-In). It is a type I CDG — a defect in assembly of the
lipid-linked oligosaccharide donor — and so is mechanistically adjacent to the
other dolichol-linked-oligosaccharide disorders (ALG series, DPM1/2/3, DOLK,
MPDU1) rather than to the type II processing defects.
On the flippase question. Readers of older sources will find RFT1 described
flatly as "the flippase". That attribution is not settled, and this entry
deliberately does not assert it: the pathophysiology chain states the step that
fails (transbilayer completion of the lipid-linked oligosaccharide, which is
well evidenced) while the competing readings of RFT1's molecular role are
carried in `mechanistic_hypotheses` and in an open `KNOWLEDGE_GAP` discussion.
Curators extending this entry should preserve that separation rather than
collapsing it into a transporter-deficiency narrative.
Severity spans a wide range, and the entry now reflects both ends. The lethal
pole is a floppy neonate with ventilator-dependent respiratory insufficiency
dying at 24 days, in a family with multiple neonatal deaths. The mild pole is
adult siblings with profound intellectual disability but preserved feeding and
growth, well-controlled epilepsy, clinically silent coagulopathy and normal
visual acuity, plus a further pair with neither epilepsy nor deafness. Neither
deafness nor epilepsy should be treated as required for the diagnosis, and a
normal transferrin screen does not exclude it.
Evidence base. The literature is small — the index case, a detailed phenotype
report on that same patient, a six-patient cohort establishing deafness, an
electroclinical epilepsy report, and the 2024 molecular characterization,
together with later case reports that widened the phenotype at both ends. No
treatment beyond supportive and anticonvulsant care is established, so no
`treatments` block is curated; adding one would require evidence that does not
presently exist.
Question: You are an expert researcher providing comprehensive, well-cited information.
Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies
Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.
Please provide a comprehensive research report on RFT1-congenital disorder of glycosylation covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.
For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.
Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed
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For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities
For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype
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Search first: BRENDA, UniProt, KEGG, OMIM, PubMed
Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types
Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT
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Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen
For each treatment, suggest NCIT (NCI Thesaurus) clinical-intervention terms where applicable.
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Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, NCIT, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease
This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (NCIT terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details
RFT1-congenital disorder of glycosylation (RFT1-CDG; historical CDG-In) is an ultra-rare, autosomal-recessive disorder of endoplasmic-reticulum (ER) protein N-glycosylation caused by biallelic pathogenic variants in RFT1. The best-established phenotype is congenital/early-infantile, predominantly neurologic disease comprising severe developmental impairment, hypotonia, epilepsy, feeding failure, visual dysfunction, and particularly sensorineural hearing loss. Respiratory insufficiency, coagulopathy/thrombosis, microcephaly, brain atrophy, gastrointestinal problems, and occasional hepatomegaly are variable. Published evidence is based on individual patients and very small case series—not EHR-scale cohorts—so percentages, incidence, survival estimates, and genotype–phenotype relationships remain unreliable. Early literature counted six patients in 2009; a 2021 neurological review reported only 11 described patients. (vleugels2009rft1deficiencyin pages 4-6, vleugels2009rft1deficiencyin pages 6-7, jaeken2009rft1cdgdeafnessas pages 4-7, paprocka2021congenitaldisordersof pages 14-15)
The cellular hallmark is accumulation of Man5GlcNAc2-PP-dolichol (M5-DLO), reduced mature Glc3Man9GlcNAc2-PP-dolichol, and protein hypoglycosylation. Although RFT1 was initially called the M5-DLO “flippase,” biochemical reconstitution, an Rft1-null Trypanosoma brucei model, and 2024 molecular work show that the actual transbilayer scramblase remains unidentified; RFT1 may instead facilitate M5-DLO presentation, chaperoning, or conversion to mature DLO. (hirata2024molecularcharacterizationof pages 7-8, hirata2024molecularcharacterizationof pages 1-3, a2008humanrft1deficiency pages 4-5, jelk2013glycoproteinbiosynthesisin pages 1-2)
No disease-modifying therapy, approved gene therapy, or RFT1-specific clinical trial was identified. Current care is supportive, with molecular diagnosis enabling recurrence-risk counseling, carrier testing, prenatal diagnosis, and preimplantation genetic testing.
| 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 (OpenTargets Search: RFT1-congenital disorder of glycosylation-RFT1, a2008humanrft1deficiency pages 4-5, a2008humanrft1deficiency pages 1-2) | 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 (vleugels2009rft1deficiencyin pages 4-6, vleugels2009rft1deficiencyin pages 1-3, jaeken2009rft1cdgdeafnessas pages 1-4) | 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 (vleugels2009rft1deficiencyin pages 4-6, jaeken2009rft1cdgdeafnessas pages 4-7, hirata2024molecularcharacterizationof pages 1-3, hirata2024molecularcharacterizationof pages 35-37) | 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 (vleugels2009rft1deficiencyin pages 6-7, jaeken2009rft1cdgdeafnessas pages 4-7, jaeken2009rft1cdgdeafnessas pages 1-4) | 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 (vleugels2009rft1deficiencyin pages 6-7, jaeken2009rft1cdgdeafnessas pages 4-7, jaeken2009rft1cdgdeafnessas pages 1-4) | 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 (vleugels2009rft1deficiencyin pages 4-6, vleugels2009rft1deficiencyin pages 1-3, jaeken2009rft1cdgdeafnessas pages 4-7, jaeken2009rft1cdgdeafnessas pages 1-4) | 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 (vleugels2009rft1deficiencyin pages 4-6, vleugels2009rft1deficiencyin pages 6-7) | 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 (vleugelsUnknownyearcharacterizationofnovel pages 93-96, jaeken2009rft1cdgdeafnessas pages 1-4) | 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 (vleugels2009rft1deficiencyin pages 4-6, a2008humanrft1deficiency pages 4-5, a2008humanrft1deficiency pages 1-2) | 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 (vleugels2009rft1deficiencyin pages 11-13, a2008humanrft1deficiency pages 4-5, a2008humanrft1deficiency pages 1-2) | 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 (hirata2024molecularcharacterizationof pages 1-3, a2008humanrft1deficiency pages 4-5, a2008humanrft1deficiency pages 1-2) | 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 (hirata2024molecularcharacterizationof pages 7-8, hirata2024molecularcharacterizationof pages 1-3, jelk2013glycoproteinbiosynthesisin pages 1-2) | 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 (hirata2024molecularcharacterizationof pages 7-8, hirata2024molecularcharacterizationof pages 1-3) | 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 (vleugels2009rft1deficiencyin pages 4-6, vleugels2009rft1deficiencyin pages 6-7, jaeken2009rft1cdgdeafnessas pages 4-7) | 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 (vleugels2009rft1deficiencyin pages 11-13, a2008humanrft1deficiency pages 4-5, jelk2013glycoproteinbiosynthesisin pages 1-2) | 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 (vleugelsUnknownyearcharacterizationofnovel pages 93-96, jaeken2009rft1cdgdeafnessas pages 1-4) | 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 (jaeken2009rft1cdgdeafnessas pages 1-4) | 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 (vleugels2009rft1deficiencyin pages 1-3, jaeken2009rft1cdgdeafnessas pages 1-4) | 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 (paprocka2021congenitaldisordersof pages 14-15, pajusalu2021theestimatedprevalence pages 3-4) | 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 (hirata2024molecularcharacterizationof pages 7-8, hirata2024molecularcharacterizationof pages 1-3, pajusalu2021theestimatedprevalence pages 3-4, jelk2013glycoproteinbiosynthesisin pages 1-2) | 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 (vleugels2009rft1deficiencyin pages 4-6, jaeken2009rft1cdgdeafnessas pages 4-7, hirata2024molecularcharacterizationof pages 1-3) | 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.
RFT1-CDG is a Mendelian inborn error of metabolism affecting assembly of the lipid-linked oligosaccharide donor required for N-linked protein glycosylation in the ER. The initial report demonstrated that a homozygous RFT1 variant caused intracellular DolPP-GlcNAc2Man5 accumulation and profound glycosylation dysfunction, and proposed the historical name CDG-In. (a2008humanrft1deficiency pages 4-5, a2008humanrft1deficiency pages 1-2)
Identifiers and names
Evidence provenance: chiefly aggregated disease resources plus patient-level case reports, pedigrees, fibroblast studies, and model systems. No disease registry or population-scale EHR study was found.
The cause is germline biallelic loss or severe reduction of RFT1 function. Both homozygous and compound-heterozygous missense genotypes have been reported, with autosomal-recessive segregation. Functional causality was shown by failure of mutant p.Arg67Cys to complement Rft1-deficient yeast and restoration of normal lipid-linked oligosaccharide profiles after wild-type RFT1 expression in patient fibroblasts. (vleugels2009rft1deficiencyin pages 1-3, a2008humanrft1deficiency pages 4-5, a2008humanrft1deficiency pages 1-2)
Genetic risk is therefore determined by parental carrier status. Consanguinity occurred in Italian and Algerian families, increasing the probability of homozygosity, but affected children have also been born to unrelated parents. No susceptibility loci, validated modifier genes, protective alleles, epigenetic risk factors, environmental triggers, infections, toxins, diet, sex, or lifestyle effects have been established. (vleugels2009rft1deficiencyin pages 4-6, jaeken2009rft1cdgdeafnessas pages 4-7, jaeken2009rft1cdgdeafnessas pages 1-4)
There is no demonstrated gene–environment interaction. Intercurrent infection, feeding difficulty, or respiratory stress may worsen clinical status, but these are complications rather than proven causes or modifiers.
Because cohorts are tiny and overlapping, early frequencies should not be treated as stable population estimates. In the first four compared patients, hearing loss was 4/4; by 2009, six patients were described with a highly consistent neurologic syndrome. (vleugelsUnknownyearcharacterizationofnovel pages 93-96, vleugels2009rft1deficiencyin pages 6-7, jaeken2009rft1cdgdeafnessas pages 4-7)
Respiratory insufficiency, apnea, recurrent pulmonary infection, gastrointestinal symptoms, hepatomegaly, abnormal coagulation factors, deep-venous thrombosis, stroke-like episodes, brisk reflexes, and dysmorphism occur in subsets. One patient had reduced factor XI, protein C, and antithrombin; thrombosis was reported as early as four months in one case. Suggested HPO terms include HP:0002093 respiratory insufficiency, HP:0002105 apnea, HP:0002240 hepatomegaly, HP:0012379 abnormal coagulation, HP:0002625 deep venous thrombosis, and HP:0001297 stroke-like episode. (vleugels2009rft1deficiencyin pages 4-6, vleugelsUnknownyearcharacterizationofnovel pages 93-96, jaeken2009rft1cdgdeafnessas pages 4-7, jaeken2009rft1cdgdeafnessas pages 1-4)
No validated RFT1-CDG-specific quality-of-life instrument, EQ-5D, SF-36, PROMIS dataset, or quantitative caregiver-burden study was found. Severe neurologic, auditory, visual, respiratory, and feeding impairments imply major lifelong effects, but this remains clinically inferred rather than formally measured.
RFT1-CDG is a single-gene disorder. Well-documented variants include:
Most reported alleles are missense variants affecting conserved residues. The 2024 structure/topology study found that most disease variants map to highly conserved regions, many near a central hydrophilic cavity. Variant classification should nevertheless be checked against the current ClinVar record using the exact transcript and genome build; the retrieved literature predates modern uniform ACMG/AMP classification. Population allele frequencies were not reliably available in the retrieved evidence and should not be inferred as zero. (hirata2024molecularcharacterizationof pages 7-8, hirata2024molecularcharacterizationof pages 1-3)
The variants are germline, not somatic. The likely mechanism is loss/reduction of function; dominant-negative or gain-of-function mechanisms are unsupported. No disease-causing chromosomal rearrangement, repeat expansion, mitochondrial variant, epimutation, or recurrent copy-number change was identified. No validated modifier gene or disease-specific methylation signature is known.
No toxin, radiation, pollution, occupation, smoking, alcohol, diet, exercise pattern, or infectious agent is known to cause RFT1-CDG. It is not contagious and has no zoonotic transmission. Environmental interventions cannot prevent disease occurrence in an individual who has inherited a pathogenic biallelic genotype, although good nutrition, vaccination, infection prevention, aspiration precautions, and respiratory care may reduce complications.
The 2008 primary-paper abstract states: “RFT1 deficiency in both yeast and human cells leads to the accumulation of incomplete DolPP-GlcNAc2Man5 and to a profound glycosylation disorder in humans.” Wild-type RFT1 restored complete DLO synthesis in patient fibroblasts, providing direct functional evidence for this chain. (a2008humanrft1deficiency pages 4-5, a2008humanrft1deficiency pages 1-2)
The older model assigned Rft1 as an ATP-independent M5-DLO flippase. That label is now uncertain. Rft1-null T. brucei retained normal steady-state mature DLO and substantial N-glycosylation despite 30–100-fold M5-DLO accumulation; the authors concluded that Rft1 is not required for flipping in that organism and may act as an M5-DLO chaperone. Their concise conclusion was: “The M5-DLO flippase remains to be identified.” (jelk2013glycoproteinbiosynthesisin pages 1-2)
The 2024 study found that removing Rft1 did not reduce M5-DLO scramblase activity in reconstituted proteoliposomes: approximately 65% of M5-DLO was captured in both Rft1-containing and Rft1-depleted preparations. It concluded that if Rft1 has scramblase activity, it is a minor/redundant contributor. Human Rft1 was characterized as an ER-localized, non-N-glycosylated protein with 14 predicted transmembrane helices and both termini facing the cytoplasm; its fold resembles the MOP transporter family, but its essential substrate/function remains unresolved. (hirata2024molecularcharacterizationof pages 7-8, hirata2024molecularcharacterizationof pages 1-3)
Suggested GO annotations: GO:0006487 protein N-linked glycosylation; GO:0005783 endoplasmic reticulum; GO:0005789 ER membrane; GO:0016021 integral component of membrane; lipid-linked oligosaccharide biosynthetic process and transmembrane lipid transport. Suggested cell terms: CL:0000057 fibroblast for demonstrated patient models; neurons, auditory sensory cells, and hepatocytes are biologically plausible targets but have not been directly profiled disease-specifically.
No RFT1-CDG-specific transcriptomic, proteomic, metabolomic, lipidomic, single-cell, spatial-transcriptomic, or human multi-omics dataset was identified. The disease-defining targeted lipid-glycan profile is accumulation of M5-DLO rather than a validated circulating metabolomic signature. Immune activation, oxidative stress, fibrosis, apoptosis, and epigenetic dysregulation have not been established as primary mechanisms.
The central nervous system is the primary clinically affected system, with developmental dysfunction and occasional cortical/subcortical atrophy. The inner ear/auditory pathway is strongly implicated by bilateral sensorineural deafness. The eye/visual pathway, skeletal/respiratory muscle or central respiratory control, gastrointestinal tract, liver, and vascular/coagulation system can be variably involved. No consistent lateralization has been reported. (vleugels2009rft1deficiencyin pages 4-6, vleugels2009rft1deficiencyin pages 6-7, jaeken2009rft1cdgdeafnessas pages 4-7)
Suggested UBERON mappings: brain (UBERON:0000955), cerebral cortex (UBERON:0000956), inner ear (UBERON:0001846), eye (UBERON:0000970), liver (UBERON:0002107), lung (UBERON:0002048), and ER at the subcellular level (GO:0005783/GO:0005789). These are suggested knowledge-base mappings, not all experimentally confirmed sites of primary injury.
Onset is usually congenital, neonatal, or early infantile. Hypotonia, respiratory or feeding difficulty may be evident neonatally; developmental delay, visual/auditory impairment, and seizures emerge during infancy. The course is chronic and lifelong, often severe and sometimes progressive, with brain atrophy, refractory epilepsy, respiratory morbidity, or thrombosis. One North American patient died at eight months; other patients survived through childhood, and adult siblings with milder intellectual disability have been reported, establishing marked variability. (vleugels2009rft1deficiencyin pages 4-6, vleugels2009rft1deficiencyin pages 11-13, vleugels2009rft1deficiencyin pages 6-7)
There is no validated staging system, median progression rate, remission pattern, or critical therapeutic window. Developmental infancy is logically the period of greatest vulnerability, but presymptomatic treatment benefit has not been tested.
Inheritance is autosomal recessive. For two heterozygous carrier parents, each pregnancy has a 25% affected, 50% carrier, and 25% unaffected/non-carrier probability, assuming standard Mendelian segregation. Penetrance for genuinely pathogenic biallelic genotypes appears high, but cannot be quantified; expressivity is variable from lethal neonatal disease to adult survival. Anticipation is not expected. Germline mosaicism has not been specifically reported, although residual recurrence risk remains after apparently de novo findings.
Cases have included Moroccan, Italian, Algerian, North American Scottish-English, and other European backgrounds; this distribution does not establish ethnic predilection. Consanguinity contributed in some families. No founder allele, robust carrier frequency, geographic cluster, or sex bias has been demonstrated. (vleugels2009rft1deficiencyin pages 4-6, jaeken2009rft1cdgdeafnessas pages 4-7, jaeken2009rft1cdgdeafnessas pages 1-4)
Precise incidence and prevalence are unknown. A 2021 allele-frequency study examined 27 autosomal-recessive N-glycosylation disorders and concluded that only PMM2-CDG exceeded 1:100,000 in the broad populations assessed; however, its assumptions—ClinVar classification, gnomAD ascertainment, Hardy–Weinberg equilibrium, and exclusion of many structural/regulatory variants—make extrapolation to RFT1-CDG uncertain. Therefore, “ultra-rare” and “fewer than a few dozen published patients” are more defensible than a numeric prevalence. (paprocka2021congenitaldisordersof pages 14-15, pajusalu2021theestimatedprevalence pages 3-4)
WGS can detect noncoding and structural alleles missed by exome sequencing; RNA-seq may clarify suspected splice variants, but no disease-specific validated RNA diagnostic protocol exists. CMA and karyotyping are low-yield for a sequence-level recessive disorder unless broader syndromic findings suggest a CNV. FISH, mtDNA testing, and repeat-expansion testing are not routine RFT1-CDG tests.
Recommended baseline evaluations include EEG; brain MRI; brainstem auditory evoked responses/audiology; ophthalmology; swallowing and nutritional assessment; respiratory assessment; liver enzymes; albumin; coagulation profile including antithrombin/protein C where available; developmental, physical, occupational, and speech-language evaluation. These recommendations derive from observed complications rather than a formal RFT1-specific guideline. (vleugels2009rft1deficiencyin pages 4-6, vleugelsUnknownyearcharacterizationofnovel pages 93-96, jaeken2009rft1cdgdeafnessas pages 4-7)
The differential includes PMM2-CDG and other type-I N-glycosylation defects—particularly ALG3-CDG, DPM1-CDG, MPDU1-CDG, ALG11-CDG, and disorders causing developmental epileptic encephalopathy with deafness. M5-DLO accumulation narrows the biochemical differential, but localization and complete DLO/N-glycan profiles plus sequencing distinguish the defects. The original authors noted biochemical/clinical resemblance to ALG3 and DPM1 deficiencies. (a2008humanrft1deficiency pages 4-5)
No population newborn screening program exists. Targeted cascade testing is indicated for relatives after familial variants are established.
No 5-year/10-year survival estimates, mortality rate, or formal life-expectancy analysis exists. Prognosis ranges from death in infancy due to severe respiratory/neurologic disease to survival into adulthood. Major long-term morbidity includes profound developmental disability, epilepsy, hearing and visual impairment, feeding dependence, impaired mobility, and respiratory and thrombotic complications. (vleugels2009rft1deficiencyin pages 4-6, vleugels2009rft1deficiencyin pages 11-13, vleugels2009rft1deficiencyin pages 6-7)
No validated prognostic biomarker exists. Residual RFT1 activity and genotype plausibly influence severity, but current numbers are insufficient for clinical prediction. Early respiratory failure, refractory seizures, severe feeding dysfunction, and progressive brain atrophy are clinically concerning, but not statistically validated prognostic factors. Recovery to normal function has not been documented; symptomatic improvement may occur with seizure, nutrition, hearing, and rehabilitation interventions.
No approved RFT1-directed pharmacotherapy or dietary substrate replacement is available. Management is multidisciplinary and symptom-directed:
Suggested NCIT mappings include Supportive Care, Anticonvulsant Therapy, Enteral Nutrition, Physical Therapy, Occupational Therapy, Speech and Language Therapy, Hearing Aid, Cochlear Implantation, Mechanical Ventilation, and Genetic Counseling. These are intervention annotations, not evidence of RFT1-specific efficacy.
Patient-fibroblast correction by lentiviral wild-type RFT1 provides proof of biological reversibility at the cellular level: complete DLO synthesis and DNase-1 secretion normalized. This is not a clinical gene-therapy result and does not establish safety, CNS delivery, dosing, or patient benefit. No RFT1-specific gene editing, ASO, siRNA, mRNA, cell therapy, immunotherapy, or clinical-stage small molecule was found. (vleugels2009rft1deficiencyin pages 11-13, a2008humanrft1deficiency pages 4-5)
The ClinicalTrials.gov search returned trials for other CDGs, such as PGM1-CDG and PMM2-CDG, but none relevant to RFT1-CDG; these should not be presented as treatment options for this disease.
There is no environmental or pharmacologic primary prevention. Genetic prevention and early ascertainment are applicable:
Secondary/tertiary prevention focuses on early hearing rehabilitation, seizure control, nutritional support, aspiration prevention, vaccination, respiratory infection reduction, thrombosis awareness, and developmental therapies. Routine immunizations are appropriate unless an unrelated contraindication exists. There is no RFT1-specific vaccine or prophylactic medication.
No naturally occurring RFT1-CDG-like veterinary disease, affected breed, zoonotic potential, or cross-species transmission was identified. RFT1 function is evolutionarily conserved from yeast to humans; human RFT1 can complement yeast Rft1 deficiency, whereas p.Arg67Cys cannot, supporting conserved biology. (a2008humanrft1deficiency pages 4-5, a2008humanrft1deficiency pages 1-2)
Relevant species include Homo sapiens (NCBI Taxon 9606), Saccharomyces cerevisiae (559292), and Trypanosoma brucei (5691). The parasite model is mechanistically informative but does not reproduce the human neurologic syndrome.
No validated RFT1-CDG mouse, rat, zebrafish, Drosophila, C. elegans, organoid, or patient-iPSC model reproducing the human syndrome was identified. Developing neural and inner-ear organoids or conditional mammalian knockouts would be particularly valuable because constitutive RFT1 loss is expected to compromise viability.
The most important 2024 development was the molecular characterization of human Rft1 in yeast reporter systems. It supports a 14-transmembrane, ER-localized Nin/Cin topology; shows that Rft1 itself is not N-glycosylated; maps most known disease variants to conserved regions; and strengthens evidence that the majority of measurable M5-DLO scramblase activity comes from another protein or complex. The version retrieved was posted 22 June 2024 under DOI 10.1101/2024.04.03.587922; it should be treated according to its retrieved preprint status even though bibliographic search metadata also associated it with JBC. (hirata2024molecularcharacterizationof pages 7-8, hirata2024molecularcharacterizationof pages 1-3)
Priority gaps are: a curated international natural-history registry; systematic reanalysis of all variants with current ACMG/AMP criteria and gnomAD frequencies; standardized audiologic, neurologic, coagulation, and glycomic phenotyping; identification of the M5-DLO scramblase and RFT1’s direct substrate; neural/inner-ear disease models; and testing whether early RFT1 replacement can safely restore glycosylation in relevant tissues.
The evidence base is dominated by fewer than a few dozen patients, overlapping case reports, and experimental models. Therefore, phenotype percentages beyond the earliest denominators, penetrance, carrier frequency, incidence, prevalence, survival, treatment-response rates, sex ratios, and genotype–phenotype predictions cannot currently be stated reliably. No disease-specific clinical guideline, randomized trial, registry-scale natural-history study, validated outcome measure, advanced human omics atlas, or mammalian phenocopy was identified.
References
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Checked with linkml-reference-validator 0.2.1.
| Outcome | Count |
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| References checked | 9 |
| Resolved | 9 |
| Unresolved (possible confabulation) | 0 |
| Unverifiable | 0 |
| References weighed for topical relevance | 9 |
| On topic | 3 |
| Off topic | 0 |
All extracted references resolved successfully.