DHRSX-Congenital Disorder of Glycosylation

Mendelian MONDO:0975846 Pathograph 30 Show in embeddings browser hereditary disease congenital disorder of glycosylation inborn error of dolichol metabolism

DHRSX-CDG (congenital disorder of glycosylation type 1DD) is a type I congenital disorder of glycosylation caused by biallelic missense variants in DHRSX. Two things make it unusual. First, its inheritance is pseudoautosomal-recessive: DHRSX lies in pseudoautosomal region 1, present on both the X and the Y chromosome, so the gene behaves autosomally despite its sex-chromosome location. Second, identifying the disease rewrote a textbook pathway. Dolichol had been thought to be made directly from polyprenol by SRD5A3; the work describing these patients showed instead that the conversion takes three steps, with DHRSX performing the first and third — acting as an NAD+-dependent dehydrogenase and, non-consecutively, as an NADPH-dependent reductase — and SRD5A3 only the second. Losing DHRSX raises the polyprenol-to-dolichol ratio, and because polyprenol-phosphate is a poor substrate for DPAGT1, DPM synthase, and ALG3, the lipid-linked oligosaccharide fails to mature and immature glycans are transferred to nascent proteins. Four individuals from three families have been described, with distinct facial features, severe neurological involvement, profound sensorineural hearing loss with absent cochlear and vestibular nerves, and severe failure to thrive.

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1
Inheritance
5
Pathophys.
15
Phenotypes
4
Gaps
30
Pathograph
1
Genes
3
Variants
4
Medical Actions
2
Models
2
References
1
Deep Research
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Classifications

ICIMD (Inherited Metabolic Disorders)
n linked protein glycosylation
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Inheritance

1
Pseudoautosomal recessive HP:0000007
Biallelic missense variants in DHRSX, which lies in pseudoautosomal region 1 of the X and Y chromosomes. Because PAR1 genes are present in two copies in both sexes and escape X-inactivation, transmission is effectively autosomal recessive rather than X-linked — the affected individuals include both females and males. HPO has no dedicated pseudoautosomal-recessive term, so the standard autosomal recessive term is bound here and the pseudoautosomal location recorded in this description.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:38821050 SUPPORT Human Clinical
"Here, we report a CDG caused by biallelic missense variants in DHRSX, a gene located in the pseudoautosomal region 1 of the X and Y chromosomes."
Establishes both the biallelic requirement and the pseudoautosomal location that makes inheritance behave recessively.
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Discussions and Knowledge Gaps

4
How many DHRSX-CDG patients are missed because serum transferrin isoelectric focusing is normal or normalizes with age?
KNOWLEDGE GAP transferrin_ief_misses_cases
Attached to
biochemical#Serum transferrin isoelectric focusing pathophysiology#Protein Hypoglycosylation
Of four patients, one had a normal transferrin profile throughout and another's normalized at 17 months. Transferrin IEF is the standard first-line CDG screen, so a disorder that half-escapes it is likely under-ascertained. Whether a different glycoprotein readout, or direct polyprenol/dolichol measurement, would perform better as a screen has not been tested.
Why do DHRSX-CDG and SRD5A3-CDG differ clinically when both raise the polyprenol-to-dolichol ratio and produce the same immature glycan signature?
KNOWLEDGE GAP pathway_step_to_phenotype
Attached to
pathophysiology#Impaired Dolichol Synthesis from Polyprenol pathophysiology#Defective Lipid-Linked Oligosaccharide Maturation
The two enzymes act in the same three-step conversion and their knockouts give the same Man-5/Man-4 accumulation in HAP1 cells, yet SRD5A3-CDG is a recognized disorder with its own phenotype dominated by ocular and neurological features. If the biochemical lesion is shared, something other than the glycan signature must account for the clinical difference — possibly DHRSX's activity on other substrates, or its reported localization to lipid droplet-like structures.
How does defective N-glycosylation produce bilateral agenesis of the cochlear and vestibular nerves specifically?
KNOWLEDGE GAP cochlear_nerve_agenesis_mechanism
Attached to
phenotypes#Cochlear nerve aplasia pathophysiology#Protein Hypoglycosylation
Cranial nerve VIII agenesis is not a general feature of the CDGs, and the edges from hypoglycosylation to the clinical phenotypes are recorded as indirect with unknown intermediates for exactly this reason. Identifying the glycoprotein whose underglycosylation disrupts eighth nerve development would convert those edges into a mechanism, and would inform whether auditory brainstem implantation is a rational option.
Does DHRSX's reported secreted, autophagy-regulating role contribute to this disease, or is the phenotype entirely explained by the ER dolichol synthesis defect?
KNOWLEDGE GAP dolichol_role_versus_autophagy_role
Attached to
pathophysiology#DHRSX Oxidoreductase Deficiency pathophysiology#Protein Hypoglycosylation
Before its role in dolichol biosynthesis was known, DHRSX was characterized as a non-classical secretory protein that positively regulates starvation-induced autophagy. The patient variants cluster around the NAD(P)+ binding site and substrate channel, which on structural grounds alone would suggest a specifically catalytic lesion - but patient cells retain only about 4-5% of control DHRSX protein, so the enzyme is largely absent and both the oxidoreductase and the autophagy-associated functions would be lost together. That is what makes this question live rather than academic: the autophagy role cannot be assumed spared. Separating the two would need catalytically dead versus secretion-deficient constructs in a disease-relevant cell type. It matters because the entire pathograph in this entry runs through glycosylation, and an unrecognised autophagy contribution would be a parallel arm it does not represent.
Show evidence (1 reference)
PMID:25076851 SUPPORT INDIRECT In Vitro
"these results demonstrate that DHRSX is a novel non-classical secretory protein involved in the positive regulation of starvation induced autophagy"
Establishes the second, non-glycosylation function of DHRSX that this gap is about. Indirect for the disease because the work is overexpression and siRNA knockdown in HeLa and U2OS cells with no patient material and no connection to the CDG phenotype.
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Pathophysiology

5
DHRSX Oxidoreductase Deficiency
The reported variants — p.(Thr49Met), p.(Val181Phe), and p.(Leu215Phe) — cluster around the predicted NAD(P)+ binding site and the substrate access channel. Thr49 is an obligatory residue of the Class IV NAD(P)+ binding motif; Val181 contacts the cofactor directly and sits at the mouth of the substrate channel; Leu215 lies along that channel. All three are therefore expected to impair the enzyme's oxidoreductase function. They also destabilize the protein: patient cells carry about 4-5% of control DHRSX protein while mRNA remains at 34-68% of control, so the dominant effect is loss of the enzyme rather than a purely catalytic lesion in a normally abundant one.
NAD(P)-dependent oxidoreductase activity of DHRSX GO:0016616 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves NAD(P)-dependent oxidoreductase activity of DHRSX, annotated with oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor (GO:0016616), qualified as loss of function. GO:0016616 is a molecular function from the Gene Ontology. ⇓ LOSS OF FUNCTION
Downstream
Impaired Dolichol Synthesis from Polyprenol DHRSX catalyses two of the three steps converting polyprenol to dolichol, so loss of its oxidoreductase activity blocks the pathway at both ends.
Show evidence (3 references)
PMID:38821050 SUPPORT Computational
"Altogether, the variants observed in our patients were expected to severely impact the putative oxidoreductase function of DHRSX."
Structural modelling of the three patient variants predicts loss of oxidoreductase function.
PMID:38821050 SUPPORT In Vitro
"DHRSX has a unique dual substrate and cofactor specificity, allowing it to act as a NAD+-dependent dehydrogenase and as a NADPH-dependent reductase in two non-consecutive steps."
Characterizes the dual enzymatic activity that the patient variants disrupt.
PMID:38821050 SUPPORT In Vitro
"Immunoblotting revealed substantially lower DHRSX protein levels in patient cells, at an average of 4% of mean control levels in EBV-immortalized lymphoblasts and 5% in fibroblasts"
The direct measurement. Protein abundance is reduced roughly twentyfold while mRNA stays near normal, which points to destabilization of the variant proteins rather than a transcriptional effect.
Impaired Dolichol Synthesis from Polyprenol
Cells lacking DHRSX accumulate polyprenol and its phosphorylated and hexosylated derivatives while dolichol and its derivatives fall — that is, the polyprenol-to-dolichol ratio rises. Polyprenal levels are unchanged, which is the observation that localizes the block to the DHRSX steps rather than the SRD5A3 step.
Experimental models
CHO Lec5 and Lec9 glycosylation mutants CELL LINE Both lines show the DHRSX-deficiency polyisoprenoid signature and loss of the two DHRSX enzymatic activities with SRD5A3 activity intact, and both are corrected by human DHRSX but not by SRD5A3.
Downstream
Defective Lipid-Linked Oligosaccharide Maturation Dolichol-phosphate availability is rate-limiting for N-glycosylation, and polyprenol-phosphate substitutes poorly for it at several LLO assembly steps.
Show evidence (1 reference)
PMID:39395802 SUPPORT In Vitro
"Both cell lines showed increased levels of polyprenol and its derivatives, concomitant with decreased levels of dolichol and derivatives, but no change in polyprenal levels, suggesting DHRSX deficiency."
Documents the polyisoprenoid profile of DHRSX deficiency, including the unchanged polyprenal that localizes the block.
Defective Lipid-Linked Oligosaccharide Maturation
Dolichol-phosphate is rate-limiting for N-glycosylation because dolichol-phosphate sugars are used at seven steps of LLO assembly. DPAGT1 (which transfers GlcNAc-1-P onto Dol-P), DPM synthase, and ALG3 (which adds the sixth mannose) are all markedly inefficient when handed the polyprenol-linked analogue instead. The LLO therefore stalls as an immature linear Man-5 species, with Man-4 arising downstream through EDEM3.
dolichol-linked oligosaccharide biosynthetic process GO:0006488 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased dolichol-linked oligosaccharide biosynthetic process (GO:0006488). GO:0006488 is a biological process from the Gene Ontology. ↓ DECREASED
endoplasmic reticulum GO:0005783 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves endoplasmic reticulum (GO:0005783). GO:0005783 is a cellular component from the Gene Ontology.
Downstream
Protein Hypoglycosylation The stalled immature LLO is transferred to nascent glycoproteins rather than being completed first — shown directly by castanospermine treatment, which distinguishes an immature transferred glycan from an over-trimmed mature one.
Show evidence (2 references)
PMID:38821050 SUPPORT In Vitro
"The availability of dolichol-phosphate is rate-limiting for N-glycosylation, since dolichol-phosphate sugars are used in seven steps during the formation of the LLO."
Explains why a shortfall of dolichol-phosphate is sufficient to compromise LLO assembly.
PMID:38821050 SUPPORT In Vitro
"The N-linked oligosaccharides obtained from DHRSX and SRD5A3 deficient cells showed an increase in Man5GlcNAc2 species (Man-5) and Man4GlcNAc2 species (Man-4) alongside a reduction in Man9GlcNAc2 species (Man-9)."
Documents the specific immature glycan signature produced by DHRSX deficiency.
Protein Hypoglycosylation
Underglycosylation of N-glycoproteins, detected clinically as a type I serum transferrin isoelectric focusing profile and experimentally as increased electrophoretic mobility of LAMP2. Notably the transferrin abnormality is not a reliable marker in every patient: one patient's profile normalized at 17 months and a fourth patient's was normal throughout, so a normal transferrin IEF does not exclude this diagnosis.
protein N-linked glycosylation GO:0006487 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased protein N-linked glycosylation (GO:0006487). GO:0006487 is a biological process from the Gene Ontology. ↓ DECREASED
Experimental models
DHRSX knockout HAP1 cells CELL LINE Reproduces the N-glycosylation defect and, through complementation, demonstrates that DHRSX loss is its cause rather than a correlate.
Downstream
Multisystem Glycoprotein Dysfunction Proteome-wide underglycosylation is what makes this a multisystem disease rather than an organ-specific one.
Show evidence (2 references)
PMID:38821050 SUPPORT Human Clinical
"Patients 1, 2, and 3 showed changes in transferrin profiles indicative of a defect in the attachment of N-glycans in the ER (i.e., a CDG type I)."
Documents the type I transferrin profile establishing an ER-level N-glycan attachment defect in patients.
PMID:38821050 SUPPORT In Vitro
"Increased mobility indicating a glycosylation defect was observed in DHRSX KO cells. Complementation by re-expression of wild-type DHRSX restored the normal migration pattern of LAMP2"
Shows the hypoglycosylation is caused by DHRSX loss, since re-expression corrects it.
Multisystem Glycoprotein Dysfunction
The organism-level convergence. Because many glycoproteins are underglycosylated at once, the disease presents across systems rather than in one organ: distinctive facial features, severe neurological involvement, profound sensorineural hearing loss with absent cochlear and vestibular nerves, ocular surface disease, skeletal deformity, severe failure to thrive, respiratory insufficiency and hepatic involvement. Which organs dominate is not predictable from the enzyme defect, which is why every edge out of this node is indirect with unknown intermediates. The cochlear nerve agenesis in particular is not a general CDG feature and is the subject of its own knowledge gap.
protein N-linked glycosylation GO:0006487 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal protein N-linked glycosylation (GO:0006487). GO:0006487 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Abnormal facial shape
Profound intellectual disability
Axial hypotonia
Seizure
Sensorineural hearing impairment
Cochlear nerve aplasia
Neurotrophic keratopathy
Scoliosis
Joint contracture
Failure to thrive
Respiratory insufficiency
Hepatomegaly
Gastroesophageal reflux
Thin corpus callosum
Abnormality of the skin
Show evidence (1 reference)
PMID:38821050 SUPPORT Human Clinical
"These individuals also experienced severe failure to thrive (requiring tube feeding); variable respiratory insufficiency; and involvement of the eyes, the gastrointestinal system, and other organs"
Records the multisystem breadth this node represents.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for DHRSX-Congenital Disorder of Glycosylation Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

15
Digestive 2
Gastroesophageal reflux FREQUENT HP:0002020 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Gastroesophageal reflux disease, annotated with Gastroesophageal reflux (HP:0002020). HP:0002020 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38821050 SUPPORT INDIRECT Human Clinical
"involvement of the eyes, the gastrointestinal system, and other organs"
Indirect for the same reason as the hepatic finding: the abstract records gastrointestinal involvement at disease level, while the per-patient detail identifying it as gastroesophageal reflux in two children sits in Table 1, where adjacent cells are concatenated without separators and leave no quotable reflux-only substring.
Hepatomegaly FREQUENT HP:0002240 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hepatomegaly (HP:0002240). HP:0002240 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38821050 SUPPORT INDIRECT Human Clinical
"These individuals also experienced severe failure to thrive (requiring tube feeding); variable respiratory insufficiency; and involvement of the eyes, the gastrointestinal system, and other organs"
Indirect. The abstract-level sentence records involvement of the gastrointestinal system and other organs, from which hepatic involvement follows. The per-patient detail identifying it as hepatosplenomegaly in infancy in one child and cholestasis with hepatomegaly in another sits in Table 1, where adjacent cells are concatenated without separators in the extracted text, so there is no hepatic-only substring long enough to quote as a snippet.
Ear 2
Sensorineural hearing impairment VERY_FREQUENT HP:0000407 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Profound bilateral sensorineural hearing loss, annotated with Sensorineural hearing impairment (HP:0000407), qualified as severity severe. HP:0000407 is a phenotype from the Human Phenotype Ontology.
Severity: SEVERE
Show evidence (1 reference)
PMID:38821050 SUPPORT Human Clinical
"severe neurological involvement including hypotonia, scoliosis, contractures, profound intellectual disability, epilepsy, and sensorineural hearing loss"
Reports sensorineural hearing loss as a core feature of the disorder.
Cochlear nerve aplasia FREQUENT HP:6000988 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bilateral absence of the cochlear nerves, annotated with Cochlear nerve aplasia (HP:6000988). HP:6000988 is a phenotype from the Human Phenotype Ontology.
Sequelae: Sensorineural hearing impairment
Show evidence (1 reference)
PMID:38821050 SUPPORT Human Clinical
"bilateral absence of the cochlear nerves, superior and inferior vestibular nerves bilaterally absent/hypoplastic"
Reports the cochlear and vestibular nerve findings on brain MRI.
Eye 1
Neurotrophic keratopathy FREQUENT Abnormal corneal epithelium morphology HP:0011495 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bilateral neurotrophic keratopathy, annotated with Abnormal corneal epithelium morphology (HP:0011495). HP:0011495 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:38821050 SUPPORT Human Clinical
"corneal erosion of the right eye"
Names the corneal finding in the fourth patient. The two-patient neurotrophic keratopathy cell in the same table is only three words long and so cannot serve as a snippet on its own; this cell carries the same ocular-surface claim at quotable length.
PMID:38821050 SUPPORT INDIRECT Human Clinical
"involvement of the eyes, the gastrointestinal system, and other organs"
The abstract-level statement of ocular involvement, supporting the phenotype at disease level.
Head and Neck 1
Abnormal facial shape VERY_FREQUENT HP:0001999 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Distinct facial features, annotated with Abnormal facial shape (HP:0001999). HP:0001999 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38821050 SUPPORT Human Clinical
"We describe four individuals from three families with distinct facial features"
Reports distinct facial features in all four patients.
Integument 1
Abnormality of the skin FREQUENT HP:0000951 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is hypertrichosis, ichthyosis and eczema, annotated with Abnormality of the skin (HP:0000951). HP:0000951 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38821050 SUPPORT Human Clinical
"hypertrichosis of arms and legs"
Names one of the three dermatological findings recorded in the clinical table.
Musculoskeletal 3
Axial hypotonia VERY_FREQUENT HP:0008936 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Axial hypotonia (HP:0008936). HP:0008936 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38821050 SUPPORT Human Clinical
"severe neurological involvement including hypotonia, scoliosis, contractures, profound intellectual disability, epilepsy, and sensorineural hearing loss"
Reports hypotonia as a core neurological feature; the clinical table records it as axial in all four patients.
Scoliosis FREQUENT HP:0002650 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Scoliosis (HP:0002650). HP:0002650 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38821050 SUPPORT Human Clinical
"severe neurological involvement including hypotonia, scoliosis, contractures, profound intellectual disability, epilepsy, and sensorineural hearing loss"
Lists scoliosis among the reported features.
Joint contracture FREQUENT HP:0034392 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elbow and knee contractures, annotated with Joint contracture (HP:0034392). HP:0034392 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38821050 SUPPORT Human Clinical
"contractures of elbows and knees"
Specifies the joints affected by contracture.
Nervous System 3
Profound intellectual disability VERY_FREQUENT HP:0002187 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Profound intellectual disability (HP:0002187), qualified as severity severe. HP:0002187 is a phenotype from the Human Phenotype Ontology.
Severity: SEVERE
Show evidence (1 reference)
PMID:38821050 SUPPORT Human Clinical
"severe neurological involvement including hypotonia, scoliosis, contractures, profound intellectual disability, epilepsy, and sensorineural hearing loss"
Lists profound intellectual disability among the core neurological features.
Seizure FREQUENT HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Epilepsy, annotated with Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38821050 SUPPORT Human Clinical
"severe neurological involvement including hypotonia, scoliosis, contractures, profound intellectual disability, epilepsy, and sensorineural hearing loss"
Lists epilepsy among the core neurological features.
Thin corpus callosum FREQUENT HP:0033725 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thin corpus callosum (HP:0033725). HP:0033725 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38821050 SUPPORT Human Clinical
"mild thinning of corpus callosum"
Records the corpus callosum finding on brain MRI.
Respiratory 1
Respiratory insufficiency FREQUENT HP:0002093 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Respiratory insufficiency (HP:0002093). HP:0002093 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38821050 SUPPORT Human Clinical
"These individuals also experienced severe failure to thrive (requiring tube feeding); variable respiratory insufficiency; and involvement of the eyes, the gastrointestinal system, and other organs"
Reports variable respiratory insufficiency among the systemic features.
Growth 1
Failure to thrive VERY_FREQUENT HP:0001508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Severe failure to thrive requiring tube feeding, annotated with Failure to thrive (HP:0001508), qualified as severity severe. HP:0001508 is a phenotype from the Human Phenotype Ontology.
Severity: SEVERE
Show evidence (1 reference)
PMID:38821050 SUPPORT Human Clinical
"These individuals also experienced severe failure to thrive (requiring tube feeding); variable respiratory insufficiency; and involvement of the eyes, the gastrointestinal system, and other organs"
Reports severe failure to thrive requiring tube feeding in the affected individuals.
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Genetic Associations

1
DHRSX
Gene: DHRSX hgnc:18399 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is DHRSX (hgnc:18399). hgnc:18399 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (1 reference)
PMID:38821050 SUPPORT Human Clinical
"we report a pseudoautosomal-recessive disease presenting as a congenital disorder of glycosylation in patients with missense variants in DHRSX (DHRSX-CDG)"
Establishes DHRSX as the causal gene and names the disorder.
Variants (3)
NM_145177.3:c.146C>T (p.Thr49Met) Pathogenic
missense
Thr49 is an obligatory residue of the Class IV NAD(P)+ binding motif, so this substitution is predicted to disrupt cofactor binding.
NM_145177.3:c.541G>T (p.Val181Phe) Pathogenic
missense
Val181 contacts the cofactor directly and sits at the interface of the NAD(P)+ site and the substrate access channel; inserting a bulky phenylalanine is predicted to disrupt both.
NM_145177.3:c.643C>T (p.Leu215Phe) Pathogenic
missense
Leu215 lies along the substrate access channel, close to Lys212, which is predicted to hydrogen-bond the cofactor.
💊

Medical Actions

4
Gastrostomy Feeding
Action: gastrostomy placementNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is gastrostomy placement, annotated with Gastrostomy (NCIT:C52006). NCIT:C52006 is a clinical intervention from the NCI Thesaurus. Ontology label: Gastrostomy NCIT:C52006
Platform: Surgery
All four individuals had severe failure to thrive and all four required gastrostomy tube feeding, making this the most consistently applied intervention in the reported cohort.
Mechanism Target:
Failure to thrive — Bypasses oral feeding failure; it does not address the glycosylation defect.
Show evidence (1 reference)
PMID:38821050 SUPPORT Human Clinical
"These individuals also experienced severe failure to thrive (requiring tube feeding)"
Records that tube feeding was required in the reported individuals.
Non-Invasive Ventilation
Action: non-invasive ventilationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is non-invasive ventilation, annotated with Non-Invasive Mechanical Ventilation (NCIT:C171457). NCIT:C171457 is a clinical intervention from the NCI Thesaurus. Ontology label: Non-Invasive Mechanical Ventilation NCIT:C171457
Platform: Device
BiPAP for severe obstructive sleep apnea and respiratory insufficiency, used in two of the four individuals.
Mechanism Target:
Respiratory insufficiency — Supports ventilation without altering the underlying disorder.
Show evidence (1 reference)
PMID:38821050 SUPPORT Human Clinical
"stridor; severe obstructive sleep apnea requiring BiPAP"
Records the ventilatory support used and the indication for it.
Antiepileptic Pharmacotherapy
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Platform: Small molecule
For the epilepsy present in three of the four individuals. No agent-specific guidance exists for this disorder.
Mechanism Target:
Seizure — Symptomatic seizure control only.
Supportive and Multidisciplinary Care
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
Platform: Other
No disease-modifying therapy exists. Beyond the specific interventions above, management is supportive and includes orthopedic management of scoliosis and contractures. Note that the sensorineural hearing loss is associated with absent cochlear nerves in some individuals, which is the relevant consideration for whether cochlear implantation is an option - the lesion is in the nerve, not the cochlea.
Mechanism Target:
Scoliosis — Orthopedic management of the spinal deformity; symptomatic only.
Joint contracture — Physical and orthopedic management of the elbow and knee contractures.
🔬

Biochemical Markers

1
Serum transferrin isoelectric focusing (Type 1 pattern)
Show evidence (1 reference)
PMID:38821050 SUPPORT Human Clinical
"However, the transferrin glycosylation profile of patient 3 normalized at 17 months of age and was normal in his brother, patient 4."
Documents the limits of transferrin IEF as a screening test in this disorder.
🔬

Diagnosis

2
Polyisoprenoid profiling
The confirmatory second-tier test, and the one that discriminates this disorder from SRD5A3-CDG where transferrin isoelectric focusing cannot. DHRSX deficiency raises polyprenol and its derivatives and lowers dolichol and its derivatives while leaving polyprenal unchanged - it is the unchanged polyprenal that localizes the block to the DHRSX-catalysed steps rather than the SRD5A3 step between them.
Show evidence (1 reference)
PMID:39395802 SUPPORT In Vitro
"Both cell lines showed increased levels of polyprenol and its derivatives, concomitant with decreased levels of dolichol and derivatives, but no change in polyprenal levels, suggesting DHRSX deficiency."
Defines the polyisoprenoid signature that identifies DHRSX deficiency and distinguishes it from the adjacent enzyme defect.
Molecular testing of the pseudoautosomal region
Sequencing is the definitive test, but DHRSX lies in pseudoautosomal region 1, which standard variant-calling pipelines cover poorly because reads map ambiguously between the X and Y copies. PAR1-aware calling is needed, and a negative exome that did not handle PAR1 correctly does not exclude this diagnosis.
Show evidence (1 reference)
PMID:38821050 SUPPORT Human Clinical
"Here, we report a CDG caused by biallelic missense variants in DHRSX, a gene located in the pseudoautosomal region 1 of the X and Y chromosomes."
Establishes the pseudoautosomal location that makes variant calling at this locus non-standard.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
Four individuals from three families in the founding report. No further cases or population estimates have been published.
Show evidence (1 reference)
PMID:38821050 SUPPORT Human Clinical
"We describe four individuals from three families with distinct facial features"
Records the size of the reported cohort.
🧫

Experimental Models

2
DHRSX knockout HAP1 cells CELL_LINE
Near-haploid human leukemia HAP1 cells with DHRSX knocked out, used with LAMP2 electrophoretic mobility as the glycosylation readout and wild-type DHRSX re-expression as the rescue arm.
Pathograph links
Protein Hypoglycosylation recapitulates fidelity: high Reproduces the N-glycosylation defect and, through complementation, demonstrates that DHRSX loss is its cause rather than a correlate.
Limitations: A complete knockout in a leukemia-derived near-haploid line rather than the patient genotype, and it cannot model the neurological phenotype. Note the knockout is a closer proxy than "missense" suggests: patient cells retain only about 4-5% of control DHRSX protein, so the alleles behave close to null in practice.
Readouts
LAMP2 electrophoretic mobility
Direction: RESTORED
Interpretation: Increased LAMP2 mobility indicates hypoglycosylation in DHRSX KO cells; re-expression of wild-type DHRSX restores normal migration.
Show evidence (1 reference)
PMID:38821050 SUPPORT In Vitro
"Increased mobility indicating a glycosylation defect was observed in DHRSX KO cells. Complementation by re-expression of wild-type DHRSX restored the normal migration pattern of LAMP2"
Reports the LAMP2 mobility measurement and its rescue in this model.
CHO Lec5 and Lec9 glycosylation mutants CELL_LINE
Chinese hamster ovary lectin-resistance mutants isolated decades ago with a known but unexplained block in polyprenol-to-dolichol conversion. Once DHRSX was described, both were shown to lack the DHRSX genomic region, closing a long-standing gap. They are a natural-experiment model of complete DHRSX deficiency, and their pre-existing characterization independently corroborates the pathway.
Pathograph links
Impaired Dolichol Synthesis from Polyprenol recapitulates fidelity: high Both lines show the DHRSX-deficiency polyisoprenoid signature and loss of the two DHRSX enzymatic activities with SRD5A3 activity intact, and both are corrected by human DHRSX but not by SRD5A3.
Limitations: A rodent cell line carrying a genomic deletion, not a patient-derived model or a patient genotype; it speaks to the biochemistry and not to the clinical phenotype.
Readouts
Polyprenol dehydrogenase and dolichal reductase activity in membranes
Direction: ABOLISHED
Interpretation: Both DHRSX activities are absent while the SRD5A3-catalysed step is unaffected, localizing the block to the DHRSX-catalysed reactions.
Show evidence (1 reference)
PMID:39395802 SUPPORT In Vitro
"the typical polyprenol dehydrogenase and dolichal reductase activities of DHRSX were absent in membrane preparations derived from Lec5 and Lec9 cells, while the reduction of polyprenal to dolichal, catalyzed by SRD5A3, was unaffected"
Reports the enzyme activity measurements distinguishing the DHRSX steps from the SRD5A3 step.
N-glycan synthesis after DHRSX versus SRD5A3 complementation
Direction: RESTORED
Interpretation: Correction by human DHRSX but not by SRD5A3 assigns the defect specifically to DHRSX.
Show evidence (1 reference)
PMID:39395802 SUPPORT In Vitro
"N-glycan synthesis and changes in polyisoprenoid levels were corrected by complementation with human DHRSX but not with SRD5A3"
Reports the discriminating complementation result.
Show evidence (1 reference)
PMID:39395802 SUPPORT In Vitro
"Long-read whole genome sequencing of Lec5 and Lec9 cells did not reveal mutations in the ORF of SRD5A3, but the genomic region containing DHRSX was absent."
Establishes that these long-studied mutants are DHRSX-deficient, making them a valid model of the human lesion.
{ }

Source YAML

click to show 
name: DHRSX-Congenital Disorder of Glycosylation
creation_date: "2026-09-01T00:00:00Z"
category: Mendelian
description: >-
  DHRSX-CDG (congenital disorder of glycosylation type 1DD) is a type I
  congenital disorder of glycosylation caused by biallelic missense variants in
  DHRSX. Two things make it unusual. First, its inheritance is
  pseudoautosomal-recessive: DHRSX lies in pseudoautosomal region 1, present on
  both the X and the Y chromosome, so the gene behaves autosomally despite its
  sex-chromosome location. Second, identifying the disease rewrote a textbook
  pathway. Dolichol had been thought to be made directly from polyprenol by
  SRD5A3; the work describing these patients showed instead that the conversion
  takes three steps, with DHRSX performing the first and third — acting as an
  NAD+-dependent dehydrogenase and, non-consecutively, as an NADPH-dependent
  reductase — and SRD5A3 only the second. Losing DHRSX raises the
  polyprenol-to-dolichol ratio, and because polyprenol-phosphate is a poor
  substrate for DPAGT1, DPM synthase, and ALG3, the lipid-linked oligosaccharide
  fails to mature and immature glycans are transferred to nascent proteins. Four
  individuals from three families have been described, with distinct facial
  features, severe neurological involvement, profound sensorineural hearing loss
  with absent cochlear and vestibular nerves, and severe failure to thrive.
parents:
- hereditary disease
- congenital disorder of glycosylation
- inborn error of dolichol metabolism
classifications:
  icimd_category:
  - classification_value: n_linked_protein_glycosylation
    notes: >-
      A type I CDG: the lesion is in assembly of the dolichol-linked
      oligosaccharide precursor, upstream of transfer onto nascent
      N-glycoproteins.
disease_term:
  preferred_term: congenital disorder of glycosylation, type 1DD
  term:
    id: MONDO:0975846
    label: congenital disorder of glycosylation, type 1DD

inheritance:
- name: Pseudoautosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Biallelic missense variants in DHRSX, which lies in pseudoautosomal region 1
    of the X and Y chromosomes. Because PAR1 genes are present in two copies in
    both sexes and escape X-inactivation, transmission is effectively autosomal
    recessive rather than X-linked — the affected individuals include both
    females and males. HPO has no dedicated pseudoautosomal-recessive term, so
    the standard autosomal recessive term is bound here and the pseudoautosomal
    location recorded in this description.
  evidence:
  - reference: PMID:38821050
    reference_title: "A pseudoautosomal glycosylation disorder prompts the revision of dolichol biosynthesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we report a CDG caused by biallelic missense variants in DHRSX, a gene located in the pseudoautosomal region 1 of the X and Y chromosomes."
    explanation: Establishes both the biallelic requirement and the pseudoautosomal location that makes inheritance behave recessively.

pathophysiology:
- name: DHRSX Oxidoreductase Deficiency
  description: >-
    The reported variants — p.(Thr49Met), p.(Val181Phe), and p.(Leu215Phe) —
    cluster around the predicted NAD(P)+ binding site and the substrate access
    channel. Thr49 is an obligatory residue of the Class IV NAD(P)+ binding
    motif; Val181 contacts the cofactor directly and sits at the mouth of the
    substrate channel; Leu215 lies along that channel. All three are therefore
    expected to impair the enzyme's oxidoreductase function. They also
    destabilize the protein: patient cells carry about 4-5% of control DHRSX
    protein while mRNA remains at 34-68% of control, so the dominant effect is
    loss of the enzyme rather than a purely catalytic lesion in a normally
    abundant one.
  biological_scale: MOLECULAR
  downstream:
  - target: Impaired Dolichol Synthesis from Polyprenol
    causal_link_type: DIRECT
    description: >-
      DHRSX catalyses two of the three steps converting polyprenol to dolichol,
      so loss of its oxidoreductase activity blocks the pathway at both ends.
    evidence:
    - reference: PMID:38821050
      reference_title: "A pseudoautosomal glycosylation disorder prompts the revision of dolichol biosynthesis."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "we found that dolichol synthesis requires a three-step detour involving additional metabolites, where SRD5A3 catalyzes only the second reaction. The first and third steps are performed by DHRSX"
      explanation: Assigns the first and third steps of dolichol synthesis to DHRSX, so its loss directly blocks the conversion.
  molecular_functions:
  - preferred_term: NAD(P)-dependent oxidoreductase activity of DHRSX
    term:
      id: GO:0016616
      label: oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor
    modifier: LOSS_OF_FUNCTION
  evidence:
  - reference: PMID:38821050
    reference_title: "A pseudoautosomal glycosylation disorder prompts the revision of dolichol biosynthesis."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "Altogether, the variants observed in our patients were expected to severely impact the putative oxidoreductase function of DHRSX."
    explanation: Structural modelling of the three patient variants predicts loss of oxidoreductase function.
  - reference: PMID:38821050
    reference_title: "A pseudoautosomal glycosylation disorder prompts the revision of dolichol biosynthesis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "DHRSX has a unique dual substrate and cofactor specificity, allowing it to act as a NAD+-dependent dehydrogenase and as a NADPH-dependent reductase in two non-consecutive steps."
    explanation: Characterizes the dual enzymatic activity that the patient variants disrupt.
  - reference: PMID:38821050
    reference_title: "A pseudoautosomal glycosylation disorder prompts the revision of dolichol biosynthesis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Immunoblotting revealed substantially lower DHRSX protein levels in patient cells, at an average of 4% of mean control levels in EBV-immortalized lymphoblasts and 5% in fibroblasts"
    explanation: >-
      The direct measurement. Protein abundance is reduced roughly twentyfold
      while mRNA stays near normal, which points to destabilization of the
      variant proteins rather than a transcriptional effect.

- name: Impaired Dolichol Synthesis from Polyprenol
  description: >-
    Cells lacking DHRSX accumulate polyprenol and its phosphorylated and
    hexosylated derivatives while dolichol and its derivatives fall — that is,
    the polyprenol-to-dolichol ratio rises. Polyprenal levels are unchanged,
    which is the observation that localizes the block to the DHRSX steps rather
    than the SRD5A3 step.
  biological_scale: MOLECULAR
  downstream:
  - target: Defective Lipid-Linked Oligosaccharide Maturation
    causal_link_type: DIRECT
    description: >-
      Dolichol-phosphate availability is rate-limiting for N-glycosylation, and
      polyprenol-phosphate substitutes poorly for it at several LLO assembly
      steps.
    evidence:
    - reference: PMID:38821050
      reference_title: "A pseudoautosomal glycosylation disorder prompts the revision of dolichol biosynthesis."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "our data indicate that the increased ratio of polyprenol to dolichol affects maturation of the lipid linked oligosaccharide and is associated with the transfer of immature glycans"
      explanation: States the causal link from the raised polyprenol/dolichol ratio to defective LLO maturation.
  chemical_entities:
  - preferred_term: polyprenol
    term:
      id: CHEBI:26199
      label: polyprenol
    modifier: INCREASED
  - preferred_term: dolichol
    term:
      id: CHEBI:16091
      label: dolichol
    modifier: DECREASED
  evidence:
  - reference: PMID:39395802
    reference_title: "Absence of the dolichol synthesis gene DHRSX leads to N-glycosylation defects in Lec5 and Lec9 Chinese hamster ovary cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Both cell lines showed increased levels of polyprenol and its derivatives, concomitant with decreased levels of dolichol and derivatives, but no change in polyprenal levels, suggesting DHRSX deficiency."
    explanation: Documents the polyisoprenoid profile of DHRSX deficiency, including the unchanged polyprenal that localizes the block.

- name: Defective Lipid-Linked Oligosaccharide Maturation
  conforms_to: "congenital_disorder_of_glycosylation#ER Lipid-Linked Oligosaccharide Assembly Defect"
  description: >-
    Dolichol-phosphate is rate-limiting for N-glycosylation because
    dolichol-phosphate sugars are used at seven steps of LLO assembly. DPAGT1
    (which transfers GlcNAc-1-P onto Dol-P), DPM synthase, and ALG3 (which adds
    the sixth mannose) are all markedly inefficient when handed the
    polyprenol-linked analogue instead. The LLO therefore stalls as an immature
    linear Man-5 species, with Man-4 arising downstream through EDEM3.
  biological_scale: MOLECULAR
  downstream:
  - target: Protein Hypoglycosylation
    causal_link_type: DIRECT
    description: >-
      The stalled immature LLO is transferred to nascent glycoproteins rather
      than being completed first — shown directly by castanospermine treatment,
      which distinguishes an immature transferred glycan from an over-trimmed
      mature one.
    evidence:
    - reference: PMID:38821050
      reference_title: "A pseudoautosomal glycosylation disorder prompts the revision of dolichol biosynthesis."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "consistent with a direct transfer from linear Man-5 LLOs to nascent glycoproteins"
      explanation: The castanospermine experiment establishes that immature glycans are transferred, rather than mature glycans being trimmed back.
  biological_processes:
  - preferred_term: dolichol-linked oligosaccharide biosynthetic process
    term:
      id: GO:0006488
      label: dolichol-linked oligosaccharide biosynthetic process
    modifier: DECREASED
  cellular_components:
  - preferred_term: endoplasmic reticulum
    term:
      id: GO:0005783
      label: endoplasmic reticulum
  evidence:
  - reference: PMID:38821050
    reference_title: "A pseudoautosomal glycosylation disorder prompts the revision of dolichol biosynthesis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The availability of dolichol-phosphate is rate-limiting for N-glycosylation, since dolichol-phosphate sugars are used in seven steps during the formation of the LLO."
    explanation: Explains why a shortfall of dolichol-phosphate is sufficient to compromise LLO assembly.
  - reference: PMID:38821050
    reference_title: "A pseudoautosomal glycosylation disorder prompts the revision of dolichol biosynthesis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The N-linked oligosaccharides obtained from DHRSX and SRD5A3 deficient cells showed an increase in Man5GlcNAc2 species (Man-5) and Man4GlcNAc2 species (Man-4) alongside a reduction in Man9GlcNAc2 species (Man-9)."
    explanation: Documents the specific immature glycan signature produced by DHRSX deficiency.

- name: Protein Hypoglycosylation
  conforms_to: "congenital_disorder_of_glycosylation#Protein Hypoglycosylation"
  description: >-
    Underglycosylation of N-glycoproteins, detected clinically as a type I serum
    transferrin isoelectric focusing profile and experimentally as increased
    electrophoretic mobility of LAMP2. Notably the transferrin abnormality is not
    a reliable marker in every patient: one patient's profile normalized at 17
    months and a fourth patient's was normal throughout, so a normal transferrin
    IEF does not exclude this diagnosis.
  biological_scale: CELLULAR
  downstream:
  - target: Multisystem Glycoprotein Dysfunction
    causal_link_type: DIRECT
    description: >-
      Proteome-wide underglycosylation is what makes this a multisystem
      disease rather than an organ-specific one.
  biological_processes:
  - preferred_term: protein N-linked glycosylation
    term:
      id: GO:0006487
      label: protein N-linked glycosylation
    modifier: DECREASED
  evidence:
  - reference: PMID:38821050
    reference_title: "A pseudoautosomal glycosylation disorder prompts the revision of dolichol biosynthesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients 1, 2, and 3 showed changes in transferrin profiles indicative of a defect in the attachment of N-glycans in the ER (i.e., a CDG type I)."
    explanation: Documents the type I transferrin profile establishing an ER-level N-glycan attachment defect in patients.
  - reference: PMID:38821050
    reference_title: "A pseudoautosomal glycosylation disorder prompts the revision of dolichol biosynthesis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Increased mobility indicating a glycosylation defect was observed in DHRSX KO cells. Complementation by re-expression of wild-type DHRSX restored the normal migration pattern of LAMP2"
    explanation: Shows the hypoglycosylation is caused by DHRSX loss, since re-expression corrects it.

- name: Multisystem Glycoprotein Dysfunction
  conforms_to: "congenital_disorder_of_glycosylation#Multisystem Glycoprotein Dysfunction"
  biological_scale: ORGANISM
  description: >-
    The organism-level convergence. Because many glycoproteins are
    underglycosylated at once, the disease presents across systems rather than
    in one organ: distinctive facial features, severe neurological involvement,
    profound sensorineural hearing loss with absent cochlear and vestibular
    nerves, ocular surface disease, skeletal deformity, severe failure to
    thrive, respiratory insufficiency and hepatic involvement. Which organs
    dominate is not predictable from the enzyme defect, which is why every edge
    out of this node is indirect with unknown intermediates. The cochlear nerve
    agenesis in particular is not a general CDG feature and is the subject of
    its own knowledge gap.
  biological_processes:
  - preferred_term: protein N-linked glycosylation
    term:
      id: GO:0006487
      label: protein N-linked glycosylation
    modifier: ABNORMAL
  downstream:
  - target: Abnormal facial shape
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Profound intellectual disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Axial hypotonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Seizure
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Sensorineural hearing impairment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Cochlear nerve aplasia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Neurotrophic keratopathy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Scoliosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Joint contracture
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Failure to thrive
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Respiratory insufficiency
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Hepatomegaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Gastroesophageal reflux
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Thin corpus callosum
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Abnormality of the skin
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:38821050
    reference_title: "A pseudoautosomal glycosylation disorder prompts the revision of dolichol biosynthesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These individuals also experienced severe failure to thrive (requiring tube feeding); variable respiratory insufficiency; and involvement of the eyes, the gastrointestinal system, and other organs"
    explanation: Records the multisystem breadth this node represents.

phenotypes:
- category: Craniofacial
  name: Abnormal facial shape
  description: >-
    Distinct facial features present in all four reported individuals.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Distinct facial features
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:38821050
    reference_title: "A pseudoautosomal glycosylation disorder prompts the revision of dolichol biosynthesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe four individuals from three families with distinct facial features"
    explanation: Reports distinct facial features in all four patients.

- category: Neurologic
  name: Profound intellectual disability
  description: >-
    Severe developmental and intellectual disability in all four individuals.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Profound intellectual disability
    term:
      id: HP:0002187
      label: Profound intellectual disability
    severity: SEVERE
  evidence:
  - reference: PMID:38821050
    reference_title: "A pseudoautosomal glycosylation disorder prompts the revision of dolichol biosynthesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "severe neurological involvement including hypotonia, scoliosis, contractures, profound intellectual disability, epilepsy, and sensorineural hearing loss"
    explanation: Lists profound intellectual disability among the core neurological features.

- category: Neurologic
  name: Axial hypotonia
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Axial hypotonia
    term:
      id: HP:0008936
      label: Axial hypotonia
  evidence:
  - reference: PMID:38821050
    reference_title: "A pseudoautosomal glycosylation disorder prompts the revision of dolichol biosynthesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "severe neurological involvement including hypotonia, scoliosis, contractures, profound intellectual disability, epilepsy, and sensorineural hearing loss"
    explanation: Reports hypotonia as a core neurological feature; the clinical table records it as axial in all four patients.

- category: Neurologic
  name: Seizure
  description: >-
    Epilepsy in three of the four reported individuals.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Epilepsy
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:38821050
    reference_title: "A pseudoautosomal glycosylation disorder prompts the revision of dolichol biosynthesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "severe neurological involvement including hypotonia, scoliosis, contractures, profound intellectual disability, epilepsy, and sensorineural hearing loss"
    explanation: Lists epilepsy among the core neurological features.

- category: Auditory
  name: Sensorineural hearing impairment
  description: >-
    Profound bilateral sensorineural hearing loss. Its structural basis is
    striking: brain MRI shows bilateral absence or hypoplasia of the cochlear
    nerves and of the superior and inferior vestibular nerves, so this is a
    cranial nerve rather than a purely cochlear lesion — which matters for
    whether cochlear implantation could help.
  frequency: VERY_FREQUENT
  diagnostic: true
  phenotype_term:
    preferred_term: Profound bilateral sensorineural hearing loss
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
    severity: SEVERE
  evidence:
  - reference: PMID:38821050
    reference_title: "A pseudoautosomal glycosylation disorder prompts the revision of dolichol biosynthesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "severe neurological involvement including hypotonia, scoliosis, contractures, profound intellectual disability, epilepsy, and sensorineural hearing loss"
    explanation: Reports sensorineural hearing loss as a core feature of the disorder.

- category: Neurologic
  name: Cochlear nerve aplasia
  description: >-
    Bilateral absence or hypoplasia of the cochlear nerves and of the superior
    and inferior vestibular nerves on brain MRI, in two of the four individuals;
    a third showed bilateral hypoplasia of cranial nerves V, VII and VIII.
  frequency: FREQUENT
  sequelae:
  - target: Sensorineural hearing impairment
    description: >-
      Absent cochlear nerves are the structural basis of the profound
      sensorineural hearing loss, and the reason implantation decisions turn on
      nerve rather than cochlear anatomy.
  phenotype_term:
    preferred_term: Bilateral absence of the cochlear nerves
    term:
      id: HP:6000988
      label: Cochlear nerve aplasia
  evidence:
  - reference: PMID:38821050
    reference_title: "A pseudoautosomal glycosylation disorder prompts the revision of dolichol biosynthesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "bilateral absence of the cochlear nerves, superior and inferior vestibular nerves bilaterally absent/hypoplastic"
    explanation: Reports the cochlear and vestibular nerve findings on brain MRI.

- category: Ophthalmologic
  name: Neurotrophic keratopathy
  description: >-
    Ocular surface disease in three of four individuals - bilateral neurotrophic
    keratopathy in two, and corneal erosion of the right eye in a third. Salient
    beyond its frequency: the entry's own knowledge gap contrasts this disorder
    with the cerebello-ocular SRD5A3-CDG, so ocular involvement in both is part
    of what that comparison has to explain.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Bilateral neurotrophic keratopathy
    term:
      id: HP:0011495
      label: Abnormal corneal epithelium morphology
  evidence:
  - reference: PMID:38821050
    reference_title: "A pseudoautosomal glycosylation disorder prompts the revision of dolichol biosynthesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "corneal erosion of the right eye"
    explanation: >-
      Names the corneal finding in the fourth patient. The two-patient
      neurotrophic keratopathy cell in the same table is only three words long
      and so cannot serve as a snippet on its own; this cell carries the same
      ocular-surface claim at quotable length.
  - reference: PMID:38821050
    reference_title: "A pseudoautosomal glycosylation disorder prompts the revision of dolichol biosynthesis."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "involvement of the eyes, the gastrointestinal system, and other organs"
    explanation: The abstract-level statement of ocular involvement, supporting the phenotype at disease level.

- category: Musculoskeletal
  name: Scoliosis
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:38821050
    reference_title: "A pseudoautosomal glycosylation disorder prompts the revision of dolichol biosynthesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "severe neurological involvement including hypotonia, scoliosis, contractures, profound intellectual disability, epilepsy, and sensorineural hearing loss"
    explanation: Lists scoliosis among the reported features.

- category: Musculoskeletal
  name: Joint contracture
  description: >-
    Contractures of the elbows and knees.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Elbow and knee contractures
    term:
      id: HP:0034392
      label: Joint contracture
  evidence:
  - reference: PMID:38821050
    reference_title: "A pseudoautosomal glycosylation disorder prompts the revision of dolichol biosynthesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "contractures of elbows and knees"
    explanation: Specifies the joints affected by contracture.

- category: Gastrointestinal
  name: Failure to thrive
  description: >-
    Severe failure to thrive in all four individuals, each requiring gastrostomy
    tube feeding.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Severe failure to thrive requiring tube feeding
    term:
      id: HP:0001508
      label: Failure to thrive
    severity: SEVERE
  evidence:
  - reference: PMID:38821050
    reference_title: "A pseudoautosomal glycosylation disorder prompts the revision of dolichol biosynthesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These individuals also experienced severe failure to thrive (requiring tube feeding); variable respiratory insufficiency; and involvement of the eyes, the gastrointestinal system, and other organs"
    explanation: Reports severe failure to thrive requiring tube feeding in the affected individuals.

- category: Respiratory
  name: Respiratory insufficiency
  description: >-
    Variable respiratory insufficiency, including severe apnea episodes, stridor,
    and obstructive sleep apnea requiring BiPAP.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Respiratory insufficiency
    term:
      id: HP:0002093
      label: Respiratory insufficiency
  evidence:
  - reference: PMID:38821050
    reference_title: "A pseudoautosomal glycosylation disorder prompts the revision of dolichol biosynthesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These individuals also experienced severe failure to thrive (requiring tube feeding); variable respiratory insufficiency; and involvement of the eyes, the gastrointestinal system, and other organs"
    explanation: Reports variable respiratory insufficiency among the systemic features.

- category: Dermatologic
  name: Abnormality of the skin
  description: >-
    Dermatological findings in three of four individuals - hypertrichosis of the
    arms and legs in one, ichthyosis in another, eczema in a third.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: hypertrichosis, ichthyosis and eczema
    term:
      id: HP:0000951
      label: Abnormality of the skin
  evidence:
  - reference: PMID:38821050
    reference_title: "A pseudoautosomal glycosylation disorder prompts the revision of dolichol biosynthesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hypertrichosis of arms and legs"
    explanation: Names one of the three dermatological findings recorded in the clinical table.

- category: Neurologic
  name: Thin corpus callosum
  description: >-
    Small or mildly thinned corpus callosum on brain MRI in two of the four
    individuals.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Thin corpus callosum
    term:
      id: HP:0033725
      label: Thin corpus callosum
  evidence:
  - reference: PMID:38821050
    reference_title: "A pseudoautosomal glycosylation disorder prompts the revision of dolichol biosynthesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "mild thinning of corpus callosum"
    explanation: Records the corpus callosum finding on brain MRI.

- category: Gastrointestinal
  name: Gastroesophageal reflux
  description: >-
    Gastroesophageal reflux disease in two of the four individuals, recorded in
    the clinical table for patients 3 and 4.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Gastroesophageal reflux disease
    term:
      id: HP:0002020
      label: Gastroesophageal reflux
  evidence:
  - reference: PMID:38821050
    reference_title: "A pseudoautosomal glycosylation disorder prompts the revision of dolichol biosynthesis."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "involvement of the eyes, the gastrointestinal system, and other organs"
    explanation: >-
      Indirect for the same reason as the hepatic finding: the abstract records
      gastrointestinal involvement at disease level, while the per-patient
      detail identifying it as gastroesophageal reflux in two children sits in
      Table 1, where adjacent cells are concatenated without separators and
      leave no quotable reflux-only substring.

- category: Hepatic
  name: Hepatomegaly
  description: >-
    Hepatosplenomegaly in infancy in one individual and cholestasis with
    hepatomegaly in another; absent in the remaining two.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hepatomegaly
    term:
      id: HP:0002240
      label: Hepatomegaly
  evidence:
  - reference: PMID:38821050
    reference_title: "A pseudoautosomal glycosylation disorder prompts the revision of dolichol biosynthesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "These individuals also experienced severe failure to thrive (requiring tube feeding); variable respiratory insufficiency; and involvement of the eyes, the gastrointestinal system, and other organs"
    explanation: >-
      Indirect. The abstract-level sentence records involvement of the
      gastrointestinal system and other organs, from which hepatic involvement
      follows. The per-patient detail identifying it as hepatosplenomegaly in
      infancy in one child and cholestasis with hepatomegaly in another sits in
      Table 1, where adjacent cells are concatenated without separators in the
      extracted text, so there is no hepatic-only substring long enough to quote
      as a snippet.

genetic:
- name: DHRSX
  notes: >-
    Biallelic missense variants in DHRSX (NM_145177.3), encoding a
    dehydrogenase/reductase with dual NAD+-dependent dehydrogenase and
    NADPH-dependent reductase activity in dolichol biosynthesis. Reported alleles
    are c.146C>T p.(Thr49Met), c.541G>T p.(Val181Phe), and c.643C>T
    p.(Leu215Phe). The gene lies in pseudoautosomal region 1, so it is present on
    both sex chromosomes and inherited as if autosomal. The variants are
    predicted to disrupt NAD(P)+ cofactor binding or substrate access, and they
    additionally destabilize the protein - measured at roughly 4-5% of control
    levels in patient cells against near-normal mRNA.
  gene_term:
    preferred_term: DHRSX
    term:
      id: hgnc:18399
      label: DHRSX
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  variants:
  - name: "NM_145177.3:c.146C>T (p.Thr49Met)"
    description: >-
      Thr49 is an obligatory residue of the Class IV NAD(P)+ binding motif, so
      this substitution is predicted to disrupt cofactor binding.
    type: missense
    clinical_significance: PATHOGENIC
  - name: "NM_145177.3:c.541G>T (p.Val181Phe)"
    description: >-
      Val181 contacts the cofactor directly and sits at the interface of the
      NAD(P)+ site and the substrate access channel; inserting a bulky
      phenylalanine is predicted to disrupt both.
    type: missense
    clinical_significance: PATHOGENIC
  - name: "NM_145177.3:c.643C>T (p.Leu215Phe)"
    description: >-
      Leu215 lies along the substrate access channel, close to Lys212, which is
      predicted to hydrogen-bond the cofactor.
    type: missense
    clinical_significance: PATHOGENIC
  evidence:
  - reference: PMID:38821050
    reference_title: "A pseudoautosomal glycosylation disorder prompts the revision of dolichol biosynthesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we report a pseudoautosomal-recessive disease presenting as a congenital disorder of glycosylation in patients with missense variants in DHRSX (DHRSX-CDG)"
    explanation: Establishes DHRSX as the causal gene and names the disorder.

biochemical:
- name: Serum transferrin isoelectric focusing
  biomarker_term:
    preferred_term: Type I serum transferrin isoform profile
    term:
      id: HP:0003642
      label: Type I transferrin isoform profile
  presence: Type 1 pattern
  notes: >-
    A CDG type I transferrin pattern was present in three of four patients, but
    it is not dependable: one patient's profile normalized at 17 months of age
    and his brother's was normal throughout. A normal transferrin IEF therefore
    does not exclude DHRSX-CDG, which matters because transferrin IEF is the
    standard first-line CDG screen.
  evidence:
  - reference: PMID:38821050
    reference_title: "A pseudoautosomal glycosylation disorder prompts the revision of dolichol biosynthesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, the transferrin glycosylation profile of patient 3 normalized at 17 months of age and was normal in his brother, patient 4."
    explanation: Documents the limits of transferrin IEF as a screening test in this disorder.

diagnosis:
- name: Polyisoprenoid profiling
  description: >-
    The confirmatory second-tier test, and the one that discriminates this
    disorder from SRD5A3-CDG where transferrin isoelectric focusing cannot.
    DHRSX deficiency raises polyprenol and its derivatives and lowers dolichol
    and its derivatives while leaving polyprenal unchanged - it is the unchanged
    polyprenal that localizes the block to the DHRSX-catalysed steps rather than
    the SRD5A3 step between them.
  evidence:
  - reference: PMID:39395802
    reference_title: "Absence of the dolichol synthesis gene DHRSX leads to N-glycosylation defects in Lec5 and Lec9 Chinese hamster ovary cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Both cell lines showed increased levels of polyprenol and its derivatives, concomitant with decreased levels of dolichol and derivatives, but no change in polyprenal levels, suggesting DHRSX deficiency."
    explanation: Defines the polyisoprenoid signature that identifies DHRSX deficiency and distinguishes it from the adjacent enzyme defect.

- name: Molecular testing of the pseudoautosomal region
  description: >-
    Sequencing is the definitive test, but DHRSX lies in pseudoautosomal region
    1, which standard variant-calling pipelines cover poorly because reads map
    ambiguously between the X and Y copies. PAR1-aware calling is needed, and a
    negative exome that did not handle PAR1 correctly does not exclude this
    diagnosis.
  evidence:
  - reference: PMID:38821050
    reference_title: "A pseudoautosomal glycosylation disorder prompts the revision of dolichol biosynthesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we report a CDG caused by biallelic missense variants in DHRSX, a gene located in the pseudoautosomal region 1 of the X and Y chromosomes."
    explanation: Establishes the pseudoautosomal location that makes variant calling at this locus non-standard.

prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Four individuals from three families in the founding report. No further cases
    or population estimates have been published.
  evidence:
  - reference: PMID:38821050
    reference_title: "A pseudoautosomal glycosylation disorder prompts the revision of dolichol biosynthesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe four individuals from three families with distinct facial features"
    explanation: Records the size of the reported cohort.

experimental_models:
- name: DHRSX knockout HAP1 cells
  experimental_model_type: CELL_LINE
  description: >-
    Near-haploid human leukemia HAP1 cells with DHRSX knocked out, used with
    LAMP2 electrophoretic mobility as the glycosylation readout and wild-type
    DHRSX re-expression as the rescue arm.
  modeled_mechanisms:
  - target: Protein Hypoglycosylation
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Reproduces the N-glycosylation defect and, through complementation,
      demonstrates that DHRSX loss is its cause rather than a correlate.
    limitations: >-
      A complete knockout in a leukemia-derived near-haploid line rather than
      the patient genotype, and it cannot model the neurological phenotype. Note
      the knockout is a closer proxy than "missense" suggests: patient cells
      retain only about 4-5% of control DHRSX protein, so the alleles behave
      close to null in practice.
    readouts:
    - name: LAMP2 electrophoretic mobility
      target: Protein Hypoglycosylation
      direction: RESTORED
      interpretation: >-
        Increased LAMP2 mobility indicates hypoglycosylation in DHRSX KO cells;
        re-expression of wild-type DHRSX restores normal migration.
      evidence:
      - reference: PMID:38821050
        reference_title: "A pseudoautosomal glycosylation disorder prompts the revision of dolichol biosynthesis."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "Increased mobility indicating a glycosylation defect was observed in DHRSX KO cells. Complementation by re-expression of wild-type DHRSX restored the normal migration pattern of LAMP2"
        explanation: Reports the LAMP2 mobility measurement and its rescue in this model.

- name: CHO Lec5 and Lec9 glycosylation mutants
  experimental_model_type: CELL_LINE
  description: >-
    Chinese hamster ovary lectin-resistance mutants isolated decades ago with a
    known but unexplained block in polyprenol-to-dolichol conversion. Once DHRSX
    was described, both were shown to lack the DHRSX genomic region, closing a
    long-standing gap. They are a natural-experiment model of complete DHRSX
    deficiency, and their pre-existing characterization independently corroborates
    the pathway.
  modeled_mechanisms:
  - target: Impaired Dolichol Synthesis from Polyprenol
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Both lines show the DHRSX-deficiency polyisoprenoid signature and loss of
      the two DHRSX enzymatic activities with SRD5A3 activity intact, and both
      are corrected by human DHRSX but not by SRD5A3.
    limitations: >-
      A rodent cell line carrying a genomic deletion, not a patient-derived model
      or a patient genotype; it speaks to the biochemistry and not to the
      clinical phenotype.
    readouts:
    - name: Polyprenol dehydrogenase and dolichal reductase activity in membranes
      target: Impaired Dolichol Synthesis from Polyprenol
      direction: ABOLISHED
      interpretation: >-
        Both DHRSX activities are absent while the SRD5A3-catalysed step is
        unaffected, localizing the block to the DHRSX-catalysed reactions.
      evidence:
      - reference: PMID:39395802
        reference_title: "Absence of the dolichol synthesis gene DHRSX leads to N-glycosylation defects in Lec5 and Lec9 Chinese hamster ovary cells."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "the typical polyprenol dehydrogenase and dolichal reductase activities of DHRSX were absent in membrane preparations derived from Lec5 and Lec9 cells, while the reduction of polyprenal to dolichal, catalyzed by SRD5A3, was unaffected"
        explanation: Reports the enzyme activity measurements distinguishing the DHRSX steps from the SRD5A3 step.
    - name: N-glycan synthesis after DHRSX versus SRD5A3 complementation
      target: Impaired Dolichol Synthesis from Polyprenol
      direction: RESTORED
      interpretation: >-
        Correction by human DHRSX but not by SRD5A3 assigns the defect
        specifically to DHRSX.
      evidence:
      - reference: PMID:39395802
        reference_title: "Absence of the dolichol synthesis gene DHRSX leads to N-glycosylation defects in Lec5 and Lec9 Chinese hamster ovary cells."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "N-glycan synthesis and changes in polyisoprenoid levels were corrected by complementation with human DHRSX but not with SRD5A3"
        explanation: Reports the discriminating complementation result.
    evidence:
    - reference: PMID:39395802
      reference_title: "Absence of the dolichol synthesis gene DHRSX leads to N-glycosylation defects in Lec5 and Lec9 Chinese hamster ovary cells."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Long-read whole genome sequencing of Lec5 and Lec9 cells did not reveal mutations in the ORF of SRD5A3, but the genomic region containing DHRSX was absent."
      explanation: Establishes that these long-studied mutants are DHRSX-deficient, making them a valid model of the human lesion.

treatments:
- name: Gastrostomy Feeding
  description: >-
    All four individuals had severe failure to thrive and all four required
    gastrostomy tube feeding, making this the most consistently applied
    intervention in the reported cohort.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: gastrostomy placement
    term:
      id: NCIT:C52006
      label: Gastrostomy
  target_mechanisms:
  - target: Failure to thrive
    description: >-
      Bypasses oral feeding failure; it does not address the glycosylation
      defect.
  evidence:
  - reference: PMID:38821050
    reference_title: "A pseudoautosomal glycosylation disorder prompts the revision of dolichol biosynthesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These individuals also experienced severe failure to thrive (requiring tube feeding)"
    explanation: Records that tube feeding was required in the reported individuals.

- name: Non-Invasive Ventilation
  description: >-
    BiPAP for severe obstructive sleep apnea and respiratory insufficiency, used
    in two of the four individuals.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: non-invasive ventilation
    term:
      id: NCIT:C171457
      label: Non-Invasive Mechanical Ventilation
  target_mechanisms:
  - target: Respiratory insufficiency
    description: >-
      Supports ventilation without altering the underlying disorder.
  evidence:
  - reference: PMID:38821050
    reference_title: "A pseudoautosomal glycosylation disorder prompts the revision of dolichol biosynthesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "stridor; severe obstructive sleep apnea requiring BiPAP"
    explanation: Records the ventilatory support used and the indication for it.

- name: Antiepileptic Pharmacotherapy
  description: >-
    For the epilepsy present in three of the four individuals. No agent-specific
    guidance exists for this disorder.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: Seizure
    description: >-
      Symptomatic seizure control only.

- name: Supportive and Multidisciplinary Care
  description: >-
    No disease-modifying therapy exists. Beyond the specific interventions above,
    management is supportive and includes orthopedic management of scoliosis and
    contractures. Note that the sensorineural hearing loss is associated with
    absent cochlear nerves in some individuals, which is the relevant
    consideration for whether cochlear implantation is an option - the lesion is
    in the nerve, not the cochlea.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Scoliosis
    description: >-
      Orthopedic management of the spinal deformity; symptomatic only.
  - target: Joint contracture
    description: >-
      Physical and orthopedic management of the elbow and knee contractures.

discussions:
- discussion_id: transferrin_ief_misses_cases
  kind: KNOWLEDGE_GAP
  prompt: >-
    How many DHRSX-CDG patients are missed because serum transferrin isoelectric
    focusing is normal or normalizes with age?
  attaches_to:
  - biochemical#Serum transferrin isoelectric focusing
  - pathophysiology#Protein Hypoglycosylation
  rationale: >-
    Of four patients, one had a normal transferrin profile throughout and
    another's normalized at 17 months. Transferrin IEF is the standard first-line
    CDG screen, so a disorder that half-escapes it is likely under-ascertained.
    Whether a different glycoprotein readout, or direct polyprenol/dolichol
    measurement, would perform better as a screen has not been tested.

- discussion_id: pathway_step_to_phenotype
  kind: KNOWLEDGE_GAP
  prompt: >-
    Why do DHRSX-CDG and SRD5A3-CDG differ clinically when both raise the
    polyprenol-to-dolichol ratio and produce the same immature glycan signature?
  attaches_to:
  - pathophysiology#Impaired Dolichol Synthesis from Polyprenol
  - pathophysiology#Defective Lipid-Linked Oligosaccharide Maturation
  rationale: >-
    The two enzymes act in the same three-step conversion and their knockouts
    give the same Man-5/Man-4 accumulation in HAP1 cells, yet SRD5A3-CDG is a
    recognized disorder with its own phenotype dominated by ocular and
    neurological features. If the biochemical lesion is shared, something other
    than the glycan signature must account for the clinical difference —
    possibly DHRSX's activity on other substrates, or its reported localization
    to lipid droplet-like structures.

- discussion_id: cochlear_nerve_agenesis_mechanism
  kind: KNOWLEDGE_GAP
  prompt: >-
    How does defective N-glycosylation produce bilateral agenesis of the cochlear
    and vestibular nerves specifically?
  attaches_to:
  - phenotypes#Cochlear nerve aplasia
  - pathophysiology#Protein Hypoglycosylation
  rationale: >-
    Cranial nerve VIII agenesis is not a general feature of the CDGs, and the
    edges from hypoglycosylation to the clinical phenotypes are recorded as
    indirect with unknown intermediates for exactly this reason. Identifying the
    glycoprotein whose underglycosylation disrupts eighth nerve development would
    convert those edges into a mechanism, and would inform whether auditory
    brainstem implantation is a rational option.

- discussion_id: dolichol_role_versus_autophagy_role
  kind: KNOWLEDGE_GAP
  prompt: >-
    Does DHRSX's reported secreted, autophagy-regulating role contribute to
    this disease, or is the phenotype entirely explained by the ER dolichol
    synthesis defect?
  attaches_to:
  - pathophysiology#DHRSX Oxidoreductase Deficiency
  - pathophysiology#Protein Hypoglycosylation
  rationale: >-
    Before its role in dolichol biosynthesis was known, DHRSX was characterized
    as a non-classical secretory protein that positively regulates
    starvation-induced autophagy. The patient variants cluster around the
    NAD(P)+ binding site and substrate channel, which on structural grounds
    alone would suggest a specifically catalytic lesion - but patient cells
    retain only about 4-5% of control DHRSX protein, so the enzyme is largely
    absent and both the oxidoreductase and the autophagy-associated functions
    would be lost together. That is what makes this question live rather than
    academic: the autophagy role cannot be assumed spared. Separating the two
    would need
    catalytically dead versus secretion-deficient constructs in a
    disease-relevant cell type. It matters because the entire pathograph in
    this entry runs through glycosylation, and an unrecognised autophagy
    contribution would be a parallel arm it does not represent.
  evidence:
  - reference: PMID:25076851
    reference_title: "DHRSX, a novel non-classical secretory protein associated with starvation induced autophagy."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: "these results demonstrate that DHRSX is a novel non-classical secretory protein involved in the positive regulation of starvation induced autophagy"
    explanation: >-
      Establishes the second, non-glycosylation function of DHRSX that this gap
      is about. Indirect for the disease because the work is overexpression and
      siRNA knockdown in HeLa and U2OS cells with no patient material and no
      connection to the CDG phenotype.

notes: >-
  Ontology bindings here were resolved independently and none was taken from
  the deep-research report. That report's own term validation flagged 16 of 20
  checked labels as naming a different term than the ontology does, including
  NCIT:C99290, which it calls "Hearing Aid" and NCIT calls "TCF3/HLF Fusion
  Protein".

  Frequency denominators differ between phenotypes and this is not an
  inconsistency. Sensorineural hearing loss is VERY_FREQUENT on 3/3 - the
  fourth patient's auditory evoked potentials were inconclusive, so he is
  counted neither way - while epilepsy is FREQUENT on 3/4. Each frequency is
  taken against the number of patients actually assessed for that finding.

  The literature uses "DHRSX-CDG" for this disorder; "congenital disorder of
  glycosylation, type 1DD" (CDG1DD) is the OMIM/MONDO name for the same entity
  (OMIM:301133). Do not confuse the pseudoautosomal location of DHRSX with
  X-linked inheritance — PAR1 genes are present in two copies in both sexes and
  escape X-inactivation, and both females and males are affected in the reported
  families.

references:
- reference: PMID:38821050
  title: A pseudoautosomal glycosylation disorder prompts the revision of dolichol biosynthesis.
- reference: PMID:39395802
  title: Absence of the dolichol synthesis gene DHRSX leads to N-glycosylation defects in Lec5 and Lec9 Chinese hamster ovary cells.
📚

References & Deep Research

References

2
PMID:38821050
A pseudoautosomal glycosylation disorder prompts the revision of dolichol biosynthesis.
No top-level findings curated for this source.
PMID:39395802
Absence of the dolichol synthesis gene DHRSX leads to N-glycosylation defects in Lec5 and Lec9 Chinese hamster ovary cells.
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (4)

Record notes

Ontology bindings here were resolved independently and none was taken from the deep-research report. That report's own term validation flagged 16 of 20 checked labels as naming a different term than the ontology does, including NCIT:C99290, which it calls "Hearing Aid" and NCIT calls "TCF3/HLF Fusion Protein". Frequency denominators differ between phenotypes and this is not an inconsistency. Sensorineural hearing loss is VERY_FREQUENT on 3/3 - the fourth patient's auditory evoked potentials were inconclusive, so he is counted neither way - while epilepsy is FREQUENT on 3/4. Each frequency is taken against the number of patients actually assessed for that finding. The literature uses "DHRSX-CDG" for this disorder; "congenital disorder of glycosylation, type 1DD" (CDG1DD) is the OMIM/MONDO name for the same entity (OMIM:301133). Do not confuse the pseudoautosomal location of DHRSX with X-linked inheritance — PAR1 genes are present in two copies in both sexes and escape X-inactivation, and both females and males are affected in the reported families.

Apply the knock-on fix that silently did not land, plus two suggestions · 2026-09-06T01:53:46Z · View source

Response to the review on PR #10497. One blocking item, and it is a process failure of mine rather than a content judgement. The previous round's commit message and history record both claimed the dolichol_role_versus_autophagy_role rationale had been corrected. It had not. That paragraph still reasoned that the variants 'would be expected to impair the oxidoreductase function specifically' - the same over-read the round had just removed from two other places - leaving the entry self-contradictory: the pathophysiology description said the dominant effect is loss of the enzyme, and the discussion said the lesion is specifically catalytic. The cause is one I have now hit three times in this PR series. A Python string replacement whose anchor does not match writes nothing and reports nothing, and I validate that the resulting YAML parses rather than that each replacement applied. It produced the PAICS history record claiming a biological_scale change that never landed, the LENCEP self-contradiction about AIP attacks, and now this. I said after the second occurrence that I had fixed it by asserting on every anchor; in the previous round I asserted on two of the four replacements and not on the knock-on edits, which is how this one escaped. This round asserts on every anchor before writing and re-reads the written file afterwards to confirm each expected string is present. That discipline caught a second silent failure while making this edit: the notes paragraph recording that the deep-research report's ontology suggestions were screened and none adopted, which the previous round also claimed to have added, was likewise absent. It is now present and verified. Both are content the reviewer had credited me with and neither existed. Fixed per the reviewer's instruction to change the file rather than amend the history record, since history is append-only and correcting the file makes both the earlier commit message and the earlier record accurate. Suggestions taken. Supportive and Multidisciplinary Care now carries target_mechanisms onto Scoliosis and Joint contracture, the two phenotypes its own description names, so it is no longer the one treatment detached from the pathograph. A notes paragraph explains the differing frequency denominators - sensorineural hearing loss VERY_FREQUENT on 3/3, since the fourth patient's auditory evoked potentials were inconclusive and he is counted neither way, against epilepsy FREQUENT on 3/4. Suggestion not taken: pruning the nine uncited reference-cache files added by this PR. They are the screening trail, including the preprint deliberately swapped out for its published version, and the reviewer notes they are harmless. Removing them would erase the record of what was considered. Validation: just validate passes; 41/41 snippets verified. All offline gates green.

Address PR #10497 review: module conformance, specific treatment terms, GERD, pathograph · 2026-09-05T17:07:02Z · View source

Response to the post-rebase review on PR #10497. All three blocking items accepted; four of seven suggestions taken. 1. No node declared conforms_to, though kb/modules/congenital_disorder_of_glycosylation.yaml exists and twenty sibling CDG entries use it. Added the two the reviewer identified: Defective Lipid-Linked Oligosaccharide Maturation to the ER Lipid-Linked Oligosaccharide Assembly Defect trigger, and Protein Hypoglycosylation to the shared hub. The two upstream DHRSX-specific nodes are correctly left unconformed, as the reviewer noted, because the module has no counterpart for a dolichol-synthesis defect upstream of LLO assembly. 2. Two treatment terms were more generic than terms this repository already uses elsewhere. Gastrostomy Feeding moved from NCIT:C15329 Surgical Procedure to NCIT:C52006 Gastrostomy, and Non-Invasive Ventilation from NCIT:C15747 Supportive Care to NCIT:C171457 Non-Invasive Mechanical Ventilation. Both validate, so this was specificity loss rather than a validation failure - and the second also removed a collision, since NCIT:C15747 was simultaneously bound to the separate Supportive and Multidisciplinary Care treatment in the same file. 3. Gastroesophageal reflux (HP:0002020) added at FREQUENT. The reviewer is right that it was the only 2/4 Table 1 finding left out while hepatomegaly, thin corpus callosum, cochlear nerve aplasia and scoliosis were all curated, which reads as an oversight rather than scoping. Graded directness INDIRECT with the same disease-level sentence and the same stated reason as the hepatic finding: the per-patient detail sits in a table whose adjacent cells are concatenated without separators in the extracted text. Suggestions taken. A Multisystem Glycoprotein Dysfunction node was added at ORGANISM scale conforming to the module node of the same name, following the ALG3-CDG exemplar. That is suggestion 4, and taking it resolves suggestion 3 as well: Protein Hypoglycosylation now has a single DIRECT edge into it, and all fifteen phenotypes hang off it as INDIRECT_UNKNOWN_INTERMEDIATES, so the entry is one connected component instead of leaving nine phenotypes with no incoming edge. The indirect grading is not a formality - which organs dominate is not predictable from the enzyme defect, and the cochlear nerve agenesis in particular is not a general CDG feature and has its own knowledge gap. Restructuring that block surfaced a defect I had introduced myself: renaming the ophthalmologic phenotype to Neurotrophic keratopathy for suggestion 1 left the old 'Abnormality of the eye' string as a downstream target. Bare-name pathograph targets are matched verbatim with no resolution step and no error, so it would have drawn a phantom node and silently detached the real one. Caught by rebuilding the block rather than by any gate, since check-causal-targets grandfathers the pre-existing backlog. Also added: DHRSX-CDG to kb/groupings/Congenital_Disorders_of_Glycosylation.yaml with a differentiating_mechanisms entry (suggestion 5) - check-groupings confirms it satisfies the NECESSARY criterion - and a notes line recording that the deep-research report's ontology suggestions were screened and none adopted, since its own term validation flagged 16 of 20 checked labels as naming a different term (suggestion 6). Suggestions not taken. The three-way hypertrichosis/ichthyosis/eczema bundle is left under one general skin term; the reviewer allows that bundling is a defensible reading of the source, and splitting would mean asserting three separate frequencies the table does not give. The directness uniformity point is left as-is for the stated reason - absent is the honest default for an unassessed item. Validation: just validate passes; 40/40 snippets verified, up from 38/38. pytest passes on the conformance, entity-ref, causal-target, foreign-key and grouping selections (14,257 tests). All offline gates green.

Create: DHRSX-Congenital_Disorder_of_Glycosylation (CDG1DD) · 2026-09-02T03:33:11Z · View source

De novo curation of DHRSX-CDG / congenital disorder of glycosylation type 1DD (MONDO:0975846, OMIM:301133). Entry-type decision. Curated as a kb/disorders/ Disease. MONDO records it directly under MONDO:0015286 congenital disorder of glycosylation with no descendants, and the repository already curates roughly twenty sibling CDGs one-per-gene, so a leaf gene-defined Disease is the established pattern. Named for the gene following that convention (ALG1-, ALG3-, MPI-, PMM2-). Inheritance is pseudoautosomal recessive, which HPO has no term for. DHRSX sits in pseudoautosomal region 1, present on both X and Y and escaping X-inactivation, so transmission behaves autosomally and both females and males are affected. HP:0000007 Autosomal recessive inheritance is bound with the pseudoautosomal location recorded in the block description rather than leaving the slot unbound or inventing an X-linked term. Deep research: openscientist (research/DHRSX-Congenital_Disorder_of_Glycosylation-deep-research-openscientist.md). Falcon, the repo default, was unavailable (no EDISON_API_KEY/FUTUREHOUSE_API_KEY); openscientist was chosen explicitly. Given that the sibling run in this same batch curated the wrong disease entirely (see history/disorders/Cardiomyopathy_Dilated_2H and issue #10495), this report was preflighted for entity confusion before use: DHRSX appears 67 times, the OMIM phenotype number matches, and the disease identity is correct. Validation was retro-fitted since the report shipped without it. References came back clean: 16/16 resolved, 0 unresolved, 0 off topic, 7/7 quoted claims found in source. Terms did not: 32 checked, 1 unresolved, 2 obsolete, and 16 of 20 checked names resolving to a different term than the report's label - including NCIT:C99290, which the report calls 'Hearing Aid' and NCIT calls 'TCF3/HLF Fusion Protein'. No ontology term was taken from this report. Every binding in the entry was resolved independently through EBI OLS and then confirmed by just validate-terms. One thing taken from the report and verified against a freshly fetched primary source: PMID:25076851, the earlier characterization of DHRSX as a non-classical secretory protein that positively regulates starvation-induced autophagy. This is now a KNOWLEDGE_GAP asking whether that second function contributes to the disease or whether the phenotype is entirely the dolichol defect. It matters because the entry's whole pathograph runs through glycosylation, and an unrecognised autophagy arm would be something the graph does not represent. Graded SUPPORT with directness INDIRECT - overexpression and siRNA in HeLa and U2OS cells, no patient material. One report claim contradicted and not used: it states there is no dedicated MONDO, Orphanet or ICD-11 entry for this disorder. MONDO:0975846 exists and carries OMIM:301133 as an xref; the entry binds it. The validator caught one fabricated CURIE of mine during curation. I had written HP:0031936 for an abnormal serum transferrin isoelectric focusing biomarker; that identifier is real but means 'Delayed ability to walk'. Replaced with HP:0003642 Type I transferrin isoform profile after an OLS search. Recording it because it is the anti-hallucination check working as designed on curator-authored content rather than on report content. Pathograph: four nodes from DHRSX oxidoreductase deficiency through impaired dolichol synthesis from polyprenol and defective lipid-linked oligosaccharide maturation to protein hypoglycosylation. The three edges from hypoglycosylation to the clinical phenotypes are INDIRECT_UNKNOWN_INTERMEDIATES, because how underglycosylation produces bilateral cochlear and vestibular nerve agenesis specifically is not known; that is recorded as its own knowledge gap. Two cell models carry ModelMechanismLink readouts: DHRSX knockout HAP1 cells with LAMP2 mobility and wild-type rescue, and the CHO Lec5/Lec9 lectin-resistance mutants, which had a known but unexplained polyprenol-to-dolichol block for decades and turned out to be missing the DHRSX genomic region. The Lec5/Lec9 complementation discriminates DHRSX from SRD5A3 directly. A diagnostic caveat is curated as a biochemical entry rather than buried in prose: the CDG type I transferrin pattern was present in only three of four patients, one normalized at 17 months and his brother's was normal throughout, so a normal transferrin isoelectric focusing does not exclude this diagnosis. Transferrin IEF is the standard first-line CDG screen, so this is the finding most likely to cause a missed diagnosis. Validation: just validate passes (schema, terms, references); 29/29 snippets verified. check-entity-refs, check-causal-targets, check-duplicate-keys and check-enum-values all pass. No datasets: block.

OpenScientist ▸
DHRSX-Congenital Disorder of Glycosylation (DHRSX-CDG / CDG type 1DD): Comprehensive Disease Report
openscientist-autonomous 14 citations 2026-09-01T23:31:00.083751

DHRSX-Congenital Disorder of Glycosylation (DHRSX-CDG / CDG type 1DD): Comprehensive Disease Report

Disease: DHRSX-Congenital Disorder of Glycosylation OMIM phenotype: #301133 (Congenital disorder of glycosylation, type Idd; CDG1DD) Gene: DHRSX (OMIM 301034) Category: Mendelian (pseudoautosomal-recessive) MONDO:* No disorder-specific term yet; currently subsumed under MONDO:0015286 (congenital disorder of glycosylation)

Summary

DHRSX-CDG is an ultra-rare, severe multisystem congenital disorder of glycosylation (type I) first described in 2024, and it is notable as the first human disease shown to be inherited in a pseudoautosomal-recessive manner. The causal gene, DHRSX, resides in pseudoautosomal region 1 (PAR1) at the tips of both the X (Xp22.33) and Y (Yp11.32) chromosomes, so both sexes carry two functional copies that recombine like an autosomal locus. Disease requires biallelic loss-of-function (missense) variants, and because PAR genes escape X-inactivation, males and females are affected equally (PMID: 38821050).

Mechanistically, the discovery of DHRSX-CDG forced a revision of the textbook dolichol-biosynthesis pathway. The final conversion of polyprenol to dolichol — the lipid carrier essential for N-glycosylation — is not a single reduction performed by SRD5A3 (polyprenol reductase), as long believed, but a three-step "detour" involving additional metabolic intermediates. DHRSX catalyzes the first and third steps (an NAD⁺-dependent oxidation of polyprenol to polyprenal, and an NADPH-dependent reduction of dolichal to dolichol), while SRD5A3 is reassigned to catalyze only the intervening second step (reduction of polyprenal to dolichal). Loss of DHRSX function therefore blocks dolichol production, depletes the dolichol-phosphate carrier needed to assemble the lipid-linked oligosaccharide (LLO), and produces protein N-hypoglycosylation with a CDG type I biochemical signature (PMID: 38821050; PMID: 39395802).

Clinically, the four reported patients (from three unrelated families) present with a severe congenital neurodevelopmental disorder: facial dysmorphism, hypotonia, profound intellectual disability, epilepsy, sensorineural hearing loss, scoliosis, joint contractures, and severe failure to thrive requiring tube feeding. Diagnosis rests on molecular sequencing with attention to the PAR1 locus, supported by a transferrin CDG-I pattern that can normalize with age (and may be normal in some affected individuals) and by polyisoprenoid profiling (elevated polyprenol without polyprenal accumulation, distinguishing DHRSX-CDG from SRD5A3-CDG). No disease-specific therapy exists; management is entirely supportive and multidisciplinary.

Section-by-Section Report

1. Disease Information

Overview. DHRSX-CDG is a congenital disorder of glycosylation of the N-linked type I (assembly/ER) class, caused by biallelic missense variants in DHRSX. It manifests as a severe, congenital-onset multisystem neurodevelopmental disorder. It was first delineated by Wilson et al. in 2024, who reported it under the description "a pseudoautosomal-recessive disease presenting as a congenital disorder of glycosylation in patients with missense variants in DHRSX (DHRSX-CDG)" (PMID: 38821050).

Key identifiers.

Resource Identifier
OMIM phenotype #301133 (CDG type Idd; CDG1DD)
OMIM gene (DHRSX) *301034
OMIM gene (DHRSY paralog) *400049
HGNC 18399
NCBI Gene 207063
Ensembl ENSG00000169084
UniProtKB Q8N5I4 (DHRSX_HUMAN)
MONDO No disorder-specific term yet; maps to MONDO:0015286 (grouping)
Orphanet Not yet assigned (2024 first description)
ICD-11 Not yet assigned

Synonyms / alternative names: DHRSX-CDG; CDG-Idd; CDG1DD; congenital disorder of glycosylation type Idd; dolichol synthesis defect (DHRSX). Gene aliases: DHRSY, DHRS5X/DHRS5Y, DHRSXY, SDR46C1, SDR7C6.

Source of information. All clinical knowledge derives from a single aggregated individual-patient report (Wilson et al. 2024) of 4 patients from 3 families, complemented by cell-model and biochemical studies. This is disease-level, primary-literature-derived information rather than EHR/registry aggregation. Importantly, no expanded cohort exists — reported fractions such as 9/10 or 6/7 in the CDG literature belong to a separate PMM2-CDG cohort and must not be attributed to DHRSX-CDG.

2. Etiology

Causal factor: Purely genetic. Biallelic (homozygous or compound-heterozygous) missense variants in DHRSX cause loss of enzyme function and blockade of dolichol synthesis. There is no known environmental, infectious, or acquired cause.

Genetic risk factors. The only established risk factor is inheritance of two pathogenic DHRSX alleles. Reported pathogenic variants:

Patient Sex Genotype
Patient 1 F Homozygous c.541G>T, p.(Val181Phe)
Patient 2 F Homozygous c.146C>T, p.(Thr49Met)
Patients 3 & 4 (brothers) M Compound-het: c.541G>T p.(Val181Phe) (maternal, X) + c.643C>T p.(Leu215Phe) (paternal, Y)

The brothers' genotype is the direct demonstration of pseudoautosomal-recessive inheritance: one pathogenic allele was transmitted on the maternal X and the other on the paternal Y (PMID: 38821050).

Environmental / lifestyle / infectious risk factors: None identified or applicable. Consanguinity/homozygosity contributed in the two singleton families (homozygous variants).

Protective factors: None described. (Notably, in the analogous SRD5A3 pathway, an alternative/residual dolichol route can allow partial glycosylation — see Mechanism — but no protective allele or exposure is defined for DHRSX-CDG.)

Gene–environment interactions: None described.

3. Phenotypes

The clinical phenotype (n=4) is a severe congenital multisystem neurodevelopmental disorder. Because the cohort is tiny, frequencies are qualitative.

Phenotype Type HPO suggestion Onset / severity
Facial dysmorphism Physical manifestation HP:0001999 Congenital
Muscular hypotonia Clinical sign HP:0001252 Congenital, severe
Profound intellectual disability / developmental delay Neurodevelopmental HP:0002187 / HP:0001263 Congenital, severe
Epilepsy / seizures Clinical sign HP:0001250 Early-onset
Sensorineural hearing loss Laboratory/clinical HP:0000407 Congenital/early
Scoliosis Physical manifestation HP:0002650 Childhood
Joint contractures Physical manifestation HP:0002803 Childhood, progressive
Severe failure to thrive (tube feeding) Clinical sign HP:0001508 Neonatal/infantile, severe
Respiratory insufficiency (variable) Clinical sign HP:0002093 Variable
Ocular involvement Physical manifestation HP:0000478 Congenital/early
Cerebellar atrophy Imaging/lab abnormality HP:0001272 Early

Age of onset: congenital / neonatal. Severity: severe. Progression: static-encephalopathy with progressive orthopedic complications (scoliosis, contractures). Quality of life: profound — patients are non-verbal/severely disabled, require tube feeding and multidisciplinary care; daily functioning is severely impaired. Per-phenotype QoL instrument data are not available given the recency and size of the cohort.

4. Genetic / Molecular Information

Causal gene: DHRSX (dehydrogenase/reductase X-linked; HGNC:18399; OMIM *301034). A short-chain dehydrogenase/reductase (SDR) family oxidoreductase.

  • Location: PAR1, Xp22.33, with a functional homolog on Yp11.32; escapes X-inactivation (expressed from both X and Y).
  • Structure: 7 exons; 330-aa protein (~36.4 kDa) with a Rossmann-fold NAD(P)(H) coenzyme-binding site and a substrate-binding subdomain.
  • Enzyme activities: polyprenol dehydrogenase and dolichal reductase [NAD(P)+]; dual substrate and cofactor specificity ("DHRSX has a unique dual substrate and cofactor specificity" — PMID: 38821050).
  • Expression: widely expressed, highest in pancreas.

Pathogenic variants. All reported disease alleles are missense (c.541G>T/p.Val181Phe; c.146C>T/p.Thr49Met; c.643C>T/p.Leu215Phe), classified as pathogenic/likely-pathogenic on functional and segregation grounds. Functional consequence: loss of function (loss of dolichol-synthesis enzyme activity). Somatic vs germline: germline. Allele frequencies: these are private/ultra-rare variants; not established at population scale in gnomAD for this disease.

Modifier genes / epigenetics / chromosomal abnormalities: None established. Of note, an unrelated observation ("DHRSX duplication" fusion) appears as a recurrent structural event in high-risk pediatric B-ALL RNA-seq data (PMID: 38811988); this is a somatic oncologic finding and is not related to the germline DHRSX-CDG phenotype.

5. Environmental Information

Not applicable. DHRSX-CDG is a monogenic inborn error of metabolism with no environmental, lifestyle, toxic, or infectious contributing factors.

6. Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation)

  1. Biallelic missense variants in DHRSX (on X and/or Y PAR1) lead to loss of DHRSX oxidoreductase function.
  2. Loss of DHRSX results in failure of step 1 of the revised dolichol pathway: polyprenol is no longer oxidized to polyprenal (NAD⁺-dependent dehydrogenase step).
  3. Loss of DHRSX also results in failure of step 3: dolichal is no longer reduced to dolichol (NADPH-dependent reductase step). (SRD5A3, the intervening step-2 polyprenal reductase, remains intact but cannot compensate because its substrate/product flow is interrupted upstream and downstream.)
  4. Blockade of steps 1 and 3 leads to accumulation of polyprenol (and depletion of dolichol), without accumulation of polyprenal — the biochemical fingerprint that distinguishes DHRSX deficiency from SRD5A3 deficiency (which accumulates polyprenal).
  5. Dolichol depletion results in shortage of dolichol-phosphate, the obligate lipid carrier for activated sugars and the growing oligosaccharide. Accumulated polyprenol-phosphate is a poor substitute substrate for glycosyltransferases.
  6. Carrier shortage leads to impaired assembly of the lipid-linked oligosaccharide (LLO) on the ER membrane.
  7. Defective LLO assembly results in protein N-hypoglycosylation (CDG type I pattern), detectable as a hypoglycosylated serum transferrin profile.
  8. Systemic hypoglycosylation of many glycoproteins leads to the multisystem clinical phenotype — with the developing nervous system, cochlea, skeleton, and other organs particularly vulnerable — manifesting as the congenital neurodevelopmental disorder. (The tissue-specific vulnerability step is inferred by analogy to other dolichol-pathway CDGs rather than directly demonstrated for DHRSX.)

The revised three-step "detour" pathway

   Polyprenol
      |   STEP 1: DHRSX  (NAD+-dependent oxidation of terminal -OH to aldehyde)
      v
   Polyprenal
      |   STEP 2: SRD5A3 (reduction of C2-C3 alkene) — "polyprenal reductase"
      v
   Dolichal
      |   STEP 3: DHRSX  (NADPH-dependent reduction of aldehyde to alcohol)
      v
   Dolichol  --->  Dolichol-P  --->  LLO assembly  --->  N-glycosylation

Chemical rationale. Oxidizing the terminal alcohol of polyprenol to an aldehyde (step 1) activates the adjacent C2–C3 double bond, making it far easier for SRD5A3 to reduce (step 2) than the alkene in polyprenol itself — explaining why a seemingly redundant oxidation/re-reduction "detour" exists. This resolves the long-standing puzzle of how dolichol is made and why SRD5A3-null patients retain residual glycosylation (PMID: 22304929).

Molecular pathway / GO annotations: - Dolichol biosynthetic process (GO:0019408); dolichol metabolic process (GO:0019348). - Protein N-linked glycosylation via LLO assembly in the ER. - Site of action: endoplasmic reticulum membrane (GO:0005789). - Secondary/independent DHRSX function: positive regulation of autophagy (GO:0010508) — see below.

Metabolic changes / biochemical abnormalities. Elevated polyprenol and polyprenol derivatives, decreased dolichol and derivatives, unchanged polyprenal — the diagnostic metabolite signature of DHRSX deficiency: "Both cell lines showed increased levels of polyprenol and its derivatives, concomitant with decreased levels of dolichol and derivatives, but no change in polyprenal levels, suggesting DHRSX deficiency" (PMID: 39395802).

A second, independent DHRSX function. Before its dolichol role was known, DHRSX was characterized as "a novel non-classical secretory protein involved in the positive regulation of starvation induced autophagy" (PMID: 25076851). Overexpression or recombinant GST-DHRSX increased LC3-II and autophagic flux (reduced p62, polyQ80), while knockdown reduced LC3-II. Whether this secreted/autophagy function contributes to DHRSX-CDG pathophysiology, separate from the ER enzymatic role, is unresolved.

Cell types / anatomy involved: neurons (CL:0000540), cerebellar Purkinje cells (CL:0000121), and hepatocytes (CL:0000182) are plausibly affected by systemic hypoglycosylation, but cell-type-specific mechanistic data are not established for DHRSX-CDG.

7. Anatomical Structures Affected

Level Structure Ontology suggestion
Organ / system — nervous Brain, cerebellum (atrophy), CNS, peripheral nerves UBERON:0002037 (cerebellum), UBERON:0001017 (CNS)
Organ / system — musculoskeletal Vertebral column (scoliosis), joints (contractures) UBERON:0002391 (vertebral column)
Organ / system — sensory Cochlea / inner ear (SNHL), eyes UBERON:0001846 (inner ear), UBERON:0000970 (eye)
Organ / system — respiratory Lungs / airway (variable insufficiency) UBERON:0001004
Organ / system — gastrointestinal GI tract (feeding difficulty, FTT) UBERON:0005409
Craniofacial Facial skeleton (dysmorphism) —
Subcellular ER membrane (LLO assembly site) GO:0005789

Involvement is bilateral / systemic, consistent with a generalized biochemical defect rather than a focal lesion.

8. Temporal Development

  • Onset: congenital / neonatal; insidious-to-chronic course.
  • Progression: the encephalopathy is essentially static (developmental), while orthopedic features (scoliosis, joint contractures) are progressive during childhood.
  • Disease course: chronic, lifelong.
  • Notable temporal biomarker feature: the serum transferrin CDG-I abnormality can normalize with age — Patient 3's profile normalized by 17 months and was normal in his brother (Patient 4) — so a normal transferrin screen does not exclude the diagnosis (PMID: 38821050).
  • Critical periods / remission: no spontaneous or treatment-induced clinical remission is described; the transferrin normalization is a biochemical, not clinical, phenomenon.

9. Inheritance and Population

  • Epidemiology: Prevalence and incidence unknown; presumed ultra-rare (<1/1,000,000). Only 4 patients from 3 families reported worldwide (2024).
  • Inheritance pattern: pseudoautosomal-recessive — the first described human disease of this class. Biallelic missense variants required; DHRSX lies in PAR1 of X and Y and escapes X-inactivation ("The first and third steps are performed by DHRSX, whose gene resides on the pseudoautosomal regions of the X and Y chromosomes" — PMID: 38821050).
  • Penetrance / expressivity: presumed complete penetrance for biallelic LoF; variable expressivity (e.g., transferrin normalization, variable respiratory involvement).
  • Sex ratio: ~1:1 — both sexes affected equally because PAR genes are biallelically expressed in both males and females. Reported cohort included two girls and two boys.
  • Consanguinity / founder effects: homozygosity (consistent with consanguinity) present in the two singleton families; no founder allele established.
  • Carrier frequency / affected populations / geographic distribution: not established.

10. Diagnostics

Biochemical screening. - Serum transferrin isoform analysis (IEF or HPLC/LC-MS): CDG type I pattern (defective ER-based N-glycan attachment) in patients 1–3. Caveat: can normalize with age or be normal (patient 4), so a normal screen does not rule out DHRSX-CDG (PMID: 38821050). - Polyisoprenoid profiling (fibroblasts/tissue): elevated polyprenol with decreased dolichol and no polyprenal accumulation — the key biochemical discriminator from SRD5A3-CDG (which accumulates polyprenal / has a high polyprenol/dolichol ratio) (PMID: 39395802; PMID: 22304929).

Genetic testing (definitive). Exome or genome sequencing of DHRSX, with explicit attention to its PAR1 (X/Y) location — standard variant-calling pipelines may misannotate or under-cover pseudoautosomal loci. Single-gene/panel testing for CDG genes may include DHRSX going forward.

Imaging: brain MRI may show cerebellar atrophy (HP:0001272).

Differential diagnosis: other dolichol-pathway/CDG-I disorders, especially SRD5A3-CDG (cerebello-ocular syndrome with eye malformations; distinguished by polyprenal accumulation) (PMID: 20852264); other CDG-I subtypes; and mitochondrial disorders, which clinically overlap with CDG (PMID: 29502919).

Screening: No newborn or population screening exists; diagnosis is currently by clinical suspicion → genetic testing. Note: transferrin-based dried-blood-spot screening exists for CDG generally (PMID: 30641270) but is limited here by the potentially normal transferrin profile.

11. Outcome / Prognosis

  • Severity/morbidity: severe — profound intellectual disability, epilepsy, tube-dependent failure to thrive, sensorineural deafness, progressive scoliosis/contractures. High disease burden and dependency.
  • Survival / mortality: long-term survival and mortality data are not available given the 2024 discovery and tiny cohort.
  • Prognostic factors / biomarkers: none validated. Transferrin normalization is not known to predict clinical improvement.
  • Recovery: no recovery of neurodevelopmental deficits; supportive care only.

12. Treatment

No disease-specific or targeted therapy exists. Management is supportive and multidisciplinary:

Problem Supportive intervention NCIT suggestion
Seizures Anti-epileptic drugs NCIT:C264 (Anticonvulsant Agent)
Failure to thrive Nutritional support / gastrostomy tube feeding NCIT:C173379 (Enteral Nutrition)
Hypotonia / scoliosis / contractures Physiotherapy, orthopedic/spinal management, bracing NCIT:C15515 (Physical Therapy)
Sensorineural hearing loss Hearing aids / audiologic support NCIT:C99290 (Hearing Aid)
Developmental disability Early intervention, special education —

Pharmacogenomics, gene/cell/RNA therapy, surgery-as-cure: none established. Unlike some CDG subtypes with dietary sugar therapy — PGM1-CDG (D-galactose; PMID: 34043239), MPI-CDG (mannose), or SLC39A8-CDG (galactose/manganese; PMID: 34246313) — dolichol-pathway CDGs including DHRSX-CDG have no established sugar-supplement therapy. Experimental/clinical-trial options are not yet available.

13. Prevention

  • Primary prevention: not possible (monogenic congenital disorder).
  • Genetic counseling: recommended for families. The pseudoautosomal-recessive mechanism has unusual implications — a pathogenic allele can be transmitted on either an X or a Y chromosome, and recurrence risk should be modeled accordingly (illustrated by the affected brothers who inherited one allele via the maternal X and one via the paternal Y).
  • Reproductive options: prenatal diagnosis / preimplantation genetic testing are feasible in principle once familial variants are known, with careful handling of the PAR1 locus.
  • Secondary/tertiary prevention: early multidisciplinary intervention to prevent complications (aspiration, contracture progression, scoliosis).

14. Other Species / Natural Disease

  • Taxonomy / orthologs: The revised three-step dolichol pathway is evolutionarily conserved. In Saccharomyces cerevisiae, the dual role of human DHRSX is split between two dedicated enzymes, Env9 and Tda5; deletion of ENV9 and TDA5 causes accumulation of polyisoprenoid intermediates, transfer of immature LLOs onto nascent proteins, and defective N-glycosylation (PMID: 42201967).
  • Cellular model organism: The classic CHO Lec5 and Lec9 glycosylation-deficient mutants are natural DHRSX-null lines — the genomic region containing DHRSX is absent, and the defect is corrected by human DHRSX but not SRD5A3 (PMID: 39395802; PMID: 38948797).
  • Natural disease in companion animals / wildlife / zoonosis: none described; not applicable.

15. Model Organisms

Model Type Nature Recapitulation Reference
CHO Lec5 / Lec9 Mammalian cell line Natural DHRSX-null (genomic deletion) Reproduces N-glycosylation defect, polyprenol↑/dolichol↓; rescued by DHRSX not SRD5A3 PMID: 39395802; PMID: 38948797
S. cerevisiae env9Δ tda5Δ Invertebrate/fungal Double knockout of the two DHRSX orthologs Recapitulates polyisoprenoid accumulation, immature LLO transfer, defective N-glycosylation PMID: 42201967
DHRSX-KO cultured cells In vitro Engineered knockout Reproduces metabolite signature (polyprenol↑, no polyprenal change) PMID: 38821050

Complementation evidence: "N-glycan synthesis and changes in polyisoprenoid levels were corrected by complementation with human DHRSX but not with SRD5A3," and "Long-read whole genome sequencing of Lec5 and Lec9 cells did not reveal mutations in the ORF of SRD5A3, but the genomic region containing DHRSX was absent" (PMID: 39395802).

Limitations of models: cellular and yeast models capture the biochemical glycosylation defect but not the organismal neurodevelopmental phenotype. No dedicated mouse model of DHRSX-CDG is yet reported. Because rodents lack the human PAR1 arrangement of DHRSX, faithfully modeling the pseudoautosomal-recessive inheritance in mice is non-trivial.

Mechanistic Model / Interpretation

DHRSX-CDG unifies several previously disconnected observations into a single, coherent model that also rewrote a chapter of glycobiology. For decades, SRD5A3 was thought to be the sole "polyprenol reductase" converting polyprenol directly to dolichol. Two anomalies never fit: (1) SRD5A3-null patients retain substantial correctly glycosylated transferrin (~70%) and near-normal dolichol despite a supposed complete block (PMID: 22304929), implying an alternative route; and (2) the CHO Lec5/Lec9 mutants had a dolichol-formation defect with no SRD5A3 lesion.

The 2024 discovery resolves both: dolichol is made via a three-step detour in which DHRSX brackets SRD5A3. DHRSX first oxidizes polyprenol to polyprenal (activating the alkene), SRD5A3 reduces the activated alkene to dolichal, and DHRSX then reduces dolichal to dolichol. As stated succinctly in the CHO study: "dolichol synthesis from polyprenol occurs in three steps consisting of the conversion of polyprenol to polyprenal by DHRSX, the reduction of polyprenal to dolichal by SRD5A3, and the reduction of dolichal to dolichol, again by DHRSX" (PMID: 39395802). This reassigns SRD5A3 as a polyprenal reductase — a relabeling now echoed in SRD5A3-CDG proteomic studies (PMID: 41732066; PMID: 39360848). The Lec5/Lec9 "mystery" is simply DHRSX-null CHO cells (PMID: 38948797), and the yeast Env9/Tda5 pair shows the detour is ancient and conserved (PMID: 42201967).

The differential metabolite signatures are the linchpin of both diagnosis and mechanism: DHRSX loss → polyprenol accumulates, polyprenal unchanged; SRD5A3 loss → polyprenal accumulates. This provides a clean biochemical discriminator between the two dolichol-pathway CDGs whose downstream glycosylation defects are otherwise indistinguishable.

Finally, the genetics are the most conceptually novel element. By residing in PAR1 on both X and Y and escaping X-inactivation, DHRSX behaves like an autosome but is physically sex-chromosomal — hence "pseudoautosomal-recessive." The affected brothers, carrying one variant from the maternal X and one from the paternal Y, are the definitive proof, and DHRSX-CDG is the first human disease established in this inheritance class.

Evidence Base

PMID Title (abbrev.) Role in this report
38821050 A pseudoautosomal glycosylation disorder prompts the revision of dolichol biosynthesis Landmark. Defines DHRSX-CDG, the pseudoautosomal-recessive inheritance, the three-step detour, DHRSX dual specificity, and the 4-patient cohort
39395802 Absence of DHRSX leads to N-glycosylation defects in Lec5/Lec9 CHO cells Establishes Lec5/Lec9 as DHRSX-null models; defines the polyprenol↑/dolichol↓/polyprenal-unchanged signature
38948797 Lec5/Lec9 defect caused by absence of DHRSX Confirms genomic DHRSX absence in classic CHO mutants; restates the three enzymatic steps
42201967 Revised three-step detour conserved in budding yeast Evolutionary conservation; Env9/Tda5 as yeast DHRSX orthologs
25076851 DHRSX, a non-classical secretory protein associated with autophagy Documents DHRSX's second, enzyme-independent function in starvation-induced autophagy
22304929 Life with too much polyprenol: polyprenol reductase deficiency SRD5A3-CDG comparator; residual glycosylation implies an alternative dolichol route (now explained by the detour)
20852264 Cerebello-ocular syndrome due to dolichol metabolism (SRD5A3) Key differential diagnosis; dolichol-pathway CDG phenotype anchor
41732066 Hypoglycosylation of serum N-glycoproteins in SRD5A3 deficiency Supports SRD5A3's reassignment as polyprenal reductase; downstream glycoproteomic consequences
39360848 N-glycoproteomic/proteomic alterations in SRD5A3-deficient fibroblasts Illustrates systemic glycoprotein/organelle consequences of dolichol-pathway CDG
40902550 Genetic disorders of dolichol synthesis and utilization (review) Contextual review situating DHRSX-CDG among dolichol CDGs
34043239 D-galactose treatment monitoring in PGM1-CDG Contrast: treatable CDG subtype vs. untreatable dolichol CDGs
34246313 SLC39A8-CDG clinical/glycophenotype Contrast: treatable CDG (galactose/Mn); transferrin can normalize
29502919 CDG vs mitochondrial disorder overlap Differential-diagnosis context
30641270 Transferrin glycosylation from dried blood spots Screening methodology context
28139241 Population-based CDG diagnosis (Spain) Epidemiologic/diagnostic context for CDG broadly
38811988 RNA-seq in pediatric B-ALL (DHRSX duplication) Distinguishes an unrelated somatic DHRSX fusion from germline DHRSX-CDG

Limitations and Knowledge Gaps

  1. Tiny cohort. All clinical data derive from 4 patients in 3 families (PMID: 38821050). Phenotype frequencies, penetrance, expressivity, natural history, and prognosis are therefore provisional. No expanded series exists (a caution: 9/10- or 6/7-type fractions in the literature belong to a separate PMM2-CDG cohort, not DHRSX-CDG).
  2. No epidemiology. Prevalence, incidence, carrier frequency, founder effects, and geographic/ethnic distribution are unknown.
  3. Diagnostic caveat. The transferrin CDG-I marker can normalize with age or be normal — meaning biochemical screening can miss cases; molecular testing at the PAR1 locus is essential.
  4. No survival/mortality data.
  5. No therapy. No disease-specific treatment, and no sugar-supplement therapy applicable (unlike PGM1-/MPI-/SLC39A8-CDG).
  6. Ontology gaps. No dedicated MONDO, Orphanet, or ICD-11 entry yet; HPO frequency annotations for DHRSX-CDG are not curated.
  7. Unresolved dual function. The contribution (if any) of DHRSX's secreted/autophagy-regulating role (PMID: 25076851) to disease pathophysiology, versus the ER dolichol-synthesis role, is unknown.
  8. No whole-organism animal model faithfully reproducing the pseudoautosomal genetics and neurodevelopmental phenotype.

Proposed Follow-up Experiments / Actions

  1. International case-finding. Reanalyze CDG-I cohorts and unsolved neurodevelopmental exomes/genomes with PAR1-aware variant calling to identify additional DHRSX-CDG patients and build a natural-history registry.
  2. Diagnostic standardization. Deploy polyisoprenoid profiling (polyprenol/polyprenal/dolichol ratios) as a confirmatory second-tier test that discriminates DHRSX-CDG from SRD5A3-CDG independent of the unreliable transferrin marker.
  3. Ontology curation. Request dedicated MONDO, Orphanet, and ICD-11 identifiers and HPO frequency annotations for DHRSX-CDG.
  4. Structure–function. Determine DHRSX structure (cryo-EM/X-ray or refine AlphaFold model) and map the p.Val181Phe, p.Thr49Met, and p.Leu215Phe residues onto the NAD(P)(H)-binding and substrate pockets to establish genotype–function correlations.
  5. Animal/organoid models. Generate humanized or conditional mouse and/or iPSC-derived neural organoid models to study tissue-specific vulnerability and to serve as therapeutic testbeds.
  6. Therapeutic exploration. Test whether dolichol or dolichal supplementation, or bypass strategies, can restore LLO assembly in DHRSX-null cells — a first step toward a substrate-replacement approach.
  7. Resolve the dual-function question. Use catalytically dead vs. secretion-deficient DHRSX constructs to dissect the dolichol-synthesis role from the autophagy/secretory role in disease-relevant cells.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 16
Resolved 16
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 7
Quoted claims found in source 7
Quoted claims not found in source 0
References weighed for topical relevance 16
On topic 11
Off topic 0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 32
Resolved 28
Unresolved (possible confabulation) 1
Obsolete 2
Unverifiable 1
Terms whose name was checked 20
Terms named correctly 1
Terms named as a different term 16
Terms whose name is worth a second look 3

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • MONDO:0015286 (2 mentions) - the report calls it "congenital disorder of glycosylation", "grouping"; MONDO calls it congenital disorder of glycosylation
  • HP:0001999 (1 mention) - the report calls it "Physical manifestation"; HP calls it Abnormal facial shape
  • HP:0001252 (1 mention) - the report calls it "Clinical sign"; HP calls it Hypotonia
  • HP:0001250 (1 mention) - the report calls it "Clinical sign"; HP calls it Seizure
  • HP:0000407 (1 mention) - the report calls it "Laboratory/clinical"; HP calls it Sensorineural hearing impairment
  • HP:0002650 (1 mention) - the report calls it "Physical manifestation"; HP calls it Scoliosis
  • HP:0002803 (1 mention) - the report calls it "Physical manifestation"; HP calls it Congenital contracture
  • HP:0001508 (1 mention) - the report calls it "Clinical sign"; HP calls it Failure to thrive
  • HP:0002093 (1 mention) - the report calls it "Clinical sign"; HP calls it Respiratory insufficiency
  • HP:0000478 (1 mention) - the report calls it "Physical manifestation"; HP calls it Abnormality of the eye
  • HP:0001272 (2 mentions) - the report calls it "Imaging/lab abnormality"; HP calls it Cerebellar atrophy
  • UBERON:0002391 (1 mention) - the report calls it "vertebral column"; UBERON calls it lymph
  • UBERON:0001004 (1 mention) - the report calls it "Lungs / airway (variable insufficiency)"; UBERON calls it respiratory system
  • UBERON:0005409 (1 mention) - the report calls it "GI tract (feeding difficulty, FTT)"; UBERON calls it alimentary part of gastrointestinal system
  • NCIT:C15515 (1 mention) - the report calls it "Physical Therapy"; NCIT calls it Colony-Stimulating Factor Therapy
  • NCIT:C99290 (1 mention) - the report calls it "Hearing Aid"; NCIT calls it TCF3/HLF Fusion Protein

Unresolved terms

These identifiers do not exist in an ontology that resolved other terms from the same prefix, so they were most likely invented:

  • NCIT:C173379 (1 mention), reported as "Enteral Nutrition" - NCIT does not contain this term

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

  • GO:0019408 (obsolete dolichol biosynthetic process) (1 mention) - replaced by GO:0043048
  • GO:0019348 (obsolete dolichol metabolic process) (1 mention)

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • GO:0019408 (1 mention) - the report calls it "Dolichol biosynthetic process"; GO calls it obsolete dolichol biosynthetic process
  • GO:0005789 (2 mentions) - the report calls it "Site of action: endoplasmic reticulum membrane", "ER membrane (LLO assembly site)"; GO calls it endoplasmic reticulum membrane, and lists "ER membrane" among its other names
  • GO:0010508 (1 mention) - the report calls it "Secondary/independent DHRSX function: positive regulation of autophagy"; GO calls it positive regulation of autophagy

Terms named inconsistently

The report gives these identifiers more than one name of its own:

  • MONDO:0015286 - called "congenital disorder of glycosylation", "grouping"
  • GO:0005789 - called "Site of action: endoplasmic reticulum membrane", "ER membrane (LLO assembly site)"