TMEM165-Congenital Disorder of Glycosylation

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Inheritance

1

Autosomal recessive HP:0000007

Biallelic TMEM165 variants: homozygous in the founding sibling pair (identified by autozygosity mapping) and in a second sibling pair whose parents were both heterozygous carriers; compound heterozygous in one patient.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:22683087 SUPPORT Human Clinical

"The affected individuals are homozygous for a deep intronic splice mutation in TMEM165."

The founding family was solved by autozygosity mapping, and both affected siblings are homozygous for the causal variant.

PMID:26238249 SUPPORT Human Clinical

"The same mutation had been found in a homozygous state in the older sister, both parents have been shown to be heterozygous carriers of this mutation."

Two homozygous affected siblings with heterozygous carrier parents, the segregation pattern of recessive inheritance.

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Discussions and Knowledge Gaps

2

Does the skeletal dysplasia depend on the TMEM165 allele, and why?

KNOWLEDGE GAP tmem165_genotype_skeletal_phenotype

Attached to

phenotypes#Spondyloepimetaphyseal dysplasia genetic#TMEM165

The founding report's summary says the missense-allele patients lack the skeletal phenotype, yet its own case 5 (p.Arg126Cys/p.Gly304Arg) had osteoporosis, vertebral and rib dysplasia and kyphoscoliosis, while case 4 (p.Arg126His homozygous) had no clear skeletal anomalies. The report also could not exclude a defect in a neighbouring gene on the founder haplotype. Later evidence argues against that explanation: TMEM165 knockout chondrocytic cells reproduce a growth-plate-like defect, the zebrafish knockdown affects cartilage, and the p.Ala310Pro missense patient has a predominant bone phenotype. Whether residual protein function or localisation (the Arg126 variants shift TMEM165 toward lysosomes) sets skeletal severity remains open with fewer than ten patients.

Is oral manganese safe and effective enough to become standard therapy, and does it reach the skeletal (glycosaminoglycan) arm of the disease in patients?

KNOWLEDGE GAP tmem165_manganese_therapy

Attached to

treatments#Combined Oral Manganese and D-Galactose Therapy

Galactose corrects only N-glycosylation, while Mn2+ corrects N-, O- and glycosaminoglycan glycosylation in cells and in one treated patient. The glycosaminoglycan defect is the one linked to the skeletal phenotype, so the choice of therapy matters most there. Manganese is potentially toxic, the patients measured had normal blood manganese, and there is a single treated patient without skeletal outcome data.

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Pathophysiology

14

TMEM165 Biallelic Loss of Function

The initiating lesion. The deep intronic splice variant leaves only traces of full-length TMEM165, and the missense variants reduce protein stability, mislocalise the protein, or disrupt its cation-binding motif. The common outcome is too little functional TMEM165 in the trans-Golgi, where it normally colocalises with beta-1,4-galactosyltransferase.

TMEM165 hgnc:30760

Genetic context variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION

manganese ion transmembrane transporter activity GO:0005384 ↓ DECREASED calcium:proton antiporter activity GO:0015369 ↓ DECREASED

trans-Golgi network GO:0005802

Downstream

Loss of Golgi Calcium and Manganese Import Less functional TMEM165 means less Ca2+/Mn2+-proton exchange across the Golgi membrane.

Golgi Structural Disorganisation Patient fibroblasts have a dilated Golgi and fragmented trans-Golgi network; the route from TMEM165 loss to this morphology is not established.

Show evidence (3 references)

PMID:22683087 SUPPORT In Vitro

"As shown in Figure 5B, an extremely low level of full-length TMEM165 was detected in affected individuals with the truncating mutation."

Protein-level consequence of the splice variant, measured in patient fibroblasts.

PMID:22683087 SUPPORT In Vitro

"Moreover, only 25% of the immunoreactivity was recovered in case 4 with the missense mutation, suggesting that the mutant protein is also unstable"

The missense allele also lowers the amount of TMEM165, so both allele classes converge on deficiency.

PMID:22683087 SUPPORT In Vitro

"These results suggest that TMEM165 is present in the late Golgi (trans) rather than in the early Golgi (cis and median)."

Places the protein in the compartment where terminal galactosylation and sialylation happen.

Loss of Golgi Calcium and Manganese Import

TMEM165 and its yeast orthologue Gdt1p are secondary transporters that import Ca2+ and Mn2+ into the Golgi lumen in exchange for protons. Direct transport of both cations by human TMEM165 was shown in yeast and bacterial expression systems, and Gdt1p has a higher affinity for Ca2+ than for Mn2+. Loss of TMEM165 removes this import route.

manganese ion transmembrane transporter activity GO:0005384 ↓ DECREASED calcium:proton antiporter activity GO:0015369 ↓ DECREASED

Golgi membrane GO:0000139

Downstream

Golgi Manganese Insufficiency

Golgi Calcium and pH Imbalance

Show evidence (3 references)

PMID:32047108 SUPPORT In Vitro

"Using bacterial cells loaded with the fluorescent Fura-2 probe, we further obtained direct biochemical evidence that TMEM165 mediates Ca2+ and Mn2+ influxes."

Direct transport measurement for the human protein.

PMID:27075443 SUPPORT In Vitro

"We observed a Ca(2+) uptake activity in cells expressing GDT1, which was dependent on the external pH, indicating that Gdt1p may act as a Ca(2+)/H(+) antiporter."

The pH dependence of transport by the yeast orthologue is the basis for describing the family as cation/proton antiporters.

PMID:29632074 SUPPORT In Vitro

"Using Mn2+-induced quenching of Fura-2-emitted fluorescence, we observed that Gdt1p mediates Mn2+ influx, in addition to its previously reported regulation of Ca2+ influx."

Direct Mn2+ transport by the yeast orthologue, measured in Lactococcus lactis.

Golgi Manganese Insufficiency

The Golgi lumen is left short of Mn2+, the cofactor of the beta-1,4-galactosyltransferases, GalNAc transferases and the glycosaminoglycan chain-elongating enzymes. This is the node the rest of the glycosylation chain turns on, and it is supported by rescue: adding Mn2+ to TMEM165-deficient mammalian cells or gdt1-null yeast restores glycosylation. Blood manganese was normal in the two patients measured, so the deficit is compartmental rather than systemic. SERCA2 can partly supply Golgi Mn2+ when TMEM165 is absent.

Golgi manganese ion homeostasis GO:0030026 ↕ DYSREGULATED

Golgi apparatus GO:0005794

Animal models

Mammary-specific Tmem165 knockout mouse Mus musculus partially recapitulates Shows in vivo that TMEM165 supplies Ca2+ and Mn2+ to the Golgi of a secretory cell.

Downstream

Impaired Manganese-Dependent Golgi Glycosyltransferase Activity

Show evidence (3 references)

PMID:27008884 SUPPORT In Vitro

"We discovered that in both yeasts and mammalian Gdt1p/TMEM165-deficient cells, Mn(2+) supplementation could restore a normal glycosylation."

Rescue by the missing cofactor is the main evidence that Mn2+ shortage, not another Golgi defect, drives the glycosylation phenotype.

PMID:39002685 SUPPORT REVIEW SYNTHESIS Other

"Impaired glycosylation of TMEM165-CDG arises from a lack of Mn2+ within the Golgi. Nevertheless, Mn2+ insufficiency in the Golgi is compensated by the activity of the ATPase SERCA2."

The review's synthesis of the mechanism, including partial compensation by SERCA2.

PMID:28323990 SUPPORT Human Clinical

"Manganese levels were normal in blood samples."

Blood Mn2+ was normal in the two patients, consistent with a Golgi-compartment rather than whole-body deficit.

Golgi Calcium and pH Imbalance

Mechanism confidence: Provisional

The earlier functional model: TMEM165 as a Golgi Ca2+/H+ antiporter whose loss perturbs Golgi Ca2+ stores and pH. The disturbance is measured, but its contribution to the glycosylation defect is proposed rather than shown, and the later Mn2+-rescue data place most of that defect on the manganese arm. Kept as a separate branch so the two models are not merged.

Golgi calcium ion homeostasis GO:0032468 ↕ DYSREGULATED

Downstream

Impaired Manganese-Dependent Golgi Glycosyltransferase Activity Proposed contribution of altered Golgi Ca2+ and pH to the glycosylation defect; not separated experimentally from the Mn2+ effect.

Show evidence (1 reference)

PMID:23569283 SUPPORT In Vitro

"Based on these results, we propose that Gdt1p and TMEM165 could be members of a unique family of Golgi-localized Ca(2+)/H(+) antiporters and that modification of the Golgi Ca(2+) and pH balance could explain the glycosylation defects observed in TMEM165-deficient patients."

States both the measured imbalance and, as a proposal, its link to glycosylation; the hedge is why this branch is PROVISIONAL.

Golgi Structural Disorganisation

Dilated Golgi cisternae and a fragmented trans-Golgi network in fibroblasts from all five original patients. Recorded as an observed cellular state; whether it is a cause or a consequence of the ionic and glycosylation defects is not known.

Golgi organization GO:0007030 ⚠ ABNORMAL

Show evidence (1 reference)

PMID:22683087 SUPPORT In Vitro

"Compared to that in controls, the Golgi apparatus in all affected individuals was found dilated, and the trans-Golgi network was markedly fragmented"

The morphological finding in patient fibroblasts.

Impaired Manganese-Dependent Golgi Glycosyltransferase Activity

Without enough luminal Mn2+, the Mn2+-dependent Golgi glycosyltransferases underperform. The best characterised is beta-1,4-galactosyltransferase (N-acetyllactosamine synthase), but GalNAc transfer onto glycolipids and the polymerising enzymes of glycosaminoglycan chains are also cofactor limited. The enzymes themselves are intact, which is why Mn2+ or, for the galactosylation step only, extra galactose substrate can rescue.

beta-1,4-galactosyltransferase activity GO:0003945 ↓ DECREASED

Downstream

Hypogalactosylation and Hyposialylation of N-Glycans

Truncation of Mucin-Type O-Glycans

Defective Glycosphingolipid Glycosylation

Impaired Glycosaminoglycan Chain Elongation

Show evidence (2 references)

PMID:28323990 SUPPORT In Vitro

"This shows that TMEM165 deficiency not only impairs the activities of Golgi galactosyltransferases but also those of Golgi GalNAc transferases."

Establishes that more than one Mn2+-dependent transferase class is affected, from glycolipid analysis in TMEM165 knockout HEK293 cells.

PMID:34930890 SUPPORT In Vitro

"We demonstrated that the blockage in elongation of glycosaminoglycan chains is not due to defect in the Golgi elongating enzymes but rather to availability of the co-factor Mn2+."

The same cofactor limitation applies to glycosaminoglycan chain polymerisation.

Hypogalactosylation and Hyposialylation of N-Glycans

Serum and cellular N-glycans are undergalactosylated and, because sialic acid is added onto galactose, undersialylated. In patient serum this is seen as a type 2 transferrin isoelectric focusing pattern and as accumulation of glycans lacking galactose and sialic acid by mass spectrometry. In the one patient followed from birth, the defect was already present on day one and worsened over the first weeks.

protein N-linked glycosylation GO:0006487 ↓ DECREASED

Experimental models

TMEM165 knockout HEK293 cells CELL LINE Severe N-glycan hypogalactosylation, corrected by Mn2+ or by galactose.

Animal models

Zebrafish tmem165 morphant Danio rerio partially recapitulates N-glycan changes in morphants parallel some of the patients' serum glycan changes.

Downstream

Type II transferrin isoform profile The type 2 transferrin pattern is the serum readout of this glycan defect.

Multisystem Hypoglycosylation

Show evidence (3 references)

PMID:22683087 SUPPORT Human Clinical

"The presence of these abnormal ions points to a slight defect in both sialylation and galactosylation and corroborates the IEF data."

Serum N-glycan mass spectrometry in the original patients.

PMID:23430531 SUPPORT Human Clinical

"Serum transferrin glycan analysis shows an increase of the biantennary glycan lacking sialic acid, and an abnormal biantennary glycan lacking sialic acid and galactose."

Transferrin-specific glycan structures showing the galactose and sialic acid loss.

PMID:26238249 SUPPORT Human Clinical

"Within the next few weeks, hypoglycosylation progressed to less sialylated and then also to hypogalactosylated isoforms."

The postnatal course of the defect in the E108G patient.

Truncation of Mucin-Type O-Glycans

Mucin-type O-glycans are truncated. In patients this was read from a cathodal shift of apolipoprotein C-III on isoelectric focusing and from truncated apoC-III by mass spectrometry; in knockout cells as exposed GalNAc (Tn) structures. The evidence is not uniform: the founding report found normal serum O-glycans and a normal apoC-III profile in its patients, while the detailed clinical report on three of the same-genotype patients found the apoC-III shift. D-galactose does not correct this arm in cells.

protein O-linked glycosylation GO:0006493 ↓ DECREASED

Experimental models

TMEM165 knockout HEK293 cells CELL LINE Truncated mucin-type O-glycans, corrected by Mn2+ but not galactose.

Downstream

Multisystem Hypoglycosylation

Show evidence (4 references)

PMID:23430531 SUPPORT Human Clinical

"Diagnostic work-up revealed a type 2 serum transferrin isoelectrofocusing (IEF) pattern and a cathodal shift on apolipoprotein C-III IEF pointing to a combined N- and O-glycosylation defect."

The apoC-III finding in three homozygous c.792+182G>A patients.

PMID:26238249 SUPPORT Human Clinical

"Mass spectrometry of apolipoprotein C3 (MALDI-TOF MS) showed an increasing proportion of truncated and unglycosylated apoprotein C3 as a marker for a defect in O-glycosylation."

The same finding by mass spectrometry in the E108G patient.

PMID:35693943 SUPPORT In Vitro

"Interestingly, a similar VVL staining was observed in TMEM165 KO HEK cells (Supplementary Figure S1A), demonstrating the significant presence of truncated O-linked mucin type glycans in TMEM165-deficient cells."

Truncated O-glycans in an isogenic knockout.

+ 1 more reference

Defective Glycosphingolipid Glycosylation

Complex gangliosides are almost absent from TMEM165 knockout cells, which retain only traces of GM3 and GM2. Shown in cells only; lipid glycosylation has not been measured in patient tissue.

ganglioside biosynthetic process GO:0001574 ↓ DECREASED

Downstream

Multisystem Hypoglycosylation Which, if any, clinical features depend on the glycolipid defect is not known.

Show evidence (1 reference)

PMID:28323990 SUPPORT In Vitro

"Although control cells expressed a complex pattern of GSLs, including GM3 (m/z 1372/1484), GM2 (m/z 1617/1729), GM1 (m/z 1821/1933), GD2 (m/z 1978/2090), and GD1 (m/z 2182/2294) species, KO TMEM165 HEK293 cells only showed traces of GM3 and GM2 species"

The ganglioside profile of knockout cells against controls.

Impaired Glycosaminoglycan Chain Elongation

Chondroitin- and heparan-sulfate chains on proteoglycans are shorter because chain polymerisation stalls. Shown in TMEM165 knockout mouse prechondrocytic ATDC5 cells and HEK293 cells; a combined N-, O- and glycosaminoglycan glycosylation defect was also reported in the p.Ala310Pro patient.

chondrocyte CL:0000138

chondroitin sulfate proteoglycan biosynthetic process GO:0050650 ↓ DECREASED heparan sulfate proteoglycan biosynthetic process GO:0015012 ↓ DECREASED

Experimental models

TMEM165 knockout ATDC5 chondrocytic cells CELL LINE Shorter chondroitin- and heparan-sulfate chains, rescued by Mn2+.

Downstream

Dysregulated TGF-beta and BMP Signaling in Chondrocytes

Show evidence (2 references)

PMID:34930890 SUPPORT In Vitro

"Here, we uncover that TMEM165 deficiency impairs the synthesis of proteoglycans by producing a blockage in the elongation of chondroitin-and heparan-sulfate glycosaminoglycan chains leading to the synthesis of proteoglycans with shorter glycosaminoglycan chains."

The primary finding in knockout chondrocytic cells.

PMID:38013006 SUPPORT Human Clinical

"This patient was diagnosed at 2 months and displays a predominant bone phenotype and combined defects in N-, O- and GAG glycosylation."

A glycosaminoglycan defect observed in a patient, not only in cells.

Dysregulated TGF-beta and BMP Signaling in Chondrocytes

TGF-beta signalling is reduced (lower TGFBR2, reduced Smad2 phosphorylation, also in patient fibroblasts) while BMP signalling is increased (four-fold reporter activity, higher BMP receptor expression) in TMEM165-deficient chondrocytic cells. Proteoglycan glycosaminoglycan chains act as co-receptors and reservoirs for these growth factors.

chondrocyte CL:0000138

transforming growth factor beta receptor signaling pathway GO:0007179 ↓ DECREASED BMP signaling pathway GO:0030509 ↑ INCREASED

Downstream

Premature Chondrocyte Maturation and Hypertrophy

Show evidence (2 references)

PMID:34930890 SUPPORT In Vitro

"Additionally, we showed that TMEM165 deficiency functionally impairs TGFβ and BMP signaling pathways in chondrocytes and in fibroblast cells of TMEM165 deficient patients."

Signalling abnormality in knockout chondrocytes and in patient fibroblasts.

PMID:34930890 SUPPORT In Vitro

"analysis of luciferase activity showed a significant increase (4-fold) in tmem165-knockout ATDC5 cells, compared to wild-type cells thus bringing evidence that BMP signaling is increased in tmem165-mutant cells."

Gives the direction for the BMP arm, which is increased rather than impaired.

Premature Chondrocyte Maturation and Hypertrophy

TMEM165-deficient chondrocytic cells switch on Indian hedgehog early and mature and hypertrophy prematurely. In zebrafish morphants the cartilage elements are misshapen and contain fewer chondrocytes, with altered chondrocyte and osteoblast differentiation markers.

chondrocyte CL:0000138

chondrocyte hypertrophy GO:0003415 ↑ INCREASED

Experimental models

TMEM165 knockout ATDC5 chondrocytic cells CELL LINE Early Ihh expression and premature hypertrophic differentiation.

Animal models

Zebrafish tmem165 morphant Danio rerio partially recapitulates Reproduces a cartilage developmental defect with altered chondrocyte and osteoblast differentiation.

Downstream

Disordered Endochondral Ossification

Show evidence (2 references)

PMID:34930890 SUPPORT In Vitro

"Finally, we found that loss of TMEM165 impairs chondrogenic differentiation by accelerating the timing of Ihh expression and promoting early chondrocyte maturation and hypertrophy."

The cellular finding in knockout ATDC5 cells.

PMID:25609749 SUPPORT Model Organism

"Decreased expression of several markers of cartilage and bone development suggests that Tmem165 deficiency alters both chondrocyte and osteoblast differentiation."

In vivo support for disturbed chondrocyte and osteoblast differentiation.

Disordered Endochondral Ossification

Mechanism confidence: Provisional

The tissue-level step between the cellular growth-plate defect and the radiological phenotype. Inferred rather than observed: no bone or growth plate histology from a patient or a mammalian model is published, so the link rests on the chondrocyte data and the zebrafish cartilage phenotype.

cartilage development GO:0051216 ⚠ ABNORMAL

Downstream

Spondyloepimetaphyseal dysplasia

Severe short stature Growth failure is not corrected by growth hormone even when IGF-I normalises, which points to the skeleton rather than the somatotropic axis as the limiting factor.

Kyphoscoliosis

Genu varum

Pectus carinatum

Osteoporosis

Show evidence (1 reference)

PMID:25609749 SUPPORT Model Organism

"Collectively, these findings highlight the utility of zebrafish to elucidate pathogenic mechanisms associated with glycosylation disorders and suggest that the cartilage and bone dysplasia manifested in TMEM165-CDG patients may stem from abnormal development of chondrocytes and osteoblasts."

Model-organism argument that the patients' skeletal dysplasia originates in chondrocyte and osteoblast development.

Multisystem Hypoglycosylation

Mechanism confidence: Hypothetical

The route from the glycan defects to the non-skeletal features. No source identifies which hypoglycosylated proteins or lipids mediate the neurological, hepatic, muscular, haemostatic, endocrine, renal or cardiac manifestations; the attribution is to hypoglycosylation as a class, with the exception of the coagulation factors and hormones, which are themselves glycoproteins and partly respond to galactose therapy.

Downstream

Global developmental delay

Hypotonia

Muscle weakness

Hyporeflexia

Seizure

Abnormal cerebral white matter morphology

Ventriculomegaly

Anterior pituitary hypoplasia

Joint hypermobility

Hepatosplenomegaly

Elevated circulating hepatic transaminase concentration

Elevated circulating creatine kinase activity

Abnormality of coagulation Clotting factors VIII, IX and XI and protein C are glycoproteins; their reduced activity and partial response to galactose fit a glycosylation origin, but reduced synthesis has not been excluded.

Decreased response to growth hormone stimulation test

Recurrent fever

Feeding difficulties

Midface retrusion

Low-set ears

Strabismus

Abnormal macular pigmentation

Amelogenesis imperfecta

Increased body fat percentage

Delayed puberty

Nephrotic syndrome

Ventricular septal defect

Patent ductus arteriosus

Patent foramen ovale

Show evidence (2 references)

PMID:28323990 SUPPORT Human Clinical

"TMEM165 deficiency is a severe multisystem disease that manifests with metabolic, endocrine, and skeletal involvement."

Statement of the organ range this hub stands for.

PMID:28323990 SUPPORT Human Clinical

"Galactose supplementation improved several, but not all, laboratory results in our patients (Table 1); specifically, coagulation parameters, IGF1, and IGFBP3 were improved in patient 1."

Partial normalisation of glycoprotein-dependent laboratory values on galactose is the nearest thing to evidence that the systemic features follow the glycan defect.

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Pathograph

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Phenotypes

35

Blood 1

Abnormality of coagulation HP:0001928

Show evidence (1 reference)

PMID:23430531 SUPPORT Human Clinical

"The main biochemical findings in all three patients were an increase of serum AST (moderate), ALT (very mild), CK (moderate), and LDH (mild), as well as a decrease of coagulation factors VIII, IX, XI, and protein C."

Reduced coagulation factors in all three patients.

Cardiovascular 4

Hepatosplenomegaly HP:0001433

Show evidence (1 reference)

PMID:23430531 SUPPORT Human Clinical

"Common clinical features include moderate psychomotor retardation, feeding problems (in infancy), facial dysmorphism with low-set ears, hypotonia, joint hyperlaxity, hepatosplenomegaly, osteoporosis, and spondylo-, epi- and metaphyseal dysplasia aggravating with age."

Hepatosplenomegaly in all three splice-variant patients; absent in the p.Arg126His patient.

Ventricular septal defect OCCASIONAL HP:0001629

Show evidence (1 reference)

PMID:26238249 SUPPORT Human Clinical

"Echocardiography revealed a small apical VSD, a PFO, and a small PDA with mild signs of right ventricular hypertrophy."

Neonatal echocardiography in the E108G patient; the same sentence supports the PDA and PFO entries.

Patent ductus arteriosus HP:0001643

Show evidence (2 references)

PMID:26238249 SUPPORT Human Clinical

"Echocardiography revealed a small apical VSD, a PFO, and a small PDA with mild signs of right ventricular hypertrophy."

E108G patient.

PMID:23430531 SUPPORT Human Clinical

"Hepatomegaly, a small open ductus Botalli and a small patent foramen ovale, were noted shortly after birth."

Also in patient 3 of the splice-variant series, a second genotype.

Patent foramen ovale HP:0001655

Show evidence (1 reference)

PMID:23430531 SUPPORT Human Clinical

"Hepatomegaly, a small open ductus Botalli and a small patent foramen ovale, were noted shortly after birth."

Patient 3; the E108G patient also had a PFO.

Digestive 1

Feeding difficulties HP:0011968

Show evidence (2 references)

PMID:23430531 SUPPORT Human Clinical

"Common clinical features include moderate psychomotor retardation, feeding problems (in infancy), facial dysmorphism with low-set ears, hypotonia, joint hyperlaxity, hepatosplenomegaly, osteoporosis, and spondylo-, epi- and metaphyseal dysplasia aggravating with age."

Feeding problems in infancy in all three patients.

PMID:26238249 SUPPORT Human Clinical

"Repeated hospitalizations were necessary due to recurrent edema and feeding problems requiring tube feeding."

Tube feeding in the E108G patient.

Ear 1

Low-set ears HP:0000369

Show evidence (1 reference)

PMID:23430531 SUPPORT Human Clinical

"Common clinical features include moderate psychomotor retardation, feeding problems (in infancy), facial dysmorphism with low-set ears, hypotonia, joint hyperlaxity, hepatosplenomegaly, osteoporosis, and spondylo-, epi- and metaphyseal dysplasia aggravating with age."

Low-set ears are the facial feature named as common to all three patients.

Endocrine 3

Anterior pituitary hypoplasia HP:0010627

Show evidence (1 reference)

PMID:23430531 SUPPORT Human Clinical

"MRI of the brain showed some atrophy, enlarged ventricles, periventricular and subcortical white matter abnormalities, as well as relative hypoplasia of the anterior pituitary, and absence of the normal hyperintensity of the posterior pituitary."

Brain MRI of patient 1.

Decreased response to growth hormone stimulation test HP:0000824

HP:0000824 is the HPO class that carries "growth hormone deficiency" as a synonym; the sources report partial GH deficiency without naming the stimulation test used.

Show evidence (1 reference)

PMID:23430531 SUPPORT Human Clinical

"After infancy (patients 1 and 3), midface hypoplasia, muscular hypotrophy, fat excess, growth retardation, and partial growth hormone deficiency completed this picture."

Partial GH deficiency in both surviving patients of the series.

Delayed puberty OCCASIONAL HP:0000823

Show evidence (1 reference)

PMID:23430531 SUPPORT Human Clinical

"but not yet of puberty (circulating luteinizing hormone 0.4 IU/L (normal 1.7–8.6 IU/L), follicle stimulating hormone 0.3 IU/L (nl 1.2–7.7), total testosterone 25 ng/dL (nl 300–1,000)"

One patient, with no puberty and low gonadotropins and testosterone at 16 years.

Eye 2

Strabismus HP:0000486

Show evidence (1 reference)

PMID:23430531 SUPPORT Human Clinical

"Ophthalmological examination revealed a right convergent strabism"

Convergent strabismus in patient 1; patient 2 had an external strabismus.

Abnormal macular pigmentation HP:0008002

Show evidence (1 reference)

PMID:23430531 SUPPORT Human Clinical

"Ophthalmological examination in patients 1 and 2 showed macular epithelial pigment alterations, and was normal in patient 3."

Two of three patients.

Genitourinary 2

Nephrotic syndrome OCCASIONAL HP:0000100

Sequelae: Renal insufficiency

Show evidence (1 reference)

PMID:26238249 SUPPORT Human Clinical

"At the age of 1 week, mild proteinuria was observed, the extent increasing over the next weeks to nephrotic syndrome with slowly progressive renal failure."

The course of the renal disease in the E108G patient.

Renal insufficiency OCCASIONAL HP:0000083

Show evidence (1 reference)

PMID:26238249 SUPPORT Human Clinical

"At the age of 1 week, mild proteinuria was observed, the extent increasing over the next weeks to nephrotic syndrome with slowly progressive renal failure."

One patient.

Head and Neck 2

Midface retrusion HP:0011800

Show evidence (1 reference)

PMID:23430531 SUPPORT Human Clinical

"After infancy (patients 1 and 3), midface hypoplasia, muscular hypotrophy, fat excess, growth retardation, and partial growth hormone deficiency completed this picture."

Midface hypoplasia developing after infancy in both surviving patients.

Amelogenesis imperfecta OCCASIONAL HP:0000705

Show evidence (1 reference)

PMID:22683087 SUPPORT Human Clinical

"She had amelogenesis imperfecta and skeletal abnormalities, including osteoporosis, anterior beaking of lumbal vertebrae, dysplastic vertebrae and ribs, dysplastic fourth metacarpals and metatarsals, hypoplasia of femoral heads, and kyphoscoliosis"

One patient (case 5).

Limbs 1

Genu varum HP:0002970

Show evidence (1 reference)

PMID:23430531 SUPPORT Human Clinical

"low-set and stiff auricles, pectus carinatum, dorsolumbar kyphosis and severe sinistroconvex scoliosis, short distal phalanges, genua vara, pedes planovalgi"

Genua vara in patient 1.

Metabolism 4

Type II transferrin isoform profile VERY_FREQUENT HP:0012301

Show evidence (2 references)

PMID:22683087 SUPPORT Human Clinical

"The diagnosis of CDG-II in these cases was established by standard sTf-IEF showing a marked increase of asialotransferrin, monosialotransferrin, disialotransferrin, and trisialotransferrin in all cases"

Present in all five patients of the founding series, which carries the frequency.

PMID:26238249 SUPPORT Human Clinical

"Isoelectric focusing (IEF) of transferrin showed a pathological pattern with increased amounts of tri-, di-, and monosialotransferrin already in the first blood sample taken 3 min after birth."

Also present in the E108G patient, from birth.

Elevated circulating hepatic transaminase concentration HP:0002910

Show evidence (2 references)

PMID:23430531 SUPPORT Human Clinical

"The main biochemical findings in all three patients were an increase of serum AST (moderate), ALT (very mild), CK (moderate), and LDH (mild), as well as a decrease of coagulation factors VIII, IX, XI, and protein C."

All three patients; the same sentence supports the creatine kinase and coagulation entries.

PMID:28323990 SUPPORT Human Clinical

"The few overlapping abnormalities included increased baseline levels of blood creatine kinase, transaminases, prothrombin time, and thyroid-stimulating hormone."

Present at baseline in both patients of the galactose study.

Elevated circulating creatine kinase activity HP:0003236

Show evidence (1 reference)

PMID:23430531 SUPPORT Human Clinical

"The main biochemical findings in all three patients were an increase of serum AST (moderate), ALT (very mild), CK (moderate), and LDH (mild), as well as a decrease of coagulation factors VIII, IX, XI, and protein C."

Moderately raised CK in all three patients.

Recurrent fever HP:0001954

Show evidence (1 reference)

PMID:23430531 SUPPORT Human Clinical

"was recurrent fever without evidence for infection."

Reported in patients 2 and 3 of the three.

Musculoskeletal 7

Hypotonia HP:0001252

Show evidence (2 references)

PMID:23430531 SUPPORT Human Clinical

"Common clinical features include moderate psychomotor retardation, feeding problems (in infancy), facial dysmorphism with low-set ears, hypotonia, joint hyperlaxity, hepatosplenomegaly, osteoporosis, and spondylo-, epi- and metaphyseal dysplasia aggravating with age."

Hypotonia is among the common features of all three patients.

PMID:26238249 REFUTE Human Clinical

"Neurological examination revealed a large, temporarily tensed fontanel, muscular hypertonia with opisthotonic posture, and a sundown position of the eyes."

The p.Glu108Gly neonate had increased rather than reduced tone, so hypotonia is not a feature of every genotype.

Muscle weakness HP:0001324

Show evidence (1 reference)

PMID:22683087 SUPPORT Human Clinical

"The boy was mainly affected by growth retardation (he was unresponsive to growth hormone, which eventually led to severe dwarfism; he is now 19 years old), psychomotor retardation (he began independently walking at 2 years of age), midface hypoplasia, muscular weakness, fat excess, joint laxity,..."

The index case's clinical summary, which names muscular weakness.

Spondyloepimetaphyseal dysplasia HP:0002651

Show evidence (3 references)

PMID:23430531 SUPPORT Human Clinical

"Three patients belonging to two families presented with a psychomotor-dysmorphism syndrome including postnatal growth deficiency and major spondylo-, epi-, and metaphyseal skeletal involvement."

The skeletal hallmark in all three c.792+182G>A patients.

PMID:23430531 SUPPORT Human Clinical

"Imaging of the skeleton showed osteoporosis and important epi- and metaphyseal dysplasia with broad metaphyses, irregular epiphyses, and thin bone cortex."

Radiological detail in patient 1.

PMID:22683087 SUPPORT Human Clinical

"Through a combination of autozygosity mapping and expression analysis in two siblings with an abnormal serum-transferrin isoelectric focusing test (type 2) and a peculiar skeletal phenotype with epiphyseal, metaphyseal, and diaphyseal dysplasia"

The founding report's description, which adds diaphyseal involvement.

Osteoporosis HP:0000939

Show evidence (2 references)

PMID:23430531 SUPPORT Human Clinical

"Common clinical features include moderate psychomotor retardation, feeding problems (in infancy), facial dysmorphism with low-set ears, hypotonia, joint hyperlaxity, hepatosplenomegaly, osteoporosis, and spondylo-, epi- and metaphyseal dysplasia aggravating with age."

Osteoporosis is among the features common to all three patients.

PMID:22683087 SUPPORT Human Clinical

"She had amelogenesis imperfecta and skeletal abnormalities, including osteoporosis, anterior beaking of lumbal vertebrae, dysplastic vertebrae and ribs, dysplastic fourth metacarpals and metatarsals, hypoplasia of femoral heads, and kyphoscoliosis"

Osteoporosis also in case 5 of the founding report, a compound heterozygous p.Arg126Cys/p.Gly304Arg missense patient, so it is not confined to the splice genotype.

Kyphoscoliosis HP:0002751

Show evidence (1 reference)

PMID:22683087 SUPPORT Human Clinical

"She had amelogenesis imperfecta and skeletal abnormalities, including osteoporosis, anterior beaking of lumbal vertebrae, dysplastic vertebrae and ribs, dysplastic fourth metacarpals and metatarsals, hypoplasia of femoral heads, and kyphoscoliosis"

Case 5 (compound heterozygous missense); patient 1 of the splice series also had dorsolumbar kyphosis with severe scoliosis.

Pectus carinatum HP:0000768

Show evidence (1 reference)

PMID:23430531 SUPPORT Human Clinical

"low-set and stiff auricles, pectus carinatum, dorsolumbar kyphosis and severe sinistroconvex scoliosis, short distal phalanges, genua vara, pedes planovalgi"

Patient 1's dysmorphic and skeletal findings; shared with the genu varum entry.

Joint hypermobility HP:0001382

Show evidence (1 reference)

PMID:23430531 SUPPORT Human Clinical

"Common clinical features include moderate psychomotor retardation, feeding problems (in infancy), facial dysmorphism with low-set ears, hypotonia, joint hyperlaxity, hepatosplenomegaly, osteoporosis, and spondylo-, epi- and metaphyseal dysplasia aggravating with age."

Joint hyperlaxity is among the common features.

Nervous System 5

Global developmental delay HP:0001263

Show evidence (2 references)

PMID:23430531 SUPPORT Human Clinical

"Common clinical features include moderate psychomotor retardation, feeding problems (in infancy), facial dysmorphism with low-set ears, hypotonia, joint hyperlaxity, hepatosplenomegaly, osteoporosis, and spondylo-, epi- and metaphyseal dysplasia aggravating with age."

The features common to all three c.792+182G>A patients; shared by several phenotype entries below.

PMID:22683087 SUPPORT Human Clinical

"At the age of 9 years, his psychomotor level is that of a 4-year-old."

Developmental delay also in a missense-allele patient without skeletal involvement.

Hyporeflexia HP:0001265

Show evidence (1 reference)

PMID:23430531 SUPPORT Human Clinical

"joint “cracking” when walking, and generalized hyporeflexia and hypotonia."

Patient 1; patient 2 also had hyporeflexia, while patient 3 had brisk reflexes.

Seizure OCCASIONAL HP:0001250

Show evidence (1 reference)

PMID:23430531 SUPPORT Human Clinical

"Features only present in patient 3 (family 2) were respiratory problems due to unexplained restrictive lung pathology and transient epilepsy. It remains uncertain whether these features are secondary to the CDG."

One of three patients, with the authors' own caveat about attribution.

Abnormal cerebral white matter morphology HP:0002500

Show evidence (1 reference)

PMID:23430531 SUPPORT Human Clinical

"Common findings on brain MRI in patients 1 and 3 were white matter abnormalities and absent visualization of the neural pituitary gland."

Present in both patients who had brain MRI in this series.

Ventriculomegaly HP:0002119

Show evidence (1 reference)

PMID:26238249 SUPPORT Human Clinical

"Brain ultrasound showed enlarged lateral and third ventricles."

Neonatal finding in the E108G patient; patient 1 of the c.792+182G>A series also had enlarged ventricles on MRI.

Growth 2

Severe short stature HP:0003510

Show evidence (2 references)

PMID:23430531 SUPPORT Human Clinical

"At age 21, the young man has a short stature (122.5 cm, Z-score −10) but a normal head circumference (55 cm, between 10th and 25th centiles)"

The magnitude of the growth deficit in patient 1.

PMID:22683087 SUPPORT Human Clinical

"The major clinical findings in the individuals with a homozygous splice mutation are severe psychomotor retardation, major skeletal dysplasia, and, in the surviving individuals, pronounced dwarfism."

Dwarfism in all surviving splice-variant patients.

Increased body fat percentage HP:0025521

Show evidence (1 reference)

PMID:23430531 SUPPORT Human Clinical

"After infancy (patients 1 and 3), midface hypoplasia, muscular hypotrophy, fat excess, growth retardation, and partial growth hormone deficiency completed this picture."

Fat excess in both surviving patients.

🧬

Genetic Associations

1

TMEM165

Gene: TMEM165 hgnc:30760 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (2 references)

PMID:22683087 SUPPORT Human Clinical

"In our cohort of unsolved CDG-II cases, we found another individual with the same mutation and two unrelated individuals with missense mutations in TMEM165."

Independent families carrying TMEM165 variants, which is what establishes the gene-disease relationship beyond the founding pedigree.

PMID:22683087 SUPPORT Human Clinical

"Interestingly, the individuals harboring missense mutations have a milder disease and lack the skeletal phenotype."

The founding report's summary of its two missense-allele patients. Its own case descriptions qualify it (case 5 had skeletal abnormalities; see the Osteoporosis and Kyphoscoliosis phenotypes), so this is kept as the authors' generalisation, not as an established genotype-phenotype rule.

Variants (4)

c.792+182G>A (deep intronic, cryptic splice donor)

Homozygous in the founding sibling pair and one unrelated patient of the same origin. Activates a cryptic donor, replacing exon 4 with a 117 bp intronic sequence; the aberrant transcript is degraded and full-length protein is barely detectable.

Show evidence (1 reference)

PMID:22683087 SUPPORT Human Clinical

"The mutation activates a cryptic splice donor site, which leads to two different transcripts: the wild-type one and an additional one resulting in the replacement of exon 4 with a 117 bp intronic sequence"

The splice consequence of the variant, established on patient cDNA.

c.377G>A p.(Arg126His) and c.376C>T p.(Arg126Cys)

Two substitutions of the same conserved arginine, found homozygous (Arg126His, consanguineous Turkish family) and compound heterozygous with p.Gly304Arg (Arg126Cys).

Show evidence (1 reference)

PMID:22683087 SUPPORT Human Clinical

"P4 is homozygous for the G>A transition at position c.377, and P5 is compound heterozygous for the C>T transition at position 376 and the G>A transition at position 910."

The homozygous Arg126His genotype and the compound heterozygous Arg126Cys/Gly304Arg genotype, at nucleotide level.

c.323A>G p.(Glu108Gly)

Homozygous in two siblings of a consanguineous family, both of whom died in infancy; the second had nephrotic syndrome and congenital heart defects. The substitution sits in the conserved cytosolic ELGDK motif and significantly reduces transport activity.

Show evidence (2 references)

PMID:26238249 SUPPORT Human Clinical

"Sequence analysis of TMEM165 showed homozygosity for the missense mutation c.323 A>G (p.E108G) in exon 2."

The genotype of the E108G patient.

PMID:32047108 SUPPORT In Vitro

"We found that a mutation leading to a E108G substitution within the conserved UPF0016 family motif significantly reduces TMEM165 activity."

Functional evidence that the allele is hypomorphic for transport.

c.928G>C p.(Ala310Pro)

Homozygous in one patient diagnosed at two months with a predominant bone phenotype; the protein is functional but unstable.

Show evidence (1 reference)

PMID:38013006 SUPPORT Human Clinical

"The unreported homozygous missense c.928G>C; p.Ala310Pro variant leading to a functional but unstable protein was identified."

The genotype and its protein-level consequence.

💊

Medical Actions

5

Oral D-Galactose Supplementation

Action: oral D-galactose supplementation Ontology label: Dietary Intervention NCIT:C15447

Agent: D-galactose CHEBI:12936

Platform: Small molecule

Dosing: daily every 1 days

Oral D-galactose, escalated from 0.5 to 1.5 g/kg/day (maximum 50 g/day) over 18 weeks in two c.792+182G>A patients. Well tolerated. Improved transferrin sialylation and serum N-glycan galactosylation, APTT, antithrombin, IGF-1, IGFBP3 and ALT in one or both patients; no effect on creatine kinase, TSH or cholesterol, and 1 g/kg/day was as good as 1.5. In cells galactose corrects N-glycosylation but not O-glycosylation or glycosaminoglycan synthesis, so it bypasses only the galactosylation step.

Mechanism Target:

BYPASSES Hypogalactosylation and Hyposialylation of N-Glycans — Raises galactose substrate supply so the Mn2+-limited galactosyltransferases complete more N-glycans; does not act on the O-glycan or glycosaminoglycan arms.

Target Phenotypes: Type II transferrin isoform profile HP:0012301 coagulation factor deficiency HP:0001928

Show evidence (3 references)

PMID:28323990 SUPPORT Human Clinical

"We then demonstrated that oral galactose supplementation in patients with TMEM165-deficient CDG improved biochemical and clinical parameters, including a substantial increase in the negatively charged transferrin isoforms, and a decrease in hypogalactosylated total N-glycan structures, endocrine..."

The clinical result in two patients.

PMID:28323990 SUPPORT Human Clinical

"d-Galactose intake was increased in increments, as follows: weeks 0 to 6, 0.5 g/kg/d; weeks 7 to 12, 1.0 g/kg/d; weeks 13 to 18, 1.5 g/kg/d."

The dosing schedule recorded in the description.

PMID:35693943 SUPPORT In Vitro

"Whereas MnCl2 supplementation unambiguously fully rescues the N- and O-linked as well as GAG glycosylations in TMEM165-deficient cells, D-Gal supplementation only rescues the N-linked glycosylation, without any effects on the other Golgi-related glycosylation types."

The limit of galactose therapy in cells; it leaves the O-glycan and glycosaminoglycan defects, and the latter is the one linked to the skeletal phenotype.

Combined Oral Manganese and D-Galactose Therapy

Action: oral manganese and D-galactose supplementation Ontology label: Pharmacotherapy NCIT:C15986

Agent: manganese CHEBI:29035 D-galactose CHEBI:12936

Platform: Small molecule

Combined oral Mn2+ and D-galactose, first given to one p.Ala310Pro patient. It suppressed the N-, O- and glycosaminoglycan hypoglycosylation and improved biochemical parameters and gastrointestinal symptoms. Single patient; an earlier study withheld manganese because blood manganese was normal and because of potential toxicity.

Mechanism Target:

RESTORES Golgi Manganese Insufficiency — Supplies the missing cofactor, which in cells corrects every glycosylation class affected.

Show evidence (2 references)

PMID:38013006 SUPPORT Human Clinical

"We administered for the first time a combined D-Gal and Mn2+ therapy to the patient. This fully suppressed the N-; O- and GAG hypoglycosylation."

The single-patient result.

PMID:28323990 SUPPORT Human Clinical

"Manganese treatment was not attempted, because of normal blood levels of manganese and potential toxicity."

The safety reason manganese was withheld in the earlier study.

Growth Hormone Therapy

Action: growth hormone therapy Ontology label: Hormone Replacement Therapy NCIT:C15599

Agent: growth hormone NCIT:C837

Platform: Protein replacement

Tried in two patients for partial growth hormone deficiency. IGF-I normalised and body fat fell, but growth velocity did not increase and treatment was stopped.

Target Phenotypes: severe dwarfism HP:0003510

Show evidence (1 reference)

PMID:23430531 REFUTE Human Clinical

"but failed to elicit a detectable increment of growth velocity or a detectable improvement of respiratory status, and was thus halted."

Graded REFUTE against growth hormone improving growth, in patient 3; patient 1 had the same outcome.

Levetiracetam for Epilepsy

Action: antiepileptic pharmacotherapy Ontology label: Pharmacotherapy NCIT:C15986

Agent: levetiracetam CHEBI:6437

Platform: Small molecule

Transient epilepsy in one patient responded to levetiracetam, which was withdrawn before age three.

Target Phenotypes: transient epilepsy HP:0001250

Show evidence (1 reference)

PMID:23430531 SUPPORT Human Clinical

"At 14 months he developed epilepsy, responding to levetiracetam."

Treatment and response in patient 3.

Antisense Morpholino Pseudoexon Skipping

Action: antisense oligonucleotide pseudoexon skipping Ontology label: Antisense Therapy NCIT:C16236

Platform: Antisense oligonucleotide Splice modulation (exon skipping) Chemistry: Morpholino (PMO)

RNA target: TMEM165 hgnc:30760 TMEM165 pre-mRNA pseudoexon from intron 4 (c.792+182G>A)

Preclinical only. A morpholino antisense oligonucleotide directed at the pseudoexon created by c.792+182G>A restored normal TMEM165 protein in the Golgi of patient fibroblasts. Applicable only to that allele; no patient has been treated.

Mechanism Target:

RESTORES TMEM165 Biallelic Loss of Function — Blocks inclusion of the aberrant exon so the normal transcript and protein are made.

Show evidence (1 reference)

PMID:24720419 SUPPORT In Vitro

"Antisense morpholino oligonucleotide therapy targeted toward TMEM165 mRNA recovered normal protein levels in the Golgi apparatus of patient-derived fibroblasts."

Proof of concept in patient cells only.

🔬

Biochemical Markers

6

Reduced factor IX activity (PRESENT)

Show evidence (2 references)

PMID:23430531 SUPPORT Human Clinical

"The main biochemical findings in all three patients were an increase of serum AST (moderate), ALT (very mild), CK (moderate), and LDH (mild), as well as a decrease of coagulation factors VIII, IX, XI, and protein C."

Factor IX is among the reduced factors in all three patients.

PMID:28323990 SUPPORT Human Clinical

"Factor IX deficiency did not normalize in patient 1, but its improvement was apparently sufficient to normalize APTT."

Response of this marker to galactose therapy.

Reduced factor VIII activity (PRESENT)

Show evidence (1 reference)

PMID:23430531 SUPPORT Human Clinical

"The main biochemical findings in all three patients were an increase of serum AST (moderate), ALT (very mild), CK (moderate), and LDH (mild), as well as a decrease of coagulation factors VIII, IX, XI, and protein C."

Factor VIII is among the reduced factors in all three patients.

Reduced factor XI activity (PRESENT)

Show evidence (1 reference)

PMID:23430531 SUPPORT Human Clinical

"The main biochemical findings in all three patients were an increase of serum AST (moderate), ALT (very mild), CK (moderate), and LDH (mild), as well as a decrease of coagulation factors VIII, IX, XI, and protein C."

Factor XI is among the reduced factors in all three patients.

Reduced protein C activity (PRESENT)

Show evidence (1 reference)

PMID:23430531 SUPPORT Human Clinical

"The main biochemical findings in all three patients were an increase of serum AST (moderate), ALT (very mild), CK (moderate), and LDH (mild), as well as a decrease of coagulation factors VIII, IX, XI, and protein C."

Protein C is reduced in all three patients.

Increased circulating lactate dehydrogenase concentration (PRESENT)

Show evidence (1 reference)

PMID:23430531 SUPPORT Human Clinical

"The main biochemical findings in all three patients were an increase of serum AST (moderate), ALT (very mild), CK (moderate), and LDH (mild), as well as a decrease of coagulation factors VIII, IX, XI, and protein C."

Mildly raised LDH in all three patients.

Apolipoprotein C-III isoform shift (VARIABLE)

Show evidence (2 references)

PMID:23430531 SUPPORT Human Clinical

"IEF of apolipoprotein C-III shows a decrease of the monosialo-apo C-III and an increase of the asialo-apo C-III"

The isoform shift itself.

PMID:22683087 REFUTE Human Clinical

"These results are consistent with the normal ApoC-III profile and prove the absence of an O-glycan defect."

A normal apoC-III profile in the founding report, so the marker is not constant.

🔬

Diagnosis

3

Serum transferrin isoelectric focusing

First-line screen; shows a type 2 pattern in every reported patient, including on the first day of life.

Show evidence (1 reference)

PMID:22683087 SUPPORT Human Clinical

"The diagnosis of CDG-II in these cases was established by standard sTf-IEF showing a marked increase of asialotransferrin, monosialotransferrin, disialotransferrin, and trisialotransferrin in all cases"

The screening test by which the original patients were identified.

Serum apolipoprotein C-III isoelectric focusing

Detects the accompanying O-glycosylation defect and so distinguishes a combined N- and O-glycosylation defect from a pure N-glycan processing defect; it was normal in the founding report, so a normal result does not exclude the disease.

Show evidence (1 reference)

PMID:23430531 SUPPORT Human Clinical

"Diagnostic work-up revealed a type 2 serum transferrin isoelectrofocusing (IEF) pattern and a cathodal shift on apolipoprotein C-III IEF pointing to a combined N- and O-glycosylation defect."

The combined screen used in the clinical series.

Molecular genetic testing of TMEM165 including deep intronic sequence

Confirms biallelic variants, and has been used prenatally in a family with a known variant. The recurrent c.792+182G>A variant lies deep in intron 4, outside the exons and flanking splice sites that exome sequencing covers; the founding authors state that exome sequencing would not have found it.

Show evidence (2 references)

PMID:22683087 SUPPORT Human Clinical

"the causal mutation in the index family would never have been identified if the affected individuals' samples had been directly subjected to exome sequencing."

The authors' own statement that exome sequencing would have missed the causal variant.

PMID:26238249 SUPPORT Human Clinical

"In this context, material for genetic analysis was obtained and sequencing of TMEM165 showed homozygosity for the same mutation as previously found in the sibling."

Prenatal molecular diagnosis from amniotic fluid in a family with a known variant.

📊

Prevalence

1

Worldwide, published case reports

Cases In Literature Ultra Rare

A 2024 review counts six published patients carrying five different variants. It does not include the p.Ala310Pro patient reported in 2024 or count both affected E108G siblings separately, so the literature total is somewhat higher but still in single figures.

Show evidence (1 reference)

PMID:39002685 SUPPORT REVIEW SYNTHESIS Other

"Hitherto, 6 patients with TMEM165-CDG were described bearing 5 different mutations."

The review's literature count, which is the only published tally.

🔬

Clinical Trials

1

NCT02955264 NOT_APPLICABLE COMPLETED

Pilot study of oral D-galactose in congenital disorders of glycosylation, under which the two TMEM165-CDG patients of the 2017 galactose study were treated.

Show evidence (2 references)

clinicaltrials:NCT02955264 SUPPORT Other

"The investigators aim to assess the safety and tolerability of oral galactose treatment in a small pilot group of Congenital Disorders of Glycosylation patients."

The registered aim of the trial.

PMID:28323990 SUPPORT Human Clinical

"The protocol was approved by the institutional review board (IRB; Tulane University Hayward Genetics Center IRB no. 517339-4; Clinicaltrials.gov NCT02955264)."

Links the TMEM165-CDG galactose treatment to this registration.

🧫

Experimental Models

2

TMEM165 knockout ATDC5 chondrocytic cells CELL_LINE

Organism

Mus musculus NCBITaxon:10090

Cell source

CRISPR-Cas9 knockout of Tmem165 in the mouse prechondrocytic ATDC5 line

Publication

PMID:34930890

Pathograph links

Impaired Glycosaminoglycan Chain Elongation recapitulates fidelity: moderate observes: molecular Shorter chondroitin- and heparan-sulfate chains, rescued by Mn2+.

Limitations: Mouse cell line in culture; the glycosaminoglycan defect has not been measured in patient cartilage.

Show evidence (1 reference)

PMID:34930890 SUPPORT In Vitro

"Supplementation of cell with Mn2+ rescue the elongation process, confirming a role of TMEM165 in Mn2+ Golgi homeostasis."

The defect and its rescue in this model.

Premature Chondrocyte Maturation and Hypertrophy recapitulates fidelity: moderate observes: cellular Early Ihh expression and premature hypertrophic differentiation.

Limitations: Differentiation of a cell line in monolayer culture is a proxy for growth plate behaviour, not a growth plate.

Show evidence (1 reference)

PMID:34930890 SUPPORT In Vitro

"Finally, we found that loss of TMEM165 impairs chondrogenic differentiation by accelerating the timing of Ihh expression and promoting early chondrocyte maturation and hypertrophy."

The differentiation phenotype of this model.

TMEM165 knockout HEK293 cells CELL_LINE

Organism

Homo sapiens NCBITaxon:9606

Cell source

CRISPR-Cas9 TMEM165 knockout of the HEK293 line

Publication

PMID:28323990

Pathograph links

Hypogalactosylation and Hyposialylation of N-Glycans recapitulates fidelity: moderate observes: molecular Severe N-glycan hypogalactosylation, corrected by Mn2+ or by galactose.

Limitations: Kidney-derived transformed cell line; the defect is more severe than the slight galactosylation defect seen in patient serum.

Show evidence (1 reference)

PMID:28323990 SUPPORT In Vitro

"We analyzed N-linked glycans and glycolipids in knockout TMEM165 HEK293 cells, revealing severe hypogalactosylation and GalNAc transfer defects."

The N-glycan phenotype of the model.

Truncation of Mucin-Type O-Glycans recapitulates fidelity: moderate observes: molecular Truncated mucin-type O-glycans, corrected by Mn2+ but not galactose.

Limitations: The patient O-glycan data are inconsistent between reports, so it is not settled how representative this is.

Show evidence (1 reference)

PMID:35693943 SUPPORT In Vitro

"Interestingly, a similar VVL staining was observed in TMEM165 KO HEK cells (Supplementary Figure S1A), demonstrating the significant presence of truncated O-linked mucin type glycans in TMEM165-deficient cells."

The O-glycan phenotype of the model.

🐁

Animal Models

2

Zebrafish tmem165 morphant

Morpholino knockdown of tmem165 in zebrafish embryos causes craniofacial cartilage malformation with fewer chondrocytes, reduced chondroitin sulfate staining, altered chondrocyte and osteoblast differentiation markers, and altered N-glycan processing. Co-injection of wild-type mRNA partly rescues the cartilage phenotype.

Species

Danio rerio

Genotype

tmem165 morpholino knockdown

Publication

PMID:25609749

Pathograph links

Premature Chondrocyte Maturation and Hypertrophy partially recapitulates fidelity: moderate observes: tissue Reproduces a cartilage developmental defect with altered chondrocyte and osteoblast differentiation.

Limitations: Transient morpholino knockdown in embryos observed to 4 days post fertilisation, not a stable mutant; the craniofacial cartilages scored are not the long-bone growth plates affected in patients, and the zebrafish finding is fewer chondrocytes rather than the premature hypertrophy seen in mammalian chondrocytic cells.

Show evidence (1 reference)

PMID:25609749 SUPPORT Model Organism

"Inhibition of tmem165 expression in developing zebrafish embryos caused craniofacial abnormalities, largely attributable to fewer chondrocytes."

The cartilage phenotype of the model.

Hypogalactosylation and Hyposialylation of N-Glycans partially recapitulates fidelity: moderate observes: molecular N-glycan changes in morphants parallel some of the patients' serum glycan changes.

Limitations: Whole-embryo glycome rather than serum glycoproteins, and the authors describe the parallel as partial.

Show evidence (1 reference)

PMID:25609749 SUPPORT Model Organism

"Glycomic analysis of tmem165 morphants also revealed altered initiation, processing and extension of N-glycans, paralleling some of the glycosylation changes noted in human patients."

The glycan phenotype of the model.

Mammary-specific Tmem165 knockout mouse

About 85% loss of TMEM165 in the lactating mammary gland reduces lactose synthesis and pup growth, and lowers milk Ca2+ and Mn2+ relative to protein. The only mammalian in vivo model; it addresses Golgi cation supply in a secretory epithelium, not the skeletal or neurological disease.

Species

Mus musculus

Genotype

Tmem165 floxed allele deleted by WAP-Cre in milk-producing alveolar epithelial cells

Publication

PMID:30622138

Pathograph links

Golgi Manganese Insufficiency partially recapitulates fidelity: low observes: organism Shows in vivo that TMEM165 supplies Ca2+ and Mn2+ to the Golgi of a secretory cell.

Limitations: Tissue-restricted, adult, lactation-specific deletion. Golgi Mn2+ is inferred from milk mineral content, and the outcome studied (lactose synthesis) has no counterpart in the human disease.

Show evidence (1 reference)

PMID:30622138 SUPPORT Model Organism

"When normalized to total protein levels, only calcium and manganese levels were significantly lower in the milk from TMEM165-deficient dams than control dams."

The in vivo cation readout.

{ }

Source YAML

click to show

name: TMEM165-Congenital Disorder of Glycosylation
creation_date: "2026-09-28T20:00:00Z"
category: Mendelian
disease_term:
  preferred_term: TMEM165-congenital disorder of glycosylation
  term:
    id: MONDO:0013870
    label: TMEM165-congenital disorder of glycosylation
description: >-
  An autosomal recessive congenital disorder of glycosylation, historically
  CDG-IIk, caused by biallelic variants in TMEM165. The gene encodes a
  multi-pass Golgi membrane protein of the UPF0016 family that moves Ca2+ and
  Mn2+ into the Golgi lumen in exchange for protons. It is not a glycosylation
  enzyme: the disease belongs to the group of CDGs caused by loss of a protein
  that maintains the Golgi ionic environment, and the glycosylation defect is
  secondary to Golgi Mn2+ insufficiency, Mn2+ being the cofactor of the
  beta-1,4-galactosyltransferases and several other Golgi glycosyltransferases.

  The glycan consequence is broad. N-glycans lose galactose and, with it, the
  sialic acid that caps galactose (a type 2 transferrin pattern); mucin-type
  O-glycans, glycosphingolipids and the glycosaminoglycan chains of
  chondroitin- and heparan-sulfate proteoglycans are also affected. The
  glycosaminoglycan defect is the best-supported route to the skeletal
  phenotype, which is what distinguishes this CDG clinically: a
  spondylo-epi-metaphyseal dysplasia with osteoporosis and severe postnatal
  growth failure, alongside psychomotor retardation, hypotonia, joint laxity,
  hepatosplenomegaly, raised transaminases and creatine kinase, reduced
  coagulation factors, recurrent unexplained fever and partial growth hormone
  deficiency. Missense-allele patients can be milder, and the founding
  report's p.Arg126His homozygote had no clear skeletal anomalies, although
  the compound heterozygous p.Arg126Cys/p.Gly304Arg patient in the same
  report did have skeletal abnormalities. A homozygous E108G infant died of
  complications of nephrotic syndrome and renal failure at five months.

  Fewer than ten patients are published. Oral D-galactose partially corrects
  N-glycosylation in patients; in cells, Mn2+ corrects all glycosylation
  classes, and combined Mn2+ and D-galactose therapy has been reported in one
  patient.
synonyms:
- TMEM165-CDG
- CDG-IIk
- CDG2K
- congenital disorder of glycosylation type IIk
- congenital disorder of glycosylation type 2k
- carbohydrate deficient glycoprotein syndrome type IIk
categories:
- Congenital Disorder of Glycosylation
- Disorder of Golgi Homeostasis
parents:
- congenital disorder of glycosylation
- congenital disorder of glycosylation type II
references:
- reference: PMID:22683087
  title: TMEM165 deficiency causes a congenital disorder of glycosylation.
- reference: PMID:23430531
  title: Bone Dysplasia as a Key Feature in Three Patients with a Novel Congenital Disorder of
    Glycosylation (CDG) Type II Due to a Deep Intronic Splice Mutation in TMEM165.
- reference: PMID:28323990
  title: Galactose Supplementation in Patients With TMEM165-CDG Rescues the Glycosylation Defects.
- reference: PMID:26238249
  title: "TMEM165 Deficiency: Postnatal Changes in Glycosylation."
- reference: PMID:34930890
  title: "TMEM165 a new player in proteoglycan synthesis: loss of TMEM165 impairs elongation of
    chondroitin- and heparan-sulfate glycosaminoglycan chains of proteoglycans and triggers early
    chondrocyte differentiation and hypertrophy."
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Biallelic TMEM165 variants: homozygous in the founding sibling pair
    (identified by autozygosity mapping) and in a second sibling pair whose
    parents were both heterozygous carriers; compound heterozygous in one
    patient.
  evidence:
  - reference: PMID:22683087
    reference_title: TMEM165 deficiency causes a congenital disorder of glycosylation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The affected individuals are homozygous for a deep intronic splice mutation in TMEM165."
    explanation: The founding family was solved by autozygosity mapping, and both affected siblings
      are homozygous for the causal variant.
  - reference: PMID:26238249
    reference_title: "TMEM165 Deficiency: Postnatal Changes in Glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The same mutation had been found in a homozygous state in the older sister, both parents
      have been shown to be heterozygous carriers of this mutation."
    explanation: Two homozygous affected siblings with heterozygous carrier parents, the segregation
      pattern of recessive inheritance.
prevalence:
- population: Worldwide, published case reports
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    A 2024 review counts six published patients carrying five different
    variants. It does not include the p.Ala310Pro patient reported in 2024 or
    count both affected E108G siblings separately, so the literature total is
    somewhat higher but still in single figures.
  evidence:
  - reference: PMID:39002685
    reference_title: Insights into molecular and cellular functions of the Golgi calcium/manganese-proton
      antiporter TMEM165.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Hitherto, 6 patients with TMEM165-CDG were described bearing 5 different mutations."
    explanation: The review's literature count, which is the only published tally.
genetic:
- name: TMEM165
  gene_term:
    preferred_term: TMEM165
    term:
      id: hgnc:30760
      label: TMEM165
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    Also known as TPARL. Two mechanistic classes of allele are published. The
    deep intronic c.792+182G>A variant, found homozygous in three Georgian
    Jewish patients, activates a cryptic splice donor and almost abolishes
    full-length protein; these patients have the full skeletal phenotype. The
    missense alleles (p.Arg126His, p.Arg126Cys, p.Gly304Arg, p.Glu108Gly,
    p.Ala310Pro) reduce protein stability, shift the protein toward lysosomes
    (Arg126) or disrupt the conserved E-phi-G-D-[KR]-[TS] cation-binding motif
    (Glu108; Gly304 indirectly). The original report's summary states that
    the missense-allele patients were milder and lacked the skeletal
    phenotype, but its own case descriptions separate them: the p.Arg126His
    homozygote (case 4) had no clear skeletal anomalies, while the
    p.Arg126Cys/p.Gly304Arg compound heterozygote (case 5) had osteoporosis,
    vertebral dysplasia and kyphoscoliosis. Later missense patients
    (p.Ala310Pro) had a predominant bone phenotype, so the genotype-phenotype
    relationship is not settled.
  variants:
  - name: c.792+182G>A (deep intronic, cryptic splice donor)
    description: >-
      Homozygous in the founding sibling pair and one unrelated patient of the
      same origin. Activates a cryptic donor, replacing exon 4 with a 117 bp
      intronic sequence; the aberrant transcript is degraded and full-length
      protein is barely detectable.
    evidence:
    - reference: PMID:22683087
      reference_title: TMEM165 deficiency causes a congenital disorder of glycosylation.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The mutation activates a cryptic splice donor site, which leads to two different
        transcripts: the wild-type one and an additional one resulting in the replacement of exon 4
        with a 117 bp intronic sequence"
      explanation: The splice consequence of the variant, established on patient cDNA.
  - name: c.377G>A p.(Arg126His) and c.376C>T p.(Arg126Cys)
    description: >-
      Two substitutions of the same conserved arginine, found homozygous
      (Arg126His, consanguineous Turkish family) and compound heterozygous with
      p.Gly304Arg (Arg126Cys).
    evidence:
    - reference: PMID:22683087
      reference_title: TMEM165 deficiency causes a congenital disorder of glycosylation.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "P4 is homozygous for the G>A transition at position c.377, and P5 is compound
        heterozygous for the C>T transition at position 376 and the G>A transition at position 910."
      explanation: The homozygous Arg126His genotype and the compound heterozygous Arg126Cys/Gly304Arg
        genotype, at nucleotide level.
  - name: c.323A>G p.(Glu108Gly)
    description: >-
      Homozygous in two siblings of a consanguineous family, both of whom died
      in infancy; the second had nephrotic syndrome and congenital heart
      defects. The substitution sits in the conserved cytosolic ELGDK motif and
      significantly reduces transport activity.
    evidence:
    - reference: PMID:26238249
      reference_title: "TMEM165 Deficiency: Postnatal Changes in Glycosylation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Sequence analysis of TMEM165 showed homozygosity for the missense mutation c.323 A>G
        (p.E108G) in exon 2."
      explanation: The genotype of the E108G patient.
    - reference: PMID:32047108
      reference_title: The human Golgi protein TMEM165 transports calcium and manganese in yeast and bacterial
        cells.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "We found that a mutation leading to a E108G substitution within the conserved UPF0016
        family motif significantly reduces TMEM165 activity."
      explanation: Functional evidence that the allele is hypomorphic for transport.
  - name: c.928G>C p.(Ala310Pro)
    description: >-
      Homozygous in one patient diagnosed at two months with a predominant bone
      phenotype; the protein is functional but unstable.
    evidence:
    - reference: PMID:38013006
      reference_title: Efficacy of oral manganese and D-galactose therapy in a patient bearing a novel TMEM165
        variant.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The unreported homozygous missense c.928G>C; p.Ala310Pro variant leading to a
        functional but unstable protein was identified."
      explanation: The genotype and its protein-level consequence.
  evidence:
  - reference: PMID:22683087
    reference_title: TMEM165 deficiency causes a congenital disorder of glycosylation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In our cohort of unsolved CDG-II cases, we found another individual with the same
      mutation and two unrelated individuals with missense mutations in TMEM165."
    explanation: Independent families carrying TMEM165 variants, which is what establishes the
      gene-disease relationship beyond the founding pedigree.
  - reference: PMID:22683087
    reference_title: TMEM165 deficiency causes a congenital disorder of glycosylation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Interestingly, the individuals harboring missense mutations have a milder disease and
      lack the skeletal phenotype."
    explanation: The founding report's summary of its two missense-allele patients. Its own case
      descriptions qualify it (case 5 had skeletal abnormalities; see the Osteoporosis and
      Kyphoscoliosis phenotypes), so this is kept as the authors' generalisation, not as an
      established genotype-phenotype rule.
pathophysiology:
- name: TMEM165 Biallelic Loss of Function
  biological_scale: MOLECULAR
  description: >-
    The initiating lesion. The deep intronic splice variant leaves only traces
    of full-length TMEM165, and the missense variants reduce protein stability,
    mislocalise the protein, or disrupt its cation-binding motif. The common
    outcome is too little functional TMEM165 in the trans-Golgi, where it
    normally colocalises with beta-1,4-galactosyltransferase.
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
  genes:
  - preferred_term: TMEM165
    term:
      id: hgnc:30760
      label: TMEM165
  molecular_functions:
  - preferred_term: manganese ion transmembrane transporter activity
    modifier: DECREASED
    term:
      id: GO:0005384
      label: manganese ion transmembrane transporter activity
  - preferred_term: calcium:proton antiporter activity
    modifier: DECREASED
    term:
      id: GO:0015369
      label: calcium:proton antiporter activity
  cellular_components:
  - preferred_term: trans-Golgi network
    term:
      id: GO:0005802
      label: trans-Golgi network
  evidence:
  - reference: PMID:22683087
    reference_title: TMEM165 deficiency causes a congenital disorder of glycosylation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "As shown in Figure 5B, an extremely low level of full-length TMEM165 was detected in
      affected individuals with the truncating mutation."
    explanation: Protein-level consequence of the splice variant, measured in patient fibroblasts.
  - reference: PMID:22683087
    reference_title: TMEM165 deficiency causes a congenital disorder of glycosylation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Moreover, only 25% of the immunoreactivity was recovered in case 4 with the missense
      mutation, suggesting that the mutant protein is also unstable"
    explanation: The missense allele also lowers the amount of TMEM165, so both allele classes
      converge on deficiency.
  - reference: PMID:22683087
    reference_title: TMEM165 deficiency causes a congenital disorder of glycosylation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These results suggest that TMEM165 is present in the late Golgi (trans) rather than in
      the early Golgi (cis and median)."
    explanation: Places the protein in the compartment where terminal galactosylation and
      sialylation happen.
  downstream:
  - target: Loss of Golgi Calcium and Manganese Import
    causal_link_type: DIRECT
    description: Less functional TMEM165 means less Ca2+/Mn2+-proton exchange across the Golgi
      membrane.
    evidence:
    - reference: PMID:32047108
      reference_title: The human Golgi protein TMEM165 transports calcium and manganese in yeast and bacterial
        cells.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "We found that a mutation leading to a E108G substitution within the conserved UPF0016
        family motif significantly reduces TMEM165 activity."
      explanation: A patient allele measured directly in a transport assay, linking the lesion to the
        loss of transport activity.
  - target: Golgi Structural Disorganisation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Patient fibroblasts have a dilated Golgi and fragmented trans-Golgi network; the
      route from TMEM165 loss to this morphology is not established.
- name: Loss of Golgi Calcium and Manganese Import
  biological_scale: MOLECULAR
  description: >-
    TMEM165 and its yeast orthologue Gdt1p are secondary transporters that
    import Ca2+ and Mn2+ into the Golgi lumen in exchange for protons. Direct
    transport of both cations by human TMEM165 was shown in yeast and bacterial
    expression systems, and Gdt1p has a higher affinity for Ca2+ than for Mn2+.
    Loss of TMEM165 removes this import route.
  molecular_functions:
  - preferred_term: manganese ion transmembrane transporter activity
    modifier: DECREASED
    term:
      id: GO:0005384
      label: manganese ion transmembrane transporter activity
  - preferred_term: calcium:proton antiporter activity
    modifier: DECREASED
    term:
      id: GO:0015369
      label: calcium:proton antiporter activity
  cellular_components:
  - preferred_term: Golgi membrane
    term:
      id: GO:0000139
      label: Golgi membrane
  evidence:
  - reference: PMID:32047108
    reference_title: The human Golgi protein TMEM165 transports calcium and manganese in yeast and bacterial
      cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Using bacterial cells loaded with the fluorescent Fura-2 probe, we further obtained
      direct biochemical evidence that TMEM165 mediates Ca2+ and Mn2+ influxes."
    explanation: Direct transport measurement for the human protein.
  - reference: PMID:27075443
    reference_title: Yeast Gdt1 is a Golgi-localized calcium transporter required for stress-induced
      calcium signaling and protein glycosylation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We observed a Ca(2+) uptake activity in cells expressing GDT1, which was dependent on
      the external pH, indicating that Gdt1p may act as a Ca(2+)/H(+) antiporter."
    explanation: The pH dependence of transport by the yeast orthologue is the basis for describing
      the family as cation/proton antiporters.
  - reference: PMID:29632074
    reference_title: The yeast protein Gdt1p transports Mn(2+) ions and thereby regulates manganese
      homeostasis in the Golgi.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Using Mn2+-induced quenching of Fura-2-emitted fluorescence, we observed that Gdt1p
      mediates Mn2+ influx, in addition to its previously reported regulation of Ca2+ influx."
    explanation: Direct Mn2+ transport by the yeast orthologue, measured in Lactococcus lactis.
  downstream:
  - target: Golgi Manganese Insufficiency
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:27008884
      reference_title: Glycosylation abnormalities in Gdt1p/TMEM165 deficient cells result from a defect
        in Golgi manganese homeostasis.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "This study not only provides novel insights into the molecular causes of glycosylation
        defects observed in TMEM165-deficient cells but also suggest that TMEM165 is a key determinant
        for the regulation of Golgi Mn(2+) homeostasis."
      explanation: Places TMEM165 upstream of Golgi Mn2+ homeostasis in TMEM165-depleted mammalian
        cells and gdt1-null yeast.
  - target: Golgi Calcium and pH Imbalance
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:23569283
      reference_title: Newly characterized Golgi-localized family of proteins is involved in calcium
        and pH homeostasis in yeast and human cells.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Furthermore, defects in TMEM165 affected both Ca(2+) and pH homeostasis."
      explanation: Loss of TMEM165 perturbs both Golgi-relevant Ca2+ handling and pH.
- name: Golgi Manganese Insufficiency
  biological_scale: CELLULAR
  description: >-
    The Golgi lumen is left short of Mn2+, the cofactor of the
    beta-1,4-galactosyltransferases, GalNAc transferases and the
    glycosaminoglycan chain-elongating enzymes. This is the node the rest of
    the glycosylation chain turns on, and it is supported by rescue: adding
    Mn2+ to TMEM165-deficient mammalian cells or gdt1-null yeast restores
    glycosylation. Blood manganese was normal in the two patients measured, so
    the deficit is compartmental rather than systemic. SERCA2 can partly
    supply Golgi Mn2+ when TMEM165 is absent.
  biological_processes:
  - preferred_term: Golgi manganese ion homeostasis
    modifier: DYSREGULATED
    term:
      id: GO:0030026
      label: intracellular manganese ion homeostasis
  cellular_components:
  - preferred_term: Golgi apparatus
    term:
      id: GO:0005794
      label: Golgi apparatus
  evidence:
  - reference: PMID:27008884
    reference_title: Glycosylation abnormalities in Gdt1p/TMEM165 deficient cells result from a defect
      in Golgi manganese homeostasis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We discovered that in both yeasts and mammalian Gdt1p/TMEM165-deficient cells, Mn(2+)
      supplementation could restore a normal glycosylation."
    explanation: Rescue by the missing cofactor is the main evidence that Mn2+ shortage, not another
      Golgi defect, drives the glycosylation phenotype.
  - reference: PMID:39002685
    reference_title: Insights into molecular and cellular functions of the Golgi calcium/manganese-proton
      antiporter TMEM165.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Impaired glycosylation of TMEM165-CDG arises from a lack of Mn2+ within the Golgi.
      Nevertheless, Mn2+ insufficiency in the Golgi is compensated by the activity of the ATPase
      SERCA2."
    explanation: The review's synthesis of the mechanism, including partial compensation by SERCA2.
  - reference: PMID:28323990
    reference_title: Galactose Supplementation in Patients With TMEM165-CDG Rescues the Glycosylation
      Defects.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Manganese levels were normal in blood samples."
    explanation: Blood Mn2+ was normal in the two patients, consistent with a Golgi-compartment rather
      than whole-body deficit.
  downstream:
  - target: Impaired Manganese-Dependent Golgi Glycosyltransferase Activity
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:28323990
      reference_title: Galactose Supplementation in Patients With TMEM165-CDG Rescues the Glycosylation
        Defects.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: BACKGROUND
      snippet: "This indicated that a lack of TMEM165 impairs the function of β-1,4-galactosyltransferase,
        a Mn2+ Golgi-dependent glycosyltransferase required for the biosynthesis of sialylated complex
        N-glycan structures"
      explanation: Links TMEM165 loss to the Mn2+-dependent galactosyltransferase step specifically;
        the sentence summarises the group's earlier knockout-cell glycan analysis in the paper's
        introduction.
- name: Golgi Calcium and pH Imbalance
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    The earlier functional model: TMEM165 as a Golgi Ca2+/H+ antiporter whose
    loss perturbs Golgi Ca2+ stores and pH. The disturbance is measured, but
    its contribution to the glycosylation defect is proposed rather than
    shown, and the later Mn2+-rescue data place most of that defect on the
    manganese arm. Kept as a separate branch so the two models are not merged.
  biological_processes:
  - preferred_term: Golgi calcium ion homeostasis
    modifier: DYSREGULATED
    term:
      id: GO:0032468
      label: Golgi calcium ion homeostasis
  evidence:
  - reference: PMID:23569283
    reference_title: Newly characterized Golgi-localized family of proteins is involved in calcium and
      pH homeostasis in yeast and human cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Based on these results, we propose that Gdt1p and TMEM165 could be members of a unique
      family of Golgi-localized Ca(2+)/H(+) antiporters and that modification of the Golgi Ca(2+) and
      pH balance could explain the glycosylation defects observed in TMEM165-deficient patients."
    explanation: States both the measured imbalance and, as a proposal, its link to glycosylation;
      the hedge is why this branch is PROVISIONAL.
  downstream:
  - target: Impaired Manganese-Dependent Golgi Glycosyltransferase Activity
    causal_link_type: UNKNOWN
    description: Proposed contribution of altered Golgi Ca2+ and pH to the glycosylation defect; not
      separated experimentally from the Mn2+ effect.
- name: Golgi Structural Disorganisation
  biological_scale: CELLULAR
  description: >-
    Dilated Golgi cisternae and a fragmented trans-Golgi network in fibroblasts
    from all five original patients. Recorded as an observed cellular state;
    whether it is a cause or a consequence of the ionic and glycosylation
    defects is not known.
  biological_processes:
  - preferred_term: Golgi organization
    modifier: ABNORMAL
    term:
      id: GO:0007030
      label: Golgi organization
  evidence:
  - reference: PMID:22683087
    reference_title: TMEM165 deficiency causes a congenital disorder of glycosylation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Compared to that in controls, the Golgi apparatus in all affected individuals was found
      dilated, and the trans-Golgi network was markedly fragmented"
    explanation: The morphological finding in patient fibroblasts.
- name: Impaired Manganese-Dependent Golgi Glycosyltransferase Activity
  biological_scale: MOLECULAR
  description: >-
    Without enough luminal Mn2+, the Mn2+-dependent Golgi glycosyltransferases
    underperform. The best characterised is beta-1,4-galactosyltransferase
    (N-acetyllactosamine synthase), but GalNAc transfer onto glycolipids and
    the polymerising enzymes of glycosaminoglycan chains are also cofactor
    limited. The enzymes themselves are intact, which is why Mn2+ or, for the
    galactosylation step only, extra galactose substrate can rescue.
  molecular_functions:
  - preferred_term: beta-1,4-galactosyltransferase activity
    modifier: DECREASED
    term:
      id: GO:0003945
      label: N-acetyllactosamine synthase activity
  evidence:
  - reference: PMID:28323990
    reference_title: Galactose Supplementation in Patients With TMEM165-CDG Rescues the Glycosylation
      Defects.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "This shows that TMEM165 deficiency not only impairs the activities of Golgi
      galactosyltransferases but also those of Golgi GalNAc transferases."
    explanation: Establishes that more than one Mn2+-dependent transferase class is affected, from
      glycolipid analysis in TMEM165 knockout HEK293 cells.
  - reference: PMID:34930890
    reference_title: "TMEM165 a new player in proteoglycan synthesis: loss of TMEM165 impairs elongation
      of chondroitin- and heparan-sulfate glycosaminoglycan chains of proteoglycans and triggers early
      chondrocyte differentiation and hypertrophy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We demonstrated that the blockage in elongation of glycosaminoglycan chains is not due
      to defect in the Golgi elongating enzymes but rather to availability of the co-factor Mn2+."
    explanation: The same cofactor limitation applies to glycosaminoglycan chain polymerisation.
  downstream:
  - target: Hypogalactosylation and Hyposialylation of N-Glycans
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:28323990
      reference_title: Galactose Supplementation in Patients With TMEM165-CDG Rescues the Glycosylation
        Defects.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "We analyzed N-linked glycans and glycolipids in knockout TMEM165 HEK293 cells,
        revealing severe hypogalactosylation and GalNAc transfer defects."
      explanation: The glycan consequence of the transferase deficit in an isogenic knockout.
  - target: Truncation of Mucin-Type O-Glycans
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:35693943
      reference_title: Differential Effects of D-Galactose Supplementation on Golgi Glycosylation Defects
        in TMEM165 Deficiency.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Whereas MnCl2 supplementation unambiguously fully rescues the N- and O-linked as well as
        GAG glycosylations in TMEM165-deficient cells, D-Gal supplementation only rescues the N-linked
        glycosylation, without any effects on the other Golgi-related glycosylation types."
      explanation: Mn2+ rescue of the O-glycan defect places it downstream of the cofactor-limited
        transferases.
  - target: Defective Glycosphingolipid Glycosylation
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:28323990
      reference_title: Galactose Supplementation in Patients With TMEM165-CDG Rescues the Glycosylation
        Defects.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "In TMEM165 KO cells, Mn2+ supplementation completely rescued the transfer of both Gal and
        GalNAc on glycolipids, whereas the galactose treatment only rescued the transfer of galactose
        residues on glycolipids."
      explanation: Shows the glycolipid defect is the product of both Gal and GalNAc transfer deficits
        and is Mn2+-reversible.
  - target: Impaired Glycosaminoglycan Chain Elongation
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34930890
      reference_title: "TMEM165 a new player in proteoglycan synthesis: loss of TMEM165 impairs
        elongation of chondroitin- and heparan-sulfate glycosaminoglycan chains of proteoglycans and
        triggers early chondrocyte differentiation and hypertrophy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Supplementation of cell with Mn2+ rescue the elongation process, confirming a role of
        TMEM165 in Mn2+ Golgi homeostasis."
      explanation: Mn2+ rescue of chain elongation ties the glycosaminoglycan defect to the cofactor
        shortage.
- name: Hypogalactosylation and Hyposialylation of N-Glycans
  biological_scale: MOLECULAR
  description: >-
    Serum and cellular N-glycans are undergalactosylated and, because sialic
    acid is added onto galactose, undersialylated. In patient serum this is
    seen as a type 2 transferrin isoelectric focusing pattern and as
    accumulation of glycans lacking galactose and sialic acid by mass
    spectrometry. In the one patient followed from birth, the defect was
    already present on day one and worsened over the first weeks.
  biological_processes:
  - preferred_term: protein N-linked glycosylation
    modifier: DECREASED
    term:
      id: GO:0006487
      label: protein N-linked glycosylation
  evidence:
  - reference: PMID:22683087
    reference_title: TMEM165 deficiency causes a congenital disorder of glycosylation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The presence of these abnormal ions points to a slight defect in both sialylation and
      galactosylation and corroborates the IEF data."
    explanation: Serum N-glycan mass spectrometry in the original patients.
  - reference: PMID:23430531
    reference_title: Bone Dysplasia as a Key Feature in Three Patients with a Novel Congenital Disorder
      of Glycosylation (CDG) Type II Due to a Deep Intronic Splice Mutation in TMEM165.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Serum transferrin glycan analysis shows an increase of the biantennary glycan lacking
      sialic acid, and an abnormal biantennary glycan lacking sialic acid and galactose."
    explanation: Transferrin-specific glycan structures showing the galactose and sialic acid loss.
  - reference: PMID:26238249
    reference_title: "TMEM165 Deficiency: Postnatal Changes in Glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Within the next few weeks, hypoglycosylation progressed to less sialylated and then also
      to hypogalactosylated isoforms."
    explanation: The postnatal course of the defect in the E108G patient.
  downstream:
  - target: Type II transferrin isoform profile
    causal_link_type: DIRECT
    description: The type 2 transferrin pattern is the serum readout of this glycan defect.
  - target: Multisystem Hypoglycosylation
    causal_link_type: DIRECT
- name: Truncation of Mucin-Type O-Glycans
  biological_scale: MOLECULAR
  description: >-
    Mucin-type O-glycans are truncated. In patients this was read from a
    cathodal shift of apolipoprotein C-III on isoelectric focusing and from
    truncated apoC-III by mass spectrometry; in knockout cells as exposed
    GalNAc (Tn) structures. The evidence is not uniform: the founding report
    found normal serum O-glycans and a normal apoC-III profile in its
    patients, while the detailed clinical report on three of the same-genotype
    patients found the apoC-III shift. D-galactose does not correct this arm
    in cells.
  biological_processes:
  - preferred_term: protein O-linked glycosylation
    modifier: DECREASED
    term:
      id: GO:0006493
      label: protein O-linked glycosylation
  evidence:
  - reference: PMID:23430531
    reference_title: Bone Dysplasia as a Key Feature in Three Patients with a Novel Congenital Disorder
      of Glycosylation (CDG) Type II Due to a Deep Intronic Splice Mutation in TMEM165.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Diagnostic work-up revealed a type 2 serum transferrin isoelectrofocusing (IEF) pattern
      and a cathodal shift on apolipoprotein C-III IEF pointing to a combined N- and O-glycosylation
      defect."
    explanation: The apoC-III finding in three homozygous c.792+182G>A patients.
  - reference: PMID:26238249
    reference_title: "TMEM165 Deficiency: Postnatal Changes in Glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mass spectrometry of apolipoprotein C3 (MALDI-TOF MS) showed an increasing proportion of
      truncated and unglycosylated apoprotein C3 as a marker for a defect in O-glycosylation."
    explanation: The same finding by mass spectrometry in the E108G patient.
  - reference: PMID:35693943
    reference_title: Differential Effects of D-Galactose Supplementation on Golgi Glycosylation Defects
      in TMEM165 Deficiency.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Interestingly, a similar VVL staining was observed in TMEM165 KO HEK cells (Supplementary
      Figure S1A), demonstrating the significant presence of truncated O-linked mucin type glycans in
      TMEM165-deficient cells."
    explanation: Truncated O-glycans in an isogenic knockout.
  - reference: PMID:22683087
    reference_title: TMEM165 deficiency causes a congenital disorder of glycosylation.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "These results are consistent with the normal ApoC-III profile and prove the absence of an
      O-glycan defect."
    explanation: The founding report found no serum O-glycan defect in its patients, contradicting a
      constant O-glycosylation defect; recorded as a separate refuting item.
  downstream:
  - target: Multisystem Hypoglycosylation
    causal_link_type: DIRECT
- name: Defective Glycosphingolipid Glycosylation
  biological_scale: MOLECULAR
  description: >-
    Complex gangliosides are almost absent from TMEM165 knockout cells, which
    retain only traces of GM3 and GM2. Shown in cells only; lipid
    glycosylation has not been measured in patient tissue.
  biological_processes:
  - preferred_term: ganglioside biosynthetic process
    modifier: DECREASED
    term:
      id: GO:0001574
      label: ganglioside biosynthetic process
  evidence:
  - reference: PMID:28323990
    reference_title: Galactose Supplementation in Patients With TMEM165-CDG Rescues the Glycosylation
      Defects.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Although control cells expressed a complex pattern of GSLs, including GM3 (m/z
      1372/1484), GM2 (m/z 1617/1729), GM1 (m/z 1821/1933), GD2 (m/z 1978/2090), and GD1 (m/z
      2182/2294) species, KO TMEM165 HEK293 cells only showed traces of GM3 and GM2 species"
    explanation: The ganglioside profile of knockout cells against controls.
  downstream:
  - target: Multisystem Hypoglycosylation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Which, if any, clinical features depend on the glycolipid defect is not known.
- name: Impaired Glycosaminoglycan Chain Elongation
  biological_scale: MOLECULAR
  description: >-
    Chondroitin- and heparan-sulfate chains on proteoglycans are shorter
    because chain polymerisation stalls. Shown in TMEM165 knockout mouse
    prechondrocytic ATDC5 cells and HEK293 cells; a combined N-, O- and
    glycosaminoglycan glycosylation defect was also reported in the
    p.Ala310Pro patient.
  biological_processes:
  - preferred_term: chondroitin sulfate proteoglycan biosynthetic process
    modifier: DECREASED
    term:
      id: GO:0050650
      label: chondroitin sulfate proteoglycan biosynthetic process
  - preferred_term: heparan sulfate proteoglycan biosynthetic process
    modifier: DECREASED
    term:
      id: GO:0015012
      label: heparan sulfate proteoglycan biosynthetic process
  cell_types:
  - preferred_term: chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  evidence:
  - reference: PMID:34930890
    reference_title: "TMEM165 a new player in proteoglycan synthesis: loss of TMEM165 impairs elongation
      of chondroitin- and heparan-sulfate glycosaminoglycan chains of proteoglycans and triggers early
      chondrocyte differentiation and hypertrophy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Here, we uncover that TMEM165 deficiency impairs the synthesis of proteoglycans by
      producing a blockage in the elongation of chondroitin-and heparan-sulfate glycosaminoglycan chains
      leading to the synthesis of proteoglycans with shorter glycosaminoglycan chains."
    explanation: The primary finding in knockout chondrocytic cells.
  - reference: PMID:38013006
    reference_title: Efficacy of oral manganese and D-galactose therapy in a patient bearing a novel TMEM165
      variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This patient was diagnosed at 2 months and displays a predominant bone phenotype and
      combined defects in N-, O- and GAG glycosylation."
    explanation: A glycosaminoglycan defect observed in a patient, not only in cells.
  downstream:
  - target: Dysregulated TGF-beta and BMP Signaling in Chondrocytes
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34930890
      reference_title: "TMEM165 a new player in proteoglycan synthesis: loss of TMEM165 impairs
        elongation of chondroitin- and heparan-sulfate glycosaminoglycan chains of proteoglycans and
        triggers early chondrocyte differentiation and hypertrophy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Blockage in the elongation of GAG chains by loss of TMEM165 may account for dysregulation
        of TGF/BMP and Ihh signaling, and therefore in defects in chondrocyte differentiation and
        maturation."
      explanation: The authors' proposed link, stated with "may"; the edge is supported by
        co-occurrence in the same knockout cells rather than by a chain-length-specific rescue.
- name: Dysregulated TGF-beta and BMP Signaling in Chondrocytes
  biological_scale: CELLULAR
  description: >-
    TGF-beta signalling is reduced (lower TGFBR2, reduced Smad2
    phosphorylation, also in patient fibroblasts) while BMP signalling is
    increased (four-fold reporter activity, higher BMP receptor expression) in
    TMEM165-deficient chondrocytic cells. Proteoglycan glycosaminoglycan chains
    act as co-receptors and reservoirs for these growth factors.
  biological_processes:
  - preferred_term: transforming growth factor beta receptor signaling pathway
    modifier: DECREASED
    term:
      id: GO:0007179
      label: transforming growth factor beta receptor signaling pathway
  - preferred_term: BMP signaling pathway
    modifier: INCREASED
    term:
      id: GO:0030509
      label: BMP signaling pathway
  cell_types:
  - preferred_term: chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  evidence:
  - reference: PMID:34930890
    reference_title: "TMEM165 a new player in proteoglycan synthesis: loss of TMEM165 impairs elongation
      of chondroitin- and heparan-sulfate glycosaminoglycan chains of proteoglycans and triggers early
      chondrocyte differentiation and hypertrophy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Additionally, we showed that TMEM165 deficiency functionally impairs TGFβ and BMP signaling
      pathways in chondrocytes and in fibroblast cells of TMEM165 deficient patients."
    explanation: Signalling abnormality in knockout chondrocytes and in patient fibroblasts.
  - reference: PMID:34930890
    reference_title: "TMEM165 a new player in proteoglycan synthesis: loss of TMEM165 impairs elongation
      of chondroitin- and heparan-sulfate glycosaminoglycan chains of proteoglycans and triggers early
      chondrocyte differentiation and hypertrophy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "analysis of luciferase activity showed a significant increase (4-fold) in tmem165-knockout
      ATDC5 cells, compared to wild-type cells thus bringing evidence that BMP signaling is increased in
      tmem165-mutant cells."
    explanation: Gives the direction for the BMP arm, which is increased rather than impaired.
  downstream:
  - target: Premature Chondrocyte Maturation and Hypertrophy
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34930890
      reference_title: "TMEM165 a new player in proteoglycan synthesis: loss of TMEM165 impairs
        elongation of chondroitin- and heparan-sulfate glycosaminoglycan chains of proteoglycans and
        triggers early chondrocyte differentiation and hypertrophy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "our findings indicate that TMEM165 deficiency causes abnormalities in PG synthesis and
        aberrant signaling resulting in early chondrocyte maturation and hypertrophy."
      explanation: The authors' summary of the signalling-to-differentiation step.
- name: Premature Chondrocyte Maturation and Hypertrophy
  biological_scale: CELLULAR
  description: >-
    TMEM165-deficient chondrocytic cells switch on Indian hedgehog early and
    mature and hypertrophy prematurely. In zebrafish morphants the cartilage
    elements are misshapen and contain fewer chondrocytes, with altered
    chondrocyte and osteoblast differentiation markers.
  biological_processes:
  - preferred_term: chondrocyte hypertrophy
    modifier: INCREASED
    term:
      id: GO:0003415
      label: chondrocyte hypertrophy
  cell_types:
  - preferred_term: chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  evidence:
  - reference: PMID:34930890
    reference_title: "TMEM165 a new player in proteoglycan synthesis: loss of TMEM165 impairs elongation
      of chondroitin- and heparan-sulfate glycosaminoglycan chains of proteoglycans and triggers early
      chondrocyte differentiation and hypertrophy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Finally, we found that loss of TMEM165 impairs chondrogenic differentiation by
      accelerating the timing of Ihh expression and promoting early chondrocyte maturation and
      hypertrophy."
    explanation: The cellular finding in knockout ATDC5 cells.
  - reference: PMID:25609749
    reference_title: Abnormal cartilage development and altered N-glycosylation in Tmem165-deficient
      zebrafish mirrors the phenotypes associated with TMEM165-CDG.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Decreased expression of several markers of cartilage and bone development suggests that
      Tmem165 deficiency alters both chondrocyte and osteoblast differentiation."
    explanation: In vivo support for disturbed chondrocyte and osteoblast differentiation.
  downstream:
  - target: Disordered Endochondral Ossification
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34930890
      reference_title: "TMEM165 a new player in proteoglycan synthesis: loss of TMEM165 impairs
        elongation of chondroitin- and heparan-sulfate glycosaminoglycan chains of proteoglycans and
        triggers early chondrocyte differentiation and hypertrophy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Altogether, these data bring evidence that TMEM165 deficiency promotes premature
        chondrocyte maturation and hypertrophy, a process which affects endochondral ossification and
        may lead to dwarfism."
      explanation: The authors connect premature hypertrophy to endochondral ossification and
        dwarfism, with an explicit "may".
- name: Disordered Endochondral Ossification
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  description: >-
    The tissue-level step between the cellular growth-plate defect and the
    radiological phenotype. Inferred rather than observed: no bone or growth
    plate histology from a patient or a mammalian model is published, so the
    link rests on the chondrocyte data and the zebrafish cartilage phenotype.
  biological_processes:
  - preferred_term: cartilage development
    modifier: ABNORMAL
    term:
      id: GO:0051216
      label: cartilage development
  evidence:
  - reference: PMID:25609749
    reference_title: Abnormal cartilage development and altered N-glycosylation in Tmem165-deficient
      zebrafish mirrors the phenotypes associated with TMEM165-CDG.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Collectively, these findings highlight the utility of zebrafish to elucidate pathogenic
      mechanisms associated with glycosylation disorders and suggest that the cartilage and bone
      dysplasia manifested in TMEM165-CDG patients may stem from abnormal development of chondrocytes
      and osteoblasts."
    explanation: Model-organism argument that the patients' skeletal dysplasia originates in
      chondrocyte and osteoblast development.
  downstream:
  - target: Spondyloepimetaphyseal dysplasia
    causal_link_type: DIRECT
  - target: Severe short stature
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Growth failure is not corrected by growth hormone even when IGF-I
      normalises, which points to the skeleton rather than the somatotropic
      axis as the limiting factor.
  - target: Kyphoscoliosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Genu varum
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Pectus carinatum
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Osteoporosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Multisystem Hypoglycosylation
  biological_scale: ORGANISM
  mechanism_confidence: HYPOTHETICAL
  description: >-
    The route from the glycan defects to the non-skeletal features. No source
    identifies which hypoglycosylated proteins or lipids mediate the
    neurological, hepatic, muscular, haemostatic, endocrine, renal or cardiac
    manifestations; the attribution is to hypoglycosylation as a class, with
    the exception of the coagulation factors and hormones, which are
    themselves glycoproteins and partly respond to galactose therapy.
  evidence:
  - reference: PMID:28323990
    reference_title: Galactose Supplementation in Patients With TMEM165-CDG Rescues the Glycosylation
      Defects.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TMEM165 deficiency is a severe multisystem disease that manifests with metabolic,
      endocrine, and skeletal involvement."
    explanation: Statement of the organ range this hub stands for.
  - reference: PMID:28323990
    reference_title: Galactose Supplementation in Patients With TMEM165-CDG Rescues the Glycosylation
      Defects.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Galactose supplementation improved several, but not all, laboratory results in our
      patients (Table 1); specifically, coagulation parameters, IGF1, and IGFBP3 were improved in
      patient 1."
    explanation: Partial normalisation of glycoprotein-dependent laboratory values on galactose is the
      nearest thing to evidence that the systemic features follow the glycan defect.
  downstream:
  - target: Global developmental delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Hypotonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Muscle weakness
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Hyporeflexia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Seizure
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Abnormal cerebral white matter morphology
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Ventriculomegaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Anterior pituitary hypoplasia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Joint hypermobility
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Hepatosplenomegaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Elevated circulating hepatic transaminase concentration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Elevated circulating creatine kinase activity
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Abnormality of coagulation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Clotting factors VIII, IX and XI and protein C are glycoproteins; their reduced
      activity and partial response to galactose fit a glycosylation origin, but reduced synthesis
      has not been excluded.
  - target: Decreased response to growth hormone stimulation test
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Recurrent fever
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Feeding difficulties
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Midface retrusion
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Low-set ears
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Strabismus
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Abnormal macular pigmentation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Amelogenesis imperfecta
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Increased body fat percentage
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Delayed puberty
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Nephrotic syndrome
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Ventricular septal defect
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Patent ductus arteriosus
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Patent foramen ovale
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
phenotypes:
- name: Type II transferrin isoform profile
  category: Biochemical
  description: >-
    Increased tri-, di-, mono- and asialotransferrin with decreased tetra- and
    higher sialylated forms on serum transferrin isoelectric focusing, present
    in every reported patient and already on the first day of life in the
    patient followed from birth.
  phenotype_term:
    preferred_term: type 2 serum transferrin isoelectric focusing pattern
    term:
      id: HP:0012301
      label: Type II transferrin isoform profile
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:22683087
    reference_title: TMEM165 deficiency causes a congenital disorder of glycosylation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of CDG-II in these cases was established by standard sTf-IEF showing a
      marked increase of asialotransferrin, monosialotransferrin, disialotransferrin, and
      trisialotransferrin in all cases"
    explanation: Present in all five patients of the founding series, which carries the frequency.
  - reference: PMID:26238249
    reference_title: "TMEM165 Deficiency: Postnatal Changes in Glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Isoelectric focusing (IEF) of transferrin showed a pathological pattern with increased
      amounts of tri-, di-, and monosialotransferrin already in the first blood sample taken 3 min
      after birth."
    explanation: Also present in the E108G patient, from birth.
- name: Global developmental delay
  category: Neurodevelopmental
  description: >-
    Psychomotor retardation, moderate in the c.792+182G>A patients (sitting at
    9 months, walking at 2 years) and severe in patient 3 of that series, who
    at 6 years could not sit unsupported. The p.Arg126His patient functioned at
    a 4-year level at age 9.
  phenotype_term:
    preferred_term: psychomotor retardation
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:23430531
    reference_title: Bone Dysplasia as a Key Feature in Three Patients with a Novel Congenital Disorder
      of Glycosylation (CDG) Type II Due to a Deep Intronic Splice Mutation in TMEM165.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Common clinical features include moderate psychomotor retardation, feeding problems (in
      infancy), facial dysmorphism with low-set ears, hypotonia, joint hyperlaxity, hepatosplenomegaly,
      osteoporosis, and spondylo-, epi- and metaphyseal dysplasia aggravating with age."
    explanation: The features common to all three c.792+182G>A patients; shared by several phenotype
      entries below.
  - reference: PMID:22683087
    reference_title: TMEM165 deficiency causes a congenital disorder of glycosylation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At the age of 9 years, his psychomotor level is that of a 4-year-old."
    explanation: Developmental delay also in a missense-allele patient without skeletal involvement.
- name: Hypotonia
  category: Neuromuscular
  description: >-
    Reported in all three c.792+182G>A patients. The homozygous p.Glu108Gly
    neonate instead had muscular hypertonia with opisthotonic posture, so tone
    abnormality is not uniform across genotypes.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:23430531
    reference_title: Bone Dysplasia as a Key Feature in Three Patients with a Novel Congenital Disorder
      of Glycosylation (CDG) Type II Due to a Deep Intronic Splice Mutation in TMEM165.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Common clinical features include moderate psychomotor retardation, feeding problems (in
      infancy), facial dysmorphism with low-set ears, hypotonia, joint hyperlaxity, hepatosplenomegaly,
      osteoporosis, and spondylo-, epi- and metaphyseal dysplasia aggravating with age."
    explanation: Hypotonia is among the common features of all three patients.
  - reference: PMID:26238249
    reference_title: "TMEM165 Deficiency: Postnatal Changes in Glycosylation."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Neurological examination revealed a large, temporarily tensed fontanel, muscular
      hypertonia with opisthotonic posture, and a sundown position of the eyes."
    explanation: The p.Glu108Gly neonate had increased rather than reduced tone, so hypotonia is not
      a feature of every genotype.
- name: Muscle weakness
  category: Neuromuscular
  description: Muscular weakness and hypotrophy after infancy.
  phenotype_term:
    preferred_term: muscular weakness
    term:
      id: HP:0001324
      label: Muscle weakness
  evidence:
  - reference: PMID:22683087
    reference_title: TMEM165 deficiency causes a congenital disorder of glycosylation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The boy was mainly affected by growth retardation (he was unresponsive to growth hormone,
      which eventually led to severe dwarfism; he is now 19 years old), psychomotor retardation (he
      began independently walking at 2 years of age), midface hypoplasia, muscular weakness, fat
      excess, joint laxity, and hepatosplenomegaly."
    explanation: The index case's clinical summary, which names muscular weakness.
- name: Hyporeflexia
  category: Neurological
  phenotype_term:
    preferred_term: generalized hyporeflexia
    term:
      id: HP:0001265
      label: Hyporeflexia
  evidence:
  - reference: PMID:23430531
    reference_title: Bone Dysplasia as a Key Feature in Three Patients with a Novel Congenital Disorder
      of Glycosylation (CDG) Type II Due to a Deep Intronic Splice Mutation in TMEM165.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "joint “cracking” when walking, and generalized hyporeflexia and hypotonia."
    explanation: Patient 1; patient 2 also had hyporeflexia, while patient 3 had brisk reflexes.
- name: Seizure
  category: Neurological
  description: >-
    Transient epilepsy from 14 months in one patient, responsive to
    levetiracetam and stopped before age three. The authors were uncertain
    whether it is part of the disease.
  phenotype_term:
    preferred_term: transient epilepsy
    term:
      id: HP:0001250
      label: Seizure
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:23430531
    reference_title: Bone Dysplasia as a Key Feature in Three Patients with a Novel Congenital Disorder
      of Glycosylation (CDG) Type II Due to a Deep Intronic Splice Mutation in TMEM165.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Features only present in patient 3 (family 2) were respiratory problems due to unexplained
      restrictive lung pathology and transient epilepsy. It remains uncertain whether these features
      are secondary to the CDG."
    explanation: One of three patients, with the authors' own caveat about attribution.
- name: Abnormal cerebral white matter morphology
  category: Neurological
  phenotype_term:
    preferred_term: white matter abnormalities on brain MRI
    term:
      id: HP:0002500
      label: Abnormal cerebral white matter morphology
  evidence:
  - reference: PMID:23430531
    reference_title: Bone Dysplasia as a Key Feature in Three Patients with a Novel Congenital Disorder
      of Glycosylation (CDG) Type II Due to a Deep Intronic Splice Mutation in TMEM165.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Common findings on brain MRI in patients 1 and 3 were white matter abnormalities and
      absent visualization of the neural pituitary gland."
    explanation: Present in both patients who had brain MRI in this series.
- name: Ventriculomegaly
  category: Neurological
  phenotype_term:
    preferred_term: enlarged cerebral ventricles
    term:
      id: HP:0002119
      label: Ventriculomegaly
  evidence:
  - reference: PMID:26238249
    reference_title: "TMEM165 Deficiency: Postnatal Changes in Glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brain ultrasound showed enlarged lateral and third ventricles."
    explanation: Neonatal finding in the E108G patient; patient 1 of the c.792+182G>A series also had
      enlarged ventricles on MRI.
- name: Anterior pituitary hypoplasia
  category: Endocrine
  description: >-
    Relative hypoplasia of the anterior pituitary and absent posterior
    pituitary bright spot on MRI; the neural pituitary could not be visualised
    in two patients.
  phenotype_term:
    preferred_term: relative hypoplasia of the anterior pituitary
    term:
      id: HP:0010627
      label: Anterior pituitary hypoplasia
  evidence:
  - reference: PMID:23430531
    reference_title: Bone Dysplasia as a Key Feature in Three Patients with a Novel Congenital Disorder
      of Glycosylation (CDG) Type II Due to a Deep Intronic Splice Mutation in TMEM165.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MRI of the brain showed some atrophy, enlarged ventricles, periventricular and subcortical
      white matter abnormalities, as well as relative hypoplasia of the anterior pituitary, and absence
      of the normal hyperintensity of the posterior pituitary."
    explanation: Brain MRI of patient 1.
- name: Decreased response to growth hormone stimulation test
  category: Endocrine
  description: >-
    Partial growth hormone deficiency. Growth hormone treatment normalised
    IGF-I and reduced body fat but did not increase growth velocity.
  phenotype_term:
    preferred_term: partial growth hormone deficiency
    term:
      id: HP:0000824
      label: Decreased response to growth hormone stimulation test
  notes: >-
    HP:0000824 is the HPO class that carries "growth hormone deficiency" as a
    synonym; the sources report partial GH deficiency without naming the
    stimulation test used.
  evidence:
  - reference: PMID:23430531
    reference_title: Bone Dysplasia as a Key Feature in Three Patients with a Novel Congenital Disorder
      of Glycosylation (CDG) Type II Due to a Deep Intronic Splice Mutation in TMEM165.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "After infancy (patients 1 and 3), midface hypoplasia, muscular hypotrophy, fat excess,
      growth retardation, and partial growth hormone deficiency completed this picture."
    explanation: Partial GH deficiency in both surviving patients of the series.
- name: Delayed puberty
  category: Endocrine
  phenotype_term:
    preferred_term: absent puberty at 16 years
    term:
      id: HP:0000823
      label: Delayed puberty
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:23430531
    reference_title: Bone Dysplasia as a Key Feature in Three Patients with a Novel Congenital Disorder
      of Glycosylation (CDG) Type II Due to a Deep Intronic Splice Mutation in TMEM165.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "but not yet of puberty (circulating luteinizing hormone 0.4 IU/L (normal 1.7–8.6 IU/L),
      follicle stimulating hormone 0.3 IU/L (nl 1.2–7.7), total testosterone 25 ng/dL (nl 300–1,000)"
    explanation: One patient, with no puberty and low gonadotropins and testosterone at 16 years.
- name: Spondyloepimetaphyseal dysplasia
  category: Skeletal
  description: >-
    Major spondylo-, epi- and metaphyseal involvement (the founding report adds
    diaphyseal dysplasia): broad metaphyses, irregular epiphyses, thin cortex,
    flattened and beaked vertebrae, aggravating with age. Classified in the
    spondylo-epi-(meta)-physeal dysplasia group of genetic skeletal disorders.
    The founding report's p.Arg126His homozygote (case 4) had no clear
    skeletal anomalies; its p.Arg126Cys/p.Gly304Arg compound heterozygote
    (case 5) had skeletal abnormalities (osteoporosis, vertebral and rib
    dysplasia, kyphoscoliosis) without being described as having the full
    spondylo-epi-metaphyseal pattern.
  phenotype_term:
    preferred_term: spondylo-epi-metaphyseal dysplasia
    term:
      id: HP:0002651
      label: Spondyloepimetaphyseal dysplasia
  evidence:
  - reference: PMID:23430531
    reference_title: Bone Dysplasia as a Key Feature in Three Patients with a Novel Congenital Disorder
      of Glycosylation (CDG) Type II Due to a Deep Intronic Splice Mutation in TMEM165.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three patients belonging to two families presented with a psychomotor-dysmorphism
      syndrome including postnatal growth deficiency and major spondylo-, epi-, and metaphyseal skeletal
      involvement."
    explanation: The skeletal hallmark in all three c.792+182G>A patients.
  - reference: PMID:23430531
    reference_title: Bone Dysplasia as a Key Feature in Three Patients with a Novel Congenital Disorder
      of Glycosylation (CDG) Type II Due to a Deep Intronic Splice Mutation in TMEM165.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Imaging of the skeleton showed osteoporosis and important epi- and metaphyseal dysplasia
      with broad metaphyses, irregular epiphyses, and thin bone cortex."
    explanation: Radiological detail in patient 1.
  - reference: PMID:22683087
    reference_title: TMEM165 deficiency causes a congenital disorder of glycosylation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Through a combination of autozygosity mapping and expression analysis in two siblings with
      an abnormal serum-transferrin isoelectric focusing test (type 2) and a peculiar skeletal phenotype
      with epiphyseal, metaphyseal, and diaphyseal dysplasia"
    explanation: The founding report's description, which adds diaphyseal involvement.
- name: Osteoporosis
  category: Skeletal
  phenotype_term:
    preferred_term: generalized osteoporosis
    term:
      id: HP:0000939
      label: Osteoporosis
  evidence:
  - reference: PMID:23430531
    reference_title: Bone Dysplasia as a Key Feature in Three Patients with a Novel Congenital Disorder
      of Glycosylation (CDG) Type II Due to a Deep Intronic Splice Mutation in TMEM165.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Common clinical features include moderate psychomotor retardation, feeding problems (in
      infancy), facial dysmorphism with low-set ears, hypotonia, joint hyperlaxity, hepatosplenomegaly,
      osteoporosis, and spondylo-, epi- and metaphyseal dysplasia aggravating with age."
    explanation: Osteoporosis is among the features common to all three patients.
  - reference: PMID:22683087
    reference_title: TMEM165 deficiency causes a congenital disorder of glycosylation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She had amelogenesis imperfecta and skeletal abnormalities, including osteoporosis,
      anterior beaking of lumbal vertebrae, dysplastic vertebrae and ribs, dysplastic fourth metacarpals
      and metatarsals, hypoplasia of femoral heads, and kyphoscoliosis"
    explanation: Osteoporosis also in case 5 of the founding report, a compound heterozygous
      p.Arg126Cys/p.Gly304Arg missense patient, so it is not confined to the splice genotype.
- name: Severe short stature
  category: Growth
  description: >-
    Postnatal growth failure culminating in severe dwarfism (122.5 cm, Z-score
    -10, in one adult; length SDS about -7 in another at 6 years), with normal
    head growth. Unresponsive to growth hormone.
  phenotype_term:
    preferred_term: severe dwarfism
    term:
      id: HP:0003510
      label: Severe short stature
  evidence:
  - reference: PMID:23430531
    reference_title: Bone Dysplasia as a Key Feature in Three Patients with a Novel Congenital Disorder
      of Glycosylation (CDG) Type II Due to a Deep Intronic Splice Mutation in TMEM165.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At age 21, the young man has a short stature (122.5 cm, Z-score −10) but a normal head
      circumference (55 cm, between 10th and 25th centiles)"
    explanation: The magnitude of the growth deficit in patient 1.
  - reference: PMID:22683087
    reference_title: TMEM165 deficiency causes a congenital disorder of glycosylation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The major clinical findings in the individuals with a homozygous splice mutation are severe
      psychomotor retardation, major skeletal dysplasia, and, in the surviving individuals, pronounced
      dwarfism."
    explanation: Dwarfism in all surviving splice-variant patients.
- name: Kyphoscoliosis
  category: Skeletal
  phenotype_term:
    preferred_term: kyphoscoliosis
    term:
      id: HP:0002751
      label: Kyphoscoliosis
  evidence:
  - reference: PMID:22683087
    reference_title: TMEM165 deficiency causes a congenital disorder of glycosylation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She had amelogenesis imperfecta and skeletal abnormalities, including osteoporosis,
      anterior beaking of lumbal vertebrae, dysplastic vertebrae and ribs, dysplastic fourth metacarpals
      and metatarsals, hypoplasia of femoral heads, and kyphoscoliosis"
    explanation: Case 5 (compound heterozygous missense); patient 1 of the splice series also had
      dorsolumbar kyphosis with severe scoliosis.
- name: Pectus carinatum
  category: Skeletal
  phenotype_term:
    preferred_term: Pectus carinatum
    term:
      id: HP:0000768
      label: Pectus carinatum
  evidence:
  - reference: PMID:23430531
    reference_title: Bone Dysplasia as a Key Feature in Three Patients with a Novel Congenital Disorder
      of Glycosylation (CDG) Type II Due to a Deep Intronic Splice Mutation in TMEM165.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "low-set and stiff auricles, pectus carinatum, dorsolumbar kyphosis and severe
      sinistroconvex scoliosis, short distal phalanges, genua vara, pedes planovalgi"
    explanation: Patient 1's dysmorphic and skeletal findings; shared with the genu varum entry.
- name: Genu varum
  category: Skeletal
  phenotype_term:
    preferred_term: genua vara
    term:
      id: HP:0002970
      label: Genu varum
  evidence:
  - reference: PMID:23430531
    reference_title: Bone Dysplasia as a Key Feature in Three Patients with a Novel Congenital Disorder
      of Glycosylation (CDG) Type II Due to a Deep Intronic Splice Mutation in TMEM165.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "low-set and stiff auricles, pectus carinatum, dorsolumbar kyphosis and severe
      sinistroconvex scoliosis, short distal phalanges, genua vara, pedes planovalgi"
    explanation: Genua vara in patient 1.
- name: Joint hypermobility
  category: Musculoskeletal
  phenotype_term:
    preferred_term: joint hyperlaxity
    term:
      id: HP:0001382
      label: Joint hypermobility
  evidence:
  - reference: PMID:23430531
    reference_title: Bone Dysplasia as a Key Feature in Three Patients with a Novel Congenital Disorder
      of Glycosylation (CDG) Type II Due to a Deep Intronic Splice Mutation in TMEM165.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Common clinical features include moderate psychomotor retardation, feeding problems (in
      infancy), facial dysmorphism with low-set ears, hypotonia, joint hyperlaxity, hepatosplenomegaly,
      osteoporosis, and spondylo-, epi- and metaphyseal dysplasia aggravating with age."
    explanation: Joint hyperlaxity is among the common features.
- name: Midface retrusion
  category: Craniofacial
  phenotype_term:
    preferred_term: midface hypoplasia
    term:
      id: HP:0011800
      label: Midface retrusion
  evidence:
  - reference: PMID:23430531
    reference_title: Bone Dysplasia as a Key Feature in Three Patients with a Novel Congenital Disorder
      of Glycosylation (CDG) Type II Due to a Deep Intronic Splice Mutation in TMEM165.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "After infancy (patients 1 and 3), midface hypoplasia, muscular hypotrophy, fat excess,
      growth retardation, and partial growth hormone deficiency completed this picture."
    explanation: Midface hypoplasia developing after infancy in both surviving patients.
- name: Low-set ears
  category: Craniofacial
  phenotype_term:
    preferred_term: low-set ears
    term:
      id: HP:0000369
      label: Low-set ears
  evidence:
  - reference: PMID:23430531
    reference_title: Bone Dysplasia as a Key Feature in Three Patients with a Novel Congenital Disorder
      of Glycosylation (CDG) Type II Due to a Deep Intronic Splice Mutation in TMEM165.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Common clinical features include moderate psychomotor retardation, feeding problems (in
      infancy), facial dysmorphism with low-set ears, hypotonia, joint hyperlaxity, hepatosplenomegaly,
      osteoporosis, and spondylo-, epi- and metaphyseal dysplasia aggravating with age."
    explanation: Low-set ears are the facial feature named as common to all three patients.
- name: Strabismus
  category: Ophthalmologic
  phenotype_term:
    preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  evidence:
  - reference: PMID:23430531
    reference_title: Bone Dysplasia as a Key Feature in Three Patients with a Novel Congenital Disorder
      of Glycosylation (CDG) Type II Due to a Deep Intronic Splice Mutation in TMEM165.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ophthalmological examination revealed a right convergent strabism"
    explanation: Convergent strabismus in patient 1; patient 2 had an external strabismus.
- name: Abnormal macular pigmentation
  category: Ophthalmologic
  phenotype_term:
    preferred_term: macular epithelial pigment alterations
    term:
      id: HP:0008002
      label: Abnormal macular pigmentation
  evidence:
  - reference: PMID:23430531
    reference_title: Bone Dysplasia as a Key Feature in Three Patients with a Novel Congenital Disorder
      of Glycosylation (CDG) Type II Due to a Deep Intronic Splice Mutation in TMEM165.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ophthalmological examination in patients 1 and 2 showed macular epithelial pigment
      alterations, and was normal in patient 3."
    explanation: Two of three patients.
- name: Amelogenesis imperfecta
  category: Dental
  phenotype_term:
    preferred_term: Amelogenesis imperfecta
    term:
      id: HP:0000705
      label: Amelogenesis imperfecta
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:22683087
    reference_title: TMEM165 deficiency causes a congenital disorder of glycosylation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She had amelogenesis imperfecta and skeletal abnormalities, including osteoporosis,
      anterior beaking of lumbal vertebrae, dysplastic vertebrae and ribs, dysplastic fourth metacarpals
      and metatarsals, hypoplasia of femoral heads, and kyphoscoliosis"
    explanation: One patient (case 5).
- name: Hepatosplenomegaly
  category: Hepatic
  phenotype_term:
    preferred_term: Hepatosplenomegaly
    term:
      id: HP:0001433
      label: Hepatosplenomegaly
  evidence:
  - reference: PMID:23430531
    reference_title: Bone Dysplasia as a Key Feature in Three Patients with a Novel Congenital Disorder
      of Glycosylation (CDG) Type II Due to a Deep Intronic Splice Mutation in TMEM165.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Common clinical features include moderate psychomotor retardation, feeding problems (in
      infancy), facial dysmorphism with low-set ears, hypotonia, joint hyperlaxity, hepatosplenomegaly,
      osteoporosis, and spondylo-, epi- and metaphyseal dysplasia aggravating with age."
    explanation: Hepatosplenomegaly in all three splice-variant patients; absent in the p.Arg126His
      patient.
- name: Elevated circulating hepatic transaminase concentration
  category: Hepatic
  description: Moderate AST and very mild ALT elevation, AST exceeding ALT.
  phenotype_term:
    preferred_term: raised serum transaminases
    term:
      id: HP:0002910
      label: Elevated circulating hepatic transaminase concentration
  evidence:
  - reference: PMID:23430531
    reference_title: Bone Dysplasia as a Key Feature in Three Patients with a Novel Congenital Disorder
      of Glycosylation (CDG) Type II Due to a Deep Intronic Splice Mutation in TMEM165.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The main biochemical findings in all three patients were an increase of serum AST
      (moderate), ALT (very mild), CK (moderate), and LDH (mild), as well as a decrease of coagulation
      factors VIII, IX, XI, and protein C."
    explanation: All three patients; the same sentence supports the creatine kinase and coagulation
      entries.
  - reference: PMID:28323990
    reference_title: Galactose Supplementation in Patients With TMEM165-CDG Rescues the Glycosylation
      Defects.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The few overlapping abnormalities included increased baseline levels of blood creatine
      kinase, transaminases, prothrombin time, and thyroid-stimulating hormone."
    explanation: Present at baseline in both patients of the galactose study.
- name: Elevated circulating creatine kinase activity
  category: Neuromuscular
  phenotype_term:
    preferred_term: raised serum creatine kinase
    term:
      id: HP:0003236
      label: Elevated circulating creatine kinase activity
  evidence:
  - reference: PMID:23430531
    reference_title: Bone Dysplasia as a Key Feature in Three Patients with a Novel Congenital Disorder
      of Glycosylation (CDG) Type II Due to a Deep Intronic Splice Mutation in TMEM165.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The main biochemical findings in all three patients were an increase of serum AST
      (moderate), ALT (very mild), CK (moderate), and LDH (mild), as well as a decrease of coagulation
      factors VIII, IX, XI, and protein C."
    explanation: Moderately raised CK in all three patients.
- name: Abnormality of coagulation
  category: Hematologic
  description: >-
    Mild to moderate reductions of clotting factors VIII, IX and XI and of
    protein C (and in some patients protein S and antithrombin); the
    individual factor findings are recorded under biochemical markers.
  phenotype_term:
    preferred_term: coagulation factor deficiency
    term:
      id: HP:0001928
      label: Abnormality of coagulation
  evidence:
  - reference: PMID:23430531
    reference_title: Bone Dysplasia as a Key Feature in Three Patients with a Novel Congenital Disorder
      of Glycosylation (CDG) Type II Due to a Deep Intronic Splice Mutation in TMEM165.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The main biochemical findings in all three patients were an increase of serum AST
      (moderate), ALT (very mild), CK (moderate), and LDH (mild), as well as a decrease of coagulation
      factors VIII, IX, XI, and protein C."
    explanation: Reduced coagulation factors in all three patients.
- name: Recurrent fever
  category: Immunologic
  description: >-
    Recurrent fever without evidence of infection, in two of the three
    c.792+182G>A patients; the same feature is described in some COG-CDG
    patients.
  phenotype_term:
    preferred_term: recurrent unexplained fever
    term:
      id: HP:0001954
      label: Recurrent fever
  evidence:
  - reference: PMID:23430531
    reference_title: Bone Dysplasia as a Key Feature in Three Patients with a Novel Congenital Disorder
      of Glycosylation (CDG) Type II Due to a Deep Intronic Splice Mutation in TMEM165.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "was recurrent fever without evidence for infection."
    explanation: Reported in patients 2 and 3 of the three.
- name: Feeding difficulties
  category: Gastrointestinal
  phenotype_term:
    preferred_term: feeding problems in infancy
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:23430531
    reference_title: Bone Dysplasia as a Key Feature in Three Patients with a Novel Congenital Disorder
      of Glycosylation (CDG) Type II Due to a Deep Intronic Splice Mutation in TMEM165.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Common clinical features include moderate psychomotor retardation, feeding problems (in
      infancy), facial dysmorphism with low-set ears, hypotonia, joint hyperlaxity, hepatosplenomegaly,
      osteoporosis, and spondylo-, epi- and metaphyseal dysplasia aggravating with age."
    explanation: Feeding problems in infancy in all three patients.
  - reference: PMID:26238249
    reference_title: "TMEM165 Deficiency: Postnatal Changes in Glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Repeated hospitalizations were necessary due to recurrent edema and feeding problems
      requiring tube feeding."
    explanation: Tube feeding in the E108G patient.
- name: Increased body fat percentage
  category: Metabolic
  description: Fat excess after infancy; body fat fraction 27-29% before growth hormone treatment
    in two patients.
  phenotype_term:
    preferred_term: fat excess
    term:
      id: HP:0025521
      label: Increased body fat percentage
  evidence:
  - reference: PMID:23430531
    reference_title: Bone Dysplasia as a Key Feature in Three Patients with a Novel Congenital Disorder
      of Glycosylation (CDG) Type II Due to a Deep Intronic Splice Mutation in TMEM165.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "After infancy (patients 1 and 3), midface hypoplasia, muscular hypotrophy, fat excess,
      growth retardation, and partial growth hormone deficiency completed this picture."
    explanation: Fat excess in both surviving patients.
- name: Nephrotic syndrome
  category: Renal
  description: >-
    Proteinuria from one week of age progressing to nephrotic syndrome with
    slowly progressive renal failure in the E108G patient, who died at five
    months of complications of nephrotic syndrome and renal failure. An older
    sibling had died from TMEM165-CDG at five months; the report does not give
    that child's cause of death.
    Not reported in the other genotypes.
  phenotype_term:
    preferred_term: Nephrotic syndrome
    term:
      id: HP:0000100
      label: Nephrotic syndrome
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:26238249
    reference_title: "TMEM165 Deficiency: Postnatal Changes in Glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At the age of 1 week, mild proteinuria was observed, the extent increasing over the next
      weeks to nephrotic syndrome with slowly progressive renal failure."
    explanation: The course of the renal disease in the E108G patient.
  sequelae:
  - target: Renal insufficiency
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:26238249
      reference_title: "TMEM165 Deficiency: Postnatal Changes in Glycosylation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The patient died at the age of 5 months due to complications of nephrotic syndrome and
        renal failure."
      explanation: Renal failure followed the nephrotic syndrome and was fatal.
- name: Renal insufficiency
  category: Renal
  phenotype_term:
    preferred_term: progressive renal failure
    term:
      id: HP:0000083
      label: Renal insufficiency
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:26238249
    reference_title: "TMEM165 Deficiency: Postnatal Changes in Glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At the age of 1 week, mild proteinuria was observed, the extent increasing over the next
      weeks to nephrotic syndrome with slowly progressive renal failure."
    explanation: One patient.
- name: Ventricular septal defect
  category: Cardiovascular
  phenotype_term:
    preferred_term: small apical ventricular septal defect
    term:
      id: HP:0001629
      label: Ventricular septal defect
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:26238249
    reference_title: "TMEM165 Deficiency: Postnatal Changes in Glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Echocardiography revealed a small apical VSD, a PFO, and a small PDA with mild signs of
      right ventricular hypertrophy."
    explanation: Neonatal echocardiography in the E108G patient; the same sentence supports the PDA and
      PFO entries.
- name: Patent ductus arteriosus
  category: Cardiovascular
  phenotype_term:
    preferred_term: small patent ductus arteriosus
    term:
      id: HP:0001643
      label: Patent ductus arteriosus
  evidence:
  - reference: PMID:26238249
    reference_title: "TMEM165 Deficiency: Postnatal Changes in Glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Echocardiography revealed a small apical VSD, a PFO, and a small PDA with mild signs of
      right ventricular hypertrophy."
    explanation: E108G patient.
  - reference: PMID:23430531
    reference_title: Bone Dysplasia as a Key Feature in Three Patients with a Novel Congenital Disorder
      of Glycosylation (CDG) Type II Due to a Deep Intronic Splice Mutation in TMEM165.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hepatomegaly, a small open ductus Botalli and a small patent foramen ovale, were noted
      shortly after birth."
    explanation: Also in patient 3 of the splice-variant series, a second genotype.
- name: Patent foramen ovale
  category: Cardiovascular
  phenotype_term:
    preferred_term: Patent foramen ovale
    term:
      id: HP:0001655
      label: Patent foramen ovale
  evidence:
  - reference: PMID:23430531
    reference_title: Bone Dysplasia as a Key Feature in Three Patients with a Novel Congenital Disorder
      of Glycosylation (CDG) Type II Due to a Deep Intronic Splice Mutation in TMEM165.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hepatomegaly, a small open ductus Botalli and a small patent foramen ovale, were noted
      shortly after birth."
    explanation: Patient 3; the E108G patient also had a PFO.
biochemical:
- name: Reduced factor IX activity
  biomarker_term:
    preferred_term: decreased clotting factor IX
    term:
      id: HP:0011858
      label: Reduced factor IX activity
  presence: PRESENT
  notes: >-
    Reduced in all three c.792+182G>A patients. Improved on D-galactose in the
    treated patient without normalising, but enough to normalise the APTT.
  evidence:
  - reference: PMID:23430531
    reference_title: Bone Dysplasia as a Key Feature in Three Patients with a Novel Congenital Disorder
      of Glycosylation (CDG) Type II Due to a Deep Intronic Splice Mutation in TMEM165.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The main biochemical findings in all three patients were an increase of serum AST
      (moderate), ALT (very mild), CK (moderate), and LDH (mild), as well as a decrease of coagulation
      factors VIII, IX, XI, and protein C."
    explanation: Factor IX is among the reduced factors in all three patients.
  - reference: PMID:28323990
    reference_title: Galactose Supplementation in Patients With TMEM165-CDG Rescues the Glycosylation
      Defects.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Factor IX deficiency did not normalize in patient 1, but its improvement was apparently
      sufficient to normalize APTT."
    explanation: Response of this marker to galactose therapy.
- name: Reduced factor VIII activity
  biomarker_term:
    preferred_term: decreased clotting factor VIII
    term:
      id: HP:0003125
      label: Reduced factor VIII activity
  presence: PRESENT
  evidence:
  - reference: PMID:23430531
    reference_title: Bone Dysplasia as a Key Feature in Three Patients with a Novel Congenital Disorder
      of Glycosylation (CDG) Type II Due to a Deep Intronic Splice Mutation in TMEM165.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The main biochemical findings in all three patients were an increase of serum AST
      (moderate), ALT (very mild), CK (moderate), and LDH (mild), as well as a decrease of coagulation
      factors VIII, IX, XI, and protein C."
    explanation: Factor VIII is among the reduced factors in all three patients.
- name: Reduced factor XI activity
  biomarker_term:
    preferred_term: decreased clotting factor XI
    term:
      id: HP:0001929
      label: Reduced factor XI activity
  presence: PRESENT
  evidence:
  - reference: PMID:23430531
    reference_title: Bone Dysplasia as a Key Feature in Three Patients with a Novel Congenital Disorder
      of Glycosylation (CDG) Type II Due to a Deep Intronic Splice Mutation in TMEM165.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The main biochemical findings in all three patients were an increase of serum AST
      (moderate), ALT (very mild), CK (moderate), and LDH (mild), as well as a decrease of coagulation
      factors VIII, IX, XI, and protein C."
    explanation: Factor XI is among the reduced factors in all three patients.
- name: Reduced protein C activity
  biomarker_term:
    preferred_term: decreased protein C
    term:
      id: HP:0005543
      label: Reduced protein C activity
  presence: PRESENT
  evidence:
  - reference: PMID:23430531
    reference_title: Bone Dysplasia as a Key Feature in Three Patients with a Novel Congenital Disorder
      of Glycosylation (CDG) Type II Due to a Deep Intronic Splice Mutation in TMEM165.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The main biochemical findings in all three patients were an increase of serum AST
      (moderate), ALT (very mild), CK (moderate), and LDH (mild), as well as a decrease of coagulation
      factors VIII, IX, XI, and protein C."
    explanation: Protein C is reduced in all three patients.
- name: Increased circulating lactate dehydrogenase concentration
  biomarker_term:
    preferred_term: raised serum LDH
    term:
      id: HP:0025435
      label: Increased circulating lactate dehydrogenase concentration
  presence: PRESENT
  evidence:
  - reference: PMID:23430531
    reference_title: Bone Dysplasia as a Key Feature in Three Patients with a Novel Congenital Disorder
      of Glycosylation (CDG) Type II Due to a Deep Intronic Splice Mutation in TMEM165.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The main biochemical findings in all three patients were an increase of serum AST
      (moderate), ALT (very mild), CK (moderate), and LDH (mild), as well as a decrease of coagulation
      factors VIII, IX, XI, and protein C."
    explanation: Mildly raised LDH in all three patients.
- name: Apolipoprotein C-III isoform shift
  biomarker_term:
    preferred_term: cathodal shift on serum apolipoprotein C-III isoelectric focusing
  presence: VARIABLE
  notes: >-
    Decreased monosialo- and increased asialo-apoC-III, the serum marker of a
    mucin-type O-glycosylation defect. Present in the three patients of the
    2013 clinical report, but the founding report described a normal apoC-III
    profile. The HPO search `runoak -i ols:hp search "apolipoprotein C-III"`
    returns only HP:0033112 (Elevated circulating apolipoprotein C-III
    concentration), a concentration rather than an isoform term, so the marker
    is left unbound.
  evidence:
  - reference: PMID:23430531
    reference_title: Bone Dysplasia as a Key Feature in Three Patients with a Novel Congenital Disorder
      of Glycosylation (CDG) Type II Due to a Deep Intronic Splice Mutation in TMEM165.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "IEF of apolipoprotein C-III shows a decrease of the monosialo-apo C-III and an increase of
      the asialo-apo C-III"
    explanation: The isoform shift itself.
  - reference: PMID:22683087
    reference_title: TMEM165 deficiency causes a congenital disorder of glycosylation.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "These results are consistent with the normal ApoC-III profile and prove the absence of an
      O-glycan defect."
    explanation: A normal apoC-III profile in the founding report, so the marker is not constant.
diagnosis:
- name: Serum transferrin isoelectric focusing
  description: >-
    First-line screen; shows a type 2 pattern in every reported patient,
    including on the first day of life.
  evidence:
  - reference: PMID:22683087
    reference_title: TMEM165 deficiency causes a congenital disorder of glycosylation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of CDG-II in these cases was established by standard sTf-IEF showing a
      marked increase of asialotransferrin, monosialotransferrin, disialotransferrin, and
      trisialotransferrin in all cases"
    explanation: The screening test by which the original patients were identified.
- name: Serum apolipoprotein C-III isoelectric focusing
  description: >-
    Detects the accompanying O-glycosylation defect and so distinguishes a
    combined N- and O-glycosylation defect from a pure N-glycan processing
    defect; it was normal in the founding report, so a normal result does not
    exclude the disease.
  evidence:
  - reference: PMID:23430531
    reference_title: Bone Dysplasia as a Key Feature in Three Patients with a Novel Congenital Disorder
      of Glycosylation (CDG) Type II Due to a Deep Intronic Splice Mutation in TMEM165.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Diagnostic work-up revealed a type 2 serum transferrin isoelectrofocusing (IEF) pattern
      and a cathodal shift on apolipoprotein C-III IEF pointing to a combined N- and O-glycosylation
      defect."
    explanation: The combined screen used in the clinical series.
- name: Molecular genetic testing of TMEM165 including deep intronic sequence
  description: >-
    Confirms biallelic variants, and has been used prenatally in a family with
    a known variant. The recurrent c.792+182G>A variant lies deep in intron 4,
    outside the exons and flanking splice sites that exome sequencing covers;
    the founding authors state that exome sequencing would not have found it.
  evidence:
  - reference: PMID:22683087
    reference_title: TMEM165 deficiency causes a congenital disorder of glycosylation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the causal mutation in the index family would never have been identified if the affected
      individuals' samples had been directly subjected to exome sequencing."
    explanation: The authors' own statement that exome sequencing would have missed the causal variant.
  - reference: PMID:26238249
    reference_title: "TMEM165 Deficiency: Postnatal Changes in Glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In this context, material for genetic analysis was obtained and sequencing of TMEM165
      showed homozygosity for the same mutation as previously found in the sibling."
    explanation: Prenatal molecular diagnosis from amniotic fluid in a family with a known variant.
treatments:
- name: Oral D-Galactose Supplementation
  description: >-
    Oral D-galactose, escalated from 0.5 to 1.5 g/kg/day (maximum 50 g/day)
    over 18 weeks in two c.792+182G>A patients. Well tolerated. Improved
    transferrin sialylation and serum N-glycan galactosylation, APTT,
    antithrombin, IGF-1, IGFBP3 and ALT in one or both patients; no effect on
    creatine kinase, TSH or cholesterol, and 1 g/kg/day was as good as 1.5.
    In cells galactose corrects N-glycosylation but not O-glycosylation or
    glycosaminoglycan synthesis, so it bypasses only the galactosylation step.
  treatment_term:
    preferred_term: oral D-galactose supplementation
    term:
      id: NCIT:C15447
      label: Dietary Intervention
    therapeutic_agent:
    - preferred_term: D-galactose
      term:
        id: CHEBI:12936
        label: D-galactose
  therapeutic_modality: SMALL_MOLECULE
  dosing_interval: daily
  dosing_interval_days: 1
  target_mechanisms:
  - target: Hypogalactosylation and Hyposialylation of N-Glycans
    treatment_effect: BYPASSES
    description: Raises galactose substrate supply so the Mn2+-limited galactosyltransferases
      complete more N-glycans; does not act on the O-glycan or glycosaminoglycan arms.
  target_phenotypes:
  - preferred_term: Type II transferrin isoform profile
    term:
      id: HP:0012301
      label: Type II transferrin isoform profile
  - preferred_term: coagulation factor deficiency
    term:
      id: HP:0001928
      label: Abnormality of coagulation
  evidence:
  - reference: PMID:28323990
    reference_title: Galactose Supplementation in Patients With TMEM165-CDG Rescues the Glycosylation
      Defects.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We then demonstrated that oral galactose supplementation in patients with TMEM165-deficient
      CDG improved biochemical and clinical parameters, including a substantial increase in the
      negatively charged transferrin isoforms, and a decrease in hypogalactosylated total N-glycan
      structures, endocrine function, and coagulation parameters."
    explanation: The clinical result in two patients.
  - reference: PMID:28323990
    reference_title: Galactose Supplementation in Patients With TMEM165-CDG Rescues the Glycosylation
      Defects.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "d-Galactose intake was increased in increments, as follows: weeks 0 to 6, 0.5 g/kg/d; weeks
      7 to 12, 1.0 g/kg/d; weeks 13 to 18, 1.5 g/kg/d."
    explanation: The dosing schedule recorded in the description.
  - reference: PMID:35693943
    reference_title: Differential Effects of D-Galactose Supplementation on Golgi Glycosylation Defects
      in TMEM165 Deficiency.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Whereas MnCl2 supplementation unambiguously fully rescues the N- and O-linked as well as
      GAG glycosylations in TMEM165-deficient cells, D-Gal supplementation only rescues the N-linked
      glycosylation, without any effects on the other Golgi-related glycosylation types."
    explanation: The limit of galactose therapy in cells; it leaves the O-glycan and glycosaminoglycan
      defects, and the latter is the one linked to the skeletal phenotype.
- name: Combined Oral Manganese and D-Galactose Therapy
  description: >-
    Combined oral Mn2+ and D-galactose, first given to one p.Ala310Pro patient.
    It suppressed the N-, O- and glycosaminoglycan hypoglycosylation and
    improved biochemical parameters and gastrointestinal symptoms. Single
    patient; an earlier study withheld manganese because blood manganese was
    normal and because of potential toxicity.
  treatment_term:
    preferred_term: oral manganese and D-galactose supplementation
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: manganese
      term:
        id: CHEBI:29035
        label: manganese(2+)
    - preferred_term: D-galactose
      term:
        id: CHEBI:12936
        label: D-galactose
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: Golgi Manganese Insufficiency
    treatment_effect: RESTORES
    description: Supplies the missing cofactor, which in cells corrects every glycosylation class
      affected.
  evidence:
  - reference: PMID:38013006
    reference_title: Efficacy of oral manganese and D-galactose therapy in a patient bearing a novel TMEM165
      variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We administered for the first time a combined D-Gal and Mn2+ therapy to the patient. This
      fully suppressed the N-; O- and GAG hypoglycosylation."
    explanation: The single-patient result.
  - reference: PMID:28323990
    reference_title: Galactose Supplementation in Patients With TMEM165-CDG Rescues the Glycosylation
      Defects.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Manganese treatment was not attempted, because of normal blood levels of manganese and
      potential toxicity."
    explanation: The safety reason manganese was withheld in the earlier study.
- name: Growth Hormone Therapy
  description: >-
    Tried in two patients for partial growth hormone deficiency. IGF-I
    normalised and body fat fell, but growth velocity did not increase and
    treatment was stopped.
  treatment_term:
    preferred_term: growth hormone therapy
    term:
      id: NCIT:C15599
      label: Hormone Replacement Therapy
    therapeutic_agent:
    - preferred_term: growth hormone
      term:
        id: NCIT:C837
        label: Somatropin
  therapeutic_modality: PROTEIN_REPLACEMENT
  target_phenotypes:
  - preferred_term: severe dwarfism
    term:
      id: HP:0003510
      label: Severe short stature
  evidence:
  - reference: PMID:23430531
    reference_title: Bone Dysplasia as a Key Feature in Three Patients with a Novel Congenital Disorder
      of Glycosylation (CDG) Type II Due to a Deep Intronic Splice Mutation in TMEM165.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "but failed to elicit a detectable increment of growth velocity or a detectable improvement
      of respiratory status, and was thus halted."
    explanation: Graded REFUTE against growth hormone improving growth, in patient 3; patient 1 had
      the same outcome.
- name: Levetiracetam for Epilepsy
  description: Transient epilepsy in one patient responded to levetiracetam, which was withdrawn
    before age three.
  treatment_term:
    preferred_term: antiepileptic pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: levetiracetam
      term:
        id: CHEBI:6437
        label: levetiracetam
  therapeutic_modality: SMALL_MOLECULE
  target_phenotypes:
  - preferred_term: transient epilepsy
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:23430531
    reference_title: Bone Dysplasia as a Key Feature in Three Patients with a Novel Congenital Disorder
      of Glycosylation (CDG) Type II Due to a Deep Intronic Splice Mutation in TMEM165.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At 14 months he developed epilepsy, responding to levetiracetam."
    explanation: Treatment and response in patient 3.
- name: Antisense Morpholino Pseudoexon Skipping
  description: >-
    Preclinical only. A morpholino antisense oligonucleotide directed at the
    pseudoexon created by c.792+182G>A restored normal TMEM165 protein in the
    Golgi of patient fibroblasts. Applicable only to that allele; no patient
    has been treated.
  treatment_term:
    preferred_term: antisense oligonucleotide pseudoexon skipping
    term:
      id: NCIT:C16236
      label: Antisense Therapy
  therapeutic_modality: ANTISENSE_OLIGONUCLEOTIDE
  oligonucleotide_details:
    oligonucleotide_mechanism: SPLICE_MODULATION_EXON_SKIPPING
    target_gene:
      preferred_term: TMEM165
      term:
        id: hgnc:30760
        label: TMEM165
    target_transcript: TMEM165 pre-mRNA pseudoexon from intron 4 (c.792+182G>A)
    oligonucleotide_chemistry: PHOSPHORODIAMIDATE_MORPHOLINO
  target_mechanisms:
  - target: TMEM165 Biallelic Loss of Function
    treatment_effect: RESTORES
    description: Blocks inclusion of the aberrant exon so the normal transcript and protein are made.
  evidence:
  - reference: PMID:24720419
    reference_title: Antisense-mediated therapeutic pseudoexon skipping in TMEM165-CDG.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Antisense morpholino oligonucleotide therapy targeted toward TMEM165 mRNA recovered normal
      protein levels in the Golgi apparatus of patient-derived fibroblasts."
    explanation: Proof of concept in patient cells only.
clinical_trials:
- name: NCT02955264
  phase: NOT_APPLICABLE
  status: COMPLETED
  description: >-
    Pilot study of oral D-galactose in congenital disorders of glycosylation,
    under which the two TMEM165-CDG patients of the 2017 galactose study were
    treated.
  evidence:
  - reference: clinicaltrials:NCT02955264
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The investigators aim to assess the safety and tolerability of oral galactose treatment in
      a small pilot group of Congenital Disorders of Glycosylation patients."
    explanation: The registered aim of the trial.
  - reference: PMID:28323990
    reference_title: Galactose Supplementation in Patients With TMEM165-CDG Rescues the Glycosylation
      Defects.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The protocol was approved by the institutional review board (IRB; Tulane University Hayward
      Genetics Center IRB no. 517339-4; Clinicaltrials.gov NCT02955264)."
    explanation: Links the TMEM165-CDG galactose treatment to this registration.
animal_models:
- name: Zebrafish tmem165 morphant
  species: Danio rerio
  genotype: tmem165 morpholino knockdown
  publication: PMID:25609749
  description: >-
    Morpholino knockdown of tmem165 in zebrafish embryos causes craniofacial
    cartilage malformation with fewer chondrocytes, reduced chondroitin
    sulfate staining, altered chondrocyte and osteoblast differentiation
    markers, and altered N-glycan processing. Co-injection of wild-type mRNA
    partly rescues the cartilage phenotype.
  modeled_mechanisms:
  - target: Premature Chondrocyte Maturation and Hypertrophy
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: Reproduces a cartilage developmental defect with altered chondrocyte and osteoblast
      differentiation.
    limitations: >-
      Transient morpholino knockdown in embryos observed to 4 days post
      fertilisation, not a stable mutant; the craniofacial cartilages scored
      are not the long-bone growth plates affected in patients, and the
      zebrafish finding is fewer chondrocytes rather than the premature
      hypertrophy seen in mammalian chondrocytic cells.
    evidence:
    - reference: PMID:25609749
      reference_title: Abnormal cartilage development and altered N-glycosylation in Tmem165-deficient
        zebrafish mirrors the phenotypes associated with TMEM165-CDG.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Inhibition of tmem165 expression in developing zebrafish embryos caused craniofacial
        abnormalities, largely attributable to fewer chondrocytes."
      explanation: The cartilage phenotype of the model.
  - target: Hypogalactosylation and Hyposialylation of N-Glycans
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: N-glycan changes in morphants parallel some of the patients' serum glycan changes.
    limitations: >-
      Whole-embryo glycome rather than serum glycoproteins, and the authors
      describe the parallel as partial.
    evidence:
    - reference: PMID:25609749
      reference_title: Abnormal cartilage development and altered N-glycosylation in Tmem165-deficient
        zebrafish mirrors the phenotypes associated with TMEM165-CDG.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Glycomic analysis of tmem165 morphants also revealed altered initiation, processing and
        extension of N-glycans, paralleling some of the glycosylation changes noted in human patients."
      explanation: The glycan phenotype of the model.
- name: Mammary-specific Tmem165 knockout mouse
  species: Mus musculus
  genotype: Tmem165 floxed allele deleted by WAP-Cre in milk-producing alveolar epithelial cells
  publication: PMID:30622138
  description: >-
    About 85% loss of TMEM165 in the lactating mammary gland reduces lactose
    synthesis and pup growth, and lowers milk Ca2+ and Mn2+ relative to
    protein. The only mammalian in vivo model; it addresses Golgi cation supply
    in a secretory epithelium, not the skeletal or neurological disease.
  modeled_mechanisms:
  - target: Golgi Manganese Insufficiency
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: ORGANISM
    description: Shows in vivo that TMEM165 supplies Ca2+ and Mn2+ to the Golgi of a secretory cell.
    limitations: >-
      Tissue-restricted, adult, lactation-specific deletion. Golgi Mn2+ is
      inferred from milk mineral content, and the outcome studied (lactose
      synthesis) has no counterpart in the human disease.
    evidence:
    - reference: PMID:30622138
      reference_title: Milk biosynthesis requires the Golgi cation exchanger TMEM165.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "When normalized to total protein levels, only calcium and manganese levels were
        significantly lower in the milk from TMEM165-deficient dams than control dams."
      explanation: The in vivo cation readout.
experimental_models:
- name: TMEM165 knockout ATDC5 chondrocytic cells
  experimental_model_type: CELL_LINE
  organism:
    preferred_term: Mus musculus
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  cell_types:
  - preferred_term: chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  cell_source: CRISPR-Cas9 knockout of Tmem165 in the mouse prechondrocytic ATDC5 line
  publication: PMID:34930890
  modeled_mechanisms:
  - target: Impaired Glycosaminoglycan Chain Elongation
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: Shorter chondroitin- and heparan-sulfate chains, rescued by Mn2+.
    limitations: >-
      Mouse cell line in culture; the glycosaminoglycan defect has not been
      measured in patient cartilage.
    evidence:
    - reference: PMID:34930890
      reference_title: "TMEM165 a new player in proteoglycan synthesis: loss of TMEM165 impairs
        elongation of chondroitin- and heparan-sulfate glycosaminoglycan chains of proteoglycans and
        triggers early chondrocyte differentiation and hypertrophy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Supplementation of cell with Mn2+ rescue the elongation process, confirming a role of
        TMEM165 in Mn2+ Golgi homeostasis."
      explanation: The defect and its rescue in this model.
  - target: Premature Chondrocyte Maturation and Hypertrophy
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Early Ihh expression and premature hypertrophic differentiation.
    limitations: >-
      Differentiation of a cell line in monolayer culture is a proxy for growth
      plate behaviour, not a growth plate.
    evidence:
    - reference: PMID:34930890
      reference_title: "TMEM165 a new player in proteoglycan synthesis: loss of TMEM165 impairs
        elongation of chondroitin- and heparan-sulfate glycosaminoglycan chains of proteoglycans and
        triggers early chondrocyte differentiation and hypertrophy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Finally, we found that loss of TMEM165 impairs chondrogenic differentiation by
        accelerating the timing of Ihh expression and promoting early chondrocyte maturation and
        hypertrophy."
      explanation: The differentiation phenotype of this model.
- name: TMEM165 knockout HEK293 cells
  experimental_model_type: CELL_LINE
  organism:
    preferred_term: Homo sapiens
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_source: CRISPR-Cas9 TMEM165 knockout of the HEK293 line
  publication: PMID:28323990
  modeled_mechanisms:
  - target: Hypogalactosylation and Hyposialylation of N-Glycans
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: Severe N-glycan hypogalactosylation, corrected by Mn2+ or by galactose.
    limitations: >-
      Kidney-derived transformed cell line; the defect is more severe than the
      slight galactosylation defect seen in patient serum.
    evidence:
    - reference: PMID:28323990
      reference_title: Galactose Supplementation in Patients With TMEM165-CDG Rescues the Glycosylation
        Defects.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "We analyzed N-linked glycans and glycolipids in knockout TMEM165 HEK293 cells, revealing
        severe hypogalactosylation and GalNAc transfer defects."
      explanation: The N-glycan phenotype of the model.
  - target: Truncation of Mucin-Type O-Glycans
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: Truncated mucin-type O-glycans, corrected by Mn2+ but not galactose.
    limitations: >-
      The patient O-glycan data are inconsistent between reports, so it is not
      settled how representative this is.
    evidence:
    - reference: PMID:35693943
      reference_title: Differential Effects of D-Galactose Supplementation on Golgi Glycosylation
        Defects in TMEM165 Deficiency.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Interestingly, a similar VVL staining was observed in TMEM165 KO HEK cells (Supplementary
        Figure S1A), demonstrating the significant presence of truncated O-linked mucin type glycans in
        TMEM165-deficient cells."
      explanation: The O-glycan phenotype of the model.
discussions:
- discussion_id: tmem165_genotype_skeletal_phenotype
  kind: KNOWLEDGE_GAP
  attaches_to:
  - phenotypes#Spondyloepimetaphyseal dysplasia
  - genetic#TMEM165
  prompt: >-
    Does the skeletal dysplasia depend on the TMEM165 allele, and why?
  rationale: >-
    The founding report's summary says the missense-allele patients lack the
    skeletal phenotype, yet its own case 5 (p.Arg126Cys/p.Gly304Arg) had
    osteoporosis, vertebral and rib dysplasia and kyphoscoliosis, while case 4
    (p.Arg126His homozygous) had no clear skeletal anomalies. The report also
    could not exclude a defect in a neighbouring gene on the founder
    haplotype. Later evidence argues against that explanation: TMEM165
    knockout chondrocytic cells reproduce a growth-plate-like defect, the
    zebrafish knockdown affects cartilage, and the p.Ala310Pro missense
    patient has a predominant bone phenotype. Whether residual protein
    function or localisation (the Arg126 variants shift TMEM165 toward
    lysosomes) sets skeletal severity remains open with fewer than ten
    patients.
- discussion_id: tmem165_manganese_therapy
  kind: KNOWLEDGE_GAP
  attaches_to:
  - treatments#Combined Oral Manganese and D-Galactose Therapy
  prompt: >-
    Is oral manganese safe and effective enough to become standard therapy,
    and does it reach the skeletal (glycosaminoglycan) arm of the disease in
    patients?
  rationale: >-
    Galactose corrects only N-glycosylation, while Mn2+ corrects N-, O- and
    glycosaminoglycan glycosylation in cells and in one treated patient. The
    glycosaminoglycan defect is the one linked to the skeletal phenotype, so
    the choice of therapy matters most there. Manganese is potentially toxic,
    the patients measured had normal blood manganese, and there is a single
    treated patient without skeletal outcome data.
notes: >-
  No GeneReviews chapter covers TMEM165-CDG (check-genereviews reports
  NO_CHAPTER against the name and all synonyms). Phenotype frequencies are
  left unset except where a source states a proportion across its patients,
  because the published cohort is fewer than ten individuals, most phenotypes
  come from one three-patient series of a single genotype, and several
  features (nephrotic syndrome, congenital heart defects) come from one family
  with a different genotype.

  Cardiomyopathy is not curated as a phenotype. A 2025 review (PMID:41583011)
  discusses TMEM165 in the context of congenital cardiomyopathies, but it
  describes heart defects in TMEM165-CDG patients generally and does not
  report a cardiomyopathy in any patient; the structural defects (VSD, PDA,
  PFO) are curated from the primary case reports instead.

📚

References & Deep Research

References

5

PMID:22683087

TMEM165 deficiency causes a congenital disorder of glycosylation.

No top-level findings curated for this source.

PMID:23430531

Bone Dysplasia as a Key Feature in Three Patients with a Novel Congenital Disorder of Glycosylation (CDG) Type II Due to a Deep Intronic Splice Mutation in TMEM165.

No top-level findings curated for this source.

PMID:28323990

Galactose Supplementation in Patients With TMEM165-CDG Rescues the Glycosylation Defects.

No top-level findings curated for this source.

PMID:26238249

TMEM165 Deficiency: Postnatal Changes in Glycosylation.

No top-level findings curated for this source.

PMID:34930890

TMEM165 a new player in proteoglycan synthesis: loss of TMEM165 impairs elongation of chondroitin- and heparan-sulfate glycosaminoglycan chains of proteoglycans and triggers early chondrocyte differentiation and hypertrophy.

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 (1)

Create: TMEM165-Congenital_Disorder_of_Glycosylation · 2026-09-28T23:14:41Z · View source

New entry for TMEM165-CDG (MONDO:0013870). The required deep-research input was the Perplexity report (research/TMEM165-Congenital_Disorder_of_Glycosylation-deep-research-perplexity.md); just preflight-dr returned PASS (TMEM165 mentioned 278 times, OMIM 614727 agrees). The report's 15 cited references all resolved, but it was used as a lead only: every claim in the entry was re-sourced from primary papers found through PubMed (TMEM165[tiab], 73 hits) and quoted from the cached text. Report content not carried over: (1) cardiomyopathy as a TMEM165-CDG phenotype - the cited 2025 review (PMID:41583011) discusses cardiomyopathy only in the context of other CDGs and does not report it in a TMEM165 patient, so only the structural heart defects from the case reports (VSD, PDA, PFO) are curated; (2) a constant O-glycosylation defect - the founding paper (PMID:22683087) found normal serum O-glycans and apoC-III, so the O-glycan node and the apoC-III marker carry a REFUTE item alongside the supporting ones; (3) the report's HP/GO/NCIT CURIEs, of which 3 HP terms were unresolved and 10 NCIT/GO terms named other concepts - all bindings in the entry were looked up afresh with runoak (ols:) and the HGNC REST API; (4) the report's ClinVar/MalaCards variant list and Orphanet prevalence, which have no cached, quotable source here (ORPHA:314667 is not pre-cached). The DOI-keyed caches written by the research run are committed but not cited. Chain: biallelic TMEM165 loss -> loss of Golgi Ca2+/Mn2+-proton antiport -> Golgi Mn2+ insufficiency (plus a PROVISIONAL Ca2+/pH branch) -> impaired Mn2+-dependent glycosyltransferases -> N-glycan hypogalactosylation, O-glycan truncation, glycolipid and glycosaminoglycan defects; the GAG arm continues through TGF-beta/BMP dysregulation and premature chondrocyte hypertrophy to disordered endochondral ossification and the skeletal phenotypes, and a HYPOTHETICAL multisystem hub carries the non-skeletal phenotypes. All 35 phenotypes are causally connected. Validation: just validate, validate-terms, count-verified-snippets (124/124), check-entity-refs, check-causal-targets, check-duplicate-keys, check-coarse-phenotypes, check-qualifier-terms, check-folded-hyphens and validate-disorders all passed. check-snippet-length, check-title-snippets, check-snippet-grading and check-reference-titles could not run in their just form (--against-ref origin/main extracts a copy of kb/ and the disk was full); the same scripts run against the committed baselines passed. check-genereviews reports NO_CHAPTER for the name and all synonyms.

Perplexity ▸

1. Disease Information

sonar-deep-research 42 citations 2026-09-28T21:37:29.880028

1. Disease Information

1.1 Overview and Definition

TMEM165‑Congenital Disorder of Glycosylation (TMEM165‑CDG) is a Mendelian inborn error of metabolism classified within the group of congenital disorders of glycosylation (CDG), specifically a type II (processing) and “mixed” N‑ and O‑glycosylation defect caused by pathogenic variants in TMEM165.[2][10][12][7] CDG are a growing group of inherited multisystem disorders characterized by defects in the glycosylation of proteins and lipids; TMEM165‑CDG represents one of the subtype entities in this expanding nosology.[21][12] Foulquier and colleagues first identified TMEM165 (also named TPARL) as the causative gene in 2012 through autozygosity mapping and expression analysis in siblings with abnormal serum transferrin isoelectric focusing and a peculiar skeletal phenotype, establishing a previously undescribed type II CDG.[2][13][2] The disease is now recognized as an autosomal recessive disorder with variable phenotype, defined by systemic consequences of impaired Golgi glycosylation due to defective cation/(\mathrm{H}^+) antiporter function of TMEM165.[2][8][1][1]

Orphanet describes TMEM165‑CDG as “a form of congenital disorders of N‑linked glycosylation characterized by a psychomotor delay‑dysmorphism (pectus carinatum, dorsolumbar kyphosis and severe sinistroconvex scoliosis, short distal phalanges, genua vara, pedes planovalgi syndrome) with postnatal growth deficiency and major spondylo‑, epi‑, and metaphyseal skeletal involvement,” with additional features including facial dysmorphism, nephrotic syndrome, cardiac defects, and feeding problems.[3][3][3][3] OMIM entry #614727 similarly characterizes congenital disorder of glycosylation type IIk (CDG2K) as a variable autosomal recessive disease whose cardinal manifestations include psychomotor retardation, growth retardation and short stature, dysmorphism, hypotonia, eye abnormalities, acquired microcephaly, hepatomegaly, and skeletal dysplasia.[10][8] These authoritative disease‑level descriptions synthesize data from individual case reports, small case series, and biochemical studies, and therefore largely reflect aggregated disease‑level information rather than single EHR‑derived narratives.[2][15][15][12]

1.2 Key Identifiers and Ontology Placement

The primary identifiers for TMEM165‑CDG across major databases are well established. OMIM lists congenital disorder of glycosylation, type IIk under entry 614727, associated with TMEM165 (gene OMIM:614726) on cytogenetic location 4q12.[8][10] Orphanet assigns TMEM165‑CDG the Orpha number 314667, noting a prevalence <1/1,000,000, autosomal recessive inheritance, and infancy/neonatal age of onset.[3][3][3] In the Mondo Disease Ontology, TMEM165‑CDG corresponds to MONDO:0013870, designated as “congenital disorder of glycosylation type IIk” or TMEM165‑CDG.[9][38] ICD‑10 classifies this disease under E77.8 (“Other specified disorders of glycoprotein metabolism”), and ICD‑11 under 5C54.0 (“Congenital disorders of glycosylation”), with TMEM165‑CDG recognized among specific subtypes.[3][3][3] SNOMED CT includes an associated concept (732252005) for congenital disorders of glycosylation, which can be further specialized by the TMEM165‑CDG subtype according to OMIM and Orphanet mappings.[8][10][12]

These identifiers ensure interoperability across clinical and research systems and allow integration into resources such as GlyCosmos, which lists TMEM165‑CDG (congenital disorder of glycosylation type IIk; DOID:0070263) with synonyms and an association to TMEM165 gene ID 55858.[38] Human Phenotype Ontology (HPO) mapping for TMEM165‑CDG includes terms such as hepatomegaly (HP:0002240), hypotonia (HP:0001252), midface retrusion (HP:0011800), low‑set ears (HP:0000369), elevated creatine kinase (HP:0003236), failure to thrive (HP:0001508), malar flattening (HP:0000272), thrombocytopenia (HP:0001873), secondary microcephaly (HP:0005484), and osteoporosis (HP:0000939), among others.[38] Collectively, these identifiers and ontology placements position TMEM165‑CDG within broader frameworks of metabolic disorders, skeletal dysplasias, and neurodevelopmental conditions, facilitating standardized phenotype annotation and computational analysis.

1.3 Synonyms and Alternative Names

TMEM165‑CDG has accumulated a set of synonymous names across the CDG literature and disease databases, reflecting historical nomenclature evolution. Orphanet lists the following synonyms: “Carbohydrate deficient glycoprotein syndrome type IIk,” “Congenital disorder of glycosylation type 2k,” “Congenital disorder of glycosylation type IIk,” “CDG syndrome type IIk,” “CDG‑IIk,” and “CDG2K.”[3][3][3][38][3] ClinVar and ClinGen entries similarly use “TMEM165‑congenital disorder of glycosylation,” “CDG IIk,” and “TMEM165‑CDG” as synonyms.[6][6][6][6] In early reports, patients were described as having “a novel congenital disorder of glycosylation type II” due to a TMEM165 mutation, before the specific type IIk designation was widely adopted.[2][15][15][2]

Gene‑centric databases also list alternative gene names that may appear in older literature or in cross‑species studies, including FT27, GDT1 (yeast ortholog), CDG2K, TPARL, TMPT27, and SLC64A1.[5][21][5][1][41] From an ontology perspective, the preferred disease name for knowledge‑base usage is TMEM165‑CDG (also captured by MONDO:0013870 and DOID:0070263), while the exact OMIM name is “Congenital disorder of glycosylation, type IIk.”[8][10][38] For clarity in clinical contexts, describing the condition as a “TMEM165‑related congenital disorder of glycosylation (type IIk; mixed N‑ and O‑glycosylation defect)” can help clinicians recognize the mechanistic and biochemical specificity.

1.4 Evidence Source Types

Information about TMEM165‑CDG is derived from multiple evidence streams, which should be distinguished in a structured knowledge base. The initial disease characterization was based on human clinical case series combining clinical phenotyping, biochemical glycosylation profiling (serum transferrin isoelectric focusing, ApoC‑III isoelectric focusing, plasma N‑ and O‑glycan analysis), and molecular genetics (autozygosity mapping, Sanger sequencing, deep intronic variant identification) in a small number of families.[2][13][15][15] Subsequent clinical reports have added individual patient histories across different age ranges and geographic settings, including adolescence and childhood diagnoses, with detailed neurological and skeletal descriptions.[9][15][9]

Model organism studies, especially in Saccharomyces cerevisiae (Gdt1p) and conditional knockout mice, provide mechanistic insight into TMEM165 function in Golgi cation transport, lactose biosynthesis, and proteoglycan synthesis, and are distinct from but complementary to human clinical data.[4][19][23][26][31][35][1][26][39][40] In vitro cell culture studies using HEK293, ATDC5 and fibroblast lines offer molecular and biochemical evidence on glycosylation defects, Mn(^2+)/Ca(^2+) transport, and signaling pathway disruption.[4][1][35][19][7] Computational and evolutionary analyses of UPF0016 family proteins further inform structural and phylogenetic aspects of TMEM165 but are more peripheral to direct clinical characterization.[41]

Aggregated disease‑level resources such as OMIM, Orphanet, GlyCosmos, and GeneReviews‑style articles synthesize these various evidence types, and most of the disease‑level descriptors used here rely on such aggregation rather than individual EHR‑level data.[3][8][10][21][12][38][7] For knowledge‑base purposes, tagging each claim with its primary evidence type—human clinical, model organism, in vitro, or computational—allows downstream reasoning about evidentiary strength and translational relevance.

2. Etiology

2.1 Primary Causal Factors: Genetic Etiology

TMEM165‑CDG is unequivocally a genetically determined Mendelian disorder, with biallelic pathogenic variants in TMEM165 as the primary causal factor.[2][8][10][24][5] TMEM165 encodes a 324‑amino‑acid multi‑pass transmembrane protein with a perinuclear Golgi‑like distribution in fibroblasts and is part of the conserved UPF0016 family of cation transporters.[5][21][1][41] Foulquier et al. identified homozygous or compound heterozygous mutations in TMEM165 in five patients from four families with CDG2K, including deep intronic splice variants, missense mutations, and nonsense alleles.[8][10][13][15][15] ClinVar and Malacards list several pathogenic variants: c.792+182G>A (deep intronic splice site), c.377G>A (p.Arg126His), c.747G>A (p.Trp249Ter), and c.910G>A (p.Gly304Arg), among others.[20][24][25]

At the functional level, TMEM165 operates as a cation/(\mathrm{H}^+) antiporter that supplies the Golgi and secretory pathway with the Mn(^2+) and Ca(^2+) required for glycosyltransferases and glycosidases, including galactosyltransferases and sialyltransferases.[1][1][19][7] Loss of TMEM165 leads to impaired Mn(^2+) homeostasis in the Golgi, defective N‑ and O‑glycosylation, hypogalactosylation and hyposialylation of N‑glycans, and shortened glycosaminoglycan chains on proteoglycans.[4][1][35][19][7] Thus, TMEM165‑CDG is etiologically a loss‑of‑function glycosylation disorder rooted in defective Golgi ion transport rather than primary defects in glycosyltransferase catalytic domains.

Environmental, infectious, or acquired factors are not known to cause TMEM165‑CDG in the absence of TMEM165 mutations, and there is no evidence of somatic variants driving an analogous acquired condition.[20][21][12] Consequently, the etiologic classification is a monogenic autosomal recessive disease with complete dependence on germline biallelic pathogenic variants in TMEM165, consistent with MONDO:0013870 and DOID:0070263 definitions.[8][10][38]

2.2 Genetic Risk Factors: Pathogenic Variants and Susceptibility

The primary genetic risk factors for TMEM165‑CDG are pathogenic or likely pathogenic variants in TMEM165 that disrupt protein expression or function. ClinVar pathogenic entries include the deep intronic splice mutation c.792+182G>A, identified in three related patients and classified as pathogenic based on segregation and functional evidence showing TMEM165 deficiency and glycosylation defects.[15][20][24][15] Missense variants such as c.377G>A (p.Arg126His), c.781G>A (p.Ala261Thr), and c.910G>A (p.Gly304Arg) are reported as pathogenic or likely pathogenic in patients with TMEM165‑CDG, often found in compound heterozygous configurations.[8][20][24][6][6]

Malacards reports at least 113 ClinVar genetic variation entries associated with congenital disorder of glycosylation, type IIk, spanning single‑nucleotide variants and larger deletions encompassing TMEM165.[24] Most variants are extremely rare or absent in large population datasets (gnomAD, ExAC), consistent with the ultra‑rare prevalence of TMEM165‑CDG, although specific allele frequencies are not detailed in the available summaries.[24][5][38] The functional consequences at the protein level are largely loss‑of‑function, via impaired splicing, premature truncation, or disruption of conserved transmembrane or cation‑binding motifs in TMEM165, as inferred from conservation and UPF0016 family studies.[1][21][19][41]

Modifier genes and susceptibility loci outside TMEM165 have not been systematically identified for TMEM165‑CDG, although theoretical modifiers could include genes affecting manganese transport (e.g., SLC39A8, Pmr1 orthologs), galactosyltransferases (e.g., B4GALT1), or other Golgi ion pumps (e.g., ATP2C1, ATP2A2).[4][19][23][19][7] Current literature has not established specific modifier alleles that consistently alter disease severity or penetrance, and the small number of reported patients limits statistical detection of such factors.[12][7]

2.3 Environmental Risk and Protective Factors

There is no evidence that environmental exposures such as toxins, lifestyle factors, radiation, or diet independently cause TMEM165‑CDG, given its clear monogenic etiology.[2][8][10][12] However, environmental factors can modulate the phenotypic expression and may act as protective factors when targeted therapeutically. The most notable protective factor is oral D‑galactose supplementation, which has been shown to rescue glycosylation defects in TMEM165‑CDG fibroblasts and in patients.[27][29][32] A clinical study in multiple TMEM165‑CDG patients demonstrated that titrated oral D‑galactose (0.5–2.5 g/kg/day up to 50 g/day) improved transferrin glycosylation profiles, decreased hypogalactosylated N‑glycan structures, and ameliorated endocrine and coagulation abnormalities.[27][29][32] Nutritional therapy reviews further emphasize that galactose supplementation reduced hypoglycemic episodes and improved seizure control, although some biochemical markers, such as transaminases, remain elevated.[29][30]

Mechanistically, galactose likely acts as a secondary modulator of glycosyltransferase activity, particularly B4GALT1, whose function is both manganese and galactose concentration sensitive; increased substrate availability may partially compensate for reduced Mn(^2+) delivery to the Golgi by TMEM165.[29][32][7] Manganese supplementation has also been used experimentally to correct glycosylation defects in TMEM165‑deficient cell lines and yeast, suggesting that controlled Mn(^2+) intake might be protective at the cellular level, though systemic therapeutic use in humans requires careful toxicity monitoring.[4][19][23][19][16] There is no evidence that lifestyle factors such as exercise, smoking, or alcohol consumption significantly influence disease risk, though general metabolic health may impact overall morbidity.

2.4 Gene–Environment Interactions

Gene–environment interactions in TMEM165‑CDG primarily concern how nutritional interventions and trace element availability modulate the phenotypic consequences of TMEM165 mutations. The causal chain begins with TMEM165 loss‑of‑function, which reduces Mn(^2+) and Ca(^2+) delivery to the Golgi, impairing glycosylation. Supplementation with Mn(^2+) in cell models and yeast restores glycosylation, indicating that environmental Mn(^2+) availability can partially compensate for the defective transporter.[4][19][23][19][16] In humans, D‑galactose supplementation modulates glycosyltransferase efficiency and improves glycan structures, demonstrating a gene–diet interaction where substrate supply mitigates the impact of impaired Mn(^2+) homeostasis.[27][29][32]

More broadly, the lactating mammary gland studies show that TMEM165 conditional knockout in mouse milk‑producing cells leads to decreased lactose biosynthesis and lower milk Ca(^2+)/Mn(^2+) content, with secondary changes in milk composition (relative increases in fat, protein, iron, and zinc) driven by altered osmosis and nutrient transport.[1][31] These findings highlight how TMEM165 function interacts with dietary mineral and carbohydrate flux to shape secretory product composition, although they do not directly map to human protective factors in the congenital disease context. No CTD‑style associations linking environmental toxicants to TMEM165‑CDG onset have been reported, underscoring its purely genetic etiology.[21][12][7]

From an ontology perspective, gene–environment interaction could be modeled with GO Biological Process terms such as “response to manganese ion” (GO:0010043) and “regulation of glycosylation” (GO:0060590), and CHEBI terms for D‑galactose (CHEBI:28260) and manganese(2+) (CHEBI:29074). CL terms for relevant cell types would include chondrocytes (CL:0000138), hepatocytes (CL:0000182), and mammary gland epithelial cells (CL:0002327), all of which participate in TMEM165‑mediated glycosylation processes and may be sensitive to nutritional modulation.[31][35][7]

3. Phenotypes

3.1 Global Clinical Phenotype Spectrum

TMEM165‑CDG presents as a multisystem disorder with a characteristic combination of neurodevelopmental, skeletal, endocrine, hepatic, renal, cardiac, and dysmorphic features.[2][10][15][15][3][12][7] The global phenotype is shaped by defective glycosylation across diverse proteins, proteoglycans, and lipids, which impacts extracellular matrix integrity, hormone and coagulation factor function, cell adhesion, and organ development.[4][35][12][7] Human clinical reports, Orphanet summaries, and GlyCosmos HPO mappings converge on a relatively consistent core phenotype, albeit with variable severity and some heterogeneity among affected individuals.[3][9][15][3][12][38]

In general, affected individuals show psychomotor retardation, including delayed achievement of motor milestones (sitting, walking) and speech, often with hypotonia and seizures.[2][10][9][15][9][12] Growth retardation and short stature are almost universal, with marked postnatal growth deficiency and failure to thrive.[3][10][15][3][12][38] Bone dysplasia is a striking hallmark, involving epiphyseal, metaphyseal, and diaphyseal abnormalities, osteoporosis, broad metaphyses, irregular epiphyses, thin bone cortex, genu varum, scoliosis, and pectus carinatum.[15][15][3][35][37] Facial dysmorphism includes midface hypoplasia, malar flattening, low‑set ears, small teeth, and a moderately high arched palate.[3][15][3][38]

Visceral involvement spans hepatomegaly and hepatosplenomegaly, nephrotic syndrome, cardiac defects (including cardiomyopathy), restrictive lung pathology, and feeding problems with pseudo‑obstruction.[2][10][9][15][33][12] Endocrine abnormalities such as partial growth hormone deficiency, hypoglycemia, and pituitary hypoplasia have been reported.[9][27][32][9] Laboratory abnormalities include abnormal transferrin isoform profiles (type II pattern), ApoC‑III glycoform shifts reflecting O‑glycosylation defects, elevated creatine kinase, and coagulopathy with abnormal coagulation parameters.[2][15][27][32][36][12][38] These phenotypes typically manifest in infancy and childhood, with some patients diagnosed later in adolescence, and symptom severity can range from moderate multisystem disease to severe psychomotor retardation and skeletal deformity.[9][15][15][3][12]

3.2 Neurological and Developmental Phenotypes

Neurological involvement in TMEM165‑CDG is prominent and contributes significantly to morbidity and quality‑of‑life impairment. Common neurological phenotypes include global developmental delay, psychomotor retardation, hypotonia, seizures, and structural brain abnormalities.[2][10][9][15][9][12] Foulquier et al. described two siblings with severe psychomotor delay, hypotonia, white‑matter abnormalities, pituitary hypoplasia, and acquired microcephaly.[2][9][9] Zeevaert et al. reported psychomotor‑dysmorphism syndrome with unsupported sitting at 9 months, independent walking at 2 years, and first words at 18 months, accompanied by brain atrophy, enlarged ventricles, periventricular and subcortical white matter abnormalities, hyporeflexia, and pituitary hypoplasia.[15][15][9][9]

A recent review on the putative role of TMEM165 in congenital cardiomyopathies summarized that TMEM165 deficiency causes neurological alterations in TMEM165‑CDG patients, frequently including global developmental/psychomotor delay, CNS abnormalities (white matter changes, cerebellar atrophy), seizures, and hypotonia.[9][9][9] The HPO terms capturing these phenotypes include developmental delay (HP:0001263), psychomotor retardation (HP:0001265), muscular hypotonia (HP:0001252), seizures (HP:0001250), white matter abnormalities (HP:0002500), cerebellar atrophy (HP:0001272), microcephaly (HP:0000252), and pituitary hypoplasia (HP:0007910).[9][12][38]

Age of onset for neurological symptoms is typically in infancy or early childhood, with early developmental delay and hypotonia evident in the first year of life.[2][15][15][3][12] Symptom severity ranges from moderate delay with eventual acquisition of ambulation and speech to severe psychomotor retardation and neuromotor regression.[9][15][15][9][12] Progression can be variable; some structural changes such as white matter abnormalities may be relatively stable, while neurodevelopmental gains may continue slowly with supportive therapies.[12][37] Quality‑of‑life impact is substantial, affecting motor, cognitive, and social functioning and necessitating long‑term multidisciplinary rehabilitation, special education, and caregiver support.

3.3 Skeletal and Musculoskeletal Phenotypes

Skeletal manifestations are among the most distinctive phenotypes of TMEM165‑CDG and were key to its original clinical recognition. Bone dysplasia with major spondylo‑, epiphyseal, metaphyseal, and diaphyseal involvement has been consistently documented.[2][15][15][3][35][37][12] Zeevaert et al. described osteoporosis and important epi‑ and metaphyseal dysplasia with broad metaphyses, irregular epiphyses, and thin bone cortex in three patients homozygous for the deep intronic splice mutation c.792+182G>A.[15][15] Orphanet emphasizes skeletal dysplasia manifested by pectus carinatum, dorsolumbar kyphosis, severe sinistroconvex scoliosis, short distal phalanges, genua vara, and pedes planovalgi.[3][3][3]

At the molecular level, TMEM165 deficiency in prechondrocyte mouse ATDC5 and human HEK293 cells impairs polymerization of heparan‑sulfate and chondroitin‑sulfate glycosaminoglycan chains of proteoglycans, producing shortened GAG chains and altered proteoglycan synthesis.[35] This leads to aberrant TGF‑β/BMP signaling, accelerated timing of Indian hedgehog (Ihh) expression, and early chondrocyte maturation and hypertrophy, providing a mechanistic explanation for skeletal dysplasia and dwarfism.[35] The authors conclude that “TMEM165 deficiency leads to skeletal disorder characterized by major skeletal dysplasia and pronounced dwarfism.”[28][35]

HPO terms applicable to these skeletal phenotypes include skeletal dysplasia (HP:0002652), osteoporosis (HP:0000939), short stature (HP:0004322), genu varum (HP:0002970), scoliosis (HP:0002650), pectus carinatum (HP:0000768), kyphosis (HP:0002808), epiphyseal dysplasia (HP:0002658), metaphyseal dysplasia (HP:0002816), diaphyseal dysplasia (HP:0002759), and joint hyperlaxity (HP:0001387).[15][15][3][35][37][38] Age of onset is early, often in childhood as growth delays and deformities become apparent, while progression may involve worsening spinal curvature and joint anomalies.[15][15][3] The quality‑of‑life impact includes pain, mobility limitations, orthopedic complications, and psychosocial effects related to short stature and skeletal deformities.

3.4 Dysmorphic, Hepatic, Renal, Cardiac, and Endocrine Phenotypes

TMEM165‑CDG is associated with characteristic facial dysmorphism, visceral involvement, and endocrine abnormalities. Orphanet and case reports describe midface hypoplasia or retrusion, malar flattening, low‑set ears, small teeth, and moderately high arched palate.[3][15][15][3][38] Eye abnormalities such as strabismus, ptosis, nystagmus, and retinal pigment alterations (“in fundo” temporal epithelial pigment changes) are frequently noted.[2][9][15][15][9] HPO terms capturing these features include midface retrusion (HP:0011800), malar flattening (HP:0000272), low‑set ears (HP:0000369), strabismus (HP:0000486), ptosis (HP:0000508), and nystagmus (HP:0000639).[38]

Hepatic manifestations include hepatomegaly, hepatosplenomegaly, elevated transaminases, and liver injury patterns that fit within the broader CDG spectrum.[2][10][15][33][34][12] A cohort study of 39 CDG patients, including one with TMEM165‑CDG, found complex liver injury patterns with predominant hepatocellular injury (elevated ALT and AST) and variable fibrosis, emphasizing the need for regular liver surveillance in all CDG types.[33][34] HPO terms include hepatomegaly (HP:0002240), hepatosplenomegaly (HP:0001433), abnormal liver function (HP:0002910), and elevated alanine aminotransferase (HP:0002910).[33][38]

Renal involvement, particularly nephrotic syndrome and renal failure, has been reported by Orphanet and recent neurological/cardiomyopathy reviews.[3][9][9][12] Cardiac defects in TMEM165‑CDG include structural heart defects and cardiomyopathy, which align with the broader observation that glycosylation defects are recurrently associated with hypertrophic or dilated cardiomyopathy.[9][21][12] Endocrine features include partial growth hormone deficiency, pituitary hypoplasia, hypoglycemia, and other endocrinopathies improved by galactose therapy.[9][27][32][12] HPO terms for these include nephrotic syndrome (HP:0000108), renal insufficiency (HP:0000083), cardiomyopathy (HP:0001638), congenital heart malformation (HP:0001272), growth hormone deficiency (HP:0000824), hypoglycemia (HP:0001943), and pituitary hypoplasia (HP:0007910).[9][27][12][38]

Symptom onset for these visceral and endocrine phenotypes is generally in infancy or childhood, with episodic manifestations such as fever episodes and transient epilepsy noted in some cases.[9][15][9] Severity is variable; some patients experience mild liver enzyme elevations or subclinical cardiac changes, while others develop overt nephrotic syndrome or cardiomyopathy.[33][12] Quality‑of‑life impact ranges from asymptomatic biochemical changes to life‑threatening organ dysfunction requiring specialized care.

3.5 Laboratory Abnormalities and Glycosylation Profiles

Laboratory phenotypes in TMEM165‑CDG are central to its diagnosis and mechanistic classification. Patients exhibit an abnormal type II profile on serum transferrin isoelectric focusing, characterized by increased disialotransferrin and asialotransferrin isoforms reflecting defective N‑linked glycan processing.[2][13][36] Apolipoprotein C‑III isoform analysis shows decreased monosialo‑forms and increased asialo‑forms, indicating defective mucin‑type O‑glycosylation in the Golgi.[12][12] Plasma N‑glycan and O‑glycan analyses reveal undersialylation and undergalactosylation of N‑glycans and combined N‑ and O‑glycosylation defects.[2][4][27][32][12][7]

A key biochemical hallmark is hypogalactosylation of N‑glycans and defective terminal sialylation, consistent with TMEM165’s role in Mn(^2+)‑dependent galactosyltransferase and sialyltransferase function.[4][27][32][7] Abnormal glycosylation of lipids has also been reported, representing the first description of lipid glycosylation abnormalities in TMEM165‑CDG.[27][32] Additional lab abnormalities include elevated circulating creatine kinase (indicative of muscle involvement), thrombocytopenia, coagulopathy with abnormal clotting parameters, and dyslipidemia (high cholesterol).[27][32][12][38] Endocrine lab findings can include low growth hormone and hypoglycemia, which may improve on galactose therapy.[27][29][32]

HPO terms for laboratory phenotypes include abnormal transferrin isoform profile (HP:0003160), abnormal ApoC‑III isoelectric focusing (HP:0031848), elevated creatine kinase (HP:0003236), thrombocytopenia (HP:0001873), coagulopathy (HP:0001968), abnormal cholesterol level (HP:0003119), and hypoglycemia (HP:0001943).[12][27][32][12][38] Age of detection often coincides with diagnostic workup in infancy or childhood, and progression may improve partially with galactose supplementation.[27][29][32] Quality‑of‑life impact is mostly indirect through organ complications (e.g., bleeding, muscle weakness, metabolic instability).

4. Genetic and Molecular Information

4.1 Causal Gene: TMEM165

The causal gene for TMEM165‑CDG is TMEM165, also known as FT27, GDT1, CDG2K, TPARL, TMPT27, and SLC64A1.[5][21][5][1][41] TMEM165 is located on chromosome 4q12, with genomic coordinates 4:55,395,957–55,453,397 (GRCh38), and consists of six exons encoding a predicted 324‑amino‑acid multi‑pass transmembrane protein.[5][8][21] RefSeq transcript NM_018475.5 is commonly referenced for clinical variant nomenclature.[6][6][6][6] TMEM165 belongs to the UPF0016 family of uncharacterized proteins, now recognized as conserved cation transporters across eukaryotes.[21][41]

Subcellular localization studies show that TMEM165 has a perinuclear Golgi‑like distribution in fibroblasts, aligning with its role in Golgi ion homeostasis.[5][1][39][7] Gene Ontology cellular component annotations highlight the Golgi apparatus (GO:0005794), lysosome (GO:0005764), endoplasmic reticulum (GO:0005783), and plasma membrane (GO:0005886), although the primary functional localization for glycosylation is the Golgi.[1][7] HGNC approved gene symbol is TMEM165 (HGNC:30760), and NCBI Gene ID is 55858.[5][21][5][38]

4.2 Pathogenic Variants: Types, Classification, and Origin

Pathogenic variants in TMEM165 span splice‑site mutations, missense changes, nonsense truncations, and larger deletions, all of which can lead to TMEM165‑CDG when biallelic.[2][8][10][20][24] The deep intronic splice mutation c.792+182G>A was identified in three patients with TMEM165‑CDG and shown to cause aberrant splicing and TMEM165 deficiency, with corresponding glycosylation defects.[15][15] ClinVar classifies this variant (rs793888506) as pathogenic for congenital disorder of glycosylation, type IIk.[20][24][25]

Other pathogenic missense variants include c.377G>A (p.Arg126His), c.781G>A (p.Ala261Thr), and c.910G>A (p.Gly304Arg), all reported in homozygous or compound heterozygous states in affected individuals and classified as pathogenic based on segregation, functional studies, and conservation.[8][20][24][6][6] Nonsense variants such as c.747G>A (p.Trp249Ter) lead to premature truncation and are similarly pathogenic.[24] Malacards lists 113 ClinVar variants associated with congenital disorder of glycosylation type IIk, many of which map to TMEM165 and are annotated as pathogenic or likely pathogenic.[24]

These variants are germline in origin, inherited in autosomal recessive fashion, and there is no evidence for somatic TMEM165 variants causing TMEM165‑CDG in cancer or acquired disease contexts.[20][21][12] Functional consequences at the protein level predominantly represent loss of function, either through reduced or absent protein expression (nonsense, splice) or impaired cation transport activity (missense in conserved motifs).[1][21][19][41] ACMG/AMP classification criteria have not been fully formalized for all variants, but ClinVar assertions generally align with pathogenic status based on robust literature evidence.[20][24][6][6]

Allele frequencies in general populations are extremely low; TMEM165‑CDG is ultra‑rare, with Orphanet prevalence <1/1,000,000, implying carrier frequencies on the order of 1 in several thousand for specific variants, assuming Hardy–Weinberg equilibrium.[3][3][12][38] Population databases such as gnomAD and ExAC may contain occasional heterozygous carriers of some missense variants, but no homozygotes, consistent with severe autosomal recessive disease.[24][5][38] Founder effects have not been definitively documented, although clustering of cases in consanguineous families suggests local enrichment of specific variants.[2][15][15][12]

4.3 Molecular Function, Transport Activity, and Protein Dysfunction

TMEM165 is a multi‑pass transmembrane cation/(\mathrm{H}^+) antiporter that supplies the secretory pathway with Mn(^2+) and Ca(^2+), essential cofactors for Golgi glycosyltransferases and glycosidases.[1][1][19][7] Direct transport assays in reconstituted Lactococcus lactis and yeast systems established that TMEM165 and its yeast ortholog Gdt1p import Ca(^2+) and Mn(^2+) in exchange for (\mathrm{H}^+), with the direction of (\mathrm{H}^+) flux set by prevailing ion gradients, and that this activity controls Golgi pH.[1][23][26][19][39] Loss of TMEM165 leads to defective Golgi Mn(^2+) homeostasis, which impairs Mn(^2+)‑dependent glycosyltransferases such as β1,4‑galactosyltransferase (B4GALT1) and sialyltransferases, resulting in hypogalactosylation and undersialylation of N‑glycans.[4][1][27][32][19][7]

Yeast studies have shown that Gdt1p localizes to the Golgi and is required for Ca(^2+) tolerance, proper Ca(^2+) response after osmotic shock, and N‑ and O‑linked protein glycosylation in the presence of high external Ca(^2+), with glycosylation restored by Mn(^2+) supplementation.[19][23][26][26][19][40] This directly links UPF0016 family members to Mn(^2+) and Ca(^2+) homeostasis in the Golgi and supports the mechanistic inference that TMEM165 dysfunction in humans primarily affects these cations. TMEM165 also influences Golgi pH regulation, which impacts glycosylation enzyme activity and vesicular trafficking.[1][1][19][7]

Protein dysfunction in TMEM165‑CDG arises from impaired TMEM165 expression or function, leading to reduced Mn(^2+) and Ca(^2+) transport into the Golgi lumen and consequent glycosylation defects.[2][4][1][19][7] Structural modeling and evolutionary analyses suggest highly conserved transmembrane segments and acidic residues that participate in cation binding and transport; missense variants in these regions likely disrupt the electrochemical coupling required for (\mathrm{H}^+) exchange and cation movement.[21][41] GO molecular function terms relevant here include “manganese ion transmembrane transporter activity” (GO:0005384), “calcium ion transmembrane transporter activity” (GO:0015085), and “proton antiporter activity” (GO:0015078).[23][1][19][7]

4.4 Modifier Genes, Epigenetics, and Chromosomal Abnormalities

Specific modifier genes influencing TMEM165‑CDG severity have not been conclusively identified. However, genes involved in Golgi cation homeostasis, such as ATP2C1 (SPCA1), ATP2A2 (SERCA2), and SLC39A8 (ZIP8 manganese transporter), may compensate partially for TMEM165 dysfunction.[4][7][16][23][19][7] For instance, SERCA2 activity has been reported to compensate Mn(^2+) insufficiency in the Golgi when TMEM165 is disrupted, highlighting functional redundancy in maintaining Mn(^2+) levels.[7][7] Similarly, Pmr1p, the yeast Golgi P‑type ATPase importing Ca(^2+) and Mn(^2+), interacts with Gdt1p to regulate cation concentrations, suggesting that human orthologs may modulate TMEM165‑CDG phenotypes.[19][23][26][19][40]

Epigenetic changes directly linked to TMEM165‑CDG have not been reported, and there is no evidence of DNA methylation or histone modification patterns specifically affecting TMEM165 expression beyond canonical promoter regulation.[21][7] Chromosomal abnormalities such as aneuploidy or translocations are not implicated in TMEM165‑CDG; the disease is caused by point mutations and small indels within the TMEM165 locus on 4q12.[8][10][24][5][38] A large deletion encompassing the region 4:55,124,936–57,368,027 has been annotated in Malacards as a variant with no classification yet, but its clinical significance for TMEM165‑CDG remains unclear.[24]

From a genomic structural perspective, TMEM165 resides in a standard chromosomal context without known recurrent rearrangements. DECIPHER and dbVar do not highlight recurrent copy number variations specifically associated with TMEM165‑CDG, reinforcing its point‑mutation etiology.[24][5][38] In summary, modifier genes and epigenetic factors may modulate disease expression, but definitive evidence is scarce, and no large‑scale chromosomal abnormalities are part of the TMEM165‑CDG genetic landscape.

5. Environmental Information

5.1 Environmental Exposures and Toxins

No environmental toxins, radiation sources, industrial exposures, or pollutants have been identified as causal or major contributing factors for TMEM165‑CDG.[2][8][10][12] The disease is fundamentally monogenic, and there are no epidemiological signals linking chemical exposures to TMEM165‑CDG incidence in CTD or similar databases.[21][12][7] In vitro studies manipulating extracellular Ca(^2+) and Mn(^2+) concentrations demonstrate that high Ca(^2+) conditions in yeast require Gdt1p for proper glycosylation, and Mn(^2+) supplementation rescues glycosylation defects in TMEM165‑deficient cells.[19][23][26][19] However, these are experimental manipulations rather than environmental risk factors at population levels.

Given that manganese toxicity is a known concern in neurology and occupational medicine, any therapeutic Mn(^2+) supplementation for TMEM165‑CDG would need to balance potential benefit in glycosylation against neurotoxicity risk.[14][16][23] This therapeutic context is distinct from environmental exposure scenarios and does not imply that environmental Mn(^2+) levels contribute to disease onset.

5.2 Lifestyle and Diet Factors

Lifestyle factors such as smoking, alcohol consumption, and physical activity do not appear to influence TMEM165‑CDG risk, given the strong genetic basis.[2][10][12] However, dietary composition, particularly carbohydrate intake and micronutrient supplementation, can modulate disease expression as part of therapeutic interventions. Oral D‑galactose supplementation is the primary example of a diet‑based intervention that improves glycosylation and certain clinical parameters in TMEM165‑CDG.[27][29][32] Clinical studies titrating D‑galactose up to 1.5–2.5 g/kg/day (maximum 50 g) have reported safe administration and beneficial effects on endocrine and coagulation functions.[27][29][32]

Nutritional therapies reviews emphasize that galactose therapy has reduced the frequency of hypoglycemic episodes and improved seizure control in TMEM165‑CDG patients, although complete normalization of glycosylation has not been achieved.[29][30] The mechanism involves enhanced substrate availability for galactosyltransferases, particularly B4GALT1, which is sensitive to both galactose and manganese concentration.[29][32][7] Other dietary recommendations for CDG broadly focus on supporting metabolic stability, but no specific lifestyle factor is known to alter TMEM165‑CDG incidence.[29][37][12]

5.3 Infectious Agents

No infectious agents (bacteria, viruses, fungi, parasites) are known to cause or trigger TMEM165‑CDG.[2][10][12] The disease does not exhibit features of post‑infectious autoimmunity or immune dysregulation driven by pathogens, although immunodeficiency can occur in some CDG types.[12] TMEM165‑CDG patients may experience infections due to general multisystem vulnerability, but these are complications rather than etiologic drivers.[12][37] Infectious disease databases (ViPR, BV‑BRC, GIDEON) do not list TMEM165‑CDG as an infection‑related condition.

In summary, TMEM165‑CDG is etiologically a genetic disorder with minimal direct environmental or infectious contribution beyond therapeutic modulation.

6. Mechanism and Pathophysiology

6.1 Ordered Causal Chain from Mutation to Clinical Manifestation

Biallelic pathogenic variants in TMEM165 lead to loss or severe reduction of TMEM165 cation/(\mathrm{H}^+) antiporter function in the Golgi.[2][8][10][1][1]
Loss of TMEM165 transporter activity leads to decreased Mn(^2+) and Ca(^2+) import into the Golgi lumen and altered Golgi pH homeostasis.[4][1][23][26][19][7]
Decreased Golgi Mn(^2+)/Ca(^2+) availability leads to impaired activity of Mn(^2+)‑dependent and Ca(^2+)‑sensitive glycosyltransferases and glycosidases, including β1,4‑galactosyltransferase and sialyltransferases, resulting in defective N‑ and O‑glycosylation of proteins and glycosylation of lipids.[2][4][1][27][32][19][7]
Defective glycosylation leads to hypogalactosylation and hyposialylation of N‑glycans, altered O‑glycan structures on mucin‑type proteins (ApoC‑III), and abnormal glycosylation of glycolipids, disrupting multiple extracellular matrix proteins, receptors, and secreted factors.[2][4][12][27][32][35][7]
In chondrocytes and prechondrocyte cells, defective glycosylation leads to shortened chondroitin‑ and heparan‑sulfate glycosaminoglycan chains on proteoglycans, impairing proteoglycan synthesis and extracellular matrix organization.[28][35]
Shortened GAG chains and abnormal proteoglycans lead to dysregulated TGF‑β/BMP signaling and accelerated expression of Indian hedgehog (Ihh), resulting in early chondrocyte maturation, hypertrophy, and aberrant cartilage and bone development, causing skeletal dysplasia and dwarfism.[28][35]
Defective glycosylation of other proteins (e.g., hormone receptors, coagulation factors, adhesion molecules, transporters) leads to multisystem dysfunction including psychomotor retardation, hepatosplenomegaly, nephrotic syndrome, cardiomyopathy, endocrine abnormalities, and coagulopathy.[2][10][27][32][33][12][7]
The cumulative impact of skeletal dysplasia, neurodevelopmental impairment, organ dysfunction, and metabolic instability leads to the clinical TMEM165‑CDG phenotype: growth retardation, dysmorphism, hypotonia, seizures, skeletal deformities, liver injury, renal and cardiac involvement, and abnormal glycosylation profiles detectable in laboratory tests.[2][10][15][27][15][32][3][12][7]

Where specific intermediate steps (e.g., exact receptor targets, detailed signal transduction changes) are not fully experimentally demonstrated, they are inferred from known roles of glycosylation in extracellular matrix biology, growth factor signaling, and organ development.

6.2 Molecular Pathways and Glycosylation Cascades

At the molecular level, TMEM165 participates in fundamental pathways of N‑linked and O‑linked glycosylation in the Golgi apparatus. N‑glycosylation involves assembly of a lipid‑linked oligosaccharide in the ER, transfer to nascent proteins, and subsequent trimming and extension in the Golgi, including addition of galactose and sialic acid by β1,4‑galactosyltransferase and sialyltransferases.[12][12][7] O‑glycosylation comprises stepwise addition of carbohydrate chains to serine, threonine, and hydroxylysine residues by glycosyltransferases in the Golgi, generating mucin‑type and other O‑glycans.[12][12] TMEM165 deficiency interferes with terminal glycosylation steps that require Mn(^2+) as a cofactor, leading to undergalactosylation and undersialylation.[4][1][27][32][19][7]

The relevant pathways include KEGG N‑glycan biosynthesis, O‑glycan biosynthesis, and glycosaminoglycan biosynthesis (heparan‑sulfate, chondroitin‑sulfate). TMEM165’s role is upstream in these pathways, ensuring appropriate ion conditions for Golgi enzymes. Proteoglycan synthesis pathway is particularly affected; TMEM165 knockout in ATDC5 cells impairs elongation of HS and CS GAG chains, disrupting proteoglycan architecture.[35] This affects pathways such as TGF‑β signaling, BMP signaling, and Hedgehog signaling, which depend on proteoglycan interactions for gradient formation and receptor activation in cartilage.[28][35]

SERCA2 and other ATPases partially compensate Mn(^2+) insufficiency in the Golgi when TMEM165 is deficient, highlighting a network of cation transport pathways.[7][7] In yeast, Pmr1p and Gdt1p jointly regulate Ca(^2+) and Mn(^2+) concentrations at the Golgi level, affecting protein glycosylation under stress conditions.[19][23][26][19][40] Reactome and GO pathway annotations relevant to TMEM165‑CDG may include “protein glycosylation” (GO:0006486), “glycosaminoglycan biosynthetic process” (GO:0006024), “regulation of manganese ion homeostasis” (GO:0030026, inferred), and “Golgi organization” (GO:0007030).[4][35][19][7]

6.3 Cellular Processes: Golgi Homeostasis, Proteoglycan Synthesis, and Signaling

At the cellular level, TMEM165‑CDG affects critical processes within secretory pathway compartments. TMEM165 ensures Golgi luminal Mn(^2+) and Ca(^2+) levels, which are necessary not only for glycosyltransferases but also for glycosidases, quality control, and pH regulation.[4][1][19][7] Disrupted Golgi ion homeostasis alters glycosylation efficiency, glycoprotein folding, and trafficking. Golgi stress responses and altered vesicular transport may contribute to organelle dysfunction, although detailed apoptosis or autophagy changes are not well characterized in TMEM165‑CDG.[7][19][7]

Proteoglycan synthesis is particularly impacted in chondrocytes, where TMEM165 deficiency leads to shortened HS and CS chains on proteoglycans.[28][35] This impairs extracellular matrix assembly, mechanical properties, and signaling scaffold functions, influencing TGF‑β/BMP pathway activation and Indian hedgehog signaling.[35] The result is altered chondrocyte maturation dynamics, with early hypertrophy and disorganized cartilage development. These changes at the cellular level manifest as abnormal growth plate architecture, bone dysplasia, and dwarfism at the tissue and organ level.[15][28][15][35]

Beyond chondrocytes, defective glycosylation affects hepatocytes, renal tubular cells, cardiomyocytes, neurons, and endocrine cells, altering cell surface receptors, adhesion molecules, secreted hormones, and other glycoproteins.[2][10][27][32][33][12][7] For example, glycosylation defects in coagulation factors and platelet proteins contribute to coagulopathy and thrombocytopenia; glycosylation changes in hormone receptors and pituitary hormones impact endocrine axes.[27][29][32][12] GO biological process terms relevant to these cellular phenomena include “Golgi calcium ion homeostasis” (inferred), “glycosaminoglycan metabolic process” (GO:0006024), “chondrocyte differentiation” (GO:0002062), “regulation of signaling receptor activity” (GO:0010469), and “protein glycosylation” (GO:0006486).[28][35][7]

6.4 Protein Dysfunction and Structural Biology

Protein dysfunction in TMEM165‑CDG primarily involves loss of function of TMEM165 as a cation/(\mathrm{H}^+) antiporter. Structural studies and molecular evolution analyses of UPF0016 family proteins suggest conserved membrane topology and potential cation‑binding sites that are disrupted by missense mutations.[21][41] Gdt1p in yeast, a 280‑residue member of this family, has been shown to transport Mn(^2+) directly, reinforcing the link between UPF0016 and Mn(^2+) homeostasis.[23][41] Functional rescue experiments, where human TMEM165 expression suppresses yeast gdt1Δ Ca(^2+) sensitivity, indicate conserved transport function.[40][41]

In TMEM165‑CDG, missense mutations in TMEM165 likely impair cation binding, translocation pathways, or coupling to (\mathrm{H}^+) gradients. Nonsense and splice variants result in truncated or absent protein, eliminating transport activity entirely.[2][15][20][24][15] This is a classic loss‑of‑function mechanism at the protein level, distinguished from gain‑of‑function or dominant‑negative effects. There is no evidence of TMEM165 aggregation or misfolding leading to ER stress; dysfunction is mainly due to absence or reduced ionic transport capability in the Golgi.[21][19][7]

UniProt and PDB databases do not yet provide high‑resolution structures of TMEM165, but homology modeling and AlphaFold predictions can approximate transmembrane topology and potential cation interaction sites. Pfam and InterPro classify UPF0016 family domains, and these annotations support functional inference of cation transport. GO molecular function terms for TMEM165 include “manganese ion transmembrane transporter activity” (GO:0005384) and “proton antiporter activity” (GO:0015078), reflecting direct transport assays.[23][1][19][7]

6.5 Metabolic and Immune Changes

While TMEM165‑CDG is not primarily a metabolic disorder in the classical sense (e.g., energy metabolism), glycosylation defects impact metabolic pathways indirectly. Hypoglycosylation of membrane transporters and receptors may alter nutrient uptake and signaling; abnormal glycosylation of lipoproteins may influence lipid metabolism, as evidenced by high cholesterol and altered lipid glycosylation.[27][32][12] Lactose biosynthesis in the lactating mammary gland depends on TMEM165; conditional knockout mice show decreased lactose production, leading to more concentrated milk (higher fat, protein, iron, zinc) and decreased Ca(^2+)/Mn(^2+) content, illustrating metabolic consequences in a specific physiological context.[1][31]

Immune system involvement in TMEM165‑CDG is less prominent than in some other CDG types but may include immunodeficiency features, isolated leukocyte adhesion deficiency, or congenital dyserythropoietic anemia in mixed glycosylation disorders more broadly.[12][12] TMEM165‑CDG is classified under “mixed glycosylation” CDG in some reviews, with potential for immune abnormalities, though severe immunodeficiency is not a defining feature.[12][12] Glycosylation plays critical roles in immune recognition and receptor function, so subtle immune phenotypes may exist but are under‑reported due to the rarity of the disease.

6.6 Tissue Damage Mechanisms and Biochemical Abnormalities

Tissue damage in TMEM165‑CDG arises from chronic structural and functional insufficiencies rather than acute necrosis or inflammation. Skeletal tissue damage is driven by abnormal cartilage and bone matrix composition; shortened GAG chains and defective proteoglycans lead to mechanical weakness, growth plate disorganization, and increased fracture risk (osteoporosis).[15][28][15][35] Liver injury patterns in CDG, including TMEM165‑CDG, involve hepatocellular injury (elevated ALT/AST) without predominant cholangiocellular damage, suggesting metabolic stress and glycogen accumulation rather than cholestatic pathology.[33][34]

Biochemical abnormalities at the molecular level include enzyme deficiencies in effective glycosylation, receptor dysfunction due to altered glycan structures, and ion channel or transporter defects stemming from misglycosylation, though specific receptor targets in TMEM165‑CDG are not fully elucidated.[2][4][27][32][7] Coagulopathy reflects abnormal glycosylation of clotting factors and platelet glycoproteins; endocrinopathy reflects altered glycosylation of hormone receptors and pituitary hormones.[27][29][32][12] GO terms such as “abnormal blood coagulation” and “hormone metabolic process” are relevant, and CHEBI terms for manganese(2+) and D‑galactose capture key biochemical entities.[27][29][32][7]

6.7 Molecular Profiling and Advanced Technologies

Comprehensive omics‑level profiling of TMEM165‑CDG is limited due to its rarity, but some insights come from transcriptomic and proteomic analyses in model systems. TMEM165 knockout in ATDC5 cells and HEK293 cells has been used to assess proteoglycan synthesis and signaling pathway alterations, revealing profound deficiency in HS and CS GAG chain polymerization and aberrant TGF‑β/BMP signaling.[35] These studies, effectively targeted functional genomics screens using CRISPR‑Cas9, highlight cell‑type‑specific mechanisms in chondrocytes and support proteomics‑level changes in extracellular matrix composition.

Single‑cell and spatial transcriptomics data specific to TMEM165‑CDG patients are not yet reported, but the underlying mechanisms suggest that chondrocytes, hepatocytes, cardiomyocytes, neurons, and endocrine cells would exhibit distinct glycosylation‑related transcriptomic and proteomic signatures.[35][7] Multi‑omics integration remains conceptual rather than empirical in this disease context, though cross‑disease CDG analyses could highlight shared glycosylation pathway dysregulation. Functional genomics screens beyond CRISPR in ATDC5 cells have not been widely applied to TMEM165, but yeast gdt1Δ studies constitute classical genetic screens linking phenotype (Ca(^2+) sensitivity, glycosylation defects) to gene function.[19][23][26][40]

Cell Ontology terms for key cell types include chondrocyte (CL:0000138), hepatocyte (CL:0000182), cardiomyocyte (CL:0000746), neuron (CL:0000540), pituitary endocrine cell (CL:0002553), and mammary gland epithelial cell (CL:0002327), all of which participate in TMEM165‑mediated processes.[28][31][35][7] GO terms for biological processes include “protein glycosylation” (GO:0006486), “glycosaminoglycan biosynthetic process” (GO:0006024), “chondrocyte differentiation” (GO:0002062), and “Golgi organization” (GO:0007030).[35][7]

7. Anatomical Structures Affected

7.1 Organ‑Level Involvement and Body Systems

TMEM165‑CDG affects multiple organ systems, with prominent involvement of the skeletal, nervous, hepatic, renal, cardiovascular, endocrine, and hematologic systems. At the organ level, primary structures affected include bones (UBERON:0001474), cartilage (UBERON:0002418), brain (UBERON:0000955), liver (UBERON:0002107), kidneys (UBERON:0002113), heart (UBERON:0000948), pituitary gland (UBERON:0000007), and mammary gland in model organisms.[2][10][15][15][31][33][3][35][12][7]

The skeletal system exhibits major spondylo‑, epiphyseal, metaphyseal, and diaphyseal involvement, with kyphosis, scoliosis, genu varum, pectus carinatum, and short distal phalanges.[15][15][3][35][37] The nervous system is affected through psychomotor retardation, white matter abnormalities, cerebellar atrophy, seizures, and microcephaly.[2][9][15][9][12] The hepatobiliary system shows hepatomegaly and hepatosplenomegaly; the renal system manifests nephrotic syndrome and renal failure; the cardiovascular system experiences congenital heart defects and cardiomyopathy.[3][10][9][15][33][9][12] Endocrine system involvement includes pituitary hypoplasia and growth hormone deficiency.[9][27][32][9][12]

These organ‑level effects reflect systemic glycosylation defects impacting extracellular matrix, receptors, signaling molecules, and secreted proteins. The disease can thus be categorized as a multisystem metabolic and developmental disorder, with body systems including musculoskeletal, nervous, hematologic/coagulation, endocrine, cardiovascular, renal, and digestive/hepatic.

7.2 Tissue and Cell‑Type Level

At the tissue level, TMEM165‑CDG primarily affects connective tissues (cartilage, bone, extracellular matrix), neural tissue (white and gray matter), epithelial tissues (hepatic, renal tubular, endocrine, mammary), and muscular tissues (cardiac and skeletal muscle). Chondrocytes in cartilage tissue are a key cell population, exhibiting altered proteoglycan synthesis and premature hypertrophy.[28][35] Osteoblasts and osteoclasts may also be indirectly affected by extracellular matrix changes, contributing to osteoporosis.[15][15][35]

Hepatocytes in the liver accumulate abnormal glycogen and exhibit glycosylation‑related injury; renal tubular epithelial cells in the kidney likely participate in nephrotic syndrome pathophysiology.[33][34][12] Cardiomyocytes in the heart may experience altered glycosylation of membrane receptors and ion channels, contributing to cardiomyopathy.[9][21][12] Neurons and glial cells in the brain show white matter abnormalities and cerebellar atrophy, reflecting developmental glycosylation defects in axonal guidance, myelination, and synaptic function.[2][9][15][9][12] Pituitary endocrine cells are affected by hypoplasia and altered hormone glycosylation.[9][27][32][9]

Cell Ontology terms for these populations include chondrocyte (CL:0000138), osteoblast (CL:0000062), osteoclast (CL:0000063), hepatocyte (CL:0000182), renal tubular epithelial cell (CL:0000066), cardiomyocyte (CL:0000746), neuron (CL:0000540), oligodendrocyte (CL:0000128), and pituitary endocrine cell (CL:0002553).[28][33][35][7] TMEM165 expression in fibroblasts and mammary gland epithelial cells has been demonstrated, suggesting broad distribution in secretory cells.[5][31][1][7]

7.3 Subcellular Compartments

TMEM165 localizes primarily to the Golgi apparatus, with additional presence in lysosomes, ER, and plasma membrane.[5][1][7] GO cellular component terms include Golgi apparatus (GO:0005794), Golgi membrane (GO:0000139), lysosome (GO:0005764), endoplasmic reticulum (GO:0005783), and plasma membrane (GO:0005886).[1][7] The critical subcellular compartment for TMEM165‑CDG pathophysiology is the Golgi lumen, where Mn(^2+) and Ca(^2+) are required for glycosylation.

Golgi pH regulation and luminal ion homeostasis are central subcellular processes affected by TMEM165 dysfunction.[4][1][19][7] Altered Golgi ion content impacts glycosyltransferase localization and activity, vesicular trafficking, and possibly Golgi stress signaling. Lysosomal localization may relate to cation recycling or degradation pathways, but Golgi dysfunction is the dominant mechanism.[1][7] ER involvement is secondary, as initial N‑glycosylation occurs in the ER, but TMEM165 primarily affects Golgi processing.

7.4 Localization and Lateralization

Anatomical localization of skeletal deformities often exhibits bilateral symmetry, such as genu varum of both legs, scoliosis affecting the spine, and pectus carinatum affecting the chest wall.[15][15][3][35] Some features, like strabismus, can be unilateral (e.g., internal convergent strabismus of the right eye), highlighting asymmetric involvement.[3][9][15][3] White matter abnormalities and cerebellar atrophy are typically bilateral but may show regional distribution on neuroimaging.[2][9][15][9] Organ involvement (liver, kidney, heart) is systemic and not lateralized.

UBERON terms for specific anatomical sites include long bone (UBERON:0001474), vertebral column (UBERON:0002415), thoracic cage (UBERON:0006617), brain ventricles (UBERON:0003860), and pituitary gland (UBERON:0000007).[15][15][3][9] Lateralization phenotypes can be captured by HPO terms such as unilateral strabismus (HP:0012639) when appropriate.[9][15][38]

8. Temporal Development

8.1 Age of Onset and Onset Pattern

TMEM165‑CDG is a congenital disorder, with age of onset typically in infancy or early childhood.[3][10][3][12] Orphanet specifies age of onset as “Infancy, Neonatal,” indicating that symptoms may be present soon after birth or become evident during the first year of life.[3][3][3] Early manifestations include feeding difficulties, failure to thrive, hypotonia, developmental delay, and sometimes seizures, prompting metabolic evaluations and transferrin isoform testing.[2][15][15][12]

Some patients are diagnosed later in childhood or adolescence due to diagnostic delays, variable severity, or lack of initial recognition of CDG.[9][15][9][12] For example, Zeevaert et al. reported a child diagnosed at age 11 with psychomotor‑dysmorphism syndrome and major skeletal involvement.[15][15] Onset pattern is chronic and insidious, with slowly accumulating developmental and skeletal abnormalities rather than acute episodes. Episodic events such as seizures or fever episodes occur within this chronic disease course but are not primary onset manifestations.[9][9][12]

8.2 Disease Progression, Stages, and Course

Disease progression in TMEM165‑CDG is variable and depends on severity of glycosylation defects and organ involvement. Early stages involve developmental delay, hypotonia, and growth retardation, with skeletal deformities becoming more apparent as the child grows.[15][15][3][12] Intermediate stages see more pronounced skeletal dysplasia, spinal deformities, and metabolic complications such as liver injury, nephrotic syndrome, cardiomyopathy, and coagulopathy.[2][10][33][12] Advanced stages may involve chronic organ dysfunction, osteoporotic fractures, and significant neurodevelopmental disability.

The rate of progression is generally slow and chronic; TMEM165‑CDG is a lifelong condition. Some features, such as cerebellar ataxia in PMM2‑CDG, are non‑progressive and may improve with age; analogous detailed progression data for TMEM165‑CDG are lacking but may follow similar patterns where neurodevelopmental deficits stabilize rather than continually worsen.[37][12] Skeletal deformities, once established, may progress until skeletal maturity and then stabilize, while endocrine and metabolic abnormalities can be modulated by therapy (e.g., galactose supplementation).[27][29][32]

Disease course pattern is predominantly progressive in terms of skeletal changes and organ involvement, though some aspects may be relatively stable or amenable to improvement. TMEM165‑CDG is not self‑limited and persists throughout life, with chronic morbidity. Natural history studies specifically for TMEM165‑CDG are limited due to small patient numbers, but broader CDG registries, such as the Frontiers in CDG natural history study, include some TMEM165‑CDG cases and provide general guidance on monitoring liver and other organ manifestations.[33][34][12]

8.3 Remission, Critical Periods, and Intervention Windows

Spontaneous remission of TMEM165‑CDG does not occur, given its genetic basis. However, treatment‑induced partial remission of specific symptoms (hypoglycemia, seizures, coagulopathy) has been observed with galactose therapy.[27][29][32] For example, the frequency of hypoglycemic episodes improved on D‑galactose therapy, and seizures tended to improve, although transaminase elevation persisted.[29][30] These treatment responses reflect partial correction of glycosylation defects rather than full disease remission.

Critical periods for intervention include early infancy and childhood, when developmental trajectories and skeletal growth are most plastic. Early diagnosis and initiation of galactose supplementation and supportive therapies (physiotherapy, orthopedic interventions, nutritional support) may optimize neurodevelopmental outcomes and reduce severity of skeletal deformities.[27][29][32][37][12] Genetic counseling and carrier testing provide preconception and prenatal intervention windows for families at risk, allowing informed reproductive choices.[12]

Developmental biology considerations suggest that growth plate cartilage and brain white matter development are particularly vulnerable during early life, making timely management of glycosylation defects crucial.[28][35][9][12] There is currently no gene therapy available for TMEM165‑CDG, but future interventions might target these critical windows with molecular therapies.

9. Inheritance and Population

9.1 Epidemiology: Prevalence and Incidence

TMEM165‑CDG is an ultra‑rare disorder. Orphanet reports a prevalence <1/1,000,000, consistent with very low global case numbers.[3][3][12][38][3] The exact incidence (new cases per 100,000 per year) is not well quantified due to limited registries and the rarity of the disease, but it likely falls below 0.01 per 100,000 per year. Most published clinical reports describe only a handful of patients, supporting this ultra‑rare status.[2][15][15][12][7]

Global Burden of Disease (GBD) metrics for TMEM165‑CDG are not available; CDG as a group contribute minimally to overall burden statistics due to their rarity but have substantial impact on affected individuals and families. National registries and disease‑specific cohorts, such as the Frontiers in CDG natural history study, include limited numbers of TMEM165‑CDG patients among broader CDG populations.[33][34][12]

9.2 Inheritance Pattern, Penetrance, and Expressivity

TMEM165‑CDG follows an autosomal recessive inheritance pattern. OMIM, Orphanet, Malacards, and ClinVar consistently describe congenital disorder of glycosylation type IIk as autosomal recessive, with homozygous or compound heterozygous TMEM165 mutations causing disease.[3][8][10][24][3][12][38] Penetrance appears to be essentially complete for biallelic pathogenic variants; individuals with such genotypes exhibit some degree of the disease phenotype, though expressivity varies.[2][15][15][12]

Expressivity is variable, as indicated by OMIM’s description of CDG2K as an autosomal recessive disorder with a variable phenotype.[10][12] Some patients exhibit severe psychomotor retardation and marked skeletal dysplasia, while others have milder developmental delay or less pronounced skeletal involvement.[9][15][15][9][12] Organ involvement (e.g., cardiomyopathy, nephrotic syndrome) may also vary, and some features (such as seizures or microcephaly) are not universal.[12][38]

There is no evidence for genetic anticipation or germline mosaicism in TMEM165‑CDG, given the nature of point mutations and recessive inheritance.[8][10][20][24][12] Consanguinity plays a role in some cases, especially where homozygous deep intronic mutations were identified in consanguineous families.[2][15][15][12] Carrier frequency in the general population is unknown but likely extremely low; in consanguineous populations, localized founder effects may increase carrier frequency for specific variants.

9.3 Population Demographics and Geographic Distribution

TMEM165‑CDG cases have been reported in diverse geographic and ethnic contexts, including Europe and other regions, but specific ethnicity‑related prevalence has not been systematically characterized.[2][15][15][12] The small number of reported patients precludes robust analysis of ethnic or demographic trends. However, Orphanet’s prevalence estimate implies that TMEM165‑CDG is globally distributed but extremely rare.[3][3][12][38]

Geographic distribution of specific variants (e.g., c.792+182G>A) may reflect founder effects in particular regions or families, as seen in the three Belgian patients with a shared deep intronic mutation.[15][15] Sex ratio among TMEM165‑CDG patients appears roughly balanced; there is no indication of sex‑linked inheritance or marked sex bias.[2][15][15][12] Age distribution spans infancy through adulthood, with some adult patients described in CDG cohorts, but median age at diagnosis is in childhood.[33][34][12]

10. Diagnostics

10.1 Clinical and Laboratory Testing

Diagnosis of TMEM165‑CDG relies on a combination of clinical assessment, glycosylation profiling, and molecular genetic testing. Clinically, suspicion arises in infants or children with psychomotor retardation, growth deficiency, skeletal dysplasia, facial dysmorphism, hepatosplenomegaly, endocrine abnormalities, coagulopathy, and multisystem involvement suggestive of CDG.[2][15][15][3][37][12] Laboratory testing includes serum transferrin isoform analysis (transferrin isoelectric focusing) to detect type II CDG profiles, characterized by increased disialo‑ and asialotransferrin.[2][13][36][12]

Apolipoprotein C‑III isoform analysis complements transferrin testing by detecting mucin‑type O‑glycosylation defects; in TMEM165‑CDG, ApoC‑III shows decreased monosialo‑forms and increased asialo‑forms.[12][12] Plasma N‑glycan and O‑glycan analysis by mass spectrometry characterize hypogalactosylation and undersialylation patterns.[2][4][27][32][12][7] Liver function tests (ALT, AST), creatine kinase, coagulation panels, lipid profiles, and endocrine assays (growth hormone, glucose) provide additional markers.[27][32][33][34][12]

Imaging studies include skeletal radiographs demonstrating epiphyseal, metaphyseal, and diaphyseal dysplasia, osteoporosis, scoliosis, and pectus carinatum.[15][15][3][35][37] Brain MRI reveals white matter abnormalities, cerebellar atrophy, enlarged ventricles, and pituitary hypoplasia.[2][9][15][9][12] Echocardiography assesses congenital heart defects and cardiomyopathy; renal ultrasound evaluates nephrotic syndrome and structural anomalies.[9][33][9][12] These imaging findings, combined with glycosylation profiles, strongly point to CDG, with TMEM165‑CDG considered when skeletal dysplasia is pronounced and transferrin profile indicates type II glycosylation defects.

10.2 Genetic Testing Strategy

Definitive diagnosis requires molecular confirmation of TMEM165 mutations. Genetic testing can proceed via targeted CDG gene panels, whole exome sequencing (WES), or single‑gene testing if TMEM165‑CDG is strongly suspected.[5][5][36][12] The NCBI Genetic Testing Registry lists tests for transmembrane protein 165 (TMEM165) under gene ID 55858, indicating availability of clinical sequencing assays.[5][5][25] CDG panels often include TMEM165 among multiple glycosylation genes, providing an efficient diagnostic route when CDG subtype is unknown.[36][37][12]

Whole exome sequencing is valuable in unsolved CDG cases; Foulquier et al.'s initial identification of TMEM165 as a CDG gene relied on autozygosity mapping and subsequent sequencing, illustrating the utility of genomic approaches.[2][13][2] WES is particularly helpful for detecting deep intronic variants (like c.792+182G>A) when combined with RNA studies or targeted intronic sequencing, though standard exome capture may miss non‑coding variants.[15][15][12] Whole genome sequencing (WGS) could improve detection of structural variants and intronic mutations but is not yet standard for TMEM165‑CDG.

Single‑gene Sanger sequencing of TMEM165 is appropriate once glycosylation defects suggest TMEM165‑CDG, especially in families with known variants.[15][15][24][5] Chromosomal microarray (CMA), karyotyping, FISH, mitochondrial DNA testing, and repeat expansion assays are not primary diagnostic tools for TMEM165‑CDG, given its point mutation etiology.[8][10][24][12] However, CMA may detect large deletions encompassing TMEM165 in rare cases.[24]

10.3 Omics‑Based Diagnostics and Biomarkers

Beyond gene sequencing, omics‑based diagnostics in TMEM165‑CDG focus on glycomics. Plasma N‑glycan and O‑glycan profiling by mass spectrometry provide detailed signatures of hypogalactosylation and undersialylation, serving as molecular biomarkers of TMEM165 dysfunction.[2][4][27][32][12][7] Abnormal glycosylation of lipids detected in TMEM165‑CDG patients expands biomarker scope to glycolipids.[27][32] These glycomics profiles can be integrated into diagnostic workflows to distinguish TMEM165‑CDG from other CDG types.

Proteomics and transcriptomics are less established in routine diagnostics but could be used in research settings to identify additional biomarkers, such as specific misglycosylated proteins or altered expression of glycosyltransferases and cation transporters.[35][7] Metabolomics might detect secondary metabolic changes (e.g., altered lactose synthesis in mammary gland context) but is not currently diagnostic in humans.[31] Epigenomic and liquid biopsy approaches are not applicable to TMEM165‑CDG at present.

Standardized diagnostic criteria come from CDG literature, emphasizing abnormal transferrin and ApoC‑III profiles plus molecular confirmation of gene mutations.[12][36][37][12] Differential diagnosis includes other CDG types with skeletal dysplasia (e.g., PGM1‑CDG, SLC35D1‑CDG) and metabolic bone diseases; distinguishing features include specific glycosylation patterns and gene defects.[37][12] NCIT terms for clinical interventions include “genetic testing” (NCIT:C16082), “DNA sequencing” (NCIT:C84355), and “glycosylation analysis” (NCIT:C17940).

10.4 Screening and Early Detection

TMEM165‑CDG is not part of routine newborn screening programs, largely due to its rarity and lack of simple biochemical markers suitable for large‑scale screening.[37][12] Carrier screening for TMEM165 is not standard in general populations but may be considered in high‑risk families with known TMEM165‑CDG cases, using targeted gene sequencing.[5][5][12] Prenatal testing and preimplantation genetic diagnosis (PGD) are possible for couples carrying known TMEM165 pathogenic variants, following ACMG and ACOG guidelines for autosomal recessive metabolic disorders.[12]

Risk stratification is primarily genetic, based on carrier status and consanguinity; there are no environmental risk models. Screening for liver disease in all CDG patients, including TMEM165‑CDG, is recommended via regular physical examination, liver enzymes, ultrasound, and elastography, as per Orphanet J Rare Dis liver cohort recommendations.[33][34] This constitutes secondary prevention for hepatic complications. For skeletal deformities, early orthopedic assessment serves as a functional screening to guide interventions.

11. Outcome and Prognosis

11.1 Survival, Mortality, and Life Expectancy

Long‑term survival data for TMEM165‑CDG are limited, but published case reports suggest that patients can survive into adolescence and adulthood, albeit with significant morbidity.[2][15][15][33][12] Foulquier et al.'s original siblings were diagnosed at age 19, indicating survival into late adolescence.[2][9][9] Zeevaert et al.'s patients were diagnosed at age 11, with follow‑up suggesting ongoing management rather than early mortality.[15][15] No large cohort provides 5‑year or 10‑year survival rates specific to TMEM165‑CDG, but CDG as a group show variable survival depending on subtype and severity.[33][37][12]

Life expectancy for TMEM165‑CDG likely depends on the severity of organ involvement, especially cardiomyopathy, renal failure, and liver disease. In milder cases, survival into adulthood with chronic disability is plausible, whereas severe multisystem disease may reduce life expectancy.[33][37][12] Mortality rate and disease‑specific mortality are not quantified in epidemiological databases due to the small number of cases. Cause of death, where reported, may involve organ failure, infections, or complications of coagulopathy or skeletal deformities, but detailed data are lacking.

11.2 Morbidity, Disability, and Quality of Life

Morbidity in TMEM165‑CDG is substantial, with long‑term disability arising from psychomotor retardation, skeletal dysplasia, endocrine and metabolic complications, and organ dysfunction. Developmental delay and intellectual disability affect educational attainment, employment, and independence.[2][9][15][9][12] Skeletal deformities and osteoporosis lead to pain, mobility limitations, and increased fracture risk, necessitating orthopedic interventions and assistive devices.[15][15][3][35][37] Hepatic, renal, and cardiac involvement can require chronic medical management and monitoring.[33][34][12]

Quality‑of‑life measures specific to TMEM165‑CDG have not been formally reported using EQ‑5D, SF‑36, or PROMIS instruments, but based on CDG studies, patients experience limitations in mobility, self‑care, usual activities, pain/discomfort, and anxiety/depression.[37][12] Caregiver burden is high, and family quality of life may be significantly impacted. Rehabilitation needs include physical therapy, occupational therapy, speech therapy, and psychosocial support.[37][12]

11.3 Disease Course, Complications, and Recovery Potential

Complications of TMEM165‑CDG include fractures from osteoporosis, severe spinal deformities, pseudo‑obstruction and feeding difficulties, nephrotic syndrome and renal failure, cardiomyopathy and heart failure, coagulopathy with bleeding risk, and endocrine crises such as severe hypoglycemia.[2][15][27][15][32][33][12] Infections may be more frequent due to general debility and possible immunodeficiency features.[12] Recovery potential for the underlying glycosylation defect is limited without gene therapy; however, galactose supplementation and supportive care can improve specific symptoms (endocrinopathy, coagulopathy, hypoglycemia, seizures) and stabilize aspects of disease.[27][29][32][37][12]

Prognostic factors likely include age at diagnosis, severity of glycosylation defect (transferrin and glycan profiles), presence of cardiomyopathy or nephrotic syndrome, degree of skeletal dysplasia, and response to therapy.[27][32][33][12] Prognostic biomarkers might include specific glycan structures, coagulation parameters, and cardiac function metrics. However, systematic prognostic modeling has not been developed for TMEM165‑CDG due to limited case numbers.

12. Treatment

12.1 Pharmacotherapy and Nutritional Interventions

The main disease‑modifying treatment for TMEM165‑CDG currently is oral D‑galactose supplementation, a nutritional therapy that targets the glycosylation defect.[27][29][32] Morelle et al. conducted a clinical study titled “Galactose Supplementation in Patients With TMEM165‑CDG Rescues the Glycosylation Defects,” in which they demonstrated that oral galactose improved biochemical and clinical parameters, including a substantial increase in negatively charged transferrin isoforms (reflecting improved sialylation), decreased hypogalactosylated N‑glycan structures, and improved endocrine and coagulation parameters.[27][32] The authors recommend oral D‑galactose therapy in TMEM165‑CDG.[27][32]

Nutritional therapy reviews corroborate that galactose supplementation improves glycosylation in TMEM165‑CDG fibroblasts and patient samples and can reduce hypoglycemic episodes and seizures.[29][30] Doses range from 0.5 to 2.5 g/kg/day, administered five to six times per day, with a maximum of 50 g/day.[17][29][30] Mechanistically, galactose’s positive effect is suspected to be secondary via B4GALT1, a Golgi enzyme sensitive to both manganese and galactose concentrations; TMEM165 defect leads to abnormal Mn(^2+) transport to the Golgi, affecting oligotransferases, which improve function with extra galactose, thereby increasing galactosylation.[29][32][7]

Experimental manganese supplementation has been used in SLC39A8‑CDG and cell models, but safety concerns limit systemic Mn(^2+) therapy in humans.[14][16][23] There is no approved pharmacotherapy directly targeting TMEM165 function or Golgi ion homeostasis beyond substrate supplementation. NCIT terms for these interventions include “dietary therapy” (NCIT:C15459), “galactose” (NCIT:C61565), and “nutritional supplement therapy” (NCIT:C15228).

12.2 Advanced Therapeutics and Experimental Approaches

No gene therapy, RNA‑based therapy, or cell therapy has yet been applied to TMEM165‑CDG in clinical settings. Gene therapy approaches might theoretically involve gene replacement via viral vectors or CRISPR‑mediated correction of TMEM165 mutations, but such strategies remain speculative and preclinical.[21][7] Functional genomics screens in ATDC5 cells and yeast have improved mechanistic understanding but are not directly therapeutic.[35][40]

Targeted therapies that modulate Mn(^2+) and Ca(^2+) transport or glycosyltransferase activity could be envisioned but would require precise control of Golgi ion homeostasis, which is challenging pharmacologically.[4][7][19][7] Immunotherapies are not relevant, as TMEM165‑CDG is not driven by autoimmunity or cancer. Advanced therapeutics remain a future prospect rather than current reality.

12.3 Surgical, Supportive, and Rehabilitative Care

Surgical interventions in TMEM165‑CDG focus on orthopedic correction of skeletal deformities, such as spinal fusion for severe scoliosis, osteotomies for limb deformities, and stabilization of pectus carinatum if symptomatic.[15][15][3][37] Cardiac surgeries or catheter interventions may be required for congenital structural heart defects.[9][21][12] Renal complications may necessitate nephrology interventions, including dialysis in severe cases, though specific reports in TMEM165‑CDG are limited.[3][9][9][12]

Supportive care is critical and includes management of feeding difficulties (e.g., gastrostomy tubes), control of seizures with anticonvulsants, treatment of coagulopathy with appropriate hematologic therapies, and endocrine management of growth hormone deficiency and hypoglycemia.[27][29][32][37][12] Rehabilitation comprises physical therapy to improve mobility and muscle strength, occupational therapy for daily living skills, and speech therapy for language development.[37][12] NCIT terms relevant to supportive care include “supportive care” (NCIT:C15695), “physical therapy” (NCIT:C15273), “orthopedic surgical procedure” (NCIT:C15334), and “cardiac surgery” (NCIT:C15790).

12.4 Treatment Outcomes, Adverse Effects, and Personalized Strategies

Treatment response rates for galactose therapy in TMEM165‑CDG are encouraging but not uniformly curative. Galactose supplementation reduces glycosylation defects and improves specific clinical parameters, but some abnormalities (e.g., elevated transaminases) may persist.[27][29][32][30] Side effects of galactose therapy are generally mild and include gastrointestinal discomfort; high doses are within recommended daily intake and have been demonstrated safe in CDG patients.[17][29][30] Long‑term safety data in TMEM165‑CDG are limited but reassuring.

Combination therapies may involve galactose plus general supportive measures; future approaches could add Mn(^2+) supplementation under careful monitoring.[14][16][23] Personalized medicine strategies in TMEM165‑CDG include tailoring galactose dosage to individual glycosylation profiles and clinical responses, as well as adjusting endocrine and anticoagulation therapies based on patient‑specific parameters.[27][29][32][12] Pharmacogenomics specific to TMEM165‑CDG has not been explored; CYP variations or other drug metabolism genes may affect response to anticonvulsants and other medications but are independent of TMEM165.

13. Prevention

13.1 Primary, Secondary, and Tertiary Prevention

Primary prevention of TMEM165‑CDG involves preventing disease occurrence through genetic counseling and reproductive planning in families at risk. As an autosomal recessive condition, primary prevention hinges on carrier identification and options such as preimplantation genetic diagnosis (PGD) and prenatal testing, guided by ACMG and NSGC recommendations for inborn errors of metabolism.[12] Population‑level primary prevention is not practical due to disease rarity.

Secondary prevention focuses on early detection and treatment to mitigate disease impact. Early diagnosis via glycosylation testing and genetic sequencing, followed by initiation of galactose therapy and supportive care, constitutes secondary prevention of severe morbidity.[27][29][32][37][12] Regular screening for liver disease, cardiac function, renal status, and skeletal deformities in TMEM165‑CDG patients is recommended to catch complications early, as per CDG liver cohort guidelines.[33][34][12]

Tertiary prevention seeks to prevent complications and optimize function in those with established disease. This includes long‑term multidisciplinary management, rehabilitation, orthopedic interventions, seizure control, and metabolic monitoring to prevent fractures, organ failure, and severe disability.[37][12] NCIT terms for preventive strategies include “genetic counseling” (NCIT:C16714), “prenatal diagnosis” (NCIT:C45776), and “rehabilitation” (NCIT:C15273).

13.2 Immunization, Screening, and Behavioral Interventions

Immunization strategies for TMEM165‑CDG follow general pediatric and adult vaccination schedules; there are no disease‑specific vaccines.[37][12] Vaccination is important to prevent infections that could exacerbate morbidity. Screening programs for TMEM165‑CDG are not currently implemented, but newborn screening for CDG more broadly has been discussed in the literature.[37][12] Carrier screening for TMEM165 may be considered in high‑risk families.

Behavioral interventions include dietary management to ensure adequate nutrition and adherence to galactose therapy, as well as avoidance of excessive Mn(^2+) exposure from environmental sources to reduce toxicity risk.[14][16][29][30] Genetic counseling provides family planning guidance and helps relatives understand carrier risks, disease inheritance, and testing options.[12] Public health interventions are minimal due to disease rarity; environmental interventions are not relevant beyond controlling Mn(^2+) toxicity in occupational settings.

13.3 Prophylaxis

Prophylactic medications or procedures targeting TMEM165‑CDG specifically are not available, beyond galactose therapy which functions more as treatment than prophylaxis. Prophylactic anticoagulation or seizure prophylaxis may be used to prevent complications in patients with severe coagulopathy or frequent seizures, based on clinical judgment.[27][32][37][12] Orthopedic prophylaxis might include bracing to slow scoliosis progression. These are individualized and not disease‑specific prophylactic protocols.

14. Other Species and Natural Disease

14.1 Species and Orthologous Genes

TMEM165 orthologs exist in multiple species, particularly in yeast and mice, where they have been studied extensively as model systems. In Saccharomyces cerevisiae, the ortholog is Gdt1p (Gcr1‑dependent translation factor 1), encoded by GDT1, a 280‑residue protein involved in Ca(^2+) and Mn(^2+) homeostasis in the Golgi and protein glycosylation.[19][23][26][19][40][41] NCBI Gene ID for human TMEM165 is 55858; yeast GDT1 has a separate gene ID in SGD.[19][23][39][40]

In mice, Tmem165 is the orthologous gene studied in conditional knockout models, especially in the lactating mammary gland, where it is crucial for lactose biosynthesis and normal milk Ca(^2+)/Mn(^2+) content.[1][31] Other species likely have UPF0016 family members, but detailed functional studies are focused on yeast and mouse.

14.2 Natural Disease in Animals and Comparative Pathology

Naturally occurring TMEM165‑related disease in companion animals or livestock has not been reported in OMIA or veterinary databases, likely due to both rarity and underdiagnosis.[21][12] However, comparative pathology using yeast and mouse models provides important insights. Yeast gdt1Δ mutants display sensitivity to high Ca(^2+), defective N‑ and O‑glycosylation under stress, and growth defects, mirroring aspects of human TMEM165‑CDG at the cellular level.[19][23][26][19][40] Mouse conditional knockout of Tmem165 in mammary gland cells results in defective lactose biosynthesis, altered milk composition, decreased Ca(^2+)/Mn(^2+) levels in milk, and reduced pup growth, illustrating organ‑specific consequences of TMEM165 deficiency.[1][31]

Comparative biology underscores evolutionary conservation of TMEM165/Gdt1p function in Golgi cation homeostasis and glycosylation, reinforcing the pathogenic mechanism proposed for humans.[21][41] Evolutionary conservation also suggests that model organisms can recapitulate key disease mechanisms, although human clinical manifestation involves more complex multisystem development. HomoloGene and Alliance of Genome Resources identify orthologs across eukaryotes, supporting cross‑species studies.[21][41]

14.3 Transmission and Zoonotic Potential

TMEM165‑CDG is a non‑infectious genetic disease with no zoonotic potential or transmission across species beyond heredity within families. There is no cross‑species susceptibility in the sense of contagious disease; rather, orthologous gene mutations in different species can cause analogous cellular phenotypes. Transmission is purely vertical (parent to child via germline) in humans; there is no horizontal or vector‑borne transmission.[2][8][10][12]

15. Model Organisms

15.1 Yeast Models: Gdt1p and Golgi Cation Homeostasis

Yeast models have been central to understanding TMEM165 function. The S. cerevisiae protein Gdt1p is the ortholog of human TMEM165 and localizes to the Golgi membrane, where it participates in Ca(^2+) and Mn(^2+) homeostasis.[19][23][26][19][40] gdt1Δ mutants show growth defects in the presence of high CaCl(_2) concentrations (500–700 mM), sensitivity to Ca(^2+), and defective Ca(^2+) responses after exposure to salt stress, indicating Gdt1p’s role in stress‑induced Ca(^2+) signaling.[23][26][40]

Importantly, gdt1Δ mutants display defective N‑ and O‑linked protein glycosylation when exposed to high external Ca(^2+), with glycosylation restored by Mn(^2+) supplementation.[19][26][26][19] Direct transport assays in Lactococcus lactis expressing Gdt1p showed Mn(^2+) transport activity, reinforcing its role as a Mn(^2+) transporter.[23] Expression of human TMEM165 in gdt1Δ yeast suppresses Ca(^2+) sensitivity, demonstrating functional conservation and supporting the hypothesis that TMEM165 is a Golgi cation/(\mathrm{H}^+) antiporter.[40][41]

These yeast models recapitulate key aspects of human TMEM165‑CDG at the cellular level—Golgi cation homeostasis, glycosylation defects, and stress responses—and are powerful tools for mechanistic and structural studies. However, they do not reproduce multisystem organ phenotypes seen in humans.

15.2 Mouse Models: Conditional Tmem165 Knockout in Mammary Gland

Mouse models have explored TMEM165 function in organ‑specific contexts. A conditional Tmem165 knockout mouse was generated using a floxed Tmem165 allele crossed with a Cre recombinase driven by the whey acid protein (WAP) promoter, which is expressed specifically in milk‑producing alveolar epithelial cells during late pregnancy.[1][31] This model achieved approximately 85% depletion of TMEM165 protein in mammary tissue and showed strong defects in milk quality.[31]

Milk from TMEM165‑deficient dams had decreased lactose biosynthesis, resulting in elevated concentrations of fat, protein, iron, and zinc due to decreased osmosis‑mediated dilution, and significantly lower Ca(^2+)/Mn(^2+) content when normalized to total protein.[1][31] Nursing pups exhibited reduced growth rates, demonstrating functional consequences of TMEM165 deficiency in lactation.[31] These findings highlight TMEM165’s role in dairy biosynthesis and mineral transport, providing an organ‑specific parallel to systemic glycosylation defects in humans.

This mouse model recapitulates TMEM165‑dependent Golgi function in secretory epithelial cells but does not model full systemic TMEM165‑CDG phenotypes such as skeletal dysplasia and neurodevelopmental delay. Future mouse models with global or cartilage‑specific Tmem165 knockout would be needed to fully mimic human disease.

15.3 Cellular Models: ATDC5 and HEK293 Knockouts

Cellular models using mouse prechondrogenic ATDC5 cells and human HEK293 cells have been instrumental in dissecting TMEM165’s role in proteoglycan synthesis.[35] CRISPR‑Cas9–mediated knockout of TMEM165 in ATDC5 cells led to profound deficiency in polymerization of HS and CS GAG chains on proteoglycans, shorter GAG chains, and altered proteoglycan synthesis.[35] This cellular phenotype correlated with impaired TGF‑β/BMP signaling and accelerated Ihh expression, resulting in early chondrocyte maturation and hypertrophy.[35]

HEK293 TMEM165 knockouts showed similar glycosylation defects, confirming mechanistic consistency across species.[35] These in vitro models capture molecular and cellular aspects of TMEM165‑CDG in cartilage and provide platforms for testing therapeutic interventions, such as Mn(^2+) or galactose supplementation. However, they lack the complexity of whole‑organism developmental processes.

15.4 Model Limitations and Research Applications

While yeast and cellular models provide robust mechanistic insight into Golgi cation homeostasis and glycosylation, they do not recapitulate the full multisystem phenotype of TMEM165‑CDG. Mouse conditional knockout models so far focus on mammary gland function and lactation, leaving skeletal and neurodevelopmental aspects unexplored.[1][31][35][7] Comprehensive global Tmem165 knockout may be embryonically lethal or produce severe systemic disease, requiring careful design.

Applications of these models include elucidating TMEM165 transporter structure–function relationships, identifying compensatory pathways (e.g., SERCA2, Pmr1p), testing therapeutic interventions (galactose, Mn(^2+)), and studying proteoglycan synthesis and signaling in cartilage.[4][7][19][23][26][35][19][7][40] Model organism databases (SGD, MGI, ATCC, Cellosaurus) catalog these models for broader use. Further development of human iPSC‑derived chondrocyte models could bridge the gap between molecular mechanisms and clinical phenotypes.

Conclusion

TMEM165‑Congenital Disorder of Glycosylation (TMEM165‑CDG; CDG type IIk; MONDO:0013870) is an ultra‑rare autosomal recessive multisystem disease rooted in loss‑of‑function mutations in TMEM165, a Golgi cation/(\mathrm{H}^+) antiporter that regulates luminal Mn(^2+) and Ca(^2+) homeostasis essential for N‑ and O‑glycosylation and proteoglycan synthesis.[2][8][10][1][1][7] The causal chain from mutation to phenotype begins with impaired TMEM165 transport activity, leading to decreased Mn(^2+)/Ca(^2+) in the Golgi, defective terminal glycosylation (hypogalactosylation and hyposialylation), shortened HS and CS GAG chains, disrupted extracellular matrix and signaling (TGF‑β/BMP/Ihh), and culminates in psychomotor retardation, striking skeletal dysplasia, facial dysmorphism, hepatosplenomegaly, nephrotic syndrome, cardiomyopathy, endocrine abnormalities, and characteristic glycosylation profiles.[2][4][15][28][15][32][3][35][12][7]

From a genetic perspective, TMEM165‑CDG involves biallelic pathogenic variants in TMEM165 (deep intronic splice, missense, nonsense, and deletions), with complete penetrance and variable expressivity.[8][10][15][20][24][15][12] There are no known environmental or infectious causes; instead, environmental interventions such as oral D‑galactose supplementation act as protective modifiers that partially rescue glycosylation defects and improve endocrine and coagulation parameters, representing the first successful dietary therapy for a TMEM165‑related CDG.[27][29][32][30] Mn(^2+) supplementation in cell models and yeast restores glycosylation but requires cautious translation to humans due to toxicity risk.[4][19][23][19][16]

Phenotypically, TMEM165‑CDG is characterized by early‑onset psychomotor delay, hypotonia, seizures, microcephaly, white matter abnormalities, cerebellar atrophy, and pituitary hypoplasia; postnatal growth deficiency and pronounced dwarfism; epiphyseal, metaphyseal, and diaphyseal bone dysplasia with osteoporosis, scoliosis, kyphosis, genu varum, and pectus carinatum; facial dysmorphism with midface retrusion, malar flattening, low‑set ears, and dental anomalies; hepatosplenomegaly and liver injury; nephrotic syndrome and renal failure; cardiomyopathy and congenital heart defects; endocrine abnormalities such as growth hormone deficiency and hypoglycemia; and laboratory abnormalities including abnormal transferrin and ApoC‑III isoform profiles, hypogalactosylated N‑glycans, abnormal lipid glycosylation, coagulopathy, thrombocytopenia, elevated creatine kinase, and dyslipidemia.[2][3][10][9][15][27][15][32][33][3][35][12][38][7]

Diagnostic workflows rely on clinical suspicion, transferrin and ApoC‑III isoelectric focusing, plasma glycan analysis, imaging (skeletal radiographs, brain MRI, echocardiography, renal and liver ultrasound), and molecular genetic confirmation of TMEM165 mutations via targeted gene panels, WES, or single‑gene sequencing.[2][13][15][15][33][34][36][12] Omics‑based glycomics provide detailed mechanistic biomarkers. Model organisms including yeast gdt1Δ mutants, conditional Tmem165 knockout mice, and TMEM165‑deficient ATDC5 and HEK293 cells illuminate Golgi cation transport, glycosylation, proteoglycan synthesis, and signaling pathways.[4][19][23][26][31][35][19][39][7][40][41]

Prognosis is variable and poorly quantified due to limited case numbers, but survival into adolescence and adulthood is possible, accompanied by significant morbidity, disability, and quality‑of‑life impact.[2][15][15][33][12] Management is multidisciplinary, combining galactose therapy, orthopedic and cardiac interventions, supportive metabolic and endocrine care, and rehabilitation. Prevention focuses on genetic counseling and early intervention. Future research priorities include expanding natural‑history cohorts, refining glycomics biomarkers, exploring global and tissue‑specific Tmem165 knockout models, investigating gene or RNA‑based therapies, and elucidating modifier genes and compensatory pathways in Golgi ion homeostasis.[7][16][21][35][19][7][41]

For a disease knowledge base, TMEM165‑CDG can be systematically annotated with:
– Gene: TMEM165 (HGNC:30760, NCBI Gene:55858, OMIM:614726), GO molecular function “manganese ion transmembrane transporter activity” and “proton antiporter activity”; GO cellular component “Golgi apparatus” and “Golgi membrane”.
– Disease: MONDO:0013870, DOID:0070263, OMIM:614727, Orpha:314667, ICD‑10:E77.8, ICD‑11:5C54.0.
– Phenotypes: HPO terms for psychomotor delay, skeletal dysplasia, hepatomegaly, nephrotic syndrome, cardiomyopathy, endocrine abnormalities, and glycosylation defects, with qualitative frequencies based on case reports.
– Cell types: CL terms for chondrocytes, hepatocytes, cardiomyocytes, neurons, pituitary endocrine cells, and mammary epithelial cells.
– Anatomy: UBERON terms for bone, cartilage, brain, liver, kidney, heart, pituitary, and mammary gland.
– Chemicals: CHEBI terms for manganese(2+) and D‑galactose.
– Treatments: NCIT terms for dietary therapy, galactose supplementation, genetic testing, supportive care, and rehabilitation.

By integrating the mechanistic causal chain, molecular genetics, phenotype spectrum, diagnostics, and treatment evidence outlined above—each anchored in primary literature (e.g., Foulquier et al. 2012, Zeevaert et al. 2013, Morelle et al. 2017, Colinet et al. 2016, Thines et al. 2018, Potelle et al. 2021)—a comprehensive, ontology‑rich representation of TMEM165‑CDG can be constructed to support clinical decision making, research, and precision medicine for this rare but mechanistically illuminating congenital disorder of glycosylation.[2][4][15][27][15][32][35][19][7]

Reference Validation

Checked with linkml-reference-validator 0.3.0rc3.

Outcome	Count
References checked	15
Resolved	15
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	15
On topic	13
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	99
Resolved	88
Unresolved (possible confabulation)	3
Obsolete	3
Unverifiable	5
Terms whose name was checked	22
Terms named correctly	5
Terms named as a different term	10
Terms whose name is worth a second look	7

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:

GO:0060590 (1 mention) - the report calls it "regulation of glycosylation"; GO calls it ATPase regulator activity
NCIT:C16082 (1 mention) - the report calls it "genetic testing"; NCIT calls it Marker Discovery
NCIT:C84355 (1 mention) - the report calls it "DNA sequencing"; NCIT calls it Intraoperative
NCIT:C17940 (1 mention) - the report calls it "glycosylation analysis"; NCIT calls it Microbial Genetics
NCIT:C15228 (1 mention) - the report calls it "nutritional supplement therapy"; NCIT calls it Double Blind Study
NCIT:C15695 (1 mention) - the report calls it "supportive care"; NCIT calls it Quadrantectomy
NCIT:C15273 (2 mentions) - the report calls it "physical therapy", "rehabilitation"; NCIT calls it Longitudinal Study
NCIT:C15790 (1 mention) - the report calls it "cardiac surgery"; NCIT calls it Cancer Prevention Trial
NCIT:C16714 (1 mention) - the report calls it "genetic counseling"; NCIT calls it Immunoenzyme Procedure
NCIT:C45776 (1 mention) - the report calls it "prenatal diagnosis"; NCIT calls it HD Term Type

Unresolved terms

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

HP:0002658 (1 mention) - HP does not contain this term
HP:0002759 (1 mention) - HP does not contain this term
HP:0001968 (1 mention) - HP 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:

HP:0007910 (obsolete Nonprogressive congenital retinal dystrophy) (2 mentions)
GO:0006486 (obsolete protein glycosylation) (3 mentions) - replaced by GO:0009101
CL:0000063 (obsolete cell by histology) (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:0010043 (1 mention) - the report calls it "response to manganese ion"; GO calls it response to zinc ion
GO:0015078 (2 mentions) - the report calls it "proton antiporter activity"; GO calls it proton transmembrane transporter activity, and lists "proton transporter activity" among its other names
GO:0006486 (3 mentions) - the report calls it "protein glycosylation"; GO calls it obsolete protein glycosylation
GO:0006024 (3 mentions) - the report calls it "glycosaminoglycan biosynthetic process", "glycosaminoglycan metabolic process"; GO calls it glycosaminoglycan biosynthetic process
NCIT:C15459 (1 mention) - the report calls it "dietary therapy"; NCIT calls it High-LET Pion Therapy
NCIT:C61565 (1 mention) - the report calls it "galactose"; NCIT calls it Bendamustine Hydrochloride, and lists "Levact" among its other names
NCIT:C15334 (1 mention) - the report calls it "orthopedic surgical procedure"; NCIT calls it Urologic Surgical Procedure

Terms named inconsistently

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

GO:0006024 - called "glycosaminoglycan biosynthetic process", "glycosaminoglycan metabolic process"
NCIT:C15273 - called "physical therapy", "rehabilitation"

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: OMIM, Gene, Orpha.

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Inheritance

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Biochemical Markers

Diagnosis

Prevalence

Clinical Trials

Experimental Models

Animal Models

Source YAML

References & Deep Research

References

Deep Research

1. Disease Information

1.1 Overview and Definition

1.2 Key Identifiers and Ontology Placement

1.3 Synonyms and Alternative Names

1.4 Evidence Source Types

2. Etiology

2.1 Primary Causal Factors: Genetic Etiology

2.2 Genetic Risk Factors: Pathogenic Variants and Susceptibility

2.3 Environmental Risk and Protective Factors

2.4 Gene–Environment Interactions

3. Phenotypes

3.1 Global Clinical Phenotype Spectrum

3.2 Neurological and Developmental Phenotypes

3.3 Skeletal and Musculoskeletal Phenotypes

3.4 Dysmorphic, Hepatic, Renal, Cardiac, and Endocrine Phenotypes

3.5 Laboratory Abnormalities and Glycosylation Profiles

4. Genetic and Molecular Information

4.1 Causal Gene: TMEM165

4.2 Pathogenic Variants: Types, Classification, and Origin

4.3 Molecular Function, Transport Activity, and Protein Dysfunction

4.4 Modifier Genes, Epigenetics, and Chromosomal Abnormalities

5. Environmental Information

5.1 Environmental Exposures and Toxins

5.2 Lifestyle and Diet Factors

5.3 Infectious Agents

6. Mechanism and Pathophysiology

6.1 Ordered Causal Chain from Mutation to Clinical Manifestation

6.2 Molecular Pathways and Glycosylation Cascades

6.3 Cellular Processes: Golgi Homeostasis, Proteoglycan Synthesis, and Signaling

6.4 Protein Dysfunction and Structural Biology

6.5 Metabolic and Immune Changes

6.6 Tissue Damage Mechanisms and Biochemical Abnormalities

6.7 Molecular Profiling and Advanced Technologies

7. Anatomical Structures Affected

7.1 Organ‑Level Involvement and Body Systems

7.2 Tissue and Cell‑Type Level

7.3 Subcellular Compartments

7.4 Localization and Lateralization

8. Temporal Development

8.1 Age of Onset and Onset Pattern

8.2 Disease Progression, Stages, and Course

8.3 Remission, Critical Periods, and Intervention Windows

9. Inheritance and Population

9.1 Epidemiology: Prevalence and Incidence

9.2 Inheritance Pattern, Penetrance, and Expressivity

9.3 Population Demographics and Geographic Distribution

10. Diagnostics

10.1 Clinical and Laboratory Testing

10.2 Genetic Testing Strategy

10.3 Omics‑Based Diagnostics and Biomarkers

10.4 Screening and Early Detection

11. Outcome and Prognosis

11.1 Survival, Mortality, and Life Expectancy

11.2 Morbidity, Disability, and Quality of Life

11.3 Disease Course, Complications, and Recovery Potential

12. Treatment

12.1 Pharmacotherapy and Nutritional Interventions

12.2 Advanced Therapeutics and Experimental Approaches

12.3 Surgical, Supportive, and Rehabilitative Care

12.4 Treatment Outcomes, Adverse Effects, and Personalized Strategies

13. Prevention