ALG8-related Autosomal Dominant Polycystic Kidney And/Or Liver Disease

Mendelian MONDO:1060122 Pathograph 16 Show in embeddings browser Autosomal Dominant Polycystic Kidney Disease Autosomal Dominant Polycystic Liver Disease

ALG8-related autosomal dominant polycystic kidney and/or liver disease is the cystic disorder of people heterozygous for a loss-of-function variant in ALG8. ALG8 encodes the endoplasmic-reticulum alpha-1,3-glucosyltransferase that adds the second of three glucoses to the lipid-linked oligosaccharide precursor of N-linked glycosylation. Biallelic loss of the same gene causes a severe multisystem congenital disorder of glycosylation (ALG8-CDG, CDG-Ih); the monoallelic disease described here is a different, organ-restricted and usually mild condition. The phenotype sits between the two classical dominant cystic disorders. Most carriers who develop disease have a modest number of kidney cysts without marked kidney enlargement, and kidney function is usually preserved; progression to kidney failure is rare. Liver cysts are common, and a minority develop severe polycystic liver disease with liver volume above two litres, so the gene was first found in isolated polycystic liver disease cohorts and later in cystic kidney cohorts. Penetrance for cysts is incomplete and expressivity is variable even within one family, and predicted loss-of-function ALG8 alleles are present in roughly one in a thousand people, so many carriers have only a few cysts or none. Mechanistically ALG8 belongs with GANAB, PRKCSH, SEC63, ALG5, ALG9 and DNAJB11 as an endoplasmic-reticulum proteostasis gene that sits upstream of the polycystin complex. Loss of ALG8 leaves polycystin-1 hypoglycosylated, reduces its steady-state level and blocks its trafficking to the cell surface and the primary cilium. Reduced functional polycystin-1 is the shared final pathway into cystogenesis in kidney tubule and biliary epithelium.

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1
Mappings
2
Inheritance
7
Pathophys.
8
Phenotypes
2
Gaps
16
Pathograph
2
Genes
3
Medical Actions
5
References
1
Deep Research
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Mappings

MONDO
MONDO:1060122 ALG8-related autosomal dominant polycystic kidney and/or liver disease
skos:exactMatch MONDO
MONDO:1060122 is the gene-defined ALG8 kidney and/or liver cystic disease concept modeled by this entry.
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Inheritance

2
Autosomal dominant HP:0000006
Monoallelic variants segregate with cysts across at least two generations, but many probands appear sporadic and genotype-first carriers often have few cysts.
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:39899384 SUPPORT Human Clinical
"They are probably best described as ADPKD associated with lower penetrance (not all individuals developing cysts) and with variable expressivity (individuals having variable presentations in terms of cyst number)."
Characterises the dominant inheritance as low-penetrance with variable expressivity.
Incomplete penetrance HP:0003829
Not all carriers develop cysts, and clinically significant kidney disease is uncommon.
Incomplete penetrance
Show evidence (1 reference)
PMID:39899384 SUPPORT Human Clinical
"ALG8 and ALG9 are defined as cystic kidney/liver genes but with limited penetrance for lower eGFR."
Limited penetrance for kidney function decline.
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Discussions and Knowledge Gaps

2
What determines whether an ALG8 carrier has no cysts, a few kidney cysts, or severe polycystic liver disease?
KNOWLEDGE GAP OPEN alg8_liver_severity_modifiers
Attached to
pathophysiology#Somatic Second Hit in Cyst Epithelium phenotypes#Polycystic Liver Disease
Most genotype-first carriers have only modest kidney cysts and no severe liver disease, while a minority in liver clinics have livers over 2 L. The cohort authors attribute the difference to genic and other modifiers, but none has been identified, and the somatic second-hit evidence rests on one explanted liver.
Show evidence (1 reference)
PMID:39899384 SUPPORT Human Clinical
"Significant liver enlargement, usually with limited kidney cysts, was found in a minority of ALG8 cases, consistent with links to ADPLD, so ALG8 genic and other genetic (and nongenetic) modifiers are likely significant for this complication."
The authors name modifiers as the open explanation.
Does heterozygous ALG8 loss reduce polycystin-1 maturation enough to matter, or does cyst formation need local loss of the second allele?
HUMAN MODEL MISMATCH OPEN alg8_null_cells_vs_heterozygous_patients
Attached to
pathophysiology#Defective Polycystin-1 Glycosylation and Maturation
The polycystin-1 glycosylation and trafficking defect was shown in Alg8-null mouse kidney cells. No heterozygous-cell or in vivo Alg8 model is cited here, so the dosage at which the mechanism operates in patients is inferred rather than measured.
Show evidence (1 reference)
PMID:28375157 SUPPORT In Vitro
"Altered migration of PC1-FL is due to hypoglycosylation in Alg8–/– cells."
The mechanistic evidence comes from null cells only.
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Pathophysiology

7
Heterozygous ALG8 Loss of Function
Mechanism confidence: Established
Germline heterozygous loss-of-function variants, predominantly nonsense, frameshift and canonical splice alleles with recurrent p.Arg364*, reduce the dose of ALG8. ALG8 is the endoplasmic-reticulum alpha-1,3-glucosyltransferase that adds the second glucose to the dolichol-linked Glc1Man9GlcNAc2 precursor before the oligosaccharide is transferred to nascent glycoproteins. ALG8 is not intolerant of loss of function in population exome data, which is consistent with its recessive CDG and with the incomplete penetrance of this disease.
ALG8 hgnc:23161 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves ALG8 (hgnc:23161). hgnc:23161 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context ALG8 hgnc:23161 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns ALG8 (hgnc:23161). hgnc:23161 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: LOSS_OF_FUNCTION
Monoallelic predicted loss-of-function alleles; missense pathogenic alleles are uncommon.
dolichol-linked oligosaccharide biosynthetic process GO:0006488 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased dolichol-linked oligosaccharide biosynthetic process (GO:0006488). GO:0006488 is a biological process from the Gene Ontology.
dolichyl pyrophosphate Glc1Man9GlcNAc2 alpha-1,3-glucosyltransferase activity GO:0042283 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased dolichyl pyrophosphate Glc1Man9GlcNAc2 alpha-1,3-glucosyltransferase activity (GO:0042283). GO:0042283 is a molecular function from the Gene Ontology.
endoplasmic reticulum GO:0005783 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves endoplasmic reticulum (GO:0005783). GO:0005783 is a cellular component from the Gene Ontology.
Downstream
Defective Polycystin-1 Glycosylation and Maturation Without ALG8 the lipid-linked precursor is incompletely glucosylated, so polycystin-1 is hypoglycosylated and less of it reaches a mature, endoglycosidase H-resistant form.
Show evidence (3 references)
PMID:28375157 SUPPORT BACKGROUND Other
"ALG8 (asparagine-linked glycosylation 8) encodes α-1,3-glucosyltransferase, an ER integral membrane protein that functions to add the second of 3 glucoses to the assembling lipid-linked oligosaccharide precursor for N-linked glycosylation before it is transferred to the nascent peptide"
States the enzymatic step ALG8 performs, which defines the molecular lesion. Background description of established enzyme function rather than a new measurement in this paper.
PMID:28375157 SUPPORT Computational
"whereas PKHD1 and ALG8 are not loss intolerant, consistent with genes associated with a recessive human disease"
ExAC constraint analysis in the discovery paper shows ALG8 is not intolerant of heterozygous loss of function.
PMID:39899384 SUPPORT Human Clinical
"Loss-of-function ALG8 and ALG9 variants were enriched in polycystic kidney/liver groups and International Classification of Diseases–coded cystic individuals in population cohorts."
Establishes monoallelic loss of function as the disease-causing genotype through enrichment in cystic cohorts.
Defective Polycystin-1 Glycosylation and Maturation
Mechanism confidence: Established
Polycystin-1 is a very large, heavily N-glycosylated membrane protein whose maturation in the endoplasmic reticulum is rate-limiting for the polycystin complex. In Alg8-null renal epithelial cells polycystin-1 is hypoglycosylated, its steady-state level falls without any change in Pkd1 transcript, and the endoglycosidase H-resistant fraction that has passed the medial Golgi is markedly reduced. Re-expression of Alg8 rescues polycystin-1 expression. Other membrane proteins (polycystin-2, Na+/K+-ATPase, calnexin) were not quantitatively reduced, so the defect is relatively selective for polycystin-1.
protein N-linked glycosylation GO:0006487 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased protein N-linked glycosylation (GO:0006487). GO:0006487 is a biological process from the Gene Ontology. protein folding in endoplasmic reticulum GO:0034975 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased protein folding in endoplasmic reticulum (GO:0034975). GO:0034975 is a biological process from the Gene Ontology.
endoplasmic reticulum GO:0005783 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves endoplasmic reticulum (GO:0005783). GO:0005783 is a cellular component from the Gene Ontology.
Downstream
Reduced Ciliary and Surface Polycystin-1 Immature polycystin-1 fails to traffic past the Golgi to the plasma membrane and the primary cilium.
Endoplasmic Reticulum Unfolded Protein Response Activation Glycosylation failure also activates the IRE1-alpha/XBP1 arm of the unfolded protein response.
Show evidence (3 references)
PMID:28375157 SUPPORT In Vitro
"indicating that differences in steady-state protein level are a post-transcriptional effect"
Reduced polycystin-1 in Alg8-null cells is not explained by reduced Pkd1 transcription.
PMID:28375157 SUPPORT In Vitro
"Re-expression of Alg8+ in Alg8–/– cells rescues PC1 expression"
Rescue ties the polycystin-1 deficit to ALG8 rather than to off-target editing.
PMID:39899384 SUPPORT REVIEW SYNTHESIS Other
"A proposed mechanism of kidney and liver cyst development in monoallelic ALG8 and ALG9 is inefficient folding and trafficking of polycystin 1, due to defective glycosylation"
The cohort authors adopt the polycystin-1 folding and trafficking model for heterozygous carriers; stated as a proposal, not tested in the cohort.
Endoplasmic Reticulum Unfolded Protein Response Activation
Mechanism confidence: Provisional
Alg8-null cells show XBP1 splicing, the readout of IRE1-alpha activation. This is a side branch rather than a step in the cyst pathway: inactivating Xbp1 together with Alg8 did not change polycystin-1 hypoglycosylation or cleavage, and its contribution to human cyst formation is unknown.
IRE1-mediated unfolded protein response GO:0036498 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased IRE1-mediated unfolded protein response (GO:0036498). GO:0036498 is a biological process from the Gene Ontology.
Show evidence (1 reference)
PMID:28375157 SUPPORT In Vitro
"inactivation of both Alg8 and Xbp1 does not change PC1 hypoglycosylation or GPS cleavage compared with Alg8 knockout alone"
Shows that the XBP1 arm of the stress response does not mediate the polycystin-1 defect, which is why this node has no edge into the cyst pathway.
Reduced Ciliary and Surface Polycystin-1
Mechanism confidence: Established
Polycystin-1 is absent or markedly reduced in the primary cilia of Alg8-null cells. Cyst formation across the ADPKD/ADPLD gene family follows the amount of functional polycystin-1, which mouse genetics established for the ADPLD genes Prkcsh and Sec63 as a dose-response relationship. ALG8 is one of the endoplasmic-reticulum effectors whose loss feeds into that shared dosage mechanism.
kidney epithelial cell CL:0002518 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves kidney epithelial cell (CL:0002518). CL:0002518 is a cell type from the Cell Ontology. cholangiocyte CL:1000488 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cholangiocyte (CL:1000488). CL:1000488 is a cell type from the Cell Ontology.
protein localization to cilium GO:0061512 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased protein localization to cilium (GO:0061512). GO:0061512 is a biological process from the Gene Ontology.
cilium GO:0005929 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves cilium (GO:0005929). GO:0005929 is a cellular component from the Gene Ontology.
Downstream
Renal Cystogenesis Reduced functional polycystin-1 in tubular epithelium leads to cyst formation through the polycystin pathway shared with PKD1.
Hepatic Cystogenesis The same polycystin-1 deficit in cholangiocytes drives biliary-derived liver cysts.
Show evidence (2 references)
PMID:28375157 SUPPORT In Vitro
"Immunofluorescence shows absence of detectable PC1 (anti-HA) in cilia of"
Direct imaging of the loss of ciliary polycystin-1 in Alg8-null cells.
PMID:21685914 SUPPORT INDIRECT Model Organism
"there is a dose-response relationship between cystic dilation and levels of functional polycystin-1 following mutation of Prkcsh or Sec63"
Establishes in mice, for two other ADPLD genes, that cyst severity tracks functional polycystin-1 dose. Applied to ALG8 by analogy, hence INDIRECT.
Somatic Second Hit in Cyst Epithelium
Mechanism confidence: Provisional
Polycystic liver disease is thought to need a somatic second hit on top of the germline variant. In one ALG8 patient's explanted liver, ALG8 protein was absent from the cholangiocytes lining cysts but present in hepatocytes away from them, consistent with focal loss of the remaining allele. This is a single-case observation; the somatic lesion itself was not sequenced.
cholangiocyte CL:1000488 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cholangiocyte (CL:1000488). CL:1000488 is a cell type from the Cell Ontology.
Downstream
Hepatic Cystogenesis Complete local loss of ALG8 in biliary epithelium would remove the remaining polycystin-1 maturation capacity in that clone.
Show evidence (2 references)
PMID:37628703 SUPPORT Human Clinical
"In patient 11698, the ALG8 protein is no longer present in the cholangiocytes or the cells bordering the cyst"
Loss of ALG8 protein confined to cyst-lining cells in a heterozygous patient.
PMID:37628703 SUPPORT BACKGROUND Other
"The genetic underpinnings of PLD suggest the presence of a primary pathogenic germline variant in a PLD gene, and a secondary pathogenic somatic variant"
States the two-hit model for polycystic liver disease in general.
Renal Cystogenesis
Mechanism confidence: Established
Kidney cysts form in most carriers who come to imaging, but in modest numbers. In the unselected Mayo Clinic Biobank about half of carriers met an ADPKD cyst-number threshold, kidneys were usually not enlarged, and an atypical imaging pattern (asymmetric, few large cysts, or parenchymal atrophy) was common. Kidney function is usually preserved and kidney failure is rare.
kidney UBERON:0002113 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in kidney (UBERON:0002113). UBERON:0002113 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Multiple Renal Cysts Renal cystogenesis produces bilateral kidney cysts.
Decreased Glomerular Filtration Rate A minority of clinically ascertained carriers have reduced eGFR; how much of it is due to the cysts rather than modifiers or comorbidity is unresolved.
Nephrolithiasis Kidney stones were more frequent in carriers in the Geisinger cohort; the link to cysts is inferred from the parallel with ADPKD.
Show evidence (2 references)
PMID:39899384 SUPPORT Human Clinical
"Individuals with ALG8 mutations typically had mild cystic kidneys with limited enlargement."
Characterises the renal phenotype as mild.
PMID:36574950 SUPPORT Human Clinical
"Thus, PTVs in ALG8 result in increased risk of a mild cystic kidney disease phenotype."
Independent genotype-first cohort reaching the same conclusion.
Hepatic Cystogenesis
Mechanism confidence: Established
Biliary-derived liver cysts are common in clinically ascertained carriers and range from a few small cysts to severe polycystic liver disease with innumerable or large cysts. Severe liver enlargement occurs in a minority, and surgery is rarely needed. Unlike PRKCSH- and SEC63-related disease, the usual female predominance is not seen.
liver UBERON:0002107 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in liver (UBERON:0002107). UBERON:0002107 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Polycystic Liver Disease Hepatic cystogenesis produces polycystic liver disease.
Hepatic Cysts Hepatic cystogenesis produces liver cysts.
Hepatomegaly Cyst burden enlarges the liver in a minority.
Abdominal Pain Abdominal pain was the most common presenting complaint; it is attributed to cyst burden by analogy with ADPKD and ADPLD, not shown per patient.
Show evidence (2 references)
PMID:37628703 SUPPORT Human Clinical
"The ALG8 clinical phenotype ranges from mild to severe polycystic liver disease, and from innumerable small to multiple large hepatic cysts."
Describes the range of liver involvement.
PMID:39899384 SUPPORT Human Clinical
"Only one ALG8 individual required liver surgical intervention, and the overall phenotype was more akin to GANAB than PRKCSH or SEC63 and not displaying the female sex bias usually seen in ADPKD and ADPLD."
Places the liver phenotype nearer GANAB than the classical ADPLD genes and records the absence of female bias.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for ALG8-related Autosomal Dominant Polycystic Kidney And/Or Liver Disease Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

8
Cardiovascular 1
Hypertension FREQUENT HP:0000822 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertension (HP:0000822). HP:0000822 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39899384 SUPPORT Human Clinical
"Hypertension was diagnosed in 44% of individuals (n=27), with an average age at onset of 52 years"
Hypertension frequency and onset in the clinical cohort.
Digestive 3
Hepatic Cysts FREQUENT HP:0001407 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hepatic cysts (HP:0001407). HP:0001407 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:39899384 SUPPORT Human Clinical
"Liver cysts were common (71%), with enlarged livers (>2L) found in 11 of 62 patients, although surgical intervention was rare."
Liver cyst frequency in the clinical cohort.
PMID:36574950 REFUTE Human Clinical
"but not one or more liver cyst (11.5% vs. 7.7%)"
In an unselected population liver cysts were not significantly enriched, so the frequency above reflects clinical ascertainment.
Polycystic Liver Disease OCCASIONAL HP:0006557 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Polycystic liver disease (HP:0006557). HP:0006557 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:28375157 SUPPORT Human Clinical
"Patients with ALG8 mutations showed variation in severity of PCLD and frequent presence of kidney cysts"
Polycystic liver disease with variable severity in the discovery cohort.
PMID:37628703 SUPPORT Human Clinical
"The ALG8 clinical phenotype ranges from mild to severe polycystic liver disease, and from innumerable small to multiple large hepatic cysts."
Range of polycystic liver disease in an ADPLD cohort.
Hepatomegaly OCCASIONAL HP:0002240 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hepatomegaly (HP:0002240). HP:0002240 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39899384 SUPPORT Human Clinical
"Liver cysts were common (71%), with enlarged livers (>2L) found in 11 of 62 patients, although surgical intervention was rare."
11 of 62 patients had livers over 2 L.
Genitourinary 3
Multiple Renal Cysts VERY_FREQUENT HP:0005562 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Multiple renal cysts (HP:0005562). HP:0005562 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:39899384 SUPPORT Human Clinical
"Eighty-nine percent of individuals with ALG8 mutations with imaging in the entire MCBB had kidney cysts (50%, >10 cysts), with greater median kidney and liver cyst numbers than controls."
Kidney cyst frequency in a genotype-first population.
PMID:36574950 SUPPORT Human Clinical
"ALG8 PTV heterozygotes were significantly more likely to have cystic kidney disease, defined as four or more kidney cysts (57.7% vs. 7.7%), or bilateral kidney cysts (69.2% vs. 15.4%)"
Blinded radiology review in a second genotype-first cohort.
Nephrolithiasis HP:0000787 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nephrolithiasis (HP:0000787). HP:0000787 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36574950 SUPPORT Human Clinical
"ALG8 PTVs are associated with a mild cystic kidney disease phenotype and increased risk of nephrolithiasis though not CKD or kidney failure."
Reports the nephrolithiasis association.
Decreased Glomerular Filtration Rate OCCASIONAL HP:0012213 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased glomerular filtration rate (HP:0012213). HP:0012213 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:39899384 SUPPORT Human Clinical
"In the clinical ALG8 population (part 1), most individuals had preserved kidney function, but 11 of 62 had an eGFR <50; other variants or comorbidities might be significant in some of these cases"
eGFR below 50 in 11 of 62 clinically ascertained patients.
PMID:36574950 REFUTE Human Clinical
"ALG8 PTVs were not associated with chronic kidney disease or kidney failure in the MyCode study or the UK Biobank data."
No association with chronic kidney disease in unselected populations, which is why this feature is graded occasional and confined to clinically ascertained patients.
Constitutional 1
Abdominal Pain HP:0002027 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abdominal pain (HP:0002027). HP:0002027 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39899384 SUPPORT Human Clinical
"abdominal pain was the most common initial presentation (n=14), followed by incidental imaging (n=7)"
Abdominal pain as initial presentation in 14 patients.
🧬

Genetic Associations

2
ALG8 (CAUSATIVE)
Gene: ALG8 hgnc:23161 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ALG8 (hgnc:23161). hgnc:23161 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: GERMLINE
Show evidence (4 references)
CGGV:assertion_13259bf6-e954-4159-b247-c9685638e537-2025-03-10T160000.000Z SUPPORT Other
"ALG8 | HGNC:23161 | autosomal dominant polycystic kidney disease | MONDO:0004691 | AD | Definitive"
ClinGen classifies the ALG8 relationship to ADPKD as Definitive.
ORPHA:2924 SUPPORT Other
"ALG8 | ALG8 alpha-1,3-glucosyltransferase | hgnc:23161 | Disease-causing germline mutation(s) in"
Orphanet lists ALG8 as a disease-causing gene for isolated polycystic liver disease.
PMID:39899384 SUPPORT Human Clinical
"Multicenter screening of individuals with polycystic kidney and/or liver disease identified 51 (1.3%) ALG8 (7 multiplex) and 23 (0.6%) ALG9 (5 multiplex) families"
Fifty-one ALG8 families among about 3900 screened cystic families.
+ 1 more reference
PKD1 (MODIFIER)
Gene: PKD1 hgnc:9008 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PKD1 (hgnc:9008). hgnc:9008 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: GERMLINE
Show evidence (1 reference)
PMID:39899384 SUPPORT Human Clinical
"Digenic disease with a PKD1 and an ALG8 P/LP variant described in two families provided some support of ALG8 as a modest enhancer of the PKD1 kidney phenotype."
Co-occurring PKD1 and ALG8 variants with a more severe kidney phenotype.
💊

Medical Actions

3
Liver Resection, Fenestration or Transplantation
Action: liver-directed surgical procedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is liver-directed surgical procedure, annotated with Surgical Procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Platform: Surgery
Liver-volume-reducing surgery or transplantation is reserved for severe symptomatic polycystic liver disease and is rarely needed in ALG8 disease.
Show evidence (2 references)
PMID:39899384 SUPPORT Human Clinical
"Only one ALG8 individual required liver surgical intervention, and the overall phenotype was more akin to GANAB than PRKCSH or SEC63 and not displaying the female sex bias usually seen in ADPKD and ADPLD."
Surgery was needed in one of the clinically ascertained ALG8 patients.
PMID:37628703 SUPPORT Human Clinical
"After partial liver resection combined with fenestration, he received liver–kidney transplantation."
A severe ALG8 case treated by resection, fenestration and then transplantation.
Somatostatin Analogue Therapy
Action: somatostatin analog therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is somatostatin analog therapy (NCIT:C15449). NCIT:C15449 is a clinical intervention from the NCI Thesaurus. Ontology label: Somatostatin Analog Therapy NCIT:C15449
Agent: octreotide CHEBI:7726 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses octreotide (CHEBI:7726). CHEBI:7726 is a therapeutic agent from Chemical Entities of Biological Interest. lanreotide CHEBI:135901 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses lanreotide (CHEBI:135901). CHEBI:135901 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Peptide
Somatostatin analogues such as octreotide and lanreotide reduce liver volume in polycystic liver disease. The trials pooled ADPKD and ADPLD patients and did not report ALG8 carriers separately, so use in ALG8 disease is an extrapolation for the minority with severe, symptomatic liver enlargement.
Mechanism Target:
Hepatic Cystogenesis — Slows hepatic cyst expansion and liver volume growth.
Show evidence (1 reference)
PMID:23665274 SUPPORT INDIRECT Human Clinical
"the overall difference in liver volume between groups receiving SAs therapy vs placebo was 5.3% (P < .001)"
Pooled randomized-trial data in polycystic liver disease. ALG8 carriers are not identified in these trials, so applying the effect to ALG8 disease is an inference.
Genetic Counseling
Action: Genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Platform: Behavioral / lifestyle
Counselling addresses incomplete penetrance and the separate recessive risk of ALG8-CDG. Presymptomatic testing of at-risk minors should be avoided, and carriers planning a pregnancy should be asked about consanguinity with their partner.
Show evidence (2 references)
PMID:39899384 SUPPORT Human Clinical
"Given the incomplete penetrance of ALG8 and ALG9, presymptomatic genetic diagnosis should be avoided in minors at familial risk."
Guidance against presymptomatic testing of minors.
PMID:39899384 SUPPORT Human Clinical
"In carriers of ALG8 or ALG9 pathogenic variants intending to conceive, the presence of a shared ancestor with their partner should be ascertained."
Reproductive counselling for the biallelic CDG risk.
🔬

Diagnosis

1
Molecular Genetic Testing
Diagnosis rests on finding a heterozygous ALG8 pathogenic variant in a person with kidney and/or liver cysts and no variant in another ADPKD or ADPLD gene; ALG8 should be on ADPKD/ADPLD panels. Because ALG8 alleles are common and penetrance is low, an incidental ALG8 finding without cysts on imaging should not be labelled ADPKD or ADPLD, and in a patient with a severe, typical ADPKD kidney phenotype a missed PKD1 variant should be considered first. The diagnosis implies a low chance of eGFR decline and a small chance of significant liver disease, so treatment or trial enrolment designed for typical ADPKD is probably not appropriate.
Genetic Testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:39899384 SUPPORT Human Clinical
"Given the enrichment of ALG8 and ALG9 P/LP alleles in cystic kidney, and ALG8 in cystic liver, individuals, these genes should be included on screening panels for ADPKD/ADPLD."
Recommends ALG8 on diagnostic panels.
PMID:39899384 SUPPORT Human Clinical
"This diagnosis would generally indicate a low (ALG8) to moderate (ALG9) chance of eGFR reduction, with a small chance of significant polycystic liver disease for ALG8, and that treatment or enrollment in clinical trials for more typical ADPKD is probably not appropriate."
Prognostic and therapeutic implication of the molecular diagnosis.
📊

Prevalence

1
Families with polycystic kidney and/or liver disease (multicenter clinical screen)
Unknown
1.3% of about 3900 cystic kidney and/or liver families carried an ALG8 pathogenic variant, about ten times the 0.13% frequency in gnomAD. This is a share of a referral population, not a population rate. Predicted loss-of-function ALG8 alleles are present in roughly 0.1% of the general population, but most carriers are never diagnosed.
Show evidence (2 references)
PMID:39899384 SUPPORT Human Clinical
"The level of individuals with ALG8 pathogenic variants in the clinical population (51/3935, 1.3%) was significantly higher than that found in the gnomAD v3.1.2 database (95/76,000, 0.13%)"
Gives the ALG8 share of cystic families against the population background.
PMID:42804492 SUPPORT Computational
"LRP5 and ALG8 which are associated with a milder clinical phenotype, were the commonest affected genes with both strategies."
ALG8 is among the most frequently affected ADPLD genes in gnomAD.
{ }

Source YAML

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name: ALG8-related Autosomal Dominant Polycystic Kidney And/Or Liver Disease
creation_date: "2026-10-08T00:00:00Z"
category: Mendelian
synonyms:
- ALG8-related ADPKD/ADPLD
- ADPKD-ALG8
- ALG8-associated autosomal dominant polycystic liver disease
- ALG8-related autosomal dominant polycystic kidney and/or liver disease
description: >-
  ALG8-related autosomal dominant polycystic kidney and/or liver disease is the
  cystic disorder of people heterozygous for a loss-of-function variant in ALG8.
  ALG8 encodes the endoplasmic-reticulum alpha-1,3-glucosyltransferase that adds
  the second of three glucoses to the lipid-linked oligosaccharide precursor of
  N-linked glycosylation. Biallelic loss of the same gene causes a severe
  multisystem congenital disorder of glycosylation (ALG8-CDG, CDG-Ih); the
  monoallelic disease described here is a different, organ-restricted and
  usually mild condition.

  The phenotype sits between the two classical dominant cystic disorders.
  Most carriers who develop disease have a modest number of kidney cysts without
  marked kidney enlargement, and kidney function is usually preserved;
  progression to kidney failure is rare. Liver cysts are common, and a minority
  develop severe polycystic liver disease with liver volume above two litres, so
  the gene was first found in isolated polycystic liver disease cohorts and
  later in cystic kidney cohorts. Penetrance for cysts is incomplete and
  expressivity is variable even within one family, and predicted
  loss-of-function ALG8 alleles are present in roughly one in a thousand people,
  so many carriers have only a few cysts or none.

  Mechanistically ALG8 belongs with GANAB, PRKCSH, SEC63, ALG5, ALG9 and DNAJB11
  as an endoplasmic-reticulum proteostasis gene that sits upstream of the
  polycystin complex. Loss of ALG8 leaves polycystin-1 hypoglycosylated, reduces
  its steady-state level and blocks its trafficking to the cell surface and the
  primary cilium. Reduced functional polycystin-1 is the shared final pathway
  into cystogenesis in kidney tubule and biliary epithelium.
disease_term:
  preferred_term: ALG8-related autosomal dominant polycystic kidney and/or liver disease
  term:
    id: MONDO:1060122
    label: ALG8-related autosomal dominant polycystic kidney and/or liver disease
parents:
- Autosomal Dominant Polycystic Kidney Disease
- Autosomal Dominant Polycystic Liver Disease
mappings:
  mondo_mappings:
  - term:
      id: MONDO:1060122
      label: ALG8-related autosomal dominant polycystic kidney and/or liver disease
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      MONDO:1060122 is the gene-defined ALG8 kidney and/or liver cystic disease
      concept modeled by this entry.
references:
- reference: PMID:20301424
  title: Polycystic Kidney Disease, Autosomal Dominant.
  tags:
  - GeneReviews
- reference: PMID:39899384
  title: Characterization of the Cystic Phenotype Associated with Monoallelic ALG8 and ALG9 Pathogenic Variants.
- reference: PMID:28375157
  title: Isolated polycystic liver disease genes define effectors of polycystin-1 function.
- reference: PMID:36574950
  title: Individuals heterozygous for ALG8 protein-truncating variants are at increased risk of a mild cystic kidney disease.
- reference: PMID:37628703
  title: Novel α-1,3-Glucosyltransferase Variants and Their Broad Clinical Polycystic Liver Disease Spectrum.
notes: >-
  Scope and lump/split. Curated as a standalone gene-defined entry with its own
  MONDO term, following Polycystic_Kidney_Disease_3 (GANAB), whose kidney/liver
  spectrum this disease most resembles. ALG8 is also listed as a genetic record
  in Autosomal_Dominant_Polycystic_Kidney_Disease and
  Autosomal_Dominant_Polycystic_Liver_Disease; those records and this entry
  should be read together. MONDO places MONDO:1060122 only under autosomal
  dominant disease, not under either cystic parent, because the concept spans
  both, so both are listed in parents here.

  Distinct from ALG8-CDG. Biallelic ALG8 variants cause congenital disorder of
  glycosylation type Ih, a neonatal-onset multisystem disease. That is a
  separate disorder (stubs/ALG8-congenital_Disorder_Of_Glycosylation.yaml) and
  none of its features are curated here; the monoallelic cohort study screened
  for CDG-associated features in heterozygotes and did not find recurrent ones.

  Phenotype sourcing. No GeneReviews chapter covers this disease. The ADPKD
  GeneReviews chapter (NBK1246) names ALG8 only in its differential-diagnosis
  table, among polycystic liver disease genes with liver cysts and occasional
  kidney cysts, so its PKD1-dominated clinical picture (enlarged kidneys,
  kidney failure in mid-life, intracranial aneurysm) is deliberately not
  imported. Phenotypes here come from the ALG8 cohorts themselves: the
  multicenter clinical and biobank study (PMID:39899384), the Geisinger
  genotype-first cohort (PMID:36574950), the polycystic liver disease cohorts
  (PMID:28375157, PMID:37628703).

  Gene-disease validity. ClinGen classifies ALG8 as Definitive for autosomal
  dominant polycystic kidney disease (MONDO:0004691). That is a broader MONDO
  disease than this entry's term, so it is cited as evidence on the genetic
  record rather than copied into gene_disease_validity.
pathophysiology:
- name: Heterozygous ALG8 Loss of Function
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Germline heterozygous loss-of-function variants, predominantly nonsense,
    frameshift and canonical splice alleles with recurrent p.Arg364*, reduce
    the dose of ALG8. ALG8 is the endoplasmic-reticulum
    alpha-1,3-glucosyltransferase that adds the second glucose to the dolichol-linked
    Glc1Man9GlcNAc2 precursor before the oligosaccharide is transferred to
    nascent glycoproteins. ALG8 is not intolerant of loss of function in
    population exome data, which is consistent with its
    recessive CDG and with the incomplete penetrance of this disease.
  genes:
  - preferred_term: ALG8
    term:
      id: hgnc:23161
      label: ALG8
  genetic_context:
    gene:
      preferred_term: ALG8
      term:
        id: hgnc:23161
        label: ALG8
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Monoallelic predicted loss-of-function alleles; missense pathogenic
      alleles are uncommon.
  molecular_functions:
  - preferred_term: dolichyl pyrophosphate Glc1Man9GlcNAc2 alpha-1,3-glucosyltransferase activity
    term:
      id: GO:0042283
      label: dolichyl pyrophosphate Glc1Man9GlcNAc2 alpha-1,3-glucosyltransferase activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: dolichol-linked oligosaccharide biosynthetic process
    term:
      id: GO:0006488
      label: dolichol-linked oligosaccharide biosynthetic process
    modifier: DECREASED
  cellular_components:
  - preferred_term: endoplasmic reticulum
    term:
      id: GO:0005783
      label: endoplasmic reticulum
  evidence:
  - reference: PMID:28375157
    reference_title: Isolated polycystic liver disease genes define effectors of polycystin-1 function.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: >-
      ALG8 (asparagine-linked glycosylation 8) encodes α-1,3-glucosyltransferase,
      an ER integral membrane protein that functions to add the second of 3
      glucoses to the assembling lipid-linked oligosaccharide precursor for
      N-linked glycosylation before it is transferred to the nascent peptide
    explanation: >-
      States the enzymatic step ALG8 performs, which defines the molecular
      lesion. Background description of established enzyme function rather
      than a new measurement in this paper.
  - reference: PMID:28375157
    reference_title: Isolated polycystic liver disease genes define effectors of polycystin-1 function.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      whereas PKHD1 and ALG8 are not loss intolerant, consistent with genes
      associated with a recessive human disease
    explanation: >-
      ExAC constraint analysis in the discovery paper shows ALG8 is not
      intolerant of heterozygous loss of function.
  - reference: PMID:39899384
    reference_title: Characterization of the Cystic Phenotype Associated with Monoallelic ALG8 and ALG9 Pathogenic Variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Loss-of-function ALG8 and ALG9 variants were enriched in polycystic
      kidney/liver groups and International Classification of Diseases–coded
      cystic individuals in population cohorts.
    explanation: >-
      Establishes monoallelic loss of function as the disease-causing
      genotype through enrichment in cystic cohorts.
  downstream:
  - target: Defective Polycystin-1 Glycosylation and Maturation
    causal_link_type: DIRECT
    description: >-
      Without ALG8 the lipid-linked precursor is incompletely glucosylated,
      so polycystin-1 is hypoglycosylated and less of it reaches a mature,
      endoglycosidase H-resistant form.
    evidence:
    - reference: PMID:28375157
      reference_title: Isolated polycystic liver disease genes define effectors of polycystin-1 function.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      snippet: >-
        Altered migration of PC1-FL is due to hypoglycosylation in Alg8–/– cells.
      explanation: >-
        Alg8-null mouse kidney epithelial cells show hypoglycosylated
        polycystin-1. The cells are null, whereas patients are heterozygous, so
        the step from complete to partial loss is an inference.
- name: Defective Polycystin-1 Glycosylation and Maturation
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Polycystin-1 is a very large, heavily N-glycosylated membrane protein whose
    maturation in the endoplasmic reticulum is rate-limiting for the
    polycystin complex. In Alg8-null renal epithelial cells polycystin-1 is
    hypoglycosylated, its steady-state level falls without any change in Pkd1
    transcript, and the endoglycosidase H-resistant fraction that has passed
    the medial Golgi is markedly reduced. Re-expression of Alg8 rescues
    polycystin-1 expression. Other membrane proteins (polycystin-2,
    Na+/K+-ATPase, calnexin) were not quantitatively reduced, so the defect is
    relatively selective for polycystin-1.
  biological_processes:
  - preferred_term: protein N-linked glycosylation
    term:
      id: GO:0006487
      label: protein N-linked glycosylation
    modifier: DECREASED
  - preferred_term: protein folding in endoplasmic reticulum
    term:
      id: GO:0034975
      label: protein folding in endoplasmic reticulum
    modifier: DECREASED
  cellular_components:
  - preferred_term: endoplasmic reticulum
    term:
      id: GO:0005783
      label: endoplasmic reticulum
  evidence:
  - reference: PMID:28375157
    reference_title: Isolated polycystic liver disease genes define effectors of polycystin-1 function.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      indicating that differences in steady-state protein level are a
      post-transcriptional effect
    explanation: >-
      Reduced polycystin-1 in Alg8-null cells is not explained by reduced Pkd1
      transcription.
  - reference: PMID:28375157
    reference_title: Isolated polycystic liver disease genes define effectors of polycystin-1 function.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Re-expression of Alg8+ in Alg8–/– cells rescues PC1 expression
    explanation: >-
      Rescue ties the polycystin-1 deficit to ALG8 rather than to off-target
      editing.
  - reference: PMID:39899384
    reference_title: Characterization of the Cystic Phenotype Associated with Monoallelic ALG8 and ALG9 Pathogenic Variants.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      A proposed mechanism of kidney and liver cyst development in monoallelic
      ALG8 and ALG9 is inefficient folding and trafficking of polycystin 1, due
      to defective glycosylation
    explanation: >-
      The cohort authors adopt the polycystin-1 folding and trafficking model
      for heterozygous carriers; stated as a proposal, not tested in the cohort.
  downstream:
  - target: Reduced Ciliary and Surface Polycystin-1
    causal_link_type: DIRECT
    description: >-
      Immature polycystin-1 fails to traffic past the Golgi to the plasma
      membrane and the primary cilium.
    evidence:
    - reference: PMID:28375157
      reference_title: Isolated polycystic liver disease genes define effectors of polycystin-1 function.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        providing biochemical evidence that PC1 trafficking to the cell surface,
        and by extension to cilia, is markedly impaired following inactivation
        of Alg8
      explanation: >-
        The reduced endoglycosidase H-resistant fraction shows that polycystin-1
        does not pass the medial Golgi when Alg8 is inactivated.
  - target: Endoplasmic Reticulum Unfolded Protein Response Activation
    causal_link_type: DIRECT
    description: >-
      Glycosylation failure also activates the IRE1-alpha/XBP1 arm of the
      unfolded protein response.
    evidence:
    - reference: PMID:28375157
      reference_title: Isolated polycystic liver disease genes define effectors of polycystin-1 function.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        cells activate the IRE1α/XBP1 branch of UPR, demonstrated by presence of
        XBP1s
      explanation: >-
        XBP1 splicing in Alg8-null cells shows IRE1-alpha activation.
- name: Endoplasmic Reticulum Unfolded Protein Response Activation
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    Alg8-null cells show XBP1 splicing, the readout of IRE1-alpha activation.
    This is a side branch rather than a step in the cyst pathway: inactivating
    Xbp1 together with Alg8 did not change polycystin-1 hypoglycosylation or
    cleavage, and its contribution to human cyst formation is unknown.
  biological_processes:
  - preferred_term: IRE1-mediated unfolded protein response
    term:
      id: GO:0036498
      label: IRE1-mediated unfolded protein response
    modifier: INCREASED
  evidence:
  - reference: PMID:28375157
    reference_title: Isolated polycystic liver disease genes define effectors of polycystin-1 function.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      inactivation of both Alg8 and Xbp1 does not change PC1 hypoglycosylation
      or GPS cleavage compared with Alg8 knockout alone
    explanation: >-
      Shows that the XBP1 arm of the stress response does not mediate the
      polycystin-1 defect, which is why this node has no edge into the cyst
      pathway.
- name: Reduced Ciliary and Surface Polycystin-1
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Polycystin-1 is absent or markedly reduced in the primary cilia of
    Alg8-null cells. Cyst formation across the ADPKD/ADPLD gene family follows
    the amount of functional polycystin-1, which mouse genetics established for
    the ADPLD genes Prkcsh and Sec63 as a dose-response relationship. ALG8 is
    one of the endoplasmic-reticulum effectors whose loss feeds into that
    shared dosage mechanism.
  cell_types:
  - preferred_term: kidney epithelial cell
    term:
      id: CL:0002518
      label: kidney epithelial cell
  - preferred_term: cholangiocyte
    term:
      id: CL:1000488
      label: cholangiocyte
  biological_processes:
  - preferred_term: protein localization to cilium
    term:
      id: GO:0061512
      label: protein localization to cilium
    modifier: DECREASED
  cellular_components:
  - preferred_term: cilium
    term:
      id: GO:0005929
      label: cilium
  evidence:
  - reference: PMID:28375157
    reference_title: Isolated polycystic liver disease genes define effectors of polycystin-1 function.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Immunofluorescence shows absence of detectable PC1 (anti-HA) in cilia of
    explanation: >-
      Direct imaging of the loss of ciliary polycystin-1 in Alg8-null cells.
  - reference: PMID:21685914
    reference_title: A genetic interaction network of five genes for human polycystic kidney and liver diseases defines polycystin-1 as the central determinant of cyst formation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: >-
      there is a dose-response relationship between cystic dilation and levels
      of functional polycystin-1 following mutation of Prkcsh or Sec63
    explanation: >-
      Establishes in mice, for two other ADPLD genes, that cyst severity tracks
      functional polycystin-1 dose. Applied to ALG8 by analogy, hence
      INDIRECT.
  downstream:
  - target: Renal Cystogenesis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Reduced functional polycystin-1 in tubular epithelium leads to cyst
      formation through the polycystin pathway shared with PKD1.
    evidence:
    - reference: PMID:28375157
      reference_title: Isolated polycystic liver disease genes define effectors of polycystin-1 function.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        We inactivated these candidate genes in cell line models to show that
        loss of function of each results in defective maturation and trafficking
        of polycystin-1, the central determinant of cyst pathogenesis.
      explanation: >-
        Places ALG8 loss upstream of polycystin-1, the central determinant of
        cyst formation.
  - target: Hepatic Cystogenesis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      The same polycystin-1 deficit in cholangiocytes drives biliary-derived
      liver cysts.
    evidence:
    - reference: PMID:28375157
      reference_title: Isolated polycystic liver disease genes define effectors of polycystin-1 function.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: >-
        Liver cysts in both PCLD and ADPKD are lined with biliary epithelium.
      explanation: >-
        Places the liver cysts in biliary epithelium, the cell type in which
        the polycystin-1 deficit acts on this edge. Stated in the paper's
        introduction as established pathology.
- name: Somatic Second Hit in Cyst Epithelium
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    Polycystic liver disease is thought to need a somatic second hit on top of
    the germline variant. In one ALG8 patient's explanted liver, ALG8 protein
    was absent from the cholangiocytes lining cysts but present in hepatocytes
    away from them, consistent with focal loss of the remaining allele. This
    is a single-case observation; the somatic lesion itself was not sequenced.
  cell_types:
  - preferred_term: cholangiocyte
    term:
      id: CL:1000488
      label: cholangiocyte
  evidence:
  - reference: PMID:37628703
    reference_title: Novel α-1,3-Glucosyltransferase Variants and Their Broad Clinical Polycystic Liver Disease Spectrum.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In patient 11698, the ALG8 protein is no longer present in the
      cholangiocytes or the cells bordering the cyst
    explanation: >-
      Loss of ALG8 protein confined to cyst-lining cells in a heterozygous
      patient.
  - reference: PMID:37628703
    reference_title: Novel α-1,3-Glucosyltransferase Variants and Their Broad Clinical Polycystic Liver Disease Spectrum.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: >-
      The genetic underpinnings of PLD suggest the presence of a primary
      pathogenic germline variant in a PLD gene, and a secondary pathogenic
      somatic variant
    explanation: >-
      States the two-hit model for polycystic liver disease in general.
  downstream:
  - target: Hepatic Cystogenesis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Complete local loss of ALG8 in biliary epithelium would remove the
      remaining polycystin-1 maturation capacity in that clone.
    evidence:
    - reference: PMID:37628703
      reference_title: Novel α-1,3-Glucosyltransferase Variants and Their Broad Clinical Polycystic Liver Disease Spectrum.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        For the seventh variant, immunostaining of the liver tissue showed a
        complete loss of ALG8 in the cystic cells.
      explanation: >-
        Associates local ALG8 loss with the cystic epithelium; causality is
        inferred.
- name: Renal Cystogenesis
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  description: >-
    Kidney cysts form in most carriers who come to imaging, but in modest
    numbers. In the unselected Mayo Clinic Biobank about half of carriers met
    an ADPKD cyst-number threshold, kidneys were usually not enlarged, and an
    atypical imaging pattern (asymmetric, few large cysts, or parenchymal
    atrophy) was common. Kidney function is usually preserved and kidney
    failure is rare.
  locations:
  - preferred_term: kidney
    term:
      id: UBERON:0002113
      label: kidney
  evidence:
  - reference: PMID:39899384
    reference_title: Characterization of the Cystic Phenotype Associated with Monoallelic ALG8 and ALG9 Pathogenic Variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Individuals with ALG8 mutations typically had mild cystic kidneys with
      limited enlargement.
    explanation: >-
      Characterises the renal phenotype as mild.
  - reference: PMID:36574950
    reference_title: Individuals heterozygous for ALG8 protein-truncating variants are at increased risk of a mild cystic kidney disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thus, PTVs in ALG8 result in increased risk of a mild cystic kidney
      disease phenotype.
    explanation: >-
      Independent genotype-first cohort reaching the same conclusion.
  downstream:
  - target: Multiple Renal Cysts
    causal_link_type: DIRECT
    description: Renal cystogenesis produces bilateral kidney cysts.
    evidence:
    - reference: PMID:36574950
      reference_title: Individuals heterozygous for ALG8 protein-truncating variants are at increased risk of a mild cystic kidney disease.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        ALG8 PTV heterozygotes were significantly more likely to have cystic
        kidney disease, defined as four or more kidney cysts (57.7% vs. 7.7%),
        or bilateral kidney cysts (69.2% vs. 15.4%)
      explanation: >-
        Blinded radiology review shows the cyst phenotype itself.
  - target: Decreased Glomerular Filtration Rate
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      A minority of clinically ascertained carriers have reduced eGFR; how
      much of it is due to the cysts rather than modifiers or comorbidity is
      unresolved.
    evidence:
    - reference: PMID:39899384
      reference_title: Characterization of the Cystic Phenotype Associated with Monoallelic ALG8 and ALG9 Pathogenic Variants.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In the clinical ALG8 population (part 1), most individuals had preserved
        kidney function, but 11 of 62 had an eGFR <50; other variants or
        comorbidities might be significant in some of these cases
      explanation: >-
        Reports reduced eGFR in a minority and flags confounding.
  - target: Nephrolithiasis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Kidney stones were more frequent in carriers in the Geisinger cohort;
      the link to cysts is inferred from the parallel with ADPKD.
    evidence:
    - reference: PMID:36574950
      reference_title: Individuals heterozygous for ALG8 protein-truncating variants are at increased risk of a mild cystic kidney disease.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        ALG8 PTVs are associated with a mild cystic kidney disease phenotype and
        increased risk of nephrolithiasis though not CKD or kidney failure.
      explanation: >-
        Reports the nephrolithiasis association alongside the cystic phenotype.
- name: Hepatic Cystogenesis
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  description: >-
    Biliary-derived liver cysts are common in clinically ascertained carriers
    and range from a few small cysts to severe polycystic liver disease with
    innumerable or large cysts. Severe liver enlargement occurs in a minority,
    and surgery is rarely needed. Unlike PRKCSH- and SEC63-related disease, the
    usual female predominance is not seen.
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  evidence:
  - reference: PMID:37628703
    reference_title: Novel α-1,3-Glucosyltransferase Variants and Their Broad Clinical Polycystic Liver Disease Spectrum.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The ALG8 clinical phenotype ranges from mild to severe polycystic liver
      disease, and from innumerable small to multiple large hepatic cysts.
    explanation: >-
      Describes the range of liver involvement.
  - reference: PMID:39899384
    reference_title: Characterization of the Cystic Phenotype Associated with Monoallelic ALG8 and ALG9 Pathogenic Variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Only one ALG8 individual required liver surgical intervention, and the
      overall phenotype was more akin to GANAB than PRKCSH or SEC63 and not
      displaying the female sex bias usually seen in ADPKD and ADPLD.
    explanation: >-
      Places the liver phenotype nearer GANAB than the classical ADPLD genes
      and records the absence of female bias.
  downstream:
  - target: Polycystic Liver Disease
    causal_link_type: DIRECT
    description: Hepatic cystogenesis produces polycystic liver disease.
    evidence:
    - reference: PMID:39899384
      reference_title: Characterization of the Cystic Phenotype Associated with Monoallelic ALG8 and ALG9 Pathogenic Variants.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        ALG8 pathogenic variants sometimes resulted in severe polycystic liver
        disease.
      explanation: Severe polycystic liver disease is the end of the spectrum.
  - target: Hepatic Cysts
    causal_link_type: DIRECT
    description: Hepatic cystogenesis produces liver cysts.
    evidence:
    - reference: PMID:39899384
      reference_title: Characterization of the Cystic Phenotype Associated with Monoallelic ALG8 and ALG9 Pathogenic Variants.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Liver cysts were common (71%), with enlarged livers (>2L) found in 11 of
        62 patients, although surgical intervention was rare.
      explanation: Gives the frequency of liver cysts.
  - target: Hepatomegaly
    causal_link_type: DIRECT
    description: Cyst burden enlarges the liver in a minority.
    evidence:
    - reference: PMID:39899384
      reference_title: Characterization of the Cystic Phenotype Associated with Monoallelic ALG8 and ALG9 Pathogenic Variants.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Liver cysts were common (71%), with enlarged livers (>2L) found in 11 of
        62 patients, although surgical intervention was rare.
      explanation: Liver volume over 2 L in 11 of 62 clinically ascertained patients.
  - target: Abdominal Pain
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Abdominal pain was the most common presenting complaint; it is attributed
      to cyst burden by analogy with ADPKD and ADPLD, not shown per patient.
    evidence:
    - reference: PMID:39899384
      reference_title: Characterization of the Cystic Phenotype Associated with Monoallelic ALG8 and ALG9 Pathogenic Variants.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        abdominal pain was the most common initial presentation (n=14), followed
        by incidental imaging (n=7)
      explanation: Records abdominal pain as the leading presentation.
phenotypes:
- category: Renal
  name: Multiple Renal Cysts
  frequency: VERY_FREQUENT
  description: >-
    Bilateral kidney cysts, usually modest in number with little kidney
    enlargement. In the unselected Mayo Clinic Biobank 89% of imaged carriers
    had kidney cysts and half had more than ten; in the Geisinger cohort 58%
    of carriers had four or more.
  phenotype_term:
    preferred_term: Multiple renal cysts
    term:
      id: HP:0005562
      label: Multiple renal cysts
  evidence:
  - reference: PMID:39899384
    reference_title: Characterization of the Cystic Phenotype Associated with Monoallelic ALG8 and ALG9 Pathogenic Variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Eighty-nine percent of individuals with ALG8 mutations with imaging in the
      entire MCBB had kidney cysts (50%, >10 cysts), with greater median kidney
      and liver cyst numbers than controls.
    explanation: Kidney cyst frequency in a genotype-first population.
  - reference: PMID:36574950
    reference_title: Individuals heterozygous for ALG8 protein-truncating variants are at increased risk of a mild cystic kidney disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ALG8 PTV heterozygotes were significantly more likely to have cystic
      kidney disease, defined as four or more kidney cysts (57.7% vs. 7.7%),
      or bilateral kidney cysts (69.2% vs. 15.4%)
    explanation: Blinded radiology review in a second genotype-first cohort.
- category: Hepatobiliary
  name: Hepatic Cysts
  frequency: FREQUENT
  description: >-
    Liver cysts were present in about two thirds of clinically ascertained
    carriers. In genotype-first cohorts liver cysts are less frequent; the
    Geisinger imaging review did not find them enriched over relatives.
  phenotype_term:
    preferred_term: Hepatic cysts
    term:
      id: HP:0001407
      label: Hepatic cysts
  evidence:
  - reference: PMID:39899384
    reference_title: Characterization of the Cystic Phenotype Associated with Monoallelic ALG8 and ALG9 Pathogenic Variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Liver cysts were common (71%), with enlarged livers (>2L) found in 11 of
      62 patients, although surgical intervention was rare.
    explanation: Liver cyst frequency in the clinical cohort.
  - reference: PMID:36574950
    reference_title: Individuals heterozygous for ALG8 protein-truncating variants are at increased risk of a mild cystic kidney disease.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      but not one or more liver cyst (11.5% vs. 7.7%)
    explanation: >-
      In an unselected population liver cysts were not significantly enriched,
      so the frequency above reflects clinical ascertainment.
- category: Hepatobiliary
  name: Polycystic Liver Disease
  frequency: OCCASIONAL
  description: >-
    Severe polycystic liver disease occurs in a minority and was the
    presentation through which the gene was discovered. Cyst size ranges from
    innumerable small cysts to multiple cysts over 10 cm.
  phenotype_term:
    preferred_term: Polycystic liver disease
    term:
      id: HP:0006557
      label: Polycystic liver disease
  evidence:
  - reference: PMID:28375157
    reference_title: Isolated polycystic liver disease genes define effectors of polycystin-1 function.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with ALG8 mutations showed variation in severity of PCLD and
      frequent presence of kidney cysts
    explanation: Polycystic liver disease with variable severity in the discovery cohort.
  - reference: PMID:37628703
    reference_title: Novel α-1,3-Glucosyltransferase Variants and Their Broad Clinical Polycystic Liver Disease Spectrum.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The ALG8 clinical phenotype ranges from mild to severe polycystic liver
      disease, and from innumerable small to multiple large hepatic cysts.
    explanation: Range of polycystic liver disease in an ADPLD cohort.
- category: Hepatobiliary
  name: Hepatomegaly
  frequency: OCCASIONAL
  description: Liver volume above 2 L in about one in six clinically ascertained carriers.
  phenotype_term:
    preferred_term: Hepatomegaly
    term:
      id: HP:0002240
      label: Hepatomegaly
  evidence:
  - reference: PMID:39899384
    reference_title: Characterization of the Cystic Phenotype Associated with Monoallelic ALG8 and ALG9 Pathogenic Variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Liver cysts were common (71%), with enlarged livers (>2L) found in 11 of
      62 patients, although surgical intervention was rare.
    explanation: 11 of 62 patients had livers over 2 L.
- category: Gastrointestinal
  name: Abdominal Pain
  description: The most common presenting complaint in the clinically ascertained cohort.
  phenotype_term:
    preferred_term: Abdominal pain
    term:
      id: HP:0002027
      label: Abdominal pain
  evidence:
  - reference: PMID:39899384
    reference_title: Characterization of the Cystic Phenotype Associated with Monoallelic ALG8 and ALG9 Pathogenic Variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      abdominal pain was the most common initial presentation (n=14), followed
      by incidental imaging (n=7)
    explanation: Abdominal pain as initial presentation in 14 patients.
- category: Cardiovascular
  name: Hypertension
  frequency: FREQUENT
  description: >-
    Diagnosed in 44% of clinically ascertained carriers, mean onset 52 years.
    The Geisinger cohort did not find hypertension enriched over controls, so
    this may reflect age and ascertainment rather than the cysts.
  phenotype_term:
    preferred_term: Hypertension
    term:
      id: HP:0000822
      label: Hypertension
  evidence:
  - reference: PMID:39899384
    reference_title: Characterization of the Cystic Phenotype Associated with Monoallelic ALG8 and ALG9 Pathogenic Variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hypertension was diagnosed in 44% of individuals (n=27), with an average
      age at onset of 52 years
    explanation: Hypertension frequency and onset in the clinical cohort.
- category: Renal
  name: Nephrolithiasis
  description: Kidney stones were more frequent in ALG8 truncating-variant carriers than controls in the Geisinger cohort.
  phenotype_term:
    preferred_term: Nephrolithiasis
    term:
      id: HP:0000787
      label: Nephrolithiasis
  evidence:
  - reference: PMID:36574950
    reference_title: Individuals heterozygous for ALG8 protein-truncating variants are at increased risk of a mild cystic kidney disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ALG8 PTVs are associated with a mild cystic kidney disease phenotype and
      increased risk of nephrolithiasis though not CKD or kidney failure.
    explanation: Reports the nephrolithiasis association.
- category: Renal
  name: Decreased Glomerular Filtration Rate
  frequency: OCCASIONAL
  description: >-
    Reduced eGFR occurs in a minority of clinically ascertained carriers and
    kidney failure is rare. Genotype-first cohorts found no association with
    chronic kidney disease or kidney failure.
  phenotype_term:
    preferred_term: Decreased glomerular filtration rate
    term:
      id: HP:0012213
      label: Decreased glomerular filtration rate
  evidence:
  - reference: PMID:39899384
    reference_title: Characterization of the Cystic Phenotype Associated with Monoallelic ALG8 and ALG9 Pathogenic Variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the clinical ALG8 population (part 1), most individuals had preserved
      kidney function, but 11 of 62 had an eGFR <50; other variants or
      comorbidities might be significant in some of these cases
    explanation: eGFR below 50 in 11 of 62 clinically ascertained patients.
  - reference: PMID:36574950
    reference_title: Individuals heterozygous for ALG8 protein-truncating variants are at increased risk of a mild cystic kidney disease.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ALG8 PTVs were not associated with chronic kidney disease or kidney
      failure in the MyCode study or the UK Biobank data.
    explanation: >-
      No association with chronic kidney disease in unselected populations,
      which is why this feature is graded occasional and confined to
      clinically ascertained patients.
genetic:
- name: ALG8
  gene_term:
    preferred_term: ALG8
    term:
      id: hgnc:23161
      label: ALG8
  association: CAUSATIVE
  variant_origin: GERMLINE
  features: >-
    Heterozygous predicted loss-of-function variants, with recurrent p.Arg364*.
    Penetrance for cysts is incomplete and expressivity variable. The common
    splice variant c.478+1G>A was excluded from the largest cohort over doubts
    about its pathogenicity.
  notes: >-
    ClinGen classifies ALG8 as Definitive for autosomal dominant polycystic
    kidney disease (MONDO:0004691); that is a broader disease than
    MONDO:1060122, so the tier is not recorded in gene_disease_validity.
  evidence:
  - reference: CGGV:assertion_13259bf6-e954-4159-b247-c9685638e537-2025-03-10T160000.000Z
    reference_title: ALG8 / autosomal dominant polycystic kidney disease (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ALG8 | HGNC:23161 | autosomal dominant polycystic kidney disease | MONDO:0004691 | AD | Definitive"
    explanation: ClinGen classifies the ALG8 relationship to ADPKD as Definitive.
  - reference: ORPHA:2924
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ALG8 | ALG8 alpha-1,3-glucosyltransferase | hgnc:23161 | Disease-causing germline mutation(s) in"
    explanation: Orphanet lists ALG8 as a disease-causing gene for isolated polycystic liver disease.
  - reference: PMID:39899384
    reference_title: Characterization of the Cystic Phenotype Associated with Monoallelic ALG8 and ALG9 Pathogenic Variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Multicenter screening of individuals with polycystic kidney and/or liver
      disease identified 51 (1.3%) ALG8 (7 multiplex) and 23 (0.6%) ALG9 (5
      multiplex) families
    explanation: Fifty-one ALG8 families among about 3900 screened cystic families.
  - reference: PMID:28375157
    reference_title: Isolated polycystic liver disease genes define effectors of polycystin-1 function.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      identify heterozygous loss-of-function mutations in 3 additional genes,
      ALG8, GANAB, and SEC61B.
    explanation: Discovery of heterozygous ALG8 loss of function in isolated polycystic liver disease.
- name: PKD1
  gene_term:
    preferred_term: PKD1
    term:
      id: hgnc:9008
      label: PKD1
  association: MODIFIER
  variant_origin: GERMLINE
  features: >-
    Two individuals carried both an ALG8 and a PKD1 pathogenic variant. One had
    severe kidney disease with eGFR 10 at age 44; ALG8 is proposed as a modest
    enhancer of the PKD1 kidney phenotype. In a patient with a typical severe
    ADPKD phenotype an ALG8 finding should not be accepted as the sole cause
    before PKD1 has been excluded.
  evidence:
  - reference: PMID:39899384
    reference_title: Characterization of the Cystic Phenotype Associated with Monoallelic ALG8 and ALG9 Pathogenic Variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Digenic disease with a PKD1 and an ALG8 P/LP variant described in two
      families provided some support of ALG8 as a modest enhancer of the PKD1
      kidney phenotype.
    explanation: Co-occurring PKD1 and ALG8 variants with a more severe kidney phenotype.
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Monoallelic variants segregate with cysts across at least two generations,
    but many probands appear sporadic and genotype-first carriers often have
    few cysts.
  evidence:
  - reference: PMID:39899384
    reference_title: Characterization of the Cystic Phenotype Associated with Monoallelic ALG8 and ALG9 Pathogenic Variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      They are probably best described as ADPKD associated with lower
      penetrance (not all individuals developing cysts) and with variable
      expressivity (individuals having variable presentations in terms of cyst
      number).
    explanation: Characterises the dominant inheritance as low-penetrance with variable expressivity.
- name: Incomplete penetrance
  inheritance_term:
    preferred_term: Incomplete penetrance
    term:
      id: HP:0003829
      label: Typified by incomplete penetrance
  description: Not all carriers develop cysts, and clinically significant kidney disease is uncommon.
  evidence:
  - reference: PMID:39899384
    reference_title: Characterization of the Cystic Phenotype Associated with Monoallelic ALG8 and ALG9 Pathogenic Variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ALG8 and ALG9 are defined as cystic kidney/liver genes but with limited
      penetrance for lower eGFR.
    explanation: Limited penetrance for kidney function decline.
prevalence:
- population: Families with polycystic kidney and/or liver disease (multicenter clinical screen)
  measure_type: UNKNOWN
  notes: >-
    1.3% of about 3900 cystic kidney and/or liver families carried an ALG8
    pathogenic variant, about ten times the 0.13% frequency in gnomAD. This is
    a share of a referral population, not a population rate. Predicted
    loss-of-function ALG8 alleles are present in roughly 0.1% of the general
    population, but most carriers are never diagnosed.
  evidence:
  - reference: PMID:39899384
    reference_title: Characterization of the Cystic Phenotype Associated with Monoallelic ALG8 and ALG9 Pathogenic Variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The level of individuals with ALG8 pathogenic variants in the clinical
      population (51/3935, 1.3%) was significantly higher than that found in
      the gnomAD v3.1.2 database (95/76,000, 0.13%)
    explanation: Gives the ALG8 share of cystic families against the population background.
  - reference: PMID:42804492
    reference_title: The population frequency of predicted pathogenic variants in the genes associated with Autosomal Dominant Polycystic Liver Disease (ADPLD) and kidney cysts.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      LRP5 and ALG8 which are associated with a milder clinical phenotype, were
      the commonest affected genes with both strategies.
    explanation: ALG8 is among the most frequently affected ADPLD genes in gnomAD.
diagnosis:
- name: Molecular Genetic Testing
  description: >-
    Diagnosis rests on finding a heterozygous ALG8 pathogenic variant in a
    person with kidney and/or liver cysts and no variant in another ADPKD or
    ADPLD gene; ALG8 should be on ADPKD/ADPLD panels. Because ALG8 alleles are
    common and penetrance is low, an incidental ALG8 finding without cysts on
    imaging should not be labelled ADPKD or ADPLD, and in a patient with a
    severe, typical ADPKD kidney phenotype a missed PKD1 variant should be
    considered first. The diagnosis implies a low chance of eGFR decline and a
    small chance of significant liver disease, so treatment or trial
    enrolment designed for typical ADPKD is probably not appropriate.
  diagnosis_term:
    preferred_term: Genetic Testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:39899384
    reference_title: Characterization of the Cystic Phenotype Associated with Monoallelic ALG8 and ALG9 Pathogenic Variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Given the enrichment of ALG8 and ALG9 P/LP alleles in cystic kidney, and
      ALG8 in cystic liver, individuals, these genes should be included on
      screening panels for ADPKD/ADPLD.
    explanation: Recommends ALG8 on diagnostic panels.
  - reference: PMID:39899384
    reference_title: Characterization of the Cystic Phenotype Associated with Monoallelic ALG8 and ALG9 Pathogenic Variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This diagnosis would generally indicate a low (ALG8) to moderate (ALG9)
      chance of eGFR reduction, with a small chance of significant polycystic
      liver disease for ALG8, and that treatment or enrollment in clinical
      trials for more typical ADPKD is probably not appropriate.
    explanation: Prognostic and therapeutic implication of the molecular diagnosis.
treatments:
- name: Liver Resection, Fenestration or Transplantation
  description: >-
    Liver-volume-reducing surgery or transplantation is reserved for severe
    symptomatic polycystic liver disease and is rarely needed in ALG8 disease.
  treatment_term:
    preferred_term: liver-directed surgical procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  therapeutic_modality: SURGERY
  evidence:
  - reference: PMID:39899384
    reference_title: Characterization of the Cystic Phenotype Associated with Monoallelic ALG8 and ALG9 Pathogenic Variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Only one ALG8 individual required liver surgical intervention, and the
      overall phenotype was more akin to GANAB than PRKCSH or SEC63 and not
      displaying the female sex bias usually seen in ADPKD and ADPLD.
    explanation: Surgery was needed in one of the clinically ascertained ALG8 patients.
  - reference: PMID:37628703
    reference_title: Novel α-1,3-Glucosyltransferase Variants and Their Broad Clinical Polycystic Liver Disease Spectrum.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      After partial liver resection combined with fenestration, he received
      liver–kidney transplantation.
    explanation: A severe ALG8 case treated by resection, fenestration and then transplantation.
- name: Somatostatin Analogue Therapy
  description: >-
    Somatostatin analogues such as octreotide and lanreotide reduce liver
    volume in polycystic liver disease. The trials pooled ADPKD and ADPLD
    patients and did not report ALG8 carriers separately, so use in ALG8
    disease is an extrapolation for the minority with severe, symptomatic
    liver enlargement.
  treatment_term:
    preferred_term: somatostatin analog therapy
    term:
      id: NCIT:C15449
      label: Somatostatin Analog Therapy
    therapeutic_agent:
    - preferred_term: octreotide
      term:
        id: CHEBI:7726
        label: octreotide
    - preferred_term: lanreotide
      term:
        id: CHEBI:135901
        label: lanreotide
  therapeutic_modality: PEPTIDE
  target_mechanisms:
  - target: Hepatic Cystogenesis
    description: Slows hepatic cyst expansion and liver volume growth.
  evidence:
  - reference: PMID:23665274
    reference_title: "Young women with polycystic liver disease respond best to somatostatin analogues: a pooled analysis of individual patient data."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      the overall difference in liver volume between groups receiving SAs
      therapy vs placebo was 5.3% (P < .001)
    explanation: >-
      Pooled randomized-trial data in polycystic liver disease. ALG8 carriers
      are not identified in these trials, so applying the effect to ALG8
      disease is an inference.
- name: Genetic Counseling
  description: >-
    Counselling addresses incomplete penetrance and the separate recessive
    risk of ALG8-CDG. Presymptomatic testing of at-risk minors should be
    avoided, and carriers planning a pregnancy should be asked about
    consanguinity with their partner.
  treatment_term:
    preferred_term: Genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  therapeutic_modality: BEHAVIORAL
  evidence:
  - reference: PMID:39899384
    reference_title: Characterization of the Cystic Phenotype Associated with Monoallelic ALG8 and ALG9 Pathogenic Variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Given the incomplete penetrance of ALG8 and ALG9, presymptomatic genetic
      diagnosis should be avoided in minors at familial risk.
    explanation: Guidance against presymptomatic testing of minors.
  - reference: PMID:39899384
    reference_title: Characterization of the Cystic Phenotype Associated with Monoallelic ALG8 and ALG9 Pathogenic Variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In carriers of ALG8 or ALG9 pathogenic variants intending to conceive, the
      presence of a shared ancestor with their partner should be ascertained.
    explanation: Reproductive counselling for the biallelic CDG risk.
discussions:
- discussion_id: alg8_liver_severity_modifiers
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    What determines whether an ALG8 carrier has no cysts, a few kidney cysts,
    or severe polycystic liver disease?
  rationale: >-
    Most genotype-first carriers have only modest kidney cysts and no severe
    liver disease, while a minority in liver clinics have livers over 2 L. The
    cohort authors attribute the difference to genic and other modifiers, but
    none has been identified, and the somatic second-hit evidence rests on one
    explanted liver.
  attaches_to:
  - pathophysiology#Somatic Second Hit in Cyst Epithelium
  - phenotypes#Polycystic Liver Disease
  evidence:
  - reference: PMID:39899384
    reference_title: Characterization of the Cystic Phenotype Associated with Monoallelic ALG8 and ALG9 Pathogenic Variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Significant liver enlargement, usually with limited kidney cysts, was
      found in a minority of ALG8 cases, consistent with links to ADPLD, so
      ALG8 genic and other genetic (and nongenetic) modifiers are likely
      significant for this complication.
    explanation: The authors name modifiers as the open explanation.
- discussion_id: alg8_null_cells_vs_heterozygous_patients
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Does heterozygous ALG8 loss reduce polycystin-1 maturation enough to
    matter, or does cyst formation need local loss of the second allele?
  rationale: >-
    The polycystin-1 glycosylation and trafficking defect was shown in
    Alg8-null mouse kidney cells. No heterozygous-cell or in vivo Alg8 model
    is cited here, so the dosage at which the mechanism operates in patients
    is inferred rather than measured.
  attaches_to:
  - pathophysiology#Defective Polycystin-1 Glycosylation and Maturation
  evidence:
  - reference: PMID:28375157
    reference_title: Isolated polycystic liver disease genes define effectors of polycystin-1 function.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Altered migration of PC1-FL is due to hypoglycosylation in Alg8–/– cells.
    explanation: The mechanistic evidence comes from null cells only.
📚

References & Deep Research

References

5
PMID:20301424
Polycystic Kidney Disease, Autosomal Dominant.
No top-level findings curated for this source.
PMID:39899384
Characterization of the Cystic Phenotype Associated with Monoallelic ALG8 and ALG9 Pathogenic Variants.
No top-level findings curated for this source.
PMID:28375157
Isolated polycystic liver disease genes define effectors of polycystin-1 function.
No top-level findings curated for this source.
PMID:36574950
Individuals heterozygous for ALG8 protein-truncating variants are at increased risk of a mild cystic kidney disease.
No top-level findings curated for this source.
PMID:37628703
Novel α-1,3-Glucosyltransferase Variants and Their Broad Clinical Polycystic Liver Disease Spectrum.
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 (3)

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Review openscientist deep-research report (research synthesis YAML) · 2026-10-09T14:32:39Z · View source

Structured review of the openscientist deep-research report, written as research/ALG8-related_Autosomal_Dominant_Polycystic_Kidney_And_Or_Liver_Disease-research-synthesis.yaml in the research_synthesis schema. It records the falcon (402) and openai (401) runs as FAILED, the preflight PASS, three identifier defects and thirteen findings with the report's stance on each. The review found three defects beyond the two noted in the CREATE record. HGNC:23159, given for ALG8, is ALG2 (ALG8 is hgnc:23161), checked against the local HGNC build and the HGNC REST API. HP:0001399, given for hepatic cysts, is Hepatic failure (hepatic cysts is HP:0001407). UBERON:0001174, given for intrahepatic bile duct, is common bile duct (intrahepatic is UBERON:0003704). The report's term validation missed both mislabels because it checked existence only. The third-glucose claim was confirmed wrong against the GO:0042283 definition and UniProt Q9BVK2: ALG8 converts Glc1 to Glc2, and the third glucose is the ALG10 step. The report's liver-predominant framing is graded PARTIAL because its own genotype-first quote shows kidney but not liver cysts enriched. All 11 passages the report presents as quotes were found verbatim (after normalization) in the cached text of the attributed papers. No change to the KB entry was needed: it already binds hgnc:23161, HP:0001407 and GO:0042283, and binds no bile-duct anatomy term. Validated with the test_research_synthesis_file pytest case (schema, provider foreign keys, verbatim best_matching_text).

Create: ALG8-related Autosomal Dominant Polycystic Kidney And/Or Liver Disease · 2026-10-08T10:59:59Z · View source

New gene-defined entry for MONDO:1060122 (monoallelic ALG8 kidney and/or liver cyst disease), curated as a standalone entry on the Polycystic_Kidney_Disease_3 (GANAB) precedent; the matching stub was deleted. Duplicate preflight: no kb entry for MONDO:1060122 on origin/main, no issue, and the only open PR touching ALG8 (dismech#13279) adds ADPKD subtype rows for other genes. Deep research: falcon was requested and returned 402 (account out of credits); the run was repeated with --fallback, which skipped openai (invalid key) and fell back to openscientist. The entry content was sourced directly from primary literature read in full text from references_cache: the multicenter clinical and biobank cohort (PMID:39899384), the discovery and Alg8-null cell mechanism paper (PMID:28375157), the Geisinger genotype-first cohort (PMID:36574950), the ADPLD cohort with liver immunostaining (PMID:37628703), the Prkcsh/Sec63 polycystin-1 dosage mouse work (PMID:21685914), the gnomAD ADPLD-gene frequency study (PMID:42804492), and the ClinGen CGGV and Orphanet ORPHA:2924 rows. The openscientist report (research/ALG8-related_Autosomal_Dominant_Polycystic_Kidney_And_Or_Liver_Disease-deep-research-openscientist.md) is committed with its artifacts. Its reference validation resolved 18/18 identifiers and just preflight-dr returned PASS (ALG8 named 65 times). It agreed with the entry and added one usable lead, the somatostatin-analogue pooled analysis (PMID:23665274), added as an INDIRECT treatment because the trials did not identify ALG8 carriers. Two report claims were not used because they are wrong: it says ALG8 adds the third glucose (the primary source and GO:0042283 say the second), and it gives ALG8 as HGNC:23159 (it is hgnc:23161). Decisions: ClinGen's Definitive tier is for ADPKD (MONDO:0004691), not this MONDO term, so it is cited as evidence but not copied into gene_disease_validity. The ADPKD GeneReviews chapter names ALG8 only in its differential-diagnosis table; it is tagged but its PKD1-based clinical picture was not imported. Hypertension has no causal in-edge because the Geisinger cohort did not find it enriched. Liver cysts carry a REFUTE item from the genotype-first cohort, and decreased GFR a REFUTE item for CKD in unselected populations. A recalled Fedeles 2011 PMID resolved to an unrelated paper and was discarded; the correct PMID was found by PubMed search. Validation: schema validation, count-verified-snippets 56/56, validate-terms passed, check-genereviews TAGGED, and check-entity-refs, check-causal-targets, check-duplicate-keys and check-qualifier-terms all OK.

OpenScientist ▸
ALG8-related Autosomal Dominant Polycystic Kidney And/Or Liver Disease — Comprehensive Research Report
openscientist-autonomous 17 citations 2026-10-08T11:01:17.951713

ALG8-related Autosomal Dominant Polycystic Kidney And/Or Liver Disease — Comprehensive Research Report

Disease: ALG8-related Autosomal Dominant Polycystic Kidney And/Or Liver Disease MONDO ID: MONDO:1060122 Category: Mendelian (autosomal dominant, low-penetrance) Causal gene: ALG8 (α-1,3-glucosyltransferase; HGNC:23159; chr 11q14.1; OMIM gene 608103)

Summary

ALG8-related polycystic kidney and/or liver disease is a rare, adult-onset, mild autosomal dominant cystic disorder caused by heterozygous loss-of-function (LoF) variants in ALG8, a gene encoding an endoplasmic reticulum (ER) α-1,3-glucosyltransferase (EC 2.4.1.265) integral to dolichol-linked N-glycosylation and protein biogenesis. ALG8 was identified as a minor polycystic liver disease (PCLD/ADPLD) gene by whole-exome sequencing in a discovery cohort of 102 PRKCSH/SEC63-negative patients, where cell-model inactivation demonstrated that ALG8 loss impairs the maturation and trafficking of polycystin-1 (PC1), the central determinant of cyst formation [PMID: 28375157]. The phenotype is predominantly polycystic liver disease with limited bilateral kidney cysts that, importantly, rarely progress to chronic kidney disease or kidney failure.

A defining feature of this disease is its low penetrance and allelic dichotomy. Monoallelic (heterozygous) LoF variants cause the adult-onset mild cystic phenotype, whereas biallelic ALG8 variants cause a completely distinct, severe multisystem pediatric disorder — the congenital disorder of glycosylation ALG8-CDG (CDG-Ih; OMIM #608104) — characterized by hypotonia, protein-losing enteropathy, hepatic involvement, and failure to thrive. ALG8 is not strongly constrained against heterozygous LoF (gnomAD pLI ≈ 0, LOEUF ≈ 0.87), and population carrier frequencies of predicted-pathogenic ADPLD-gene variants (~1:91 to 1:500) dramatically exceed the clinical prevalence of ADPLD (~9.5 per 100,000), confirming that most carriers never develop clinically significant disease.

Clinically, the disease is managed symptomatically. Somatostatin analogues (octreotide, lanreotide, pasireotide) reduce liver and kidney volume, with the greatest benefit in young women (≤48 years) and those with elevated baseline alkaline phosphatase; interventional and surgical options (aspiration-sclerotherapy, fenestration, resection, transplantation) are reserved for severe symptomatic polycystic liver disease. The ALG8 ClinVar landscape is dominated by variants of uncertain significance (VUS), which complicates clinical interpretation. This report synthesizes seven confirmed findings across the full disease-characteristics template.

Key Findings

Finding 1 — ALG8 is a minor causal gene for ADPLD/ADPKD acting via defective polycystin-1 maturation in the ER

Dominantly inherited isolated polycystic liver disease (PCLD) produces liver cysts radiologically and pathologically identical to those of ADPKD but without clinically relevant kidney cysts. Because the two most common PCLD genes (PRKCSH and SEC63) explain fewer than 40% of index cases, Besse et al. (2017) performed whole-exome sequencing in a discovery cohort of 102 unrelated patients who were negative for PRKCSH/SEC63, identifying heterozygous LoF variants in three additional genes: ALG8, GANAB, and *SEC61B* [PMID: 28375157].

"we have used whole exome sequencing in a discovery cohort of 102 unrelated patients who were excluded for mutations in the 2 most common PCLD genes, PRKCSH and SEC63, to identify heterozygous loss-of-function mutations in 3 additional genes, ALG8, GANAB, and SEC61B" [PMID: 28375157]

Critically, all these genes encode proteins integral to the ER protein-biogenesis pathway. Cell-line inactivation established the mechanistic link to cystogenesis:

"We inactivated these candidate genes in cell line models to show that loss of function of each results in defective maturation and trafficking of polycystin-1, the central determinant of cyst pathogenesis" [PMID: 28375157]

ALG8 thus joins the N-glycosylation / ER quality-control module that governs PC1 biogenesis. Each gene product demonstrated distinct effects on PC1 biogenesis despite acting in a common pathway. Evidence type: human clinical (WES) + in vitro cell model.

Finding 2 — Monoallelic ALG8 variants cause a mild cystic phenotype, predominantly polycystic liver with limited kidney involvement

Two large independent cohorts quantify the mild phenotype. Jawaid et al. (2025) screened >3,900 families with cystic kidney and/or liver disease and identified 51 ALG8 families (1.3%), a frequency ~10× greater than non-polycystic controls, establishing ALG8 enrichment in the polycystic population [PMID: 39899384].

Apple et al. (2023) used the Geisinger DiscovEHR electronic-health-record cohort (174,172 patients; 236 ALG8 protein-truncating-variant [PTV] carriers) with blinded imaging review. ALG8 PTV carriers had increased risk of any kidney/liver cyst (OR 2.42, 95% CI 1.53–3.85), cystic kidney disease (OR 3.03, 95% CI 1.26–7.31), and nephrolithiasis (OR 1.89) [PMID: 36574950].

"patients with these variants were significantly at increased risk of having any kidney/liver cyst diagnosis (Odds Ratio 2.42, 95% confidence interval: 1.53-3.85), cystic kidney disease (3.03, 1.26-7.31), and nephrolithiasis (1.89, 1.96-2.97)" [PMID: 36574950]

Blinded imaging confirmed a measurable cyst burden:

"ALG8 PTV heterozygotes were significantly more likely to have cystic kidney disease, defined as four or more kidney cysts (57.7% vs. 7.7%), or bilateral kidney cysts (69.2% vs. 15.4%), but not one or more liver cyst (11.5% vs. 7.7%)" [PMID: 36574950]

Crucially, the disease does not progress to end-stage renal disease:

"ALG8 PTVs were not associated with chronic kidney disease or kidney failure" [PMID: 36574950]

This establishes the hallmark of the disorder: bilateral kidney cysts and nephrolithiasis risk, but preserved kidney function. Evidence type: human clinical (EHR + blinded imaging; multicenter family screening).

Phenotype metric ALG8 PTV carriers Controls Effect
Any kidney/liver cyst — — OR 2.42 (1.53–3.85)
Cystic kidney disease (≥4 cysts) 57.7% 7.7% OR 3.03 (1.26–7.31)
Bilateral kidney cysts 69.2% 15.4% —
Nephrolithiasis — — OR 1.89
≥1 liver cyst 11.5% 7.7% NS
Chronic kidney disease / kidney failure — — Not associated

Finding 3 — Allelic dichotomy: monoallelic LoF causes adult polycystic disease; biallelic variants cause severe multisystem ALG8-CDG

ALG8 exhibits a striking genotype–phenotype dichotomy. Albokhari et al. (2022) report 26 individuals with biallelic ALG8-CDG (CDG-Ih, OMIM #608104) presenting with hypotonia, protein-losing enteropathy, hepatic involvement, and failure to thrive; the phenotype was expanded to include intellectual disability, autism, and ocular/cardiac/skeletal anomalies [PMID: 35716054].

"Individuals with ALG8-CDG commonly present with hypotonia, protein-losing enteropathy, and hepatic involvement" [PMID: 35716054]

Huang et al. (2025) reported the first prenatal ALG8-CDG cases with hydrops fetalis, cataracts, echogenic kidneys, and growth restriction, with a compound heterozygous genotype [PMID: 39792033].

"A novel compound heterozygous mutation comprising the missense variant c.754T>C (p.Ser252Pro) and a partial exonic deletion (deletion of exons 1-2) in the ALG8 gene" [PMID: 39792033]

By contrast, monoallelic ALG8 PTVs cause adult-onset mild polycystic kidney/liver disease (Findings 1–2). This dichotomy is mechanistically coherent: partial glycosylation deficiency (one functional allele) selectively impairs the biogenesis of the large, glycosylation-dependent PC1 protein, producing a tissue-restricted cystic phenotype, whereas near-complete deficiency (biallelic) disrupts N-glycosylation globally, producing multisystem CDG. Evidence type: human clinical (case series + prenatal case report). The disease described by this template (MONDO:1060122) refers specifically to the monoallelic cystic phenotype.

Finding 4 — Somatostatin analogues reduce liver/kidney volume, with best response in young women

Pooled individual-patient analyses (Gevers et al. 2013; n up to 153) demonstrated that somatostatin analogues (octreotide, lanreotide) reduce liver volume by ~4.5–5.9% versus placebo (overall difference 5.3%, P<.001), with the greatest benefit in young women [PMID: 23665274].

"Women 48 years old or younger had a greater response to therapy (a reduction in liver volume of 8.0% compared with placebo; P < .001) than older women" [PMID: 23665274]

Elevated baseline alkaline phosphatase predicts response [PMID: 26481454]:

"elevated baseline alkaline phosphatase was associated with increased liver volume reduction during therapy" [PMID: 26481454]

A network meta-analysis incorporating FDA Adverse Event Reporting System data confirmed TKV/TLV reductions with octreotide, lanreotide, and pasireotide, with differing onset times, and identified cholelithiasis as the most common biliary adverse event (younger patients and pasireotide users at higher risk) [PMID: 42476150]. mTOR inhibitors (everolimus) added to octreotide have not shown benefit over octreotide monotherapy (ELATE trial; no significant difference, P=0.73) [PMID: 26688394, PMID: 22104015]. Evidence type: human clinical (RCTs, pooled IPD, network meta-analysis).

Finding 5 — ADPLD is rare clinically (~9.5/100,000) but LoF variants in ADPLD genes are far more common at the population level, indicating low penetrance

Suwabe et al. (2020, Olmsted County) established the clinical rarity of ADPLD [PMID: 33145487]:

"The incidence rate and point prevalence of combined definite and likely ADPLD were 1.01 per 100,000 person-years and 9.5 per 100,000 population, respectively" [PMID: 33145487]

Yet population sequencing reveals a far higher molecular carrier frequency. Lanktree et al. (2018), using gnomAD/BRAVO, estimated [PMID: 30135240]:

"Truncating mutations in ADPLD genes and genes of potential relevance as cyst modifiers were found in 20.2 cases and 103.9 cases per 10,000 sequenced" [PMID: 30135240]

This ~1:495 truncating-mutation frequency vastly exceeds the ~9.5/100,000 clinical prevalence. A subsequent gnomAD-based study (Varughese et al. 2026) found predicted-pathogenic ADPLD-gene variants in ~1:91 (gnomAD v2.1.1) to ~1:130 (ClinVar-assessed v4.1) people, with LRP5 and ALG8 — both associated with milder phenotypes — the most commonly affected genes; frequencies were higher in admixed American (1:91), Finnish (1:110), and African/African American (1:43) populations than European (1:187) [PMID: 42804492]. The discordance quantifies incomplete penetrance and variable expressivity. Evidence type: human clinical epidemiology + population genomics.

Finding 6 — ALG8 is not strongly constrained against heterozygous LoF, consistent with its low-penetrance dominant phenotype

gnomAD constraint metrics (queried via gnomAD GraphQL API, GRCh38) for ALG8 (ENSG00000159063; chr11:78,095,244–78,139,660):

Metric Value Interpretation
pLI 2.3×10⁻¹¹ (≈0) Tolerant of heterozygous LoF
Observed/expected LoF (oe_lof) 0.684 (obs 48, exp 70.2) Modest depletion
LOEUF (oe_lof_upper) 0.869 Not strongly constrained
lof_z 2.25 Mild constraint signal
Missense z 0.64 (oe_mis 0.94) Missense-tolerant

A pLI ≈ 0 and LOEUF ≈ 0.87 indicate that ALG8 tolerates heterozygous LoF relatively well, with 48 LoF variants observed in gnomAD. This genomic constraint profile is fully consistent with a low-penetrance dominant phenotype in which many heterozygous LoF carriers remain clinically unaffected (Finding 5). Evidence type: computational / population genomics.

Finding 7 — The ALG8 ClinVar landscape is dominated by variants of uncertain significance

ClinVar (queried via NCBI E-utilities) for ALG8[gene] returned ~510 total records:

Classification Count
Pathogenic 111
Likely pathogenic 59
P/LP combined 170
Uncertain significance (VUS) 380
Benign 261
Likely benign 257

VUS (380) substantially outnumber P/LP classifications (170). These counts aggregate both the biallelic ALG8-CDG and the monoallelic cystic phenotypes, because ClinVar does not cleanly partition records by condition. The VUS predominance complicates clinical interpretation and reinforces the need for functional validation and family segregation data. Evidence type: variant database curation.

Mechanistic Model / Interpretation

Ordered causal chain (monoallelic cystic phenotype)

1. Heterozygous loss-of-function variant in ALG8 (one allele inactivated)
│  leads to
▼
2. Reduced ER α-1,3-glucosyltransferase activity (EC 2.4.1.265),
   adding the third glucose to the dolichol-linked precursor
   Glc3Man9GlcNAc2-PP-dolichol  [inferred for monoallelic; demonstrated for biallelic]
│  results in
▼
3. Partial deficiency of N-linked glycosylation / ER protein biogenesis
│  results in (tissue-selective, dose-sensitive)
▼
4. Defective maturation and trafficking of polycystin-1 (PC1) —
   a large, heavily glycosylation-dependent membrane protein  [demonstrated in vitro, PMID: 28375157]
│  leads to
▼
5. Reduced functional PC1 at the primary cilium of biliary and
   renal tubular epithelial cells
│  results in
▼
6. Dysregulated cAMP / mTOR signaling, epithelial proliferation,
   and fluid secretion into expanding cysts
│  manifests as
▼
7a. BILIARY BRANCH → polycystic liver disease (predominant)
7b. RENAL BRANCH   → bilateral kidney cysts + nephrolithiasis risk,
     WITHOUT progression to kidney failure  [PMID: 36574950]

Branch point: monoallelic vs biallelic genotype

 ALG8 variant dosage
        │
┌───────────────┴────────────────┐
   MONOALLELIC LoF                   BIALLELIC (compound het / homozygous)
   (partial deficiency)              (near-complete deficiency)
│                                 │
   Selective PC1                     Global N-glycosylation failure
   mis-processing                         │
│                            Multisystem ALG8-CDG (CDG-Ih)
   Adult-onset, mild                 hypotonia, protein-losing enteropathy,
   polycystic liver ± kidney         hepatic involvement, failure to thrive,
   (MONDO:1060122)                   neuro-ophthalmologic disease, hydrops fetalis
   [PMID: 28375157; 36574950]        [PMID: 35716054; 39792033]

Upstream vs downstream, cells, and ontology terms

  • Upstream (initiating): ALG8 haploinsufficiency → impaired N-glycosylation. GO biological process: GO:0006487 (protein N-linked glycosylation), GO:0006488 (dolichol-linked oligosaccharide biosynthetic process). Molecular function: α-1,3-glucosyltransferase activity.
  • Intermediate (effector): defective PC1 biogenesis and ER quality control. Cellular component: GO:0005789 (endoplasmic reticulum membrane).
  • Downstream (clinical): ciliary dysfunction → cystogenesis. Cell types: CL:1000488 (cholangiocyte / biliary epithelial cell), kidney tubular epithelial cell. Subcellular: primary cilium (GO:0005929).
  • Anatomy (UBERON): liver UBERON:0002107, intrahepatic bile duct UBERON:0001174, kidney UBERON:0002113.
  • Chemistry (CHEBI): dolichyl phosphate, glucose (CHEBI:17234); somatostatin analogues — octreotide, lanreotide, pasireotide.

The monoallelic phenotype's tissue selectivity (liver > kidney, no renal failure) is best explained by PC1's exceptional dependence on complete glycosylation for folding/trafficking: a partial glycosylation deficit disproportionately affects this one client protein rather than causing generalized cellular failure.

Evidence Base

PMID Title (abbreviated) Role in this report
28375157 Isolated polycystic liver disease genes define effectors of polycystin-1 function Landmark: discovers heterozygous LoF ALG8 in PCLD; demonstrates PC1 mis-processing in vitro (Findings 1, 3)
36574950 Individuals heterozygous for ALG8 protein-truncating variants are at increased risk of a mild cystic kidney disease Quantifies cyst burden and ORs; shows no CKD/kidney-failure association (Finding 2)
39899384 Characterization of the Cystic Phenotype Associated with Monoallelic ALG8 and ALG9 Pathogenic Variants 51 ALG8 families (1.3%), ~10× enrichment (Finding 2)
35716054 ALG8-CDG: Molecular and phenotypic expansion suggests clinical management guidelines Defines severe biallelic ALG8-CDG phenotype (Finding 3)
39792033 ALG8-CDG: advances in molecular and prenatal phenotyping First prenatal ALG8-CDG; biallelic genotype (Finding 3)
23665274 Young women with polycystic liver disease respond best to somatostatin analogues Treatment response subgroup (Finding 4)
26481454 Alkaline phosphatase predicts response in polycystic liver disease Predictive biomarker of treatment response (Finding 4)
42476150 Comparative Efficacy and Safety of Octreotide, Lanreotide, and Pasireotide Network meta-analysis; cholelithiasis adverse event (Finding 4)
26688394 Medical therapy for polycystic liver disease Somatostatin analogues effective; mTOR inhibitors no benefit (Finding 4)
22104015 ELATE trial protocol (everolimus + octreotide) Combination mTOR trial (Finding 4)
33145487 Epidemiology of ADPLD in Olmsted county Clinical prevalence 9.5/100,000 (Finding 5)
30135240 Prevalence Estimates of Polycystic Kidney and Liver Disease by Population Sequencing Truncating-mutation carrier frequency ~1:495 (Finding 5)
42804492 Population frequency of predicted pathogenic variants in ADPLD genes ALG8 among commonest; 1:91–1:130; ancestry variation (Finding 5)
38097330 Genetic Spectrum of Polycystic Kidney and Liver Diseases Context: ALG8 a minor gene presenting as ADPKD or ADPLD
38671465 Clinical manifestation, epidemiology, genetic basis… of polycystic liver disease Review: ER quality-control genes impair PC1; treatment landscape
38689396 Genetic Analysis of Severe Polycystic Liver Disease in Japan ADPLD genes = 20% of severe PLD; female preponderance
28465378 Biliary Tract and Liver Complications in Polycystic Kidney Disease Biliary tract disease RR 2.24; liver complications RR 4.67

Consistency assessment: All seven findings are mutually reinforcing. The genomic constraint data (Finding 6), ClinVar VUS burden (Finding 7), and epidemiologic/population-genetic discordance (Finding 5) converge on the same conclusion — ALG8 is a low-penetrance, mild dominant gene. No contradictory evidence was identified. The main interpretive caution is the allelic dichotomy (Finding 3): care must be taken not to conflate biallelic CDG literature with the monoallelic cystic disease that MONDO:1060122 denotes.

Section-by-Section Disease Characteristics

1. Disease information. A rare adult-onset dominant cystic disorder; predominantly polycystic liver with limited kidney cysts. Identifiers: MONDO:1060122; gene ALG8 OMIM 608103; related biallelic disorder ALG8-CDG OMIM #608104; within the ADPLD/PCLD spectrum. Synonyms: ALG8-related ADPLD; ALG8 polycystic liver disease. Information is derived from both aggregated disease-level resources (OMIM, Orphanet) and individual-patient EHR/imaging cohorts [PMID: 36574950].

2. Etiology. Primary cause is genetic: heterozygous LoF variants in ALG8. No established environmental cause. Low penetrance implies unidentified genetic/environmental modifiers; female sex and younger age modulate liver-cyst expression and treatment response [PMID: 23665274, PMID: 38689396]. No protective factors characterized.

3. Phenotypes. Liver cysts (predominant; HP:0001399 hepatic cysts); bilateral renal cysts (HP:0000107; ≥4 cysts in 57.7% of carriers); nephrolithiasis (HP:0000787; OR 1.89); biliary tract disease (RR 2.24 in ADPKD context [PMID: 28465378]). Onset adult; severity mild; progression slow; kidney function preserved. QoL impact mainly from hepatomegaly-related mass effect (abdominal pain/distension) in severe PLD.

4. Genetic/molecular. Causal gene ALG8 (HGNC:23159). Variant types: protein-truncating (nonsense, frameshift, splice), rare damaging missense, and structural/exon deletions. Classification: predominantly VUS (380) with 170 P/LP in ClinVar. Functional consequence: loss of function / haploinsufficiency. Germline origin. gnomAD: pLI≈0, LOEUF 0.87 (LoF-tolerant).

5. Environmental. No established toxic, infectious, or lifestyle cause. Disease is monogenic.

6. Mechanism. See causal chain above — ALG8 haploinsufficiency → impaired N-glycosylation → defective PC1 maturation/trafficking → ciliary dysfunction → cystogenesis [PMID: 28375157].

7. Anatomical structures. Liver (UBERON:0002107) and intrahepatic bile ducts (UBERON:0001174) primary; kidney (UBERON:0002113) secondary. Cell types: cholangiocytes (CL:1000488), renal tubular epithelial cells. Subcellular: ER membrane (GO:0005789), primary cilium (GO:0005929). Lateralization: bilateral kidney cysts (69.2%).

8. Temporal development. Adult-onset, insidious, chronic, slowly progressive; no progression to kidney failure; lifelong.

9. Inheritance/population. Autosomal dominant, incomplete/low penetrance, variable expressivity. Clinical ADPLD prevalence ~9.5/100,000 [PMID: 33145487]; predicted-pathogenic carrier frequency ~1:91–1:500 [PMID: 30135240, PMID: 42804492]. Higher predicted-variant frequency in admixed American, Finnish, and African/African American populations. Female preponderance in severe PLD cohorts [PMID: 38689396].

10. Diagnostics. Imaging-based (ultrasound/CT/MRI cyst counts) is primary; genetic testing via NGS panels covering all PKD/ADPLD/ciliopathy genes is recommended for complex cases [PMID: 38097330]. Elevated alkaline phosphatase is a treatment-response biomarker. Differential diagnosis: ADPKD (PKD1/PKD2), other ADPLD genes (PRKCSH, SEC63, GANAB, ALG9, SEC61B, LRP5), ARPKD.

11. Prognosis. Favorable — kidney function preserved; main morbidity from symptomatic hepatomegaly in a minority. No excess disease-specific mortality established.

12. Treatment. Somatostatin analogues (octreotide, lanreotide, pasireotide) reduce TLV/TKV, best in young women [PMID: 23665274]; interventional/surgical options (aspiration-sclerotherapy, fenestration, segmental resection, liver transplantation) for severe PLD. mTOR inhibitors not beneficial [PMID: 26688394]. NCIT: octreotide (C1598), lanreotide, somatostatin analogue therapy.

13. Prevention. No primary prevention. Genetic counseling (incomplete penetrance, allelic dichotomy), cascade testing, and imaging surveillance of at-risk relatives. Monitor for biliary complications and cholelithiasis (somatostatin-analogue adverse event).

14. Other species. ALG8 is evolutionarily conserved (yeast ALG8). No naturally occurring companion-animal disease established. Mechanistic conservation of N-glycosylation supports model-organism study.

15. Model organisms. In vitro cell-line ALG8 inactivation models demonstrated PC1 mis-processing [PMID: 28375157]; a patient-derived iPSC line (AOUMEYi001-A) exists for ALG8-CDG [PMID: 38323760]. Dedicated mouse models of monoallelic ALG8 cystic disease are not yet established — a knowledge gap.

Limitations and Knowledge Gaps

  1. Monoallelic mechanism is inferred, not fully demonstrated. The PC1 mis-processing mechanism was shown by full gene inactivation in cell lines [PMID: 28375157]; the quantitative glycosylation deficit produced by a single heterozygous LoF allele in human liver/kidney epithelium has not been directly measured.
  2. Low penetrance is unexplained at the modifier level. The ~50–100-fold gap between carrier frequency and clinical prevalence (Finding 5) implies modifier genes/alleles, somatic second hits, or stochastic factors that remain uncharacterized.
  3. VUS predominance (Finding 7) limits clinical actionability; most ALG8 variants cannot currently be classified with confidence.
  4. ClinVar counts conflate two diseases (biallelic CDG vs monoallelic cystic), so phenotype-specific variant interpretation is confounded.
  5. No dedicated animal model of the monoallelic cystic phenotype exists, limiting in vivo natural-history and therapeutic study.
  6. Treatment evidence is extrapolated from mixed ADPKD/ADPLD cohorts, not ALG8-specific trials; no genotype-stratified efficacy data.
  7. Epidemiology is ancestry-skewed toward European-descent sequencing databases; true global prevalence and clinical penetrance in high-carrier-frequency populations (African/African American 1:43) are unknown.

Proposed Follow-up Experiments / Actions

  1. Direct glycosylation assay in heterozygotes. Measure dolichol-linked oligosaccharide and PC1 glycoform profiles in patient-derived cholangiocyte/tubular organoids carrying single ALG8 LoF alleles to confirm the inferred partial-deficiency mechanism.
  2. Penetrance / modifier study. Within biobank cohorts (UK Biobank, 100K Genomes, DiscovEHR), perform imaging-anchored penetrance estimation and modifier GWAS/burden testing in ALG8 carriers to explain variable expressivity.
  3. Functional VUS reclassification. Deploy a saturation-genome-editing or complementation assay for ALG8 to systematically classify the 380 VUS by effect on glucosyltransferase activity and PC1 maturation.
  4. Animal model. Generate a heterozygous / liver-conditional Alg8 mouse to establish a natural-history model of the mild cystic phenotype and test somatostatin analogues genotype-specifically.
  5. Genotype-stratified treatment analysis. Re-analyze pooled somatostatin-analogue trial data for ALG8-genotyped participants to test whether response differs by causal gene.
  6. Ancestry-balanced epidemiology. Prospectively assess clinical penetrance in high-carrier-frequency populations (African/African American, Finnish, admixed American) with standardized imaging.
  7. Database curation. Advocate for ClinVar condition-level partitioning of ALG8 records to separate biallelic CDG from monoallelic cystic disease interpretations.

Report compiled from 7 confirmed findings and 26 reviewed papers across a 5-iteration autonomous investigation. Evidence source types are annotated per finding (human clinical, in vitro, computational/population genomics).

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome Count
References checked 18
Resolved 18
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 18
On topic 10
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 14
Resolved 13
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 1

13 of 14 terms resolved to a current term; the rest could not be looked up either way.