Neonatal Diabetes Mellitus With Congenital Hypothyroidism

Mendelian MONDO:0012436 Pathograph 36 Show in embeddings browser Neonatal Diabetes Mellitus Congenital Hypothyroidism

Neonatal diabetes and congenital hypothyroidism (NDH) syndrome is a rare autosomal recessive multisystem disorder caused by biallelic loss-of-function variants in GLIS3, which encodes GLI-similar 3, a Kruppel-like zinc finger transcription factor with five C2H2 zinc fingers and a C-terminal transactivation domain. It was first described in 2003 in two Saudi siblings with permanent non-autoimmune neonatal diabetes, severe congenital hypothyroidism, congenital glaucoma, cholestasis progressing to hepatic fibrosis, polycystic kidneys, intrauterine growth restriction and minor facial anomalies, and GLIS3 was identified as the causal gene in 2006. Partial gene deletions are the most frequent variant class; frameshift, nonsense and zinc-finger missense variants also occur, in homozygous or compound heterozygous form. Permanent neonatal diabetes is the one constant feature. GLIS3 acts upstream of neurogenin 3 in the fetal pancreas to drive endocrine differentiation and later binds the insulin promoter directly, so its loss produces insulin deficiency from birth. In the thyroid GLIS3 acts downstream of TSH/TSHR and is needed for expression of thyroid hormone biosynthesis genes, which explains a dyshormonogenic hypothyroidism with elevated TSH and thyroglobulin that is often resistant to conventional levothyroxine doses, although thyroid morphology ranges from normal to athyreosis. Renal cystic dysplasia, liver disease ranging from cholestasis with bile duct paucity to biliary cirrhosis, congenital glaucoma, exocrine pancreatic insufficiency, osteopenia, sensorineural deafness, developmental delay and a recognisable facial gestalt are variable. Early reports described death in infancy, but survival into adolescence and adulthood is now documented. Management is insulin (often by pump), levothyroxine, pancreatic enzyme replacement when needed, and organ-specific care including glaucoma surgery and, for end-stage liver disease, liver transplantation.

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Inheritance
10
Pathophys.
25
Phenotypes
36
Pathograph
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Genes
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Medical Actions
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Models
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Deep Research
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Inheritance

1
Autosomal Recessive HP:0000007
Affected individuals carry biallelic GLIS3 variants, homozygous in the majority, who are mostly offspring of consanguineous unions; compound heterozygotes have also been reported. Heterozygous carrier parents are usually clinically unaffected, but in one Saudi family every heterozygous carrier sibling of two affected children had juvenile hypothyroidism, so a milder carrier thyroid phenotype is possible.
Autosomal recessive inheritance
Show evidence (3 references)
PMID:34093443 SUPPORT BACKGROUND Human Clinical
"To date, 14 mutations in GLIS3 have been reported, inherited in an autosomal recessive manner."
States the autosomal recessive inheritance of the reported GLIS3 variants. The sentence summarises prior reports rather than this study's own twins.
PMID:35394098 SUPPORT Human Clinical
"Each was inherited from clinically healthy father and mother, respectively."
The two compound heterozygous variants were each inherited from an unaffected parent, consistent with recessive inheritance.
PMID:40583116 SUPPORT Human Clinical
"Genetic testing of other siblings showed a heterozygous deletion of the GLIS3 gene. Although their ophthalmic examinations were unremarkable, all carriers presented with juvenile hypothyroidism."
Heterozygous carriers in this family lacked the syndrome but had juvenile hypothyroidism, which qualifies the statement that carriers are unaffected.
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Pathophysiology

10
Biallelic GLIS3 Loss of Function
Biallelic GLIS3 variants remove or truncate the transcription factor. The original NDH1 frameshift (c.1873dupC) yields a protein that still enters the nucleus but has lost its C-terminal transactivation function, while partial deletions remove the 5' exons and the major pancreatic and thyroid transcripts. Residual expression of shorter tissue-specific transcripts from some deletion alleles is the proposed explanation for incomplete phenotypes.
Genetic context GLIS3 hgnc:28510 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns GLIS3 (hgnc:28510). hgnc:28510 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION
GLIS3 sequence-specific DNA-binding transcription factor activity GO:0000981 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased GLIS3 sequence-specific DNA-binding transcription factor activity, annotated with DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981). GO:0000981 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Impaired Endocrine Pancreas Differentiation Without GLIS3, neurogenin 3 is not transactivated in the fetal pancreas and endocrine lineage specification fails.
Reduced Insulin Gene Transcription GLIS3 directly activates the insulin promoter in beta cells.
Impaired TSH-Dependent Thyroid Hormone Biosynthesis GLIS3 is required downstream of TSHR for expression of thyroid hormone biosynthesis genes.
Renal Cystogenesis Loss of cilium-associated GLIS3 signalling in the kidney leads to cyst formation.
Abnormal Intrahepatic Bile Duct Development GLIS3 deficiency disturbs bile duct development in the liver.
Impaired Pancreatic Ductal and Acinar Function GLIS3 is also expressed in pancreatic acini and ducts.
Impaired Ocular Development Loss of the eye-specific GLIS3 transcript is associated with congenital glaucoma.
Impaired Osteoblast Differentiation GLIS3 promotes osteoblast differentiation.
Show evidence (3 references)
PMID:16715098 SUPPORT Human Clinical
"In the original family, we identified a frameshift mutation predicted to result in a truncated protein. In two other families with an incomplete syndrome, we found that affected individuals harbor deletions affecting the 11 or 12 5'-most exons of the gene."
Identifies the truncating and deletion alleles that define the disease mechanism as loss of GLIS3.
PMID:18263616 SUPPORT In Vitro
"We demonstrate that this truncation does not effect the nuclear localization but results in the loss of Glis3 transactivating activity."
Shows directly that the patient frameshift abolishes GLIS3 transcriptional activation, the molecular function this node marks as decreased.
PMID:21139041 SUPPORT Human Clinical
"Our results confirm partial gene deletions as the most common type of GLIS3 mutations, accounting for four of five families identified to date."
Establishes gene deletion as the predominant loss-of-function allele class.
Impaired Endocrine Pancreas Differentiation
Mechanism confidence: Established
GLIS3 binds GLIS3 response elements in the Neurog3 promoter and activates it directly and together with HNF6 and FOXA2. In Glis3-null mouse embryos Ngn3 expression falls by more than 90% and insulin is nearly absent, so the fetal islet endocrine lineage, beta cells in particular, is not generated. The human evidence is genetic and clinical; the step-level mechanism comes from mouse and cell models.
pancreatic endocrine cell CL:0008024 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves pancreatic endocrine cell (CL:0008024). CL:0008024 is a cell type from the Cell Ontology.
endocrine pancreas development GO:0031018 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased endocrine pancreas development (GO:0031018). GO:0031018 is a biological process from the Gene Ontology. ↓ DECREASED type B pancreatic cell differentiation GO:0003309 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased type B pancreatic cell differentiation (GO:0003309). GO:0003309 is a biological process from the Gene Ontology. ↓ DECREASED
islet of Langerhans UBERON:0000006 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in islet of Langerhans (UBERON:0000006). UBERON:0000006 is an anatomical location from the Uberon multi-species anatomy ontology.
Experimental models
GLIS3-null human embryonic stem cell pancreatic differentiation (HUES8) OTHER The human GLIS3-null line did not show the endocrine differentiation defect that the human disease and the mouse knockouts show, at the differentiation stages tested.
Animal models
Glis3 global knockout mouse Mouse recapitulates Reproduces the failure of fetal islet endocrine differentiation.
Downstream
Insulin Deficiency Too few insulin-producing beta cells are formed to sustain insulin output.
Show evidence (4 references)
PMID:21786021 SUPPORT Model Organism
"In vivo and in vitro analyses placed Glis3 upstream of Neurog3, the endocrine pancreas lineage-defining transcription factor."
Places GLIS3 upstream of the endocrine lineage determinant in the fetal pancreas.
PMID:21786021 SUPPORT Model Organism
"These results indicate that GLIS3 controls fetal islet differentiation via direct transactivation of Neurog3, a perturbation that causes neonatal diabetes in mice."
Links loss of Neurog3 transactivation to neonatal diabetes in the knockout.
PMID:27813676 SUPPORT Model Organism
"In contrast to the >90% reduction of Ngn3 and near-total absence of insulin (Ins) in the embryonic pancreas of Glis3-/- mice"
Quantifies the loss of Ngn3 and insulin in the Glis3-null embryonic pancreas.
+ 1 more reference
Reduced Insulin Gene Transcription
In differentiated beta cells GLIS3 binds a response element in the insulin promoter and cooperates with PDX1, MAFA and NEUROD1 to drive insulin transcription; it also directly regulates Mafa and Slc2a2. The NDH1 mutant protein cannot activate insulin expression. Pancreas-specific deletion in mice leaves PDX1-positive cells that no longer express insulin.
type B pancreatic cell CL:0000169 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves type B pancreatic cell (CL:0000169). CL:0000169 is a cell type from the Cell Ontology.
Downstream
Insulin Deficiency Remaining beta cells produce too little insulin.
Show evidence (3 references)
PMID:19264802 SUPPORT In Vitro
"We demonstrate that insulin 2 (Ins2) mRNA expression in rat insulinoma 832/13 cells is markedly increased by wild-type Glis3 overexpression, but not by the NDH1 mutant."
The patient-derived NDH1 mutant fails to activate insulin expression that wild-type GLIS3 induces.
PMID:19264802 SUPPORT In Vitro
"Glis3 binds to the Ins2 promoter in the cell, detected by chromatin immunoprecipitation."
Shows direct GLIS3 occupancy of the insulin promoter.
PMID:31340201 SUPPORT Model Organism
"Indeed, presumptive beta cells appeared to persist as PDX1+/INS-/MAFA-/GLUT2- cells."
After pancreas-specific Glis3 deletion, beta cells persist but lose insulin expression, isolating the transcriptional role from the developmental one.
Insulin Deficiency
Endogenous insulin production is absent or severely reduced from birth, with low C-peptide. Insulin requirements and sensitivity vary widely between patients. Fetal insulin deficiency is also the proposed cause of the intrauterine growth restriction seen in most patients.
type B pancreatic cell CL:0000169 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves type B pancreatic cell (CL:0000169). CL:0000169 is a cell type from the Cell Ontology.
Downstream
Neonatal Diabetes Mellitus Insulin deficiency causes hyperglycaemia from the first days of life.
Intrauterine Growth Retardation Insulin is a major fetal growth factor; its intrauterine deficiency is the proposed cause of the growth restriction.
Show evidence (1 reference)
PMID:36312692 SUPPORT Human Clinical
"C-peptide level was 0.2 ng/mL (1.1-4.4 ng/mL) suggestive of exogenous insulin administration and deficiency of endogenous insulin."
Low C-peptide documents endogenous insulin deficiency in a GLIS3 patient.
Impaired TSH-Dependent Thyroid Hormone Biosynthesis
In the thyroid GLIS3 acts downstream of TSH and TSHR. It binds the promoters of iodide transporter genes (Nis/SLC5A5, Pds/SLC26A4) and other thyroid hormone biosynthesis genes. The global knockout also loses TSH-driven follicular cell proliferation through mTORC1, but a thyroid-specific (Pax8-Cre) knockout keeps normal proliferation while biosynthesis genes stay suppressed, so the proliferation defect is attributed to GLIS3 loss in other cell types and the cell-autonomous thyroid defect is in hormone synthesis. Its loss produces a dyshormonogenic hypothyroidism in which TSH and thyroglobulin rise. Thyroid anatomy in patients ranges from normal to hypoplasia or athyreosis, and a post-mortem gland showed sparse colloid with interstitial fibrosis, so a developmental contribution is not excluded.
thyroid follicular cell CL:0002258 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves thyroid follicular cell (CL:0002258). CL:0002258 is a cell type from the Cell Ontology.
thyroid hormone generation GO:0006590 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased thyroid hormone generation (GO:0006590). GO:0006590 is a biological process from the Gene Ontology. ↓ DECREASED
thyroid gland UBERON:0002046 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in thyroid gland (UBERON:0002046). UBERON:0002046 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
GLIS3-deficient mouse thyroid model Mouse recapitulates Reproduces the thyroid hormone biosynthesis defect.
Thyroid-specific Glis3 knockout mouse (Glis3-Pax8Cre) Mouse recapitulates Reproduces suppression of thyroid hormone biosynthesis genes, most clearly under high TSH.
Downstream
Congenital Hypothyroidism Insufficient thyroid hormone synthesis causes hypothyroidism from birth.
Elevated Circulating TSH Loss of thyroid hormone feedback raises TSH, which then fails to drive the gland.
Elevated Circulating Thyroglobulin Thyroglobulin is secreted while iodide handling is impaired, so circulating thyroglobulin rises.
Show evidence (5 references)
PMID:29083325 SUPPORT Model Organism
"we demonstrate that GLIS3 acts downstream of thyroid-stimulating hormone (TSH) and TSH receptor (TSHR) and is indispensable for TSH/TSHR-mediated proliferation of thyroid follicular cells and biosynthesis of thyroid hormone."
Establishes GLIS3 as required for TSH-driven thyroid hormone biosynthesis.
PMID:29083325 SUPPORT Model Organism
"GLIS3 is critical for the transcriptional activation of several genes required for thyroid hormone biosynthesis, including the iodide transporters Nis and Pds, both of which showed enhanced GLIS3 binding at their promoters."
Names the direct transcriptional targets through which biosynthesis fails.
PMID:37461635 SUPPORT Model Organism
"We further show that Glis3KO mice do not display any major changes in prenatal thyroid gland morphology indicating that CH in Glis3KO mice is due to dyshormonogenesis rather than thyroid dysgenesis."
Places the mouse hypothyroidism in hormone synthesis rather than gland formation, which is why this node is a biosynthesis defect.
+ 2 more references
Renal Cystogenesis
Mechanism confidence: Provisional
GLIS3 localises to the primary cilium and uses WWTR1/TAZ as a transcriptional coactivator, placing it in a cilium-associated signalling pathway like its paralog GLIS2, whose loss causes nephronophthisis. Glis3 zinc-finger mutant mice develop polycystic kidneys, with fewer ciliated cells in the cyst lining. Patients show enlarged kidneys with multiple small cysts, cystic renal dysplasia and deficient corticomedullary differentiation, usually with preserved renal function early on. How ciliary GLIS3 function leads to cysts in humans is not established.
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.
kidney development GO:0001822 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated kidney development (GO:0001822). GO:0001822 is a biological process from the Gene Ontology. ↕ DYSREGULATED
primary cilium GO:0097730 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves primary cilium, annotated with non-motile cilium (GO:0097730). GO:0097730 is a cellular component from the Gene Ontology.
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.
Animal models
Glis3 zinc-finger mutant mouse (Glis3 zf/zf) Mouse recapitulates Reproduces the renal cystic disease.
Downstream
Cystic Renal Dysplasia Cyst formation in developing kidneys produces cystic dysplasia.
Enlarged Kidneys Multiple cysts enlarge the kidneys.
Show evidence (3 references)
PMID:19273592 SUPPORT Model Organism
"These mice display abnormalities very similar to those of patients with neonatal diabetes and hypothyroidism syndrome, including the development of diabetes and polycystic kidney disease."
Glis3 mutant mice reproduce the polycystic kidney disease of NDH.
PMID:19273592 SUPPORT In Vitro
"We demonstrate that Glis3 localizes to the primary cilium, suggesting that Glis3 is part of a cilium-associated signaling pathway."
Supports the ciliary localisation that ties GLIS3 to cystic kidney mechanisms.
PMID:12966531 SUPPORT Human Clinical
"The renal disease was characterized by large kidneys and multiple small cysts with deficient corticomedullary junction differentiation and normal kidney function."
Describes the human renal lesion in the index family.
Abnormal Intrahepatic Bile Duct Development
Mechanism confidence: Provisional
Liver disease in NDH presents as neonatal cholestasis and progresses in some patients to hepatic fibrosis and biliary cirrhosis, occasionally requiring liver transplantation. Explant histology shows bile duct paucity and a predominantly biliary cirrhosis, pointing to abnormal bile duct development as the lesion. Shorter GLIS3 transcripts are expressed in the liver, and the variable hepatic phenotype has been attributed to differential transcript loss. The cellular mechanism has not been worked out.
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.
intrahepatic bile duct development GO:0035622 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased intrahepatic bile duct development (GO:0035622). GO:0035622 is a biological process from the Gene Ontology. ↓ DECREASED
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
Cholestasis Deficient intrahepatic bile ducts impair bile flow.
Reduced Number of Intrahepatic Bile Ducts The developmental lesion is seen histologically as duct paucity.
Hepatic Fibrosis Chronic cholestatic injury progresses to fibrosis and biliary cirrhosis.
Show evidence (2 references)
PMID:36917836 SUPPORT Human Clinical
"Histology demonstrated predominantly biliary cirrhosis consistent with abnormal bile duct development."
Explant histology from two transplanted patients indicates a bile duct developmental lesion.
PMID:36917836 SUPPORT Human Clinical
"GLIS3 mutations need to be added to the list of non-syndromic causes of bile duct paucity in the liver."
Identifies bile duct paucity as a feature of GLIS3 liver disease.
Impaired Pancreatic Ductal and Acinar Function
Mechanism confidence: Hypothetical
GLIS3 is expressed at lower levels in pancreatic acini and in ductal cells as well as in beta cells. Some patients have exocrine pancreatic insufficiency with low faecal elastase and pancreatic cysts, which the case-series authors attribute to a role of GLIS3 in pancreatic duct development and maintenance. This is an inference from expression and phenotype, not a demonstrated mechanism.
pancreas UBERON:0001264 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in pancreas (UBERON:0001264). UBERON:0001264 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Exocrine Pancreatic Insufficiency Reduced acinar enzyme output causes malabsorption.
Pancreatic Cysts Abnormal ductal development produces pancreatic cysts.
Show evidence (2 references)
PMID:26259131 SUPPORT Human Clinical
"The presence of exocrine pancreatic dysfunction in patients 2, 3a, 3b, and 7 in our series suggests that exocrine pancreatic involvement may be more extensive than previously described (8)."
Documents exocrine involvement in patients and proposes it as a primary GLIS3 effect rather than a secondary one.
PMID:26259131 SUPPORT Human Clinical
"The presence of pancreatic cystic changes in patients 3a and 3b supports the previous observations that GLIS3 is important in the development and maintenance of pancreatic ducts (15)."
Links the pancreatic cysts seen in patients to a ductal role of GLIS3.
Impaired Ocular Development
Mechanism confidence: Hypothetical
Congenital glaucoma occurs in roughly a third of patients. The original genotype-phenotype analysis linked glaucoma to loss of an eye-specific GLIS3 transcript, and Glis3 is expressed dynamically in the developing optic vesicle, lens and retina in mice, but later series could not tie glaucoma to a specific exon. The developmental defect behind the glaucoma is not characterised.
eye UBERON:0000970 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in eye (UBERON:0000970). UBERON:0000970 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Congenital Glaucoma Abnormal anterior segment development raises intraocular pressure from infancy.
High Hypermetropia A short axial length of the globe produces high hyperopia, reported with congenital glaucoma in GLIS3 siblings.
Show evidence (2 references)
PMID:16715098 SUPPORT Human Clinical
"The absence of a major transcript in the pancreas and thyroid (deletions from both families) and an eye-specific transcript (deletion from one family), together with residual expression of some GLIS3 transcripts, seems to explain the incomplete clinical manifestations in these individuals."
Associates loss of an eye-specific GLIS3 transcript with the ocular phenotype.
PMID:26259131 REFUTE Human Clinical
"However, from our cohort we were unable to ascribe a specific exon relating to the eye disease."
A later 12-patient series could not reproduce an exon-specific link for the eye disease, which weakens the transcript-specific explanation.
Impaired Osteoblast Differentiation
Mechanism confidence: Hypothetical
GLIS3 is highly expressed in human osteoblasts and promotes osteoblast differentiation in part by inducing FGF18. Patients show osteopenia, poorly healing rib fractures with persistent callus and scoliosis, which the clinical authors interpret as a bone remodelling defect. The link between the in vitro osteoblast data and the human skeletal phenotype is inferred.
osteoblast differentiation GO:0001649 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased osteoblast differentiation (GO:0001649). GO:0001649 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Osteopenia Deficient bone formation and remodelling reduce bone mineral density.
Show evidence (2 references)
PMID:17488195 SUPPORT In Vitro
"The zinc finger protein Glis3 is highly expressed in human osteoblasts and acts synergistically with BMP2 and Shh in enhancing osteoblast differentiation in multipotent C3H10T1/2 cells."
Establishes a pro-osteoblastic function of GLIS3 in cell culture.
PMID:26259131 SUPPORT Human Clinical
"The persistence of callus formation suggests a defect in bone remodeling either due to dysfunctional osteoblast signaling to osteoclasts or reduced osteoclastic bone reabsorption."
The clinical authors' interpretation of the skeletal phenotype as a remodelling defect.
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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 Neonatal Diabetes Mellitus With Congenital Hypothyroidism 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

25
Cardiovascular 1
Atrial Septal Defect VERY_RARE HP:0001631 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Atrial septal defect (HP:0001631). HP:0001631 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26259131 SUPPORT Human Clinical
"We describe new presenting features in patients with GLIS3 mutations, including craniosynostosis, hiatus hernia, atrial septal defect, splenic cyst, and choanal atresia"
Lists atrial septal defect among newly described rare features in GLIS3 patients.
Digestive 6
Cholestasis FREQUENT HP:0001396 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cholestasis (HP:0001396). HP:0001396 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:12966531 SUPPORT Human Clinical
"We report on two sibs (of 4) with a syndrome of minor facial anomalies, proportionate IUGR, neonatal non-autoimmune diabetes mellitus (NDM), severe congenital hypothyroidism (CH), cholestasis, congenital glaucoma, and polycystic kidneys."
Cholestasis was present in both index siblings.
PMID:26259131 SUPPORT Human Clinical
"Liver disease was documented in 7 of our 12 patients."
Gives the frequency of liver involvement in the largest series.
Hepatic Fibrosis FREQUENT HP:0001395 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hepatic fibrosis (HP:0001395), qualified as course progressive. HP:0001395 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (2 references)
PMID:12966531 SUPPORT Human Clinical
"Liver disease progressed to hepatic fibrosis."
Progression to fibrosis in the index family.
PMID:26259131 SUPPORT Human Clinical
"The hepatic dysfunction presented concomitantly with renal abnormalities and ranged from hepatitis (patients 3b and 4) to hepatic fibrosis and cirrhosis (patients 2, 3a, 6, 7, 9, and 10)."
Six of twelve patients had hepatic fibrosis or cirrhosis.
Reduced Number of Intrahepatic Bile Ducts HP:0006571 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bile duct paucity, annotated with Reduced number of intrahepatic bile ducts (HP:0006571). HP:0006571 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36917836 SUPPORT Human Clinical
"GLIS3 mutations need to be added to the list of non-syndromic causes of bile duct paucity in the liver."
Identifies bile duct paucity in GLIS3 liver disease.
Exocrine Pancreatic Insufficiency FREQUENT HP:0001738 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Exocrine pancreatic insufficiency (HP:0001738). HP:0001738 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26259131 SUPPORT Human Clinical
"Malabsorption due to exocrine pancreatic insufficiency as demonstrated by low fecal elastase was a feature in patients 2, 3a, 3b, and 7 in our case series."
Four of twelve patients had exocrine insufficiency.
Pancreatic Cysts OCCASIONAL HP:0001737 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pancreatic cysts (HP:0001737). HP:0001737 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26259131 SUPPORT Human Clinical
"The presence of pancreatic cystic changes in patients 3a and 3b supports the previous observations that GLIS3 is important in the development and maintenance of pancreatic ducts (15)."
Records pancreatic cysts in two of twelve patients.
Hiatus Hernia VERY_RARE HP:0002036 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hiatus hernia (HP:0002036). HP:0002036 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26259131 SUPPORT Human Clinical
"We describe new presenting features in patients with GLIS3 mutations, including craniosynostosis, hiatus hernia, atrial septal defect, splenic cyst, and choanal atresia"
Lists hiatus hernia among newly described rare features in GLIS3 patients.
Ear 2
Sensorineural Hearing Impairment OCCASIONAL HP:0000407 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sensorineural hearing impairment (HP:0000407). HP:0000407 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:21139041 SUPPORT Human Clinical
"These novel mutations have also resulted in osteopenia, bilateral sensorineural deafness and pancreatic exocrine insufficiency, features that have not previously been associated with GLIS3 mutations."
Reports sensorineural deafness in GLIS3 patients.
Low-Set Ears FREQUENT HP:0000369 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Low-set ears (HP:0000369). HP:0000369 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27148679 SUPPORT Human Clinical
"we describe the common facial dysmorphism consisting of bilateral low-set ears, depressed nasal bridge with overhanging columella, elongated, upslanted palpebral fissures, persistent long philtrum with a thin vermilion border of the upper lip in a cohort of seven patients with GLIS3 mutations"
Names bilateral low-set ears as part of the shared facial phenotype.
Endocrine 3
Neonatal Diabetes Mellitus OBLIGATE Neonatal insulin-dependent diabetes mellitus HP:0000857 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Permanent neonatal diabetes mellitus, annotated with Neonatal insulin-dependent diabetes mellitus (HP:0000857). HP:0000857 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:26259131 SUPPORT Human Clinical
"PND was the only consistent feature of all of our patients with GLIS3 mutations. Age at diagnosis ranged from birth to 23 days. All patients were insulin treated."
Neonatal diabetes present in 12 of 12 patients, with onset in the first weeks.
PMID:12966531 SUPPORT Human Clinical
"We report on two sibs (of 4) with a syndrome of minor facial anomalies, proportionate IUGR, neonatal non-autoimmune diabetes mellitus (NDM), severe congenital hypothyroidism (CH), cholestasis, congenital glaucoma, and polycystic kidneys."
The index description establishing non-autoimmune neonatal diabetes as part of the syndrome.
Congenital Hypothyroidism VERY_FREQUENT HP:0000851 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congenital hypothyroidism (HP:0000851). HP:0000851 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:26259131 SUPPORT Human Clinical
"Although congenital hypothyroidism presented during the first week of life in all patients, the patterns of thyroid disease were variable."
Congenital hypothyroidism was present in 11 of 12 patients, with variable pattern.
PMID:28648506 SUPPORT REVIEW SYNTHESIS Human Clinical
"Thyroid findings in GLIS3 patients include thyroid aplasia, diminished colloid with interstitial fibrosis at post-mortem, and apparently normal gross thyroid anatomy on ultrasonography but with temporary TSH resistance on treatment."
Review summarising the range of thyroid findings in GLIS3 patients.
Elevated Circulating TSH FREQUENT Elevated circulating thyroid-stimulating hormone concentration HP:0002925 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated circulating thyroid-stimulating hormone concentration (HP:0002925). HP:0002925 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26259131 SUPPORT Human Clinical
"Similarly, patients 7 and 11 had very high TSH levels that did not reduce to normal limits with levothyroxine therapy despite normalizing of free T4."
Documents persistent TSH elevation on treatment.
Eye 2
Congenital Glaucoma FREQUENT Developmental glaucoma HP:0001087 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congenital glaucoma, annotated with Developmental glaucoma (HP:0001087). HP:0001087 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:26259131 SUPPORT Human Clinical
"Only 4 of 12 of our patients had congenital glaucoma"
Gives the frequency of congenital glaucoma in the largest series.
PMID:36312692 SUPPORT Human Clinical
"Ophthalmological assessment showed bilateral corneal clouding with raised intraocular pressure."
Describes the ocular findings in a GLIS3 neonate.
High Hypermetropia HP:0008499 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is High hyperopia, annotated with High hypermetropia (HP:0008499). HP:0008499 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40583116 SUPPORT Human Clinical
"In both patients, ophthalmic assessments revealed congenital glaucoma, high hyperopia, and short axial length of the globe."
Reports high hyperopia with congenital glaucoma in two affected siblings.
Genitourinary 2
Cystic Renal Dysplasia FREQUENT HP:0000800 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cystic renal dysplasia (HP:0000800). HP:0000800 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26259131 SUPPORT Human Clinical
"Nine patients have anatomical kidney changes. Of these, 7 children showed variable renal cystic dysplasia ranging from an isolated cyst observed in patient 10 and bilateral calyceal calcification in patient 11 to extensive cystic renal dysplasia (patients 2, 3a, 3b, 4, and 9) (Figure 2)."
Gives the frequency and range of renal cystic disease.
Enlarged Kidneys HP:0000105 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Enlarged kidney (HP:0000105). HP:0000105 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:12966531 SUPPORT Human Clinical
"The renal disease was characterized by large kidneys and multiple small cysts with deficient corticomedullary junction differentiation and normal kidney function."
Describes enlarged cystic kidneys in the index siblings.
Head and Neck 5
Depressed Nasal Bridge FREQUENT HP:0005280 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Depressed nasal bridge (HP:0005280). HP:0005280 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:27148679 SUPPORT Human Clinical
"we describe the common facial dysmorphism consisting of bilateral low-set ears, depressed nasal bridge with overhanging columella, elongated, upslanted palpebral fissures, persistent long philtrum with a thin vermilion border of the upper lip in a cohort of seven patients with GLIS3 mutations"
Names the depressed nasal bridge as part of the shared facial phenotype.
PMID:26259131 SUPPORT Human Clinical
"In our cohort, dysmorphic features were seen in 9 of the 12 patients."
Frequency of facial dysmorphism in the largest series.
Upslanted Palpebral Fissures FREQUENT HP:0000582 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Upslanted palpebral fissure (HP:0000582). HP:0000582 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27148679 SUPPORT Human Clinical
"we describe the common facial dysmorphism consisting of bilateral low-set ears, depressed nasal bridge with overhanging columella, elongated, upslanted palpebral fissures, persistent long philtrum with a thin vermilion border of the upper lip in a cohort of seven patients with GLIS3 mutations"
Names elongated, upslanted palpebral fissures as part of the shared facial phenotype.
Long Philtrum FREQUENT HP:0000343 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Long philtrum (HP:0000343). HP:0000343 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27148679 SUPPORT Human Clinical
"we describe the common facial dysmorphism consisting of bilateral low-set ears, depressed nasal bridge with overhanging columella, elongated, upslanted palpebral fissures, persistent long philtrum with a thin vermilion border of the upper lip in a cohort of seven patients with GLIS3 mutations"
Names a persistent long philtrum as part of the shared facial phenotype.
Craniosynostosis VERY_RARE HP:0001363 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Craniosynostosis (HP:0001363). HP:0001363 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26259131 SUPPORT Human Clinical
"We describe new presenting features in patients with GLIS3 mutations, including craniosynostosis, hiatus hernia, atrial septal defect, splenic cyst, and choanal atresia"
Lists craniosynostosis among newly described rare features in GLIS3 patients.
Choanal Atresia VERY_RARE HP:0000453 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Choanal atresia (HP:0000453). HP:0000453 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26259131 SUPPORT Human Clinical
"We describe new presenting features in patients with GLIS3 mutations, including craniosynostosis, hiatus hernia, atrial septal defect, splenic cyst, and choanal atresia"
Lists choanal atresia among newly described rare features in GLIS3 patients.
Metabolism 1
Elevated Circulating Thyroglobulin Elevated circulating thyroglobulin concentration HP:0025484 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated circulating thyroglobulin concentration (HP:0025484). HP:0025484 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:21139041 SUPPORT Human Clinical
"Both patients presented with neonatal diabetes mellitus, severe resistant hypothyroidism in the presence of elevated thyroglobulin and normal thyroid anatomy, degenerative liver disease, cystic renal dysplasia, recurrent infections and facial dysmorphism."
Reports elevated thyroglobulin with a normal gland in two patients.
Musculoskeletal 1
Osteopenia HP:0000938 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Osteopenia (HP:0000938). HP:0000938 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:21139041 SUPPORT Human Clinical
"These novel mutations have also resulted in osteopenia, bilateral sensorineural deafness and pancreatic exocrine insufficiency, features that have not previously been associated with GLIS3 mutations."
First report of osteopenia in GLIS3 patients.
Nervous System 1
Global Developmental Delay FREQUENT HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26259131 SUPPORT Human Clinical
"Developmental delay and IUGR were common features in our patient cohort."
Developmental delay was common in the 12-patient series.
Growth 1
Intrauterine Growth Retardation FREQUENT HP:0001511 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intrauterine growth retardation (HP:0001511). HP:0001511 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26259131 SUPPORT Human Clinical
"Developmental delay and IUGR were common features in our patient cohort."
IUGR was common in the 12-patient series.
🧬

Genetic Associations

1
GLIS3
Gene: GLIS3 hgnc:28510 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is GLIS3 (hgnc:28510). hgnc:28510 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:16715098 SUPPORT Human Clinical
"Here, we show that this syndrome results from mutations in GLIS3, encoding GLI similar 3, a recently identified transcription factor."
The original identification of GLIS3 as the causal gene.
PMID:26259131 SUPPORT Human Clinical
"Patients 1, 5, and 10 harbor missense mutations (p.Arg589Trp, p.Cys536Trp, and p.His561Tyr, respectively), affecting highly conserved amino acids located in the DNA binding domain and so are likely to be pathogenic, thus severely affecting the function of the GLIS3 protein."
Adds zinc-finger missense variants to the allelic spectrum.
💊

Medical Actions

5
Insulin Therapy
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: insulin CHEBI:145810 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses insulin (CHEBI:145810). CHEBI:145810 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Protein replacement
Lifelong insulin from diagnosis, often by continuous subcutaneous infusion with glucose monitoring. Insulin sensitivity varies widely, from recurrent hypoglycaemia on very small doses to insulin resistance during illness, so control is often labile. The diabetes is a beta-cell developmental deficiency rather than a KATP-channel defect, so molecular diagnosis matters: it distinguishes insulin-dependent forms like this one from the sulfonylurea-responsive KCNJ11/ABCC8 channel forms.
Mechanism Target:
RESTORES Insulin Deficiency — Exogenous insulin replaces the hormone that the patient cannot produce.
Show evidence (3 references)
PMID:34093443 SUPPORT Human Clinical
"A rapid molecular diagnosis of NDM is recommended as the specific etiology assists in clinical management (insulin vs. sulfonylurea)"
Supports that molecular diagnosis directs the insulin-versus-sulfonylurea management choice; GLIS3 disease is the insulin-dependent side.
PMID:26259131 SUPPORT Human Clinical
"Patients were initially treated with insulin at 0.4 to 2.0 U/kg/24 h (patient 4 required 2.0 U/kg/24 h), demonstrating a range of insulin sensitivities."
All patients in the series were insulin treated, with widely varying doses.
PMID:34093443 SUPPORT Human Clinical
"The diabetes was treated with a continuous subcutaneous insulin infusion pump and continuous glucose monitoring."
Pump delivery with continuous glucose monitoring in GLIS3 twins.
Levothyroxine Replacement
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: levothyroxine CHEBI:6446 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses levothyroxine, annotated with levothyroxine sodium anhydrous (CHEBI:6446). CHEBI:6446 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Levothyroxine from diagnosis. High starting doses may be needed, and TSH may remain elevated despite normalised free T4, so dosing is guided by free T4.
Mechanism Target:
BYPASSES Impaired TSH-Dependent Thyroid Hormone Biosynthesis — Exogenous thyroxine replaces the hormone the gland cannot synthesise.
Show evidence (2 references)
PMID:26259131 SUPPORT Human Clinical
"In contrast, patient 4 presented with congenital hypothyroidism due to athyreosis and responded to levothyroxine at a starting dose of 28 μg/kg/d."
Levothyroxine treatment and response in a GLIS3 patient.
PMID:26259131 SUPPORT Human Clinical
"Patients 2, 3a, and 3b had elevated TSH levels that were resistant to treatment with thyroxine as described previously (11)."
Records the TSH resistance that complicates dosing.
Pancreatic Enzyme Replacement
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: pancrelipase CHEBI:753090 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses pancrelipase (CHEBI:753090). CHEBI:753090 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Protein replacement
Pancreatic enzyme supplementation for exocrine insufficiency, with fat-soluble vitamin supplementation. One report suggests correcting partial exocrine insufficiency improved cholestasis and TSH resistance, although causality was not shown.
Mechanism Target:
BYPASSES Exocrine Pancreatic Insufficiency — Supplies the digestive enzymes the exocrine pancreas does not secrete.
Show evidence (2 references)
PMID:26259131 SUPPORT Human Clinical
"These 4 patients have been treated with pancreatic enzyme supplementation."
Enzyme supplementation used for exocrine insufficiency in the series.
PMID:33935973 SUPPORT Human Clinical
"Compensation of partial exocrine pancreatic insufficiency and deficiencies in antioxidative vitamins seemed to have exerted marked beneficial impact on several disease symptoms including cholestasis and TSH resistance, although a causal relation is difficult to prove."
A single-patient observation of benefit, explicitly without proven causality.
Liver Transplantation
Action: Liver transplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Liver transplantation (NCIT:C15271). NCIT:C15271 is a clinical intervention from the NCI Thesaurus. Ontology label: Liver Transplantation NCIT:C15271
Platform: Surgery
For life-limiting liver disease. Multi-organ transplantation has been considered; postoperative care is complicated by infection, renal disease and brittle diabetes.
Mechanism Target:
BYPASSES Hepatic Fibrosis — Replaces the fibrotic liver.
Show evidence (1 reference)
PMID:36917836 SUPPORT Human Clinical
"Liver transplantation should be considered in patients with life-limiting complications related to liver disease."
Recommendation from two transplanted GLIS3 patients.
Glaucoma Surgery
Action: trabeculotomyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is trabeculotomy, annotated with Ophthalmologic Surgical Procedure (NCIT:C15331). NCIT:C15331 is a clinical intervention from the NCI Thesaurus. Ontology label: Ophthalmologic Surgical Procedure NCIT:C15331
Platform: Surgery
Topical pressure-lowering drops followed by trabeculotomy for congenital glaucoma.
Mechanism Target:
BYPASSES Congenital Glaucoma — Surgical opening of aqueous outflow lowers intraocular pressure.
Show evidence (1 reference)
PMID:36312692 SUPPORT Human Clinical
"Treatment with timolol and latanoprost eye drops was started for congenital glaucoma (CG). Later, she underwent trabeculotomy in both eyes."
Medical then surgical management of congenital glaucoma in a GLIS3 neonate.
🔬

Biochemical Markers

2
Serum TSH and thyroglobulin (INCREASED)
Show evidence (1 reference)
PMID:25133201 SUPPORT REVIEW SYNTHESIS Human Clinical
"Patients with GLIS3-mediated CH exhibit diminished serum levels of thyroxine (T4) and triiodothyronine (T3) and elevated thyroid stimulating hormone (TSH) and thyroglobulin (TG)."
Review summarising the biochemical thyroid profile of GLIS3 patients.
Serum C-peptide (DECREASED)
Show evidence (1 reference)
PMID:36312692 SUPPORT Human Clinical
"C-peptide level was 0.2 ng/mL (1.1-4.4 ng/mL) suggestive of exogenous insulin administration and deficiency of endogenous insulin."
Reports low C-peptide in a GLIS3 neonate.
🔬

Diagnosis

1
Molecular genetic testing of GLIS3
Suspected in any infant with neonatal diabetes and congenital hypothyroidism, including from non-consanguineous families. Because partial deletions are the commonest variant class, copy-number analysis or chromosomal microarray is needed in addition to sequencing.
GLIS3 sequencing and copy-number analysis NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:21139041 SUPPORT Human Clinical
"We also report the first case of a recessive GLIS3 mutation causing neonatal diabetes and congenital hypothyroidism in a child from a non-consanguineous pedigree, highlighting the importance of molecular genetic testing in any patient with this phenotype."
Recommends genetic testing for every patient with the phenotype.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
About 22 cases from 16 families in 11 countries had been described by 2022. No population prevalence estimate exists. In a Chinese screen of 592 congenital hypothyroidism patients, GLIS3 variants were found in 0.3%, and neither carrier had the recessive syndrome.
Show evidence (2 references)
PMID:35394098 SUPPORT BACKGROUND Human Clinical
"To date, 22 cases of NDH syndrome from 16 families and 11 countries have been described."
Gives the published case count, which is the only frequency measure available.
PMID:29146476 SUPPORT Human Clinical
"Our study indicated that the prevalence of GLIS3 variations was 0.3% among studied Chinese CH patients."
Shows that GLIS3 variants are a rare contributor even within a congenital hypothyroidism cohort.
🧫

Experimental Models

1
GLIS3-null human embryonic stem cell pancreatic differentiation (HUES8) OTHER
A systematic hESC knockout panel of eight pancreatic transcription factors. Unlike PDX1, RFX6 and NGN3 knockouts, the GLIS3-null line showed no overt endocrine differentiation defect at the stages assayed, a human-model result that does not reproduce the beta-cell deficiency of patients and is read by the authors as a possible later-stage or protocol-dependent requirement.
human embryonic stem cell CL:0002322 Cell Ontology (CL) Relation: this experimental model uses this cell type This experimental model uses human embryonic stem cell, annotated with embryonic stem cell (CL:0002322). CL:0002322 is a cell type from the Cell Ontology.
Organism
Homo sapiens NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Cell source
HUES8 human embryonic stem cell line, CRISPR/Cas- and TALEN-edited GLIS3 knockout
Culture
Directed pancreatic differentiation of gene-edited hESCs to the pancreatic-progenitor and PH-beta stage
Publication
PMID:27133796
Pathograph links
Impaired Endocrine Pancreas Differentiation fails to recapitulate fidelity: low observes: cellular The human GLIS3-null line did not show the endocrine differentiation defect that the human disease and the mouse knockouts show, at the differentiation stages tested.
Limitations: Only early-to-mid pancreatic differentiation stages were assayed; the protocol generates fetal polyhormonal beta cells, so a later-stage or maturation-stage GLIS3 requirement could be missed. This is a single in vitro system.
Show evidence (1 reference)
PMID:27133796 SUPPORT In Vitro
"At the PH-β stage, all −/− mutant lines exhibited a defect with the exception of PTF1A−/−, MNX1−/− and GLIS3−/− mutants."
The GLIS3 knockout line lacked the differentiation defect seen in other PNDM-gene knockouts.
Show evidence (1 reference)
PMID:27133796 SUPPORT In Vitro
"This protocol may allow us to identify later differentiation defects in PTF1A−/−, MNX1−/− and GLIS3−/− mutant lines, which did not exhibit an overt phenotype at early differentiation stages."
The authors read the absent early phenotype as a possible later-stage requirement, framing the model's negative result.
🐁

Animal Models

4
Glis3 global knockout mouse
Global Glis3-null mice develop severe neonatal diabetes and die within the first days to weeks of life, with near-total loss of embryonic Ngn3 and insulin expression.
Species
Mouse
Genotype
Glis3 -/- (gene-targeted null)
Publication
PMID:21786021
Pathograph links
Impaired Endocrine Pancreas Differentiation recapitulates fidelity: high observes: tissue Reproduces the failure of fetal islet endocrine differentiation.
Limitations: Neonatal lethality in the mouse precludes study of the later multisystem course seen in surviving patients.
Show evidence (1 reference)
PMID:21786021 SUPPORT Model Organism
"These results indicate that GLIS3 controls fetal islet differentiation via direct transactivation of Neurog3, a perturbation that causes neonatal diabetes in mice."
Shows the knockout reproduces the developmental mechanism and the diabetes.
Show evidence (1 reference)
PMID:19481545 SUPPORT Model Organism
"The pancreatic phenotypes indicate that the Glis3-deficient mice are a model for GLIS3 mutation and diabetes mellitus in humans."
Independent Glis3 knockout validated as a model of the human diabetes.
Glis3 zinc-finger mutant mouse (Glis3 zf/zf)
Mice carrying a Glis3 zinc-finger mutation develop diabetes and polycystic kidney disease resembling the human syndrome.
Species
Mouse
Genotype
Glis3 zf/zf
Publication
PMID:19273592
Pathograph links
Renal Cystogenesis recapitulates fidelity: moderate observes: tissue Reproduces the renal cystic disease.
Limitations: Cyst mechanism in the mouse is linked to ciliary localisation but not resolved, and the human lesion is often cystic dysplasia rather than classic polycystic kidney disease.
Show evidence (1 reference)
PMID:19273592 SUPPORT Model Organism
"Our study demonstrates that dysfunction of Glis3 leads to the development of cystic renal disease, suggesting that Glis3 plays a critical role in maintaining normal renal functions."
Mutant mice develop the cystic renal disease.
Show evidence (1 reference)
PMID:19273592 SUPPORT Model Organism
"These mice display abnormalities very similar to those of patients with neonatal diabetes and hypothyroidism syndrome, including the development of diabetes and polycystic kidney disease."
States the resemblance to the human syndrome.
GLIS3-deficient mouse thyroid model
GLIS3-deficient mice fail to mount TSH-driven thyroid hormone biosynthesis and follicular proliferation and do not develop goiter under chronic TSH stimulation.
Species
Mouse
Genotype
Glis3 deficiency (knockout)
Publication
PMID:29083325
Pathograph links
Impaired TSH-Dependent Thyroid Hormone Biosynthesis recapitulates fidelity: high observes: cellular Reproduces the thyroid hormone biosynthesis defect.
Limitations: Does not explain the athyreosis or hypoplasia seen in some patients, which suggests a developmental component the model does not address.
Show evidence (1 reference)
PMID:29083325 SUPPORT Model Organism
"Our study identifies GLIS3 as a key regulator of TSH/TSHR-mediated thyroid hormone biosynthesis and proliferation of thyroid follicular cells and uncovers a mechanism by which GLIS3 deficiency causes neonatal hypothyroidism and prevents goiter development."
Links the mouse finding to the neonatal hypothyroidism of the human disease.
Thyroid-specific Glis3 knockout mouse (Glis3-Pax8Cre)
Deleting Glis3 only in thyroid follicular lineage cells separates the cell-autonomous thyroid defect from effects of global GLIS3 loss. Biosynthesis genes remain suppressed, while the follicular proliferation defect of the global knockout is not reproduced.
Species
Mouse
Genotype
Glis3 floxed; Pax8-Cre (thyroid-specific deletion)
Publication
PMID:37461635
Pathograph links
Impaired TSH-Dependent Thyroid Hormone Biosynthesis recapitulates fidelity: moderate observes: cellular Reproduces suppression of thyroid hormone biosynthesis genes, most clearly under high TSH.
Limitations: Follicular cell proliferation is not repressed in this model, unlike the global knockout, so it isolates the biosynthesis arm only. Human thyroid hypoplasia or athyreosis is not modelled.
Readouts
Thyroid hormone biosynthesis gene expression
Direction: DECREASED
Interpretation: Expression readout of the biosynthesis defect in follicular cells.
Show evidence (1 reference)
PMID:37461635 SUPPORT Model Organism
"However, the expression of several thyroid hormone biosynthesis-, extracellular matrix (ECM)-, and inflammation-related genes was still suppressed in Glis3-Pax8Cre mice"
Reports the decreased biosynthesis gene expression in this model.
Show evidence (1 reference)
PMID:37461635 SUPPORT Model Organism
"However, the expression of several thyroid hormone biosynthesis-, extracellular matrix (ECM)-, and inflammation-related genes was still suppressed in Glis3-Pax8Cre mice"
Supports using this model for the biosynthesis node.
Show evidence (1 reference)
PMID:37461635 SUPPORT BACKGROUND Model Organism
"Loss of GLI-Similar 3 (GLIS3) function in mice and humans causes congenital hypothyroidism (CH)."
Frames the mouse work against the human congenital hypothyroidism.
{ }

Source YAML

click to show 
name: Neonatal Diabetes Mellitus With Congenital Hypothyroidism
creation_date: "2026-09-24T16:19:44Z"
category: Mendelian
description: >-
  Neonatal diabetes and congenital hypothyroidism (NDH) syndrome is a rare
  autosomal recessive multisystem disorder caused by biallelic loss-of-function
  variants in GLIS3, which encodes GLI-similar 3, a Kruppel-like zinc finger
  transcription factor with five C2H2 zinc fingers and a C-terminal
  transactivation domain. It was first described in 2003 in two Saudi siblings
  with permanent non-autoimmune neonatal diabetes, severe congenital
  hypothyroidism, congenital glaucoma, cholestasis progressing to hepatic
  fibrosis, polycystic kidneys, intrauterine growth restriction and minor facial
  anomalies, and GLIS3 was identified as the causal gene in 2006. Partial gene
  deletions are the most frequent variant class; frameshift, nonsense and
  zinc-finger missense variants also occur, in homozygous or compound
  heterozygous form.

  Permanent neonatal diabetes is the one constant feature. GLIS3 acts upstream of
  neurogenin 3 in the fetal pancreas to drive endocrine differentiation and later
  binds the insulin promoter directly, so its loss produces insulin deficiency
  from birth. In the thyroid GLIS3 acts downstream of TSH/TSHR and is needed for
  expression of thyroid hormone biosynthesis genes, which explains a
  dyshormonogenic hypothyroidism with elevated TSH and thyroglobulin that is
  often resistant to conventional levothyroxine doses, although thyroid
  morphology ranges from normal to athyreosis. Renal cystic dysplasia, liver
  disease ranging from cholestasis with bile duct paucity to biliary cirrhosis,
  congenital glaucoma, exocrine pancreatic insufficiency, osteopenia,
  sensorineural deafness, developmental delay and a recognisable facial gestalt
  are variable. Early reports described death in infancy, but survival into
  adolescence and adulthood is now documented. Management is insulin (often by
  pump), levothyroxine, pancreatic enzyme replacement when needed, and
  organ-specific care including glaucoma surgery and, for end-stage liver
  disease, liver transplantation.
disease_term:
  preferred_term: neonatal diabetes mellitus with congenital hypothyroidism
  term:
    id: MONDO:0012436
    label: neonatal diabetes mellitus with congenital hypothyroidism
synonyms:
- NDH syndrome
- neonatal diabetes and hypothyroidism syndrome
- neonatal diabetes-congenital hypothyroidism-congenital glaucoma-hepatic fibrosis-polycystic kidneys syndrome
- diabetes mellitus, neonatal, with congenital hypothyroidism
- GLIS3-related neonatal diabetes
parents:
- Neonatal Diabetes Mellitus
- Congenital Hypothyroidism
notes: >-
  Common noncoding GLIS3 variants are genome-wide association signals for type 1
  and type 2 diabetes. That susceptibility role is a different relationship from
  the biallelic loss of function curated here and is not modelled as a genetic
  cause of this entry.
inheritance:
- name: Autosomal Recessive
  description: >-
    Affected individuals carry biallelic GLIS3 variants, homozygous in the
    majority, who are mostly offspring of consanguineous unions; compound
    heterozygotes have also been reported. Heterozygous carrier parents are
    usually clinically unaffected, but in one Saudi family every heterozygous
    carrier sibling of two affected children had juvenile hypothyroidism, so a
    milder carrier thyroid phenotype is possible.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:34093443
    reference_title: "Case Report: Neonatal Diabetes Mellitus Caused by a Novel GLIS3 Mutation in Twins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To date, 14 mutations in GLIS3 have been reported, inherited in an autosomal recessive manner."
    explanation: >-
      States the autosomal recessive inheritance of the reported GLIS3 variants.
      The sentence summarises prior reports rather than this study's own twins.
    quote_role: BACKGROUND
  - reference: PMID:35394098
    reference_title: "Case report: Neonatal diabetes mellitus with congenital hypothyroidism as a result of biallelic heterozygous mutations in GLIS3 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Each was inherited from clinically healthy father and mother, respectively."
    explanation: >-
      The two compound heterozygous variants were each inherited from an
      unaffected parent, consistent with recessive inheritance.
  - reference: PMID:40583116
    reference_title: "Congenital glaucoma associated with high hyperopia, an ophthalmic phenotypical manifestation for GLIS3 deletion: case report and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic testing of other siblings showed a heterozygous deletion of the GLIS3 gene. Although their ophthalmic examinations were unremarkable, all carriers presented with juvenile hypothyroidism."
    explanation: >-
      Heterozygous carriers in this family lacked the syndrome but had juvenile
      hypothyroidism, which qualifies the statement that carriers are unaffected.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    About 22 cases from 16 families in 11 countries had been described by 2022.
    No population prevalence estimate exists. In a Chinese screen of 592
    congenital hypothyroidism patients, GLIS3 variants were found in 0.3%, and
    neither carrier had the recessive syndrome.
  evidence:
  - reference: PMID:35394098
    reference_title: "Case report: Neonatal diabetes mellitus with congenital hypothyroidism as a result of biallelic heterozygous mutations in GLIS3 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To date, 22 cases of NDH syndrome from 16 families and 11 countries have been described."
    explanation: Gives the published case count, which is the only frequency measure available.
    quote_role: BACKGROUND
  - reference: PMID:29146476
    reference_title: "Mutation screening of the GLIS3 gene in a cohort of 592 Chinese patients with congenital hypothyroidism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our study indicated that the prevalence of GLIS3 variations was 0.3% among studied Chinese CH patients."
    explanation: >-
      Shows that GLIS3 variants are a rare contributor even within a congenital
      hypothyroidism cohort.
pathophysiology:
- name: Biallelic GLIS3 Loss of Function
  biological_scale: MOLECULAR
  description: >-
    Biallelic GLIS3 variants remove or truncate the transcription factor. The
    original NDH1 frameshift (c.1873dupC) yields a protein that still enters the
    nucleus but has lost its C-terminal transactivation function, while partial
    deletions remove the 5' exons and the major pancreatic and thyroid
    transcripts. Residual expression of shorter tissue-specific transcripts from
    some deletion alleles is the proposed explanation for incomplete phenotypes.
  molecular_functions:
  - preferred_term: GLIS3 sequence-specific DNA-binding transcription factor activity
    term:
      id: GO:0000981
      label: DNA-binding transcription factor activity, RNA polymerase II-specific
    modifier: DECREASED
  genetic_context:
    gene:
      preferred_term: GLIS3
      term:
        id: hgnc:28510
        label: GLIS3
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
  evidence:
  - reference: PMID:16715098
    reference_title: "Mutations in GLIS3 are responsible for a rare syndrome with neonatal diabetes mellitus and congenital hypothyroidism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the original family, we identified a frameshift mutation predicted to result in a truncated protein. In two other families with an incomplete syndrome, we found that affected individuals harbor deletions affecting the 11 or 12 5'-most exons of the gene."
    explanation: >-
      Identifies the truncating and deletion alleles that define the disease
      mechanism as loss of GLIS3.
  - reference: PMID:18263616
    reference_title: "Functional analysis of the zinc finger and activation domains of Glis3 and mutant Glis3(NDH1)."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We demonstrate that this truncation does not effect the nuclear localization but results in the loss of Glis3 transactivating activity."
    explanation: >-
      Shows directly that the patient frameshift abolishes GLIS3 transcriptional
      activation, the molecular function this node marks as decreased.
  - reference: PMID:21139041
    reference_title: "Novel GLIS3 mutations demonstrate an extended multisystem phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our results confirm partial gene deletions as the most common type of GLIS3 mutations, accounting for four of five families identified to date."
    explanation: Establishes gene deletion as the predominant loss-of-function allele class.
  downstream:
  - target: Impaired Endocrine Pancreas Differentiation
    description: >-
      Without GLIS3, neurogenin 3 is not transactivated in the fetal pancreas and
      endocrine lineage specification fails.
  - target: Reduced Insulin Gene Transcription
    description: GLIS3 directly activates the insulin promoter in beta cells.
  - target: Impaired TSH-Dependent Thyroid Hormone Biosynthesis
    description: >-
      GLIS3 is required downstream of TSHR for expression of thyroid hormone
      biosynthesis genes.
  - target: Renal Cystogenesis
    description: Loss of cilium-associated GLIS3 signalling in the kidney leads to cyst formation.
  - target: Abnormal Intrahepatic Bile Duct Development
    description: GLIS3 deficiency disturbs bile duct development in the liver.
  - target: Impaired Pancreatic Ductal and Acinar Function
    description: GLIS3 is also expressed in pancreatic acini and ducts.
  - target: Impaired Ocular Development
    description: Loss of the eye-specific GLIS3 transcript is associated with congenital glaucoma.
  - target: Impaired Osteoblast Differentiation
    description: GLIS3 promotes osteoblast differentiation.
- name: Impaired Endocrine Pancreas Differentiation
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  description: >-
    GLIS3 binds GLIS3 response elements in the Neurog3 promoter and activates it
    directly and together with HNF6 and FOXA2. In Glis3-null mouse embryos Ngn3
    expression falls by more than 90% and insulin is nearly absent, so the fetal
    islet endocrine lineage, beta cells in particular, is not generated. The
    human evidence is genetic and clinical; the step-level mechanism comes from
    mouse and cell models.
  biological_processes:
  - preferred_term: endocrine pancreas development
    term:
      id: GO:0031018
      label: endocrine pancreas development
    modifier: DECREASED
  - preferred_term: type B pancreatic cell differentiation
    term:
      id: GO:0003309
      label: type B pancreatic cell differentiation
    modifier: DECREASED
  cell_types:
  - preferred_term: pancreatic endocrine cell
    term:
      id: CL:0008024
      label: pancreatic endocrine cell
  locations:
  - preferred_term: islet of Langerhans
    term:
      id: UBERON:0000006
      label: islet of Langerhans
  evidence:
  - reference: PMID:21786021
    reference_title: "The Krüppel-like zinc finger protein GLIS3 transactivates neurogenin 3 for proper fetal pancreatic islet differentiation in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In vivo and in vitro analyses placed Glis3 upstream of Neurog3, the endocrine pancreas lineage-defining transcription factor."
    explanation: Places GLIS3 upstream of the endocrine lineage determinant in the fetal pancreas.
  - reference: PMID:21786021
    reference_title: "The Krüppel-like zinc finger protein GLIS3 transactivates neurogenin 3 for proper fetal pancreatic islet differentiation in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "These results indicate that GLIS3 controls fetal islet differentiation via direct transactivation of Neurog3, a perturbation that causes neonatal diabetes in mice."
    explanation: Links loss of Neurog3 transactivation to neonatal diabetes in the knockout.
  - reference: PMID:27813676
    reference_title: "Differential Gene Dosage Effects of Diabetes-Associated Gene GLIS3 in Pancreatic β Cell Differentiation and Function."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In contrast to the >90% reduction of Ngn3 and near-total absence of insulin (Ins) in the embryonic pancreas of Glis3-/- mice"
    explanation: Quantifies the loss of Ngn3 and insulin in the Glis3-null embryonic pancreas.
  - reference: PMID:19481545
    reference_title: "A murine model of neonatal diabetes mellitus in Glis3-deficient mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The high levels of blood sugar are attributed to a decrease in the Insulin mRNA level in the pancreas that is caused by impaired islet development and the subsequent impairment of Insulin-producing cell formation."
    explanation: Independent knockout showing impaired islet development and insulin-producing cell formation.
  downstream:
  - target: Insulin Deficiency
    description: Too few insulin-producing beta cells are formed to sustain insulin output.
- name: Reduced Insulin Gene Transcription
  biological_scale: MOLECULAR
  description: >-
    In differentiated beta cells GLIS3 binds a response element in the insulin
    promoter and cooperates with PDX1, MAFA and NEUROD1 to drive insulin
    transcription; it also directly regulates Mafa and Slc2a2. The NDH1 mutant
    protein cannot activate insulin expression. Pancreas-specific deletion in
    mice leaves PDX1-positive cells that no longer express insulin.
  cell_types:
  - preferred_term: type B pancreatic cell
    term:
      id: CL:0000169
      label: type B pancreatic cell
  evidence:
  - reference: PMID:19264802
    reference_title: "The Krüppel-like zinc finger protein Glis3 directly and indirectly activates insulin gene transcription."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We demonstrate that insulin 2 (Ins2) mRNA expression in rat insulinoma 832/13 cells is markedly increased by wild-type Glis3 overexpression, but not by the NDH1 mutant."
    explanation: >-
      The patient-derived NDH1 mutant fails to activate insulin expression that
      wild-type GLIS3 induces.
  - reference: PMID:19264802
    reference_title: "The Krüppel-like zinc finger protein Glis3 directly and indirectly activates insulin gene transcription."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Glis3 binds to the Ins2 promoter in the cell, detected by chromatin immunoprecipitation."
    explanation: Shows direct GLIS3 occupancy of the insulin promoter.
  - reference: PMID:31340201
    reference_title: "GLIS3 binds pancreatic beta cell regulatory regions alongside other islet transcription factors."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Indeed, presumptive beta cells appeared to persist as PDX1+/INS-/MAFA-/GLUT2- cells."
    explanation: >-
      After pancreas-specific Glis3 deletion, beta cells persist but lose insulin
      expression, isolating the transcriptional role from the developmental one.
  downstream:
  - target: Insulin Deficiency
    description: Remaining beta cells produce too little insulin.
- name: Insulin Deficiency
  biological_scale: ORGANISM
  description: >-
    Endogenous insulin production is absent or severely reduced from birth, with
    low C-peptide. Insulin requirements and sensitivity vary widely between
    patients. Fetal insulin deficiency is also the proposed cause of the
    intrauterine growth restriction seen in most patients.
  cell_types:
  - preferred_term: type B pancreatic cell
    term:
      id: CL:0000169
      label: type B pancreatic cell
  evidence:
  - reference: PMID:36312692
    reference_title: "A Neonate With Diabetes Mellitus, Congenital Hypothyroidism, and Congenital Glaucoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "C-peptide level was 0.2 ng/mL (1.1-4.4 ng/mL) suggestive of exogenous insulin administration and deficiency of endogenous insulin."
    explanation: Low C-peptide documents endogenous insulin deficiency in a GLIS3 patient.
  downstream:
  - target: Neonatal Diabetes Mellitus
    description: Insulin deficiency causes hyperglycaemia from the first days of life.
  - target: Intrauterine Growth Retardation
    description: >-
      Insulin is a major fetal growth factor; its intrauterine deficiency is the
      proposed cause of the growth restriction.
    evidence:
    - reference: PMID:26259131
      reference_title: "Expanding the Clinical Spectrum Associated With GLIS3 Mutations."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "the concomitant presence of IUGR may reflect significant intrauterine insulin deficiency"
      explanation: >-
        The authors attribute the IUGR to fetal insulin deficiency; the claim is
        stated as a possibility, not demonstrated.
- name: Impaired TSH-Dependent Thyroid Hormone Biosynthesis
  biological_scale: CELLULAR
  description: >-
    In the thyroid GLIS3 acts downstream of TSH and TSHR. It binds the promoters
    of iodide transporter genes (Nis/SLC5A5, Pds/SLC26A4) and other thyroid
    hormone biosynthesis genes. The global knockout also loses TSH-driven
    follicular cell proliferation through mTORC1, but a thyroid-specific
    (Pax8-Cre) knockout keeps normal proliferation while biosynthesis genes stay
    suppressed, so the proliferation defect is attributed to GLIS3 loss in other
    cell types and the cell-autonomous thyroid defect is in hormone synthesis.
    Its loss produces a dyshormonogenic
    hypothyroidism in which TSH and thyroglobulin rise. Thyroid anatomy in
    patients ranges from normal to hypoplasia or athyreosis, and a post-mortem
    gland showed sparse colloid with interstitial fibrosis, so a developmental
    contribution is not excluded.
  biological_processes:
  - preferred_term: thyroid hormone generation
    term:
      id: GO:0006590
      label: thyroid hormone generation
    modifier: DECREASED
  cell_types:
  - preferred_term: thyroid follicular cell
    term:
      id: CL:0002258
      label: thyroid follicular cell
  locations:
  - preferred_term: thyroid gland
    term:
      id: UBERON:0002046
      label: thyroid gland
  evidence:
  - reference: PMID:29083325
    reference_title: "GLIS3 is indispensable for TSH/TSHR-dependent thyroid hormone biosynthesis and follicular cell proliferation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "we demonstrate that GLIS3 acts downstream of thyroid-stimulating hormone (TSH) and TSH receptor (TSHR) and is indispensable for TSH/TSHR-mediated proliferation of thyroid follicular cells and biosynthesis of thyroid hormone."
    explanation: Establishes GLIS3 as required for TSH-driven thyroid hormone biosynthesis.
  - reference: PMID:29083325
    reference_title: "GLIS3 is indispensable for TSH/TSHR-dependent thyroid hormone biosynthesis and follicular cell proliferation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "GLIS3 is critical for the transcriptional activation of several genes required for thyroid hormone biosynthesis, including the iodide transporters Nis and Pds, both of which showed enhanced GLIS3 binding at their promoters."
    explanation: Names the direct transcriptional targets through which biosynthesis fails.
  - reference: PMID:37461635
    reference_title: "Role of GLIS3 in thyroid development and in the regulation of gene expression in thyroid specific Glis3KO mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We further show that Glis3KO mice do not display any major changes in prenatal thyroid gland morphology indicating that CH in Glis3KO mice is due to dyshormonogenesis rather than thyroid dysgenesis."
    explanation: >-
      Places the mouse hypothyroidism in hormone synthesis rather than gland
      formation, which is why this node is a biosynthesis defect.
  - reference: PMID:37461635
    reference_title: "Role of GLIS3 in thyroid development and in the regulation of gene expression in thyroid specific Glis3KO mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "However, the expression of several thyroid hormone biosynthesis-, extracellular matrix (ECM)-, and inflammation-related genes was still suppressed in Glis3-Pax8Cre mice"
    explanation: >-
      Deleting Glis3 only in thyroid cells is enough to suppress biosynthesis
      genes, so this defect is intrinsic to the follicular cell.
  - reference: PMID:26259131
    reference_title: "Expanding the Clinical Spectrum Associated With GLIS3 Mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Notably, the postmortem examination of the thyroid gland in patient 6 demonstrated a paucity of colloid as well as extensive perifollicular and interstitial fibrosis, explaining the need for thyroxine despite apparently normal thyroid anatomy on ultrasonography."
    explanation: Human thyroid histology showing failed hormone storage in an anatomically normal gland.
  downstream:
  - target: Congenital Hypothyroidism
    description: Insufficient thyroid hormone synthesis causes hypothyroidism from birth.
  - target: Elevated Circulating TSH
    description: Loss of thyroid hormone feedback raises TSH, which then fails to drive the gland.
  - target: Elevated Circulating Thyroglobulin
    description: >-
      Thyroglobulin is secreted while iodide handling is impaired, so circulating
      thyroglobulin rises.
- name: Renal Cystogenesis
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  description: >-
    GLIS3 localises to the primary cilium and uses WWTR1/TAZ as a transcriptional
    coactivator, placing it in a cilium-associated signalling pathway like its
    paralog GLIS2, whose loss causes nephronophthisis. Glis3 zinc-finger mutant
    mice develop polycystic kidneys, with fewer ciliated cells in the cyst
    lining. Patients show enlarged kidneys with multiple small cysts, cystic
    renal dysplasia and deficient corticomedullary differentiation, usually with
    preserved renal function early on. How ciliary GLIS3 function leads to cysts
    in humans is not established.
  notes: >-
    The primary cilium is bound to GO:0097730 non-motile cilium because
    GO:0072372 primary cilium did not resolve as a live GO class in the
    CellularComponentTerm enum during term validation.
  cellular_components:
  - preferred_term: primary cilium
    term:
      id: GO:0097730
      label: non-motile cilium
  biological_processes:
  - preferred_term: kidney development
    term:
      id: GO:0001822
      label: kidney development
    modifier: DYSREGULATED
  cell_types:
  - preferred_term: kidney epithelial cell
    term:
      id: CL:0002518
      label: kidney epithelial cell
  locations:
  - preferred_term: kidney
    term:
      id: UBERON:0002113
      label: kidney
  evidence:
  - reference: PMID:19273592
    reference_title: "Glis3 is associated with primary cilia and Wwtr1/TAZ and implicated in polycystic kidney disease."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "These mice display abnormalities very similar to those of patients with neonatal diabetes and hypothyroidism syndrome, including the development of diabetes and polycystic kidney disease."
    explanation: Glis3 mutant mice reproduce the polycystic kidney disease of NDH.
  - reference: PMID:19273592
    reference_title: "Glis3 is associated with primary cilia and Wwtr1/TAZ and implicated in polycystic kidney disease."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We demonstrate that Glis3 localizes to the primary cilium, suggesting that Glis3 is part of a cilium-associated signaling pathway."
    explanation: Supports the ciliary localisation that ties GLIS3 to cystic kidney mechanisms.
  - reference: PMID:12966531
    reference_title: "Neonatal diabetes mellitus, congenital hypothyroidism, hepatic fibrosis, polycystic kidneys, and congenital glaucoma: a new autosomal recessive syndrome?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The renal disease was characterized by large kidneys and multiple small cysts with deficient corticomedullary junction differentiation and normal kidney function."
    explanation: Describes the human renal lesion in the index family.
  downstream:
  - target: Cystic Renal Dysplasia
    description: Cyst formation in developing kidneys produces cystic dysplasia.
  - target: Enlarged Kidneys
    description: Multiple cysts enlarge the kidneys.
- name: Abnormal Intrahepatic Bile Duct Development
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  description: >-
    Liver disease in NDH presents as neonatal cholestasis and progresses in some
    patients to hepatic fibrosis and biliary cirrhosis, occasionally requiring
    liver transplantation. Explant histology shows bile duct paucity and a
    predominantly biliary cirrhosis, pointing to abnormal bile duct development
    as the lesion. Shorter GLIS3 transcripts are expressed in the liver, and the
    variable hepatic phenotype has been attributed to differential transcript
    loss. The cellular mechanism has not been worked out.
  biological_processes:
  - preferred_term: intrahepatic bile duct development
    term:
      id: GO:0035622
      label: intrahepatic bile duct development
    modifier: DECREASED
  cell_types:
  - preferred_term: cholangiocyte
    term:
      id: CL:1000488
      label: cholangiocyte
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  evidence:
  - reference: PMID:36917836
    reference_title: "Liver Disease in GLIS3 Mutations: Transplant Considerations and Bile Duct Paucity on Explant Histology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Histology demonstrated predominantly biliary cirrhosis consistent with abnormal bile duct development."
    explanation: Explant histology from two transplanted patients indicates a bile duct developmental lesion.
  - reference: PMID:36917836
    reference_title: "Liver Disease in GLIS3 Mutations: Transplant Considerations and Bile Duct Paucity on Explant Histology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "GLIS3 mutations need to be added to the list of non-syndromic causes of bile duct paucity in the liver."
    explanation: Identifies bile duct paucity as a feature of GLIS3 liver disease.
  downstream:
  - target: Cholestasis
    description: Deficient intrahepatic bile ducts impair bile flow.
  - target: Reduced Number of Intrahepatic Bile Ducts
    description: The developmental lesion is seen histologically as duct paucity.
  - target: Hepatic Fibrosis
    description: Chronic cholestatic injury progresses to fibrosis and biliary cirrhosis.
- name: Impaired Pancreatic Ductal and Acinar Function
  biological_scale: TISSUE
  mechanism_confidence: HYPOTHETICAL
  description: >-
    GLIS3 is expressed at lower levels in pancreatic acini and in ductal cells as
    well as in beta cells. Some patients have exocrine pancreatic insufficiency
    with low faecal elastase and pancreatic cysts, which the case-series authors
    attribute to a role of GLIS3 in pancreatic duct development and
    maintenance. This is an inference from expression and phenotype, not a
    demonstrated mechanism.
  locations:
  - preferred_term: pancreas
    term:
      id: UBERON:0001264
      label: pancreas
  evidence:
  - reference: PMID:26259131
    reference_title: "Expanding the Clinical Spectrum Associated With GLIS3 Mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The presence of exocrine pancreatic dysfunction in patients 2, 3a, 3b, and 7 in our series suggests that exocrine pancreatic involvement may be more extensive than previously described (8)."
    explanation: >-
      Documents exocrine involvement in patients and proposes it as a primary
      GLIS3 effect rather than a secondary one.
  - reference: PMID:26259131
    reference_title: "Expanding the Clinical Spectrum Associated With GLIS3 Mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The presence of pancreatic cystic changes in patients 3a and 3b supports the previous observations that GLIS3 is important in the development and maintenance of pancreatic ducts (15)."
    explanation: Links the pancreatic cysts seen in patients to a ductal role of GLIS3.
  downstream:
  - target: Exocrine Pancreatic Insufficiency
    description: Reduced acinar enzyme output causes malabsorption.
  - target: Pancreatic Cysts
    description: Abnormal ductal development produces pancreatic cysts.
- name: Impaired Ocular Development
  biological_scale: TISSUE
  mechanism_confidence: HYPOTHETICAL
  description: >-
    Congenital glaucoma occurs in roughly a third of patients. The original
    genotype-phenotype analysis linked glaucoma to loss of an eye-specific GLIS3
    transcript, and Glis3 is expressed dynamically in the developing optic
    vesicle, lens and retina in mice, but later series could not tie glaucoma to
    a specific exon. The developmental defect behind the glaucoma is not
    characterised.
  locations:
  - preferred_term: eye
    term:
      id: UBERON:0000970
      label: eye
  evidence:
  - reference: PMID:16715098
    reference_title: "Mutations in GLIS3 are responsible for a rare syndrome with neonatal diabetes mellitus and congenital hypothyroidism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The absence of a major transcript in the pancreas and thyroid (deletions from both families) and an eye-specific transcript (deletion from one family), together with residual expression of some GLIS3 transcripts, seems to explain the incomplete clinical manifestations in these individuals."
    explanation: Associates loss of an eye-specific GLIS3 transcript with the ocular phenotype.
  - reference: PMID:26259131
    reference_title: "Expanding the Clinical Spectrum Associated With GLIS3 Mutations."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "However, from our cohort we were unable to ascribe a specific exon relating to the eye disease."
    explanation: >-
      A later 12-patient series could not reproduce an exon-specific link for the
      eye disease, which weakens the transcript-specific explanation.
  downstream:
  - target: Congenital Glaucoma
    description: Abnormal anterior segment development raises intraocular pressure from infancy.
  - target: High Hypermetropia
    description: >-
      A short axial length of the globe produces high hyperopia, reported with
      congenital glaucoma in GLIS3 siblings.
- name: Impaired Osteoblast Differentiation
  biological_scale: CELLULAR
  mechanism_confidence: HYPOTHETICAL
  description: >-
    GLIS3 is highly expressed in human osteoblasts and promotes osteoblast
    differentiation in part by inducing FGF18. Patients show osteopenia, poorly
    healing rib fractures with persistent callus and scoliosis, which the
    clinical authors interpret as a bone remodelling defect. The link between
    the in vitro osteoblast data and the human skeletal phenotype is inferred.
  biological_processes:
  - preferred_term: osteoblast differentiation
    term:
      id: GO:0001649
      label: osteoblast differentiation
    modifier: DECREASED
  evidence:
  - reference: PMID:17488195
    reference_title: "Krüppel-like zinc finger protein Glis3 promotes osteoblast differentiation by regulating FGF18 expression."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The zinc finger protein Glis3 is highly expressed in human osteoblasts and acts synergistically with BMP2 and Shh in enhancing osteoblast differentiation in multipotent C3H10T1/2 cells."
    explanation: Establishes a pro-osteoblastic function of GLIS3 in cell culture.
  - reference: PMID:26259131
    reference_title: "Expanding the Clinical Spectrum Associated With GLIS3 Mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The persistence of callus formation suggests a defect in bone remodeling either due to dysfunctional osteoblast signaling to osteoclasts or reduced osteoclastic bone reabsorption."
    explanation: The clinical authors' interpretation of the skeletal phenotype as a remodelling defect.
  downstream:
  - target: Osteopenia
    description: Deficient bone formation and remodelling reduce bone mineral density.
phenotypes:
- category: Endocrine
  name: Neonatal Diabetes Mellitus
  description: >-
    Permanent, non-autoimmune, insulin-requiring diabetes diagnosed between birth
    and about three weeks of age. It is the only feature present in every
    reported patient.
  frequency: OBLIGATE
  phenotype_term:
    preferred_term: Permanent neonatal diabetes mellitus
    term:
      id: HP:0000857
      label: Neonatal insulin-dependent diabetes mellitus
  evidence:
  - reference: PMID:26259131
    reference_title: "Expanding the Clinical Spectrum Associated With GLIS3 Mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PND was the only consistent feature of all of our patients with GLIS3 mutations. Age at diagnosis ranged from birth to 23 days. All patients were insulin treated."
    explanation: Neonatal diabetes present in 12 of 12 patients, with onset in the first weeks.
  - reference: PMID:12966531
    reference_title: "Neonatal diabetes mellitus, congenital hypothyroidism, hepatic fibrosis, polycystic kidneys, and congenital glaucoma: a new autosomal recessive syndrome?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report on two sibs (of 4) with a syndrome of minor facial anomalies, proportionate IUGR, neonatal non-autoimmune diabetes mellitus (NDM), severe congenital hypothyroidism (CH), cholestasis, congenital glaucoma, and polycystic kidneys."
    explanation: The index description establishing non-autoimmune neonatal diabetes as part of the syndrome.
- category: Endocrine
  name: Congenital Hypothyroidism
  description: >-
    Present from the first week of life in nearly all patients. Thyroid anatomy
    ranges from normal to hypoplasia or athyreosis, and in several patients TSH
    stays elevated despite normalised free T4 on levothyroxine.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Congenital hypothyroidism
    term:
      id: HP:0000851
      label: Congenital hypothyroidism
  evidence:
  - reference: PMID:26259131
    reference_title: "Expanding the Clinical Spectrum Associated With GLIS3 Mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although congenital hypothyroidism presented during the first week of life in all patients, the patterns of thyroid disease were variable."
    explanation: Congenital hypothyroidism was present in 11 of 12 patients, with variable pattern.
  - reference: PMID:28648506
    reference_title: "The role of GLIS3 in thyroid disease as part of a multisystem disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thyroid findings in GLIS3 patients include thyroid aplasia, diminished colloid with interstitial fibrosis at post-mortem, and apparently normal gross thyroid anatomy on ultrasonography but with temporary TSH resistance on treatment."
    explanation: Review summarising the range of thyroid findings in GLIS3 patients.
    quote_role: REVIEW_SYNTHESIS
- category: Endocrine
  name: Elevated Circulating TSH
  description: >-
    TSH is elevated at diagnosis and in several patients fails to normalise on
    levothyroxine even when free T4 is corrected.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Elevated circulating thyroid-stimulating hormone concentration
    term:
      id: HP:0002925
      label: Elevated circulating thyroid-stimulating hormone concentration
  evidence:
  - reference: PMID:26259131
    reference_title: "Expanding the Clinical Spectrum Associated With GLIS3 Mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Similarly, patients 7 and 11 had very high TSH levels that did not reduce to normal limits with levothyroxine therapy despite normalizing of free T4."
    explanation: Documents persistent TSH elevation on treatment.
- category: Endocrine
  name: Elevated Circulating Thyroglobulin
  description: Thyroglobulin is raised despite normal thyroid anatomy in some patients.
  phenotype_term:
    preferred_term: Elevated circulating thyroglobulin concentration
    term:
      id: HP:0025484
      label: Elevated circulating thyroglobulin concentration
  evidence:
  - reference: PMID:21139041
    reference_title: "Novel GLIS3 mutations demonstrate an extended multisystem phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both patients presented with neonatal diabetes mellitus, severe resistant hypothyroidism in the presence of elevated thyroglobulin and normal thyroid anatomy, degenerative liver disease, cystic renal dysplasia, recurrent infections and facial dysmorphism."
    explanation: Reports elevated thyroglobulin with a normal gland in two patients.
- category: Growth
  name: Intrauterine Growth Retardation
  description: Proportionate intrauterine growth restriction with low birth weight is common.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Intrauterine growth retardation
    term:
      id: HP:0001511
      label: Intrauterine growth retardation
  evidence:
  - reference: PMID:26259131
    reference_title: "Expanding the Clinical Spectrum Associated With GLIS3 Mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Developmental delay and IUGR were common features in our patient cohort."
    explanation: IUGR was common in the 12-patient series.
- category: Renal
  name: Cystic Renal Dysplasia
  description: >-
    Renal cystic disease ranging from an isolated cyst to extensive bilateral
    cystic dysplasia, the commonest renal manifestation. Nine of twelve patients
    in one series had anatomical kidney changes.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Cystic renal dysplasia
    term:
      id: HP:0000800
      label: Cystic renal dysplasia
  evidence:
  - reference: PMID:26259131
    reference_title: "Expanding the Clinical Spectrum Associated With GLIS3 Mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nine patients have anatomical kidney changes. Of these, 7 children showed variable renal cystic dysplasia ranging from an isolated cyst observed in patient 10 and bilateral calyceal calcification in patient 11 to extensive cystic renal dysplasia (patients 2, 3a, 3b, 4, and 9) (Figure 2)."
    explanation: Gives the frequency and range of renal cystic disease.
- category: Renal
  name: Enlarged Kidneys
  description: Large kidneys with multiple small cysts, described in the index family.
  phenotype_term:
    preferred_term: Enlarged kidney
    term:
      id: HP:0000105
      label: Enlarged kidney
  evidence:
  - reference: PMID:12966531
    reference_title: "Neonatal diabetes mellitus, congenital hypothyroidism, hepatic fibrosis, polycystic kidneys, and congenital glaucoma: a new autosomal recessive syndrome?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The renal disease was characterized by large kidneys and multiple small cysts with deficient corticomedullary junction differentiation and normal kidney function."
    explanation: Describes enlarged cystic kidneys in the index siblings.
- category: Hepatic
  name: Cholestasis
  description: Neonatal cholestasis is the usual first manifestation of liver disease.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Cholestasis
    term:
      id: HP:0001396
      label: Cholestasis
  evidence:
  - reference: PMID:12966531
    reference_title: "Neonatal diabetes mellitus, congenital hypothyroidism, hepatic fibrosis, polycystic kidneys, and congenital glaucoma: a new autosomal recessive syndrome?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report on two sibs (of 4) with a syndrome of minor facial anomalies, proportionate IUGR, neonatal non-autoimmune diabetes mellitus (NDM), severe congenital hypothyroidism (CH), cholestasis, congenital glaucoma, and polycystic kidneys."
    explanation: Cholestasis was present in both index siblings.
  - reference: PMID:26259131
    reference_title: "Expanding the Clinical Spectrum Associated With GLIS3 Mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Liver disease was documented in 7 of our 12 patients."
    explanation: Gives the frequency of liver involvement in the largest series.
- category: Hepatic
  name: Hepatic Fibrosis
  description: >-
    Liver disease progresses to hepatic fibrosis and cirrhosis in some patients;
    one patient died of liver failure with portal hypertension and variceal
    bleeding.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hepatic fibrosis
    term:
      id: HP:0001395
      label: Hepatic fibrosis
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:12966531
    reference_title: "Neonatal diabetes mellitus, congenital hypothyroidism, hepatic fibrosis, polycystic kidneys, and congenital glaucoma: a new autosomal recessive syndrome?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Liver disease progressed to hepatic fibrosis."
    explanation: Progression to fibrosis in the index family.
  - reference: PMID:26259131
    reference_title: "Expanding the Clinical Spectrum Associated With GLIS3 Mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The hepatic dysfunction presented concomitantly with renal abnormalities and ranged from hepatitis (patients 3b and 4) to hepatic fibrosis and cirrhosis (patients 2, 3a, 6, 7, 9, and 10)."
    explanation: Six of twelve patients had hepatic fibrosis or cirrhosis.
- category: Hepatic
  name: Reduced Number of Intrahepatic Bile Ducts
  description: Bile duct paucity on explant histology in patients transplanted for GLIS3 liver disease.
  phenotype_term:
    preferred_term: Bile duct paucity
    term:
      id: HP:0006571
      label: Reduced number of intrahepatic bile ducts
  evidence:
  - reference: PMID:36917836
    reference_title: "Liver Disease in GLIS3 Mutations: Transplant Considerations and Bile Duct Paucity on Explant Histology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "GLIS3 mutations need to be added to the list of non-syndromic causes of bile duct paucity in the liver."
    explanation: Identifies bile duct paucity in GLIS3 liver disease.
- category: Ophthalmological
  name: Congenital Glaucoma
  description: >-
    Congenital glaucoma with raised intraocular pressure and corneal clouding,
    present in about a third of patients and sometimes requiring trabeculotomy.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Congenital glaucoma
    term:
      id: HP:0001087
      label: Developmental glaucoma
  evidence:
  - reference: PMID:26259131
    reference_title: "Expanding the Clinical Spectrum Associated With GLIS3 Mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Only 4 of 12 of our patients had congenital glaucoma"
    explanation: Gives the frequency of congenital glaucoma in the largest series.
  - reference: PMID:36312692
    reference_title: "A Neonate With Diabetes Mellitus, Congenital Hypothyroidism, and Congenital Glaucoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ophthalmological assessment showed bilateral corneal clouding with raised intraocular pressure."
    explanation: Describes the ocular findings in a GLIS3 neonate.
- category: Ophthalmological
  name: High Hypermetropia
  description: >-
    High hyperopia with short axial length of the globe accompanying congenital
    glaucoma, reported in two siblings with a GLIS3 exon 1-2 deletion. Congenital
    glaucoma is otherwise usually associated with myopia, so this combination may
    be characteristic, but it rests on a single family.
  phenotype_term:
    preferred_term: High hyperopia
    term:
      id: HP:0008499
      label: High hypermetropia
  evidence:
  - reference: PMID:40583116
    reference_title: "Congenital glaucoma associated with high hyperopia, an ophthalmic phenotypical manifestation for GLIS3 deletion: case report and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In both patients, ophthalmic assessments revealed congenital glaucoma, high hyperopia, and short axial length of the globe."
    explanation: Reports high hyperopia with congenital glaucoma in two affected siblings.
- category: Gastrointestinal
  name: Exocrine Pancreatic Insufficiency
  description: Malabsorption with low faecal elastase, treated with pancreatic enzymes.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Exocrine pancreatic insufficiency
    term:
      id: HP:0001738
      label: Exocrine pancreatic insufficiency
  evidence:
  - reference: PMID:26259131
    reference_title: "Expanding the Clinical Spectrum Associated With GLIS3 Mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Malabsorption due to exocrine pancreatic insufficiency as demonstrated by low fecal elastase was a feature in patients 2, 3a, 3b, and 7 in our case series."
    explanation: Four of twelve patients had exocrine insufficiency.
- category: Gastrointestinal
  name: Pancreatic Cysts
  description: Pancreatic cysts reported in two siblings.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Pancreatic cysts
    term:
      id: HP:0001737
      label: Pancreatic cysts
  evidence:
  - reference: PMID:26259131
    reference_title: "Expanding the Clinical Spectrum Associated With GLIS3 Mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The presence of pancreatic cystic changes in patients 3a and 3b supports the previous observations that GLIS3 is important in the development and maintenance of pancreatic ducts (15)."
    explanation: Records pancreatic cysts in two of twelve patients.
- category: Skeletal
  name: Osteopenia
  description: >-
    Osteopenia, sometimes with multiple rib fractures, delayed fracture healing
    and scoliosis.
  phenotype_term:
    preferred_term: Osteopenia
    term:
      id: HP:0000938
      label: Osteopenia
  evidence:
  - reference: PMID:21139041
    reference_title: "Novel GLIS3 mutations demonstrate an extended multisystem phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These novel mutations have also resulted in osteopenia, bilateral sensorineural deafness and pancreatic exocrine insufficiency, features that have not previously been associated with GLIS3 mutations."
    explanation: First report of osteopenia in GLIS3 patients.
- category: Otological
  name: Sensorineural Hearing Impairment
  description: Uni- or bilateral sensorineural deafness in a minority of patients.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:21139041
    reference_title: "Novel GLIS3 mutations demonstrate an extended multisystem phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These novel mutations have also resulted in osteopenia, bilateral sensorineural deafness and pancreatic exocrine insufficiency, features that have not previously been associated with GLIS3 mutations."
    explanation: Reports sensorineural deafness in GLIS3 patients.
- category: Neurological
  name: Global Developmental Delay
  description: Developmental delay is common; its relation to hypothyroidism or other factors is not resolved.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:26259131
    reference_title: "Expanding the Clinical Spectrum Associated With GLIS3 Mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Developmental delay and IUGR were common features in our patient cohort."
    explanation: Developmental delay was common in the 12-patient series.
- category: Craniofacial
  name: Depressed Nasal Bridge
  description: Part of a recognisable facial gestalt that evolves with age.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Depressed nasal bridge
    term:
      id: HP:0005280
      label: Depressed nasal bridge
  evidence:
  - reference: PMID:27148679
    reference_title: "An emerging, recognizable facial phenotype in association with mutations in GLI-similar 3 (GLIS3)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we describe the common facial dysmorphism consisting of bilateral low-set ears, depressed nasal bridge with overhanging columella, elongated, upslanted palpebral fissures, persistent long philtrum with a thin vermilion border of the upper lip in a cohort of seven patients with GLIS3 mutations"
    explanation: Names the depressed nasal bridge as part of the shared facial phenotype.
  - reference: PMID:26259131
    reference_title: "Expanding the Clinical Spectrum Associated With GLIS3 Mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In our cohort, dysmorphic features were seen in 9 of the 12 patients."
    explanation: Frequency of facial dysmorphism in the largest series.
- category: Craniofacial
  name: Low-Set Ears
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Low-set ears
    term:
      id: HP:0000369
      label: Low-set ears
  evidence:
  - reference: PMID:27148679
    reference_title: "An emerging, recognizable facial phenotype in association with mutations in GLI-similar 3 (GLIS3)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we describe the common facial dysmorphism consisting of bilateral low-set ears, depressed nasal bridge with overhanging columella, elongated, upslanted palpebral fissures, persistent long philtrum with a thin vermilion border of the upper lip in a cohort of seven patients with GLIS3 mutations"
    explanation: Names bilateral low-set ears as part of the shared facial phenotype.
- category: Craniofacial
  name: Upslanted Palpebral Fissures
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Upslanted palpebral fissure
    term:
      id: HP:0000582
      label: Upslanted palpebral fissure
  evidence:
  - reference: PMID:27148679
    reference_title: "An emerging, recognizable facial phenotype in association with mutations in GLI-similar 3 (GLIS3)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we describe the common facial dysmorphism consisting of bilateral low-set ears, depressed nasal bridge with overhanging columella, elongated, upslanted palpebral fissures, persistent long philtrum with a thin vermilion border of the upper lip in a cohort of seven patients with GLIS3 mutations"
    explanation: Names elongated, upslanted palpebral fissures as part of the shared facial phenotype.
- category: Craniofacial
  name: Long Philtrum
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Long philtrum
    term:
      id: HP:0000343
      label: Long philtrum
  evidence:
  - reference: PMID:27148679
    reference_title: "An emerging, recognizable facial phenotype in association with mutations in GLI-similar 3 (GLIS3)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we describe the common facial dysmorphism consisting of bilateral low-set ears, depressed nasal bridge with overhanging columella, elongated, upslanted palpebral fissures, persistent long philtrum with a thin vermilion border of the upper lip in a cohort of seven patients with GLIS3 mutations"
    explanation: Names a persistent long philtrum as part of the shared facial phenotype.
- category: Skeletal
  name: Craniosynostosis
  description: Single-patient finding first reported in the 12-patient Dimitri 2015 series.
  frequency: VERY_RARE
  phenotype_term:
    preferred_term: Craniosynostosis
    term:
      id: HP:0001363
      label: Craniosynostosis
  evidence:
  - reference: PMID:26259131
    reference_title: "Expanding the Clinical Spectrum Associated With GLIS3 Mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe new presenting features in patients with GLIS3 mutations, including craniosynostosis, hiatus hernia, atrial septal defect, splenic cyst, and choanal atresia"
    explanation: Lists craniosynostosis among newly described rare features in GLIS3 patients.
- category: Gastrointestinal
  name: Hiatus Hernia
  description: Single-patient finding first reported in the 12-patient Dimitri 2015 series.
  frequency: VERY_RARE
  phenotype_term:
    preferred_term: Hiatus hernia
    term:
      id: HP:0002036
      label: Hiatus hernia
  evidence:
  - reference: PMID:26259131
    reference_title: "Expanding the Clinical Spectrum Associated With GLIS3 Mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe new presenting features in patients with GLIS3 mutations, including craniosynostosis, hiatus hernia, atrial septal defect, splenic cyst, and choanal atresia"
    explanation: Lists hiatus hernia among newly described rare features in GLIS3 patients.
- category: Cardiovascular
  name: Atrial Septal Defect
  description: Single-patient finding first reported in the 12-patient Dimitri 2015 series.
  frequency: VERY_RARE
  phenotype_term:
    preferred_term: Atrial septal defect
    term:
      id: HP:0001631
      label: Atrial septal defect
  evidence:
  - reference: PMID:26259131
    reference_title: "Expanding the Clinical Spectrum Associated With GLIS3 Mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe new presenting features in patients with GLIS3 mutations, including craniosynostosis, hiatus hernia, atrial septal defect, splenic cyst, and choanal atresia"
    explanation: Lists atrial septal defect among newly described rare features in GLIS3 patients.
- category: Respiratory
  name: Choanal Atresia
  description: Single-patient finding first reported in the 12-patient Dimitri 2015 series.
  frequency: VERY_RARE
  phenotype_term:
    preferred_term: Choanal atresia
    term:
      id: HP:0000453
      label: Choanal atresia
  evidence:
  - reference: PMID:26259131
    reference_title: "Expanding the Clinical Spectrum Associated With GLIS3 Mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe new presenting features in patients with GLIS3 mutations, including craniosynostosis, hiatus hernia, atrial septal defect, splenic cyst, and choanal atresia"
    explanation: Lists choanal atresia among newly described rare features in GLIS3 patients.
biochemical:
- name: Serum TSH and thyroglobulin
  presence: INCREASED
  notes: >-
    Serum T4 and T3 are low while TSH and thyroglobulin are raised, the pattern
    of a dyshormonogenic rather than purely agenetic hypothyroidism.
  evidence:
  - reference: PMID:25133201
    reference_title: "TRANSCRIPTION FACTOR GLI-SIMILAR 3 (GLIS3): IMPLICATIONS FOR THE DEVELOPMENT OF CONGENITAL HYPOTHYROIDISM."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with GLIS3-mediated CH exhibit diminished serum levels of thyroxine (T4) and triiodothyronine (T3) and elevated thyroid stimulating hormone (TSH) and thyroglobulin (TG)."
    explanation: Review summarising the biochemical thyroid profile of GLIS3 patients.
    quote_role: REVIEW_SYNTHESIS
- name: Serum C-peptide
  presence: DECREASED
  notes: Low C-peptide confirms deficient endogenous insulin secretion.
  evidence:
  - reference: PMID:36312692
    reference_title: "A Neonate With Diabetes Mellitus, Congenital Hypothyroidism, and Congenital Glaucoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "C-peptide level was 0.2 ng/mL (1.1-4.4 ng/mL) suggestive of exogenous insulin administration and deficiency of endogenous insulin."
    explanation: Reports low C-peptide in a GLIS3 neonate.
genetic:
- name: GLIS3
  gene_term:
    preferred_term: GLIS3
    term:
      id: hgnc:28510
      label: GLIS3
  relationship_type: CAUSATIVE
  notes: >-
    Biallelic variants: partial or whole-exon deletions (most frequent),
    frameshift (c.1873dupC in the index family), nonsense (p.Gln798Ter) and
    missense variants in the zinc-finger DNA-binding domain (p.Cys536Trp,
    p.His561Tyr, p.Arg589Trp, p.His647Arg). Some deletions also remove the
    neighbouring SLC1A1 gene. Common GLIS3 variants associated with type 1 and
    type 2 diabetes in GWAS are susceptibility alleles and are not part of this
    Mendelian entry.
  evidence:
  - reference: PMID:16715098
    reference_title: "Mutations in GLIS3 are responsible for a rare syndrome with neonatal diabetes mellitus and congenital hypothyroidism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we show that this syndrome results from mutations in GLIS3, encoding GLI similar 3, a recently identified transcription factor."
    explanation: The original identification of GLIS3 as the causal gene.
  - reference: PMID:26259131
    reference_title: "Expanding the Clinical Spectrum Associated With GLIS3 Mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients 1, 5, and 10 harbor missense mutations (p.Arg589Trp, p.Cys536Trp, and p.His561Tyr, respectively), affecting highly conserved amino acids located in the DNA binding domain and so are likely to be pathogenic, thus severely affecting the function of the GLIS3 protein."
    explanation: Adds zinc-finger missense variants to the allelic spectrum.
treatments:
- name: Insulin Therapy
  description: >-
    Lifelong insulin from diagnosis, often by continuous subcutaneous infusion
    with glucose monitoring. Insulin sensitivity varies widely, from recurrent
    hypoglycaemia on very small doses to insulin resistance during illness, so
    control is often labile. The diabetes is a beta-cell developmental
    deficiency rather than a KATP-channel defect, so molecular diagnosis matters:
    it distinguishes insulin-dependent forms like this one from the
    sulfonylurea-responsive KCNJ11/ABCC8 channel forms.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: insulin
      term:
        id: CHEBI:145810
        label: insulin
  target_mechanisms:
  - target: Insulin Deficiency
    treatment_effect: RESTORES
    description: Exogenous insulin replaces the hormone that the patient cannot produce.
  evidence:
  - reference: PMID:34093443
    reference_title: "Case Report: Neonatal Diabetes Mellitus Caused by a Novel GLIS3 Mutation in Twins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A rapid molecular diagnosis of NDM is recommended as the specific etiology assists in clinical management (insulin vs. sulfonylurea)"
    explanation: >-
      Supports that molecular diagnosis directs the insulin-versus-sulfonylurea
      management choice; GLIS3 disease is the insulin-dependent side.
  - reference: PMID:26259131
    reference_title: "Expanding the Clinical Spectrum Associated With GLIS3 Mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients were initially treated with insulin at 0.4 to 2.0 U/kg/24 h (patient 4 required 2.0 U/kg/24 h), demonstrating a range of insulin sensitivities."
    explanation: All patients in the series were insulin treated, with widely varying doses.
  - reference: PMID:34093443
    reference_title: "Case Report: Neonatal Diabetes Mellitus Caused by a Novel GLIS3 Mutation in Twins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diabetes was treated with a continuous subcutaneous insulin infusion pump and continuous glucose monitoring."
    explanation: Pump delivery with continuous glucose monitoring in GLIS3 twins.
- name: Levothyroxine Replacement
  description: >-
    Levothyroxine from diagnosis. High starting doses may be needed, and TSH may
    remain elevated despite normalised free T4, so dosing is guided by free T4.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: levothyroxine
      term:
        id: CHEBI:6446
        label: levothyroxine sodium anhydrous
  target_mechanisms:
  - target: Impaired TSH-Dependent Thyroid Hormone Biosynthesis
    treatment_effect: BYPASSES
    description: Exogenous thyroxine replaces the hormone the gland cannot synthesise.
  evidence:
  - reference: PMID:26259131
    reference_title: "Expanding the Clinical Spectrum Associated With GLIS3 Mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In contrast, patient 4 presented with congenital hypothyroidism due to athyreosis and responded to levothyroxine at a starting dose of 28 μg/kg/d."
    explanation: Levothyroxine treatment and response in a GLIS3 patient.
  - reference: PMID:26259131
    reference_title: "Expanding the Clinical Spectrum Associated With GLIS3 Mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients 2, 3a, and 3b had elevated TSH levels that were resistant to treatment with thyroxine as described previously (11)."
    explanation: Records the TSH resistance that complicates dosing.
- name: Pancreatic Enzyme Replacement
  description: >-
    Pancreatic enzyme supplementation for exocrine insufficiency, with
    fat-soluble vitamin supplementation. One report suggests correcting partial
    exocrine insufficiency improved cholestasis and TSH resistance, although
    causality was not shown.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: pancrelipase
      term:
        id: CHEBI:753090
        label: pancrelipase
  target_mechanisms:
  - target: Exocrine Pancreatic Insufficiency
    treatment_effect: BYPASSES
    description: Supplies the digestive enzymes the exocrine pancreas does not secrete.
  evidence:
  - reference: PMID:26259131
    reference_title: "Expanding the Clinical Spectrum Associated With GLIS3 Mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These 4 patients have been treated with pancreatic enzyme supplementation."
    explanation: Enzyme supplementation used for exocrine insufficiency in the series.
  - reference: PMID:33935973
    reference_title: "Case Report: Extended Clinical Spectrum of the Neonatal Diabetes With Congenital Hypothyroidism Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Compensation of partial exocrine pancreatic insufficiency and deficiencies in antioxidative vitamins seemed to have exerted marked beneficial impact on several disease symptoms including cholestasis and TSH resistance, although a causal relation is difficult to prove."
    explanation: A single-patient observation of benefit, explicitly without proven causality.
- name: Liver Transplantation
  description: >-
    For life-limiting liver disease. Multi-organ transplantation has been
    considered; postoperative care is complicated by infection, renal disease and
    brittle diabetes.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Liver transplantation
    term:
      id: NCIT:C15271
      label: Liver Transplantation
  target_mechanisms:
  - target: Hepatic Fibrosis
    treatment_effect: BYPASSES
    description: Replaces the fibrotic liver.
  evidence:
  - reference: PMID:36917836
    reference_title: "Liver Disease in GLIS3 Mutations: Transplant Considerations and Bile Duct Paucity on Explant Histology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Liver transplantation should be considered in patients with life-limiting complications related to liver disease."
    explanation: Recommendation from two transplanted GLIS3 patients.
- name: Glaucoma Surgery
  description: >-
    Topical pressure-lowering drops followed by trabeculotomy for congenital
    glaucoma.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: trabeculotomy
    term:
      id: NCIT:C15331
      label: Ophthalmologic Surgical Procedure
  target_mechanisms:
  - target: Congenital Glaucoma
    treatment_effect: BYPASSES
    description: Surgical opening of aqueous outflow lowers intraocular pressure.
  evidence:
  - reference: PMID:36312692
    reference_title: "A Neonate With Diabetes Mellitus, Congenital Hypothyroidism, and Congenital Glaucoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatment with timolol and latanoprost eye drops was started for congenital glaucoma (CG). Later, she underwent trabeculotomy in both eyes."
    explanation: Medical then surgical management of congenital glaucoma in a GLIS3 neonate.
diagnosis:
- name: Molecular genetic testing of GLIS3
  diagnosis_term:
    preferred_term: GLIS3 sequencing and copy-number analysis
    term:
      id: NCIT:C15709
      label: Genetic Testing
  description: >-
    Suspected in any infant with neonatal diabetes and congenital hypothyroidism,
    including from non-consanguineous families. Because partial deletions are the
    commonest variant class, copy-number analysis or chromosomal microarray is
    needed in addition to sequencing.
  evidence:
  - reference: PMID:21139041
    reference_title: "Novel GLIS3 mutations demonstrate an extended multisystem phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We also report the first case of a recessive GLIS3 mutation causing neonatal diabetes and congenital hypothyroidism in a child from a non-consanguineous pedigree, highlighting the importance of molecular genetic testing in any patient with this phenotype."
    explanation: Recommends genetic testing for every patient with the phenotype.
experimental_models:
- experimental_model_type: OTHER
  name: GLIS3-null human embryonic stem cell pancreatic differentiation (HUES8)
  organism:
    preferred_term: Homo sapiens
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_types:
  - preferred_term: human embryonic stem cell
    term:
      id: CL:0002322
      label: embryonic stem cell
  cell_source: HUES8 human embryonic stem cell line, CRISPR/Cas- and TALEN-edited GLIS3 knockout
  culture_system: Directed pancreatic differentiation of gene-edited hESCs to the pancreatic-progenitor and PH-beta stage
  publication: PMID:27133796
  description: >-
    A systematic hESC knockout panel of eight pancreatic transcription factors.
    Unlike PDX1, RFX6 and NGN3 knockouts, the GLIS3-null line showed no overt
    endocrine differentiation defect at the stages assayed, a human-model result
    that does not reproduce the beta-cell deficiency of patients and is read by
    the authors as a possible later-stage or protocol-dependent requirement.
  modeled_mechanisms:
  - target: Impaired Endocrine Pancreas Differentiation
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    model_scale: CELLULAR
    description: >-
      The human GLIS3-null line did not show the endocrine differentiation defect
      that the human disease and the mouse knockouts show, at the differentiation
      stages tested.
    limitations: >-
      Only early-to-mid pancreatic differentiation stages were assayed; the
      protocol generates fetal polyhormonal beta cells, so a later-stage or
      maturation-stage GLIS3 requirement could be missed. This is a single in
      vitro system.
    evidence:
    - reference: PMID:27133796
      reference_title: "Genome Editing of Lineage Determinants in Human Pluripotent Stem Cells Reveals Mechanisms of Pancreatic Development and Diabetes."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "At the PH-β stage, all −/− mutant lines exhibited a defect with the exception of PTF1A−/−, MNX1−/− and GLIS3−/− mutants."
      explanation: The GLIS3 knockout line lacked the differentiation defect seen in other PNDM-gene knockouts.
  evidence:
  - reference: PMID:27133796
    reference_title: "Genome Editing of Lineage Determinants in Human Pluripotent Stem Cells Reveals Mechanisms of Pancreatic Development and Diabetes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "This protocol may allow us to identify later differentiation defects in PTF1A−/−, MNX1−/− and GLIS3−/− mutant lines, which did not exhibit an overt phenotype at early differentiation stages."
    explanation: The authors read the absent early phenotype as a possible later-stage requirement, framing the model's negative result.
animal_models:
- name: Glis3 global knockout mouse
  species: Mouse
  genotype: Glis3 -/- (gene-targeted null)
  publication: PMID:21786021
  description: >-
    Global Glis3-null mice develop severe neonatal diabetes and die within the
    first days to weeks of life, with near-total loss of embryonic Ngn3 and
    insulin expression.
  modeled_mechanisms:
  - target: Impaired Endocrine Pancreas Differentiation
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: TISSUE
    description: Reproduces the failure of fetal islet endocrine differentiation.
    limitations: >-
      Neonatal lethality in the mouse precludes study of the later multisystem
      course seen in surviving patients.
    evidence:
    - reference: PMID:21786021
      reference_title: "The Krüppel-like zinc finger protein GLIS3 transactivates neurogenin 3 for proper fetal pancreatic islet differentiation in mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "These results indicate that GLIS3 controls fetal islet differentiation via direct transactivation of Neurog3, a perturbation that causes neonatal diabetes in mice."
      explanation: Shows the knockout reproduces the developmental mechanism and the diabetes.
  evidence:
  - reference: PMID:19481545
    reference_title: "A murine model of neonatal diabetes mellitus in Glis3-deficient mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The pancreatic phenotypes indicate that the Glis3-deficient mice are a model for GLIS3 mutation and diabetes mellitus in humans."
    explanation: Independent Glis3 knockout validated as a model of the human diabetes.
- name: Glis3 zinc-finger mutant mouse (Glis3 zf/zf)
  species: Mouse
  genotype: Glis3 zf/zf
  publication: PMID:19273592
  description: >-
    Mice carrying a Glis3 zinc-finger mutation develop diabetes and polycystic
    kidney disease resembling the human syndrome.
  modeled_mechanisms:
  - target: Renal Cystogenesis
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: Reproduces the renal cystic disease.
    limitations: >-
      Cyst mechanism in the mouse is linked to ciliary localisation but not
      resolved, and the human lesion is often cystic dysplasia rather than
      classic polycystic kidney disease.
    evidence:
    - reference: PMID:19273592
      reference_title: "Glis3 is associated with primary cilia and Wwtr1/TAZ and implicated in polycystic kidney disease."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Our study demonstrates that dysfunction of Glis3 leads to the development of cystic renal disease, suggesting that Glis3 plays a critical role in maintaining normal renal functions."
      explanation: Mutant mice develop the cystic renal disease.
  evidence:
  - reference: PMID:19273592
    reference_title: "Glis3 is associated with primary cilia and Wwtr1/TAZ and implicated in polycystic kidney disease."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "These mice display abnormalities very similar to those of patients with neonatal diabetes and hypothyroidism syndrome, including the development of diabetes and polycystic kidney disease."
    explanation: States the resemblance to the human syndrome.
- name: GLIS3-deficient mouse thyroid model
  species: Mouse
  genotype: Glis3 deficiency (knockout)
  publication: PMID:29083325
  description: >-
    GLIS3-deficient mice fail to mount TSH-driven thyroid hormone biosynthesis
    and follicular proliferation and do not develop goiter under chronic TSH
    stimulation.
  modeled_mechanisms:
  - target: Impaired TSH-Dependent Thyroid Hormone Biosynthesis
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: CELLULAR
    description: Reproduces the thyroid hormone biosynthesis defect.
    limitations: >-
      Does not explain the athyreosis or hypoplasia seen in some patients, which
      suggests a developmental component the model does not address.
    evidence:
    - reference: PMID:29083325
      reference_title: "GLIS3 is indispensable for TSH/TSHR-dependent thyroid hormone biosynthesis and follicular cell proliferation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Our study identifies GLIS3 as a key regulator of TSH/TSHR-mediated thyroid hormone biosynthesis and proliferation of thyroid follicular cells and uncovers a mechanism by which GLIS3 deficiency causes neonatal hypothyroidism and prevents goiter development."
      explanation: Links the mouse finding to the neonatal hypothyroidism of the human disease.
- name: Thyroid-specific Glis3 knockout mouse (Glis3-Pax8Cre)
  species: Mouse
  genotype: Glis3 floxed; Pax8-Cre (thyroid-specific deletion)
  publication: PMID:37461635
  description: >-
    Deleting Glis3 only in thyroid follicular lineage cells separates the
    cell-autonomous thyroid defect from effects of global GLIS3 loss.
    Biosynthesis genes remain suppressed, while the follicular proliferation
    defect of the global knockout is not reproduced.
  modeled_mechanisms:
  - target: Impaired TSH-Dependent Thyroid Hormone Biosynthesis
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Reproduces suppression of thyroid hormone biosynthesis genes, most clearly
      under high TSH.
    limitations: >-
      Follicular cell proliferation is not repressed in this model, unlike the
      global knockout, so it isolates the biosynthesis arm only. Human thyroid
      hypoplasia or athyreosis is not modelled.
    readouts:
    - name: Thyroid hormone biosynthesis gene expression
      target: Impaired TSH-Dependent Thyroid Hormone Biosynthesis
      direction: DECREASED
      interpretation: Expression readout of the biosynthesis defect in follicular cells.
      evidence:
      - reference: PMID:37461635
        reference_title: "Role of GLIS3 in thyroid development and in the regulation of gene expression in thyroid specific Glis3KO mice."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "However, the expression of several thyroid hormone biosynthesis-, extracellular matrix (ECM)-, and inflammation-related genes was still suppressed in Glis3-Pax8Cre mice"
        explanation: Reports the decreased biosynthesis gene expression in this model.
    evidence:
    - reference: PMID:37461635
      reference_title: "Role of GLIS3 in thyroid development and in the regulation of gene expression in thyroid specific Glis3KO mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "However, the expression of several thyroid hormone biosynthesis-, extracellular matrix (ECM)-, and inflammation-related genes was still suppressed in Glis3-Pax8Cre mice"
      explanation: Supports using this model for the biosynthesis node.
  evidence:
  - reference: PMID:37461635
    reference_title: "Role of GLIS3 in thyroid development and in the regulation of gene expression in thyroid specific Glis3KO mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Loss of GLI-Similar 3 (GLIS3) function in mice and humans causes congenital hypothyroidism (CH)."
    explanation: Frames the mouse work against the human congenital hypothyroidism.
    quote_role: BACKGROUND
📚

References & Deep Research

Deep Research

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Evaluations and curation notes (1)

Create: Neonatal_Diabetes_Mellitus_With_Congenital_Hypothyroidism · 2026-09-24T16:50:37Z · View source

New entry for GLIS3-related neonatal diabetes with congenital hypothyroidism (MONDO:0012436), claim issue #12681. Curated from PubMed primary literature: the 2003 index family (Taha et al.), the 2006 gene discovery (Senee et al.), the Dimitri et al. 2011 and 2015 case series and 2016 facial-phenotype report, later case reports, the liver transplant/bile duct paucity report, and mouse and cell studies of GLIS3 in Neurog3 transactivation, insulin promoter regulation, TSH-dependent thyroid hormone biosynthesis, primary cilium/renal cysts and osteoblast differentiation. Ten pathophysiology nodes, 21 phenotypes (15 causally connected; hearing loss, developmental delay and four facial features left unconnected because no mechanism is sourced), three mouse models. Deep research: an OpenScientist run completed (exit 0), reference validation 25/25 resolved with 25/25 quotes found, term validation needs_review for paraphrased labels only, preflight-dr PASS. Its leads added PMID:37461635 (thyroid-specific Glis3 knockout, dyshormonogenesis rather than dysgenesis) and PMID:40583116 (high hyperopia with congenital glaucoma, and juvenile hypothyroidism in heterozygous carriers), each re-read from the fetched abstract. GLIS3 GWAS susceptibility for type 1 and type 2 diabetes is recorded in notes only. GO:0072372 primary cilium failed the CellularComponentTerm enum, so the node binds GO:0097730 non-motile cilium. No GeneReviews chapter exists (check-genereviews NO_CHAPTER). Validation: validate, validate-terms, count-verified-snippets 77/77, check-entity-refs, check-causal-targets, check-duplicate-keys, check-enum-values, check-coarse-phenotypes, check-snippet-length, check-title-snippets, check-folded-hyphens, check-reference-titles, check-qualifier-terms and validate-disorders all passed.

OpenScientist ▸
Neonatal Diabetes Mellitus With Congenital Hypothyroidism (NDH Syndrome): A Comprehensive Disease Characteristics Report
openscientist-autonomous 25 citations 2026-09-24T16:41:05.271191

Neonatal Diabetes Mellitus With Congenital Hypothyroidism (NDH Syndrome): A Comprehensive Disease Characteristics Report

Disease: Neonatal Diabetes Mellitus With Congenital Hypothyroidism (NDH syndrome) MONDO ID: MONDO:0012436 · OMIM: #610199 · Causal gene: GLIS3 (HGNC:28510; NCBI Gene 169792; UniProt Q8NEA6; 9p24.2) Category: Mendelian (autosomal recessive)

Summary

Neonatal Diabetes Mellitus with Congenital Hypothyroidism (NDH syndrome) is an ultra-rare autosomal-recessive Mendelian disorder caused by biallelic loss-of-function mutations in GLIS3 (GLI-Similar 3), a Krüppel-like C2H2 zinc-finger transcription factor gene on chromosome 9p24.2. First defined molecularly by Senée and colleagues in 2006 (PMID: 16715098), the syndrome couples permanent neonatal diabetes with congenital hypothyroidism as its two defining and near-obligate features, superimposed on a variable multi-organ phenotype that can include congenital glaucoma, hepatic (biliary) fibrosis/cirrhosis, polycystic/cystic kidney disease, sensorineural deafness, and exocrine pancreatic insufficiency.

The unifying mechanism is developmental: GLIS3 is a master transcriptional regulator required simultaneously in several organ programs. In the pancreas it transactivates neurogenin 3 (Neurog3/Ngn3) and binds directly to the regulatory regions of Ins2, Slc2a2 (GLUT2), and Mafa, driving beta-cell specification, insulin production, and beta-cell survival; loss of GLIS3 therefore produces a severe developmental beta-cell deficiency and insulin-dependent diabetes rather than a channelopathy. In the thyroid, GLIS3 is required for follicular-cell maturation and thyroid-gene expression, so its loss produces congenital hypothyroidism (a "gland-in-situ" dyshormonogenesis-type defect rather than athyreosis in most cases). GLIS3 also localizes to the primary cilium and cooperates with the Hippo-pathway coactivator WWTR1/TAZ, explaining the cystic renal, hepatobiliary, and ocular manifestations.

Clinically, the most important consequence for the knowledge base is that GLIS3-NDH belongs to the transcription-factor / beta-cell-development class of neonatal diabetes, which is insulin-dependent and NOT responsive to sulfonylureas — a sharp contrast with KATP-channel (KCNJ11/ABCC8) neonatal diabetes. There is no cure. Management is lifelong, organ-directed supportive care: exogenous insulin, levothyroxine replacement, and treatment of hepatic, renal, and ophthalmic complications, with liver transplantation considered for life-limiting biliary cirrhosis. Prevention rests entirely on genetic counseling and cascade/carrier testing in at-risk (frequently consanguineous) families. This report synthesizes 14 confirmed findings from 32 reviewed papers across all 15 requested disease-characteristic domains. Evidence source types are flagged as [human clinical], [model organism], [in vitro], or [computational].

1. Disease Information

Overview. NDH syndrome is a monogenic (Mendelian) neonatal diabetes syndrome in which insulin-dependent diabetes presenting in the first weeks/months of life co-occurs with congenital hypothyroidism. It is a developmental endocrinopathy: the same transcription factor that fails to build the insulin-secreting beta cells also fails to build/maintain the thyroid follicular apparatus, and additionally disrupts cilium-dependent development of the kidney, biliary tree, and eye.

Key identifiers.

Resource Identifier
OMIM #610199 (Neonatal diabetes mellitus with congenital hypothyroidism)
MONDO MONDO:0012436
Orphanet ORPHA:79369
Gene (HGNC) GLIS3 (HGNC:28510; NCBI Gene 169792; UniProt Q8NEA6), 9p24.2
ICD-10 P70.2 (neonatal diabetes) + E03.1 (congenital hypothyroidism without goitre) as component codes
ICD-11 5A11 (monogenic/neonatal diabetes) with 5A00.1 (congenital hypothyroidism)
MeSH Diabetes Mellitus + Congenital Hypothyroidism (no single dedicated descriptor)

Synonyms / alternative names. NDH syndrome; GLIS3-related neonatal diabetes and congenital hypothyroidism; Neonatal diabetes mellitus with congenital hypothyroidism syndrome; "GLIS3 syndrome."

Source of information. Findings here are derived from aggregated, disease-level resources [human clinical] — primarily published clinical case series (e.g., Dimitri et al., 12 patients, PMID: 26259131), original gene-discovery reports (PMID: 16715098), mechanistic model-organism/cell studies, and consanguineous-cohort monogenic-diabetes registries — not individual EHR extraction.

2. Etiology

Primary cause (genetic). NDH syndrome is caused by biallelic (homozygous or compound heterozygous) loss-of-function mutations in GLIS3 [human clinical] (PMID: 16715098). The original family carried a frameshift mutation predicting a truncated protein; two additional families carried deletions of the 11–12 most 5′ exons. The disorder is autosomal recessive with a loss-of-function mechanism.

"this syndrome results from mutations in GLIS3, encoding GLI similar 3, a recently identified transcription factor. In the original family, we identified a frameshift mutation predicted to result in a truncated protein" — PMID: 16715098

Genetic risk factors. - Causal variants: biallelic GLIS3 frameshift, nonsense, splice, missense, and large multi-exon deletions (see Section 4). - Susceptibility/dosage series: common SNPs at the GLIS3 locus are established GWAS susceptibility loci for both type 1 and type 2 diabetes (PMID: 27813676; PMID: 23197416), and rare monoallelic pathogenic variants increase type 2 diabetes risk (PMID: 38051360). Thus GLIS3 shows an allelic dosage continuum (Finding F011). - Consanguinity is the dominant epidemiological risk amplifier because the disorder is recessive (Section 9).

Environmental risk factors. No specific environmental cause of the Mendelian syndrome is known; it is fully genetically determined. Sex, ethnicity, and non-genetic exposures do not cause NDH. However, in the heterozygous dosage context, gene–environment interaction is demonstrable: Glis3+/− mice on a high-fat diet develop diabetes due to impaired beta-cell-mass expansion, with GLIS3 regulating Ccnd2 (cyclin D2) [model organism] (PMID: 23197416).

Protective factors. No established genetic or environmental protective factors reduce risk of the biallelic Mendelian disease. (Not applicable — the disease is fully penetrant for neonatal diabetes given biallelic LOF.)

Gene–environment interactions. Relevant only to the susceptibility (heterozygous/common-variant) end of the spectrum: diet-induced metabolic demand unmasks beta-cell proliferation deficits via Ccnd2 (PMID: 23197416). For the syndromic biallelic disease, penetrance is essentially complete regardless of environment.

3. Phenotypes

NDH is defined by two obligate/near-obligate features plus a variable multi-organ spectrum. Frequencies below are from Dimitri et al. (n=12, PMID: 26259131) and Senée et al. (PMID: 16715098).

Phenotype Type Onset Frequency Suggested HPO
Permanent neonatal diabetes mellitus Lab/clinical (hyperglycemia, insulin deficiency) Neonatal (first days–weeks) ~100% (defining) HP:0006202 / HP:0000857
Intrauterine growth restriction / low birth weight Physical Congenital Common HP:0001511 (IUGR)
Congenital hypothyroidism Lab/clinical Congenital Highly frequent (one compound-het patient lacked it) HP:0000851
Congenital glaucoma Clinical sign Congenital Frequent HP:0008007
High hyperopia / short axial length Lab/imaging Congenital Reported (distinctive) HP:0000540
Hepatic disease (hepatitis → cirrhosis/fibrosis, bile-duct paucity) Clinical/pathology Infancy Common HP:0001394 / HP:0002908
Cystic renal dysplasia / polycystic kidneys Imaging/clinical Congenital–infancy Common HP:0000107 / HP:0000113
Sensorineural deafness Clinical Congenital/infancy Reported HP:0000407
Exocrine pancreatic insufficiency Lab/clinical Infancy Reported HP:0001738
Craniosynostosis, hiatus hernia, ASD, splenic cyst, choanal atresia Physical/structural Congenital Rare/novel HP:0001363, HP:0002036, HP:0001631, —, HP:0000453

"All patients presented with neonatal diabetes with a range of insulin sensitivities. Thyroid disease varied among patients. Hepatic and renal disease was common with liver dysfunction ranging from hepatitis to cirrhosis; cystic dysplasia was the most common renal manifestation" — PMID: 26259131

"We describe new presenting features in patients with GLIS3 mutations, including craniosynostosis, hiatus hernia, atrial septal defect, splenic cyst, and choanal atresia and confirm further cases with sensorineural deafness and exocrine pancreatic insufficiency" — PMID: 26259131

Severity/progression/QoL. Diabetes is severe and lifelong (insulin-dependent from the neonatal period). Hypothyroidism, if untreated, causes irreversible intellectual disability and short stature; treated early it is manageable. Hepatic and renal disease can be life-limiting and progressive. Overall, affected children carry a high cumulative disease burden across endocrine, hepatic, renal, ophthalmic, and auditory systems, with major QoL impact from insulin dependence, developmental risk, and organ complications.

4. Genetic / Molecular Information

Causal gene. GLIS3 (GLI-similar 3), a C2H2 zinc-finger transcription factor at 9p24.2; disease OMIM #610199. GLIS3 is expressed in the pancreas from early developmental stages, with greater expression in beta cells than other pancreatic tissues (PMID: 16715098). Its DNA-binding domain contains a repeated Cys2/His2 zinc-finger motif (PMID: 28523428).

"GLIS3 is expressed in the pancreas from early developmental stages, with greater expression in beta cells than in other pancreatic tissues" — PMID: 16715098

Pathogenic variant classes (all germline, biallelic for the syndrome): - Frameshift → truncated protein (original Senée family, PMID: 16715098). - Large multi-exon deletions (deletion of the 11–12 most 5′ exons; homozygous deletions including non-coding exon 1 + coding exon 2 in Saudi siblings, PMID: 40583116). - Missense / nonsense / splice-site variants that reduce GLIS3 transactivation of the INS promoter — of 105 rare variants resequenced in 5,471 RaDiO individuals, functional luciferase assays showed 49 variants decreased INS-promoter activation [in vitro/human] (PMID: 38051360). Variants classified per ACMG/AMP (functional assays addressing the PS3 criterion).

Allele frequency & origin. Pathogenic biallelic variants are individually ultra-rare; common tag SNPs at the locus are frequent (population susceptibility variants). All disease variants are germline (no somatic component; this is not a neoplastic disorder).

Functional consequence. Loss of function — reduced/absent GLIS3 transcriptional activity, i.e., failure to transactivate downstream targets. A critical structural determinant is the C-terminal P/LPXY motif recognized by WWTR1/TAZ; mutating this motif abrogates GLIS3 transcriptional activity (PMID: 19273592).

Dosage/allelic series (Finding F011).

"Rare pathogenic, bi-allelic mutations in GLIS3 cause syndromic neonatal diabetes whereas frequent SNPs at this locus associate with common type 2 diabetes risk" — PMID: 38051360

GLIS3 genotype Phenotype
Biallelic LOF Syndromic permanent neonatal diabetes + congenital hypothyroidism (NDH)
Monoallelic pathogenic Increased type 2 diabetes risk; subgroup sulfonylurea-sensitive (PMID: 38051360)
Common SNPs GWAS susceptibility for type 1 and type 2 diabetes (PMID: 27813676)

Modifier genes / epigenetics / chromosomal abnormalities. No specific modifier genes are established for NDH. Oligogenic contribution and epigenetic/penetrance factors have been raised generally in congenital-hypothyroidism cohorts that include GLIS3 (PMID: 36125728) but are not proven modifiers of GLIS3-NDH. The relevant "chromosomal" lesions are the large 9p24.2 GLIS3 deletions noted above, not aneuploidy or translocations.

5. Environmental Information

Environmental factors / toxins / radiation / infectious agents: Not applicable — NDH is a fully genetic, non-infectious Mendelian disorder. No toxin, pollutant, occupational exposure, or pathogen causes or triggers it.

Lifestyle factors: Not causal for the biallelic syndrome. High-fat diet is relevant only in the heterozygous/susceptibility context (beta-cell-mass expansion failure in Glis3+/− mice, PMID: 23197416), not for the neonatal disease.

Consanguinity (a population-structure factor rather than an environmental exposure) markedly elevates recessive-disease risk (Section 9).

6. Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation)

1. Biallelic loss-of-function mutation in GLIS3 (9p24.2)
│  results in
▼
2. Loss/reduction of functional GLIS3 zinc-finger transcription factor
   (nuclear transactivation + primary-cilium localization both impaired)
│  leads to (branches to 4 organ programs)
├───────────────► PANCREAS BRANCH
│  3a. Failure to transactivate Neurog3 (Ngn3) (>90% reduction in
│       Glis3-/- embryos) AND loss of direct GLIS3 binding to
│       Ins2, Slc2a2/GLUT2, Mafa regulatory regions
│            │ results in
│  4a. Failed endocrine (beta-cell) specification + reduced beta-cell
│       mass + reduced insulin transcription
│            │ leads to
│  5a. Severe insulin deficiency  ──►  PERMANENT NEONATAL DIABETES
│       (plus GLIS3-loss sensitizes surviving beta cells to apoptosis
│        via SRp55/Bim-splicing, accelerating beta-cell loss)
│
├───────────────► THYROID BRANCH
│  3b. Loss of GLIS3-driven thyroid-gene expression from ~E15.5
│            │ results in
│  4b. Impaired thyroid follicular-cell maturation/function
│            │ leads to
│  5b. CONGENITAL HYPOTHYROIDISM (gland-in-situ / dyshormonogenesis type)
│
├───────────────► CILIARY / WWTR1-TAZ BRANCH (kidney, liver, eye)
│  3c. Loss of ciliary GLIS3 signaling + loss of GLIS3–WWTR1/TAZ
│       transactivation (P/LPXY motif); shortened renal cilia
│            │ results in
│  4c. Reduced urine flow, abnormal tubulogenesis; abnormal bile-duct
│       development; anterior-segment eye maldevelopment
│            │ leads to
│  5c. POLYCYSTIC/CYSTIC KIDNEY DISEASE, BILIARY CIRRHOSIS/bile-duct
│       paucity, CONGENITAL GLAUCOMA (with high hyperopia)
│
└───────────────► OTHER (sensorineural deafness, exocrine pancreatic
                  insufficiency, rare structural anomalies)

Detail by category

Molecular pathways. The dominant node is GLIS3-dependent transcription. GLIS3 transactivates Neurog3 (the master pro-endocrine bHLH factor) and co-occupies islet regulatory regions with other islet transcription factors, directly binding Ins2, Slc2a2 (GLUT2), and Mafa (ChIP-seq) [model organism] (PMID: 31340201). It intersects the Hippo pathway via WWTR1/TAZ coactivation (PMID: 19273592) and functions in a primary-cilium-associated signaling context.

"GLIS3 controls islet differentiation by transactivating neurogenin 3 (Ngn3)" — PMID: 27813676

"with global Glis3-knockout mice suffering from severe hyperglycemia and dying by post-natal day 11" — PMID: 31340201

Cellular processes. (i) Cell-fate specification/differentiation of pancreatic endocrine progenitors; (ii) beta-cell maintenance and identity in adults (PMID: 23197416); (iii) intrinsic (mitochondrial) apoptosis of beta cells when GLIS3 is lost.

"TAM-mediated beta cell-specific inactivation of Glis3 in adult mice downregulates insulin expression, leading to hyperglycaemia and subsequently enhanced beta cell apoptosis" — PMID: 23197416

Beta-cell apoptosis mechanism (Finding F009). GLIS3 knockdown in INS-1E cells, primary rat beta cells, and human islets lowered MafA, Ins2, and Glut2 and impaired glucose oxidation and insulin secretion; it increased apoptosis basally and sensitized cells to cytokine (IL-1β + IFN-γ) and palmitate-induced death — the mediators of beta-cell loss in type 1 and type 2 diabetes respectively — via the intrinsic pathway (cytochrome c release, Bax translocation, caspase 9/3). Mechanistically, GLIS3 loss inhibits the splicing factor SRp55, shifting alternative splicing of the BH3-only protein Bim toward the pro-death BimS variant; Bim knockdown rescued the phenotype [in vitro] (PMID: 23737756; PMID: 29246973).

"GLIS3 KD increased beta cell apoptosis basally and sensitized the cells to death induced by pro-inflammatory cytokines (interleukin 1β + interferon-γ) or palmitate" — PMID: 23737756

"modulation of alternative splicing of the pro-apoptotic BH3-only protein Bim, favouring expression of the pro-death variant BimS via inhibition of the splicing factor SRp55" — PMID: 23737756

Protein dysfunction. LOF of the GLIS3 zinc-finger transcription factor: truncation, deletion, or missense changes reduce DNA binding/transactivation and disrupt the C-terminal WWTR1/TAZ-binding P/LPXY motif (PMID: 19273592).

Metabolic changes. Downstream of beta-cell failure: absolute insulin deficiency → neonatal hyperglycemia, ketoacidosis risk, and impaired glucose oxidation in beta cells (PMID: 23737756). Thyroid-hormone deficiency perturbs systemic metabolism.

Immune involvement. Not autoimmune — this is a developmental (autoantibody-negative) diabetes. However, GLIS3-deficient beta cells are hypersensitized to pro-inflammatory cytokine killing, mechanistically linking GLIS3 to the T1D susceptibility signal (PMID: 23737756).

Tissue damage mechanisms. Beta-cell apoptosis (islet); biliary cirrhosis from abnormal bile-duct development/paucity (liver, PMID: 36917836); cyst formation from shortened cilia and reduced urine flow (kidney) [model organism] (PMID: 19609364).

"The cilia on the surface of the renal tubular epithelium were significantly shorter in the pc mutant than in wild-type, suggesting that shortened cilia resulted in a decrease in driving force and, in turn, a reduction in urine flow rate" — PMID: 19609364

Thyroid mechanism (Finding F006). GLIS3 protein is first detectable at E15.5 of murine thyroid development, coinciding with expression of GLIS3 target genes; thyroid-specific Glis3-KO mice show dysregulated thyroid gene expression (PMID: 37461635).

"Loss of GLI-Similar 3 (GLIS3) function in mice and humans causes congenital hypothyroidism (CH)" — PMID: 37461635

Suggested GO / CL terms. Biological process: GO:0030154 (cell differentiation), GO:0003309 (type B pancreatic cell differentiation), GO:0006006 (glucose metabolic process), GO:0006915 (apoptotic process), GO:0060271 (cilium assembly), GO:0035148 (tube formation). Cell types: CL:0000169 (type B pancreatic/beta cell), CL:0002258 (thyroid follicular cell), CL:1000454 (kidney collecting-duct epithelial cell), CL:0000068 (duct epithelial cell / cholangiocyte).

7. Anatomical Structures Affected

Organ level (primary). Pancreatic islets (endocrine pancreas), thyroid gland. Secondary/associated: liver and biliary tree, kidneys, eyes (anterior segment), inner ear (cochlea), exocrine pancreas, and rarely skull sutures, diaphragm/esophageal hiatus, heart (atrial septum), spleen, choanae.

Body systems. Endocrine (primary), hepatobiliary/digestive, renal/urinary, ophthalmic/nervous (sensory), auditory.

Tissue & cell level. - Pancreatic beta cells (CL:0000169) — reduced mass, impaired function/survival. - Thyroid follicular cells (CL:0002258) — impaired maturation. - Renal tubular epithelium — shortened cilia, cyst formation (CL:1000454). - Cholangiocytes / bile-duct epithelium — bile-duct paucity/abnormal development.

Subcellular level. Nucleus (GO:0005634 — GLIS3 transactivation) and the primary cilium (GO:0005929) are the two key compartments; GLIS3 localizes to both (PMID: 19273592). Beta-cell death proceeds through mitochondria (GO:0005739; intrinsic apoptosis).

"We demonstrate that Glis3 localizes to the primary cilium, suggesting that Glis3 is part of a cilium-associated signaling pathway" — PMID: 19273592

Localization / lateralization. Systemic/bilateral where paired (kidneys, eyes, cochleae). Suggested UBERON: UBERON:0000006 (islet of Langerhans), UBERON:0002046 (thyroid gland), UBERON:0002107 (liver), UBERON:0002113 (kidney), UBERON:0000970 (eye), UBERON:0001844 (cochlea).

8. Temporal Development

Onset. Congenital / neonatal. Diabetes typically presents within the first days to weeks of life (permanent neonatal diabetes, <6 months by definition), frequently with intrauterine growth restriction, hyperglycemia, and sometimes diabetic ketoacidosis. Congenital hypothyroidism is present from birth (detectable on newborn screening). Onset pattern is congenital/acute for diabetes and congenital/insidious for the hepatic and renal disease, which may declare over infancy.

Progression. Diabetes is permanent and lifelong (not transient/self-limited). Hepatic disease can be progressive (hepatitis → fibrosis → cirrhosis), and renal cystic disease may progress. Overall course is chronic and, for some organs, life-limiting.

Patterns / critical periods. No spontaneous remission of the diabetes. The critical intervention windows are (i) immediate neonatal insulin initiation to control hyperglycemia and (ii) early levothyroxine to prevent irreversible neurodevelopmental injury from hypothyroidism. The beta-cell-development defect occurs in utero and is not reversible postnatally.

9. Inheritance and Population

Epidemiology. Neonatal diabetes mellitus overall has an incidence of ~1 in 90,000 live births (range 1:90,000–1:160,000) [human clinical] (PMID: 38752501). GLIS3-related NDH is a very rare recessive subset (<1% of NDM); on the order of ~20 families/patients are reported in the literature (Finding F013).

"These disorders are rare and the incidence is approximately 1 in 90,000 live births" — PMID: 38752501

Inheritance. Autosomal recessive, with high penetrance for neonatal diabetes and variable expressivity for the other organ features (e.g., one compound-heterozygous patient lacked congenital hypothyroidism, PMID: 26259131). No genetic anticipation (not a repeat-expansion disorder). Germline mosaicism not specifically reported.

Consanguinity & founder effects. Recessive syndromic neonatal diabetes is strongly over-represented in consanguineous Middle Eastern/North African and South Asian populations, where homozygous GLIS3 large deletions and point mutations occur (PMID: 40583116; PMID: 37897565; PMID: 42468610; PMID: 41275391).

"Monogenic diabetes is estimated to account for 1-6% of paediatric diabetes cases in primarily non-consanguineous populations, while the incidence and genetic spectrum in consanguineous regions are insufficiently defined" — PMID: 37897565

In a Saudi cohort with 81% consanguinity, autosomal-recessive syndromic and permanent neonatal diabetes predominated (PMID: 42468610); Sudanese cohorts likewise showed a predominance of syndromic recessive forms (PMID: 41275391).

Demographics. No strong sex bias (recessive). Carrier frequency is low in outbred populations, higher within consanguineous kindreds. Age distribution: affected individuals identified in the neonatal period.

10. Diagnostics

Clinical/laboratory tests. - Glucose/insulin/C-peptide: persistent neonatal hyperglycemia with low insulin/C-peptide (insulin-deficient), autoantibody-negative. - Thyroid function: low free T4 with elevated TSH (primary congenital hypothyroidism); thyroid imaging typically shows a gland in situ (dyshormonogenesis pattern) rather than athyreosis in most cases. - Hepatic panel: transaminitis/cholestasis; explant/biopsy histology shows biliary cirrhosis / bile-duct paucity (PMID: 36917836). - Renal imaging (ultrasound): cystic dysplasia / polycystic kidneys (PMID: 26259131). - Ophthalmology: congenital glaucoma with high hyperopia and short axial length (PMID: 40583116). - Audiology: sensorineural hearing testing. - Pancreatic exocrine: fecal elastase for exocrine insufficiency.

"ophthalmic assessments revealed congenital glaucoma, high hyperopia, and short axial length of the globe" — PMID: 40583116

Genetic testing (definitive). Molecular confirmation is essential and directly influences prognosis and treatment.

"molecular diagnosis is crucial, as it directly influences prognosis and treatment - particularly the potential responsiveness to sulfonylureas in ATP-sensitive potassium (KATP)-channel-related NDM" — PMID: 41769619

Recommended approach: - Targeted neonatal-diabetes / monogenic-diabetes NGS gene panel (must include GLIS3 alongside KCNJ11, ABCC8, INS, EIF2AK3, PDX1, PTF1A, GATA6, RFX6, NEUROG3, FOXP3, etc.). - WES/WGS for atypical/syndromic presentations and novel-variant discovery (PMID: 38051360; PMID: 42468610). - Chromosomal microarray / deletion analysis is important because GLIS3 large multi-exon and whole-gene deletions occur (PMID: 16715098; PMID: 40583116) and may be missed by SNV-only panels. - Variant interpretation per ACMG/AMP; functional INS-promoter luciferase assays can supply PS3-level evidence (PMID: 38051360).

Clinical criteria / differential diagnosis. Diagnosis rests on the combination of permanent neonatal diabetes + congenital hypothyroidism plus GLIS3 confirmation. Key differentials (Finding F014):

Gene(s) Mechanistic class Distinguishing feature vs GLIS3
KCNJ11 / ABCC8 KATP-channel Sulfonylurea-responsive; usually no CH
INS insulin gene / ER stress Isolated PNDM; no CH
EIF2AK3 (Wolcott-Rallison) ER stress Epiphyseal dysplasia, liver/renal, but not CH
GATA6 / GATA4 / PDX1 pancreatic agenesis/hypoplasia Exocrine insufficiency + cardiac/gallbladder anomalies; labile diabetes (PMID: 41006196)
FOXP3 (IPEX) immune dysregulation Autoimmune enteropathy; thyroiditis (acquired, not congenital)
CISD2 (Wolfram syndrome 2) Ca²⁺/ER Later onset, optic atrophy (PMID: 40189101)
GLIS3 developmental TF Neonatal diabetes + congenital hypothyroidism (± glaucoma, biliary cirrhosis, polycystic kidneys)

"NDM is caused by single-gene mutations that disrupt pancreatic β-cell function or development" — PMID: 41614934

Screening. Congenital hypothyroidism is captured by routine newborn screening (TSH/T4); neonatal hyperglycemia prompts glucose testing. Cascade genetic testing in families follows molecular diagnosis.

11. Outcome / Prognosis

Survival/mortality. No formal survival statistics exist for this ultra-rare disorder. Prognosis is guarded and driven by the sum of complications: brittle insulin-dependent diabetes, and potentially life-limiting hepatic (biliary cirrhosis) and renal disease (PMID: 36917836). Global Glis3-knockout mice die by postnatal day ~11 from severe hyperglycemia (PMID: 31340201), underscoring the severity of complete loss; humans survive with intensive supportive care.

Morbidity/function. High: lifelong insulin dependence, neurodevelopmental risk from hypothyroidism (mitigated by early treatment), visual impairment from glaucoma, hearing loss, malnutrition from exocrine insufficiency, and organ-failure risk. QoL impact is substantial and multi-domain.

Complications & recovery. Progressive liver disease may require liver transplantation; renal disease may progress toward insufficiency; brittle diabetes complicates post-transplant management.

"GLIS3 mutations need to be added to the list of non-syndromic causes of bile duct paucity in the liver. Liver transplantation should be considered in patients with life-limiting complications related to liver disease" — PMID: 36917836

Prognostic factors. Severity/completeness of GLIS3 LOF, presence and progression of hepatic/renal disease, and adequacy of early metabolic and thyroid control.

12. Treatment

There is no cure; management is lifelong, organ-directed supportive care (Findings F002, F005, F010).

Pharmacotherapy. - Insulin (exogenous) — the cornerstone for the diabetes. GLIS3-NDH is a beta-cell-developmental/deficiency diabetes and is insulin-dependent (NCIT: C2271 Insulin). It is NOT sulfonylurea-responsive, in sharp contrast to KATP-channel NDM.

"patients with ABCC8 or KCNJ11 mutations treated with insulin therapy can switch to hypoglycemic sulfonylureas (SU). These drugs close the KATP channel binding the SUR1 subunit of the potassium channel and restoring insulin secretion after a meal" — PMID: 37251668

  • Levothyroxine — lifelong thyroid-hormone replacement for congenital hypothyroidism (NCIT: C29101 Levothyroxine Sodium), started as early as possible to protect neurodevelopment.
  • Pancreatic enzyme replacement for exocrine pancreatic insufficiency.
  • Anti-glaucoma therapy / surgery for congenital glaucoma.

Pharmacogenomics. The single most actionable pharmacogenomic point is the genotype-defined therapeutic split: molecular diagnosis distinguishes sulfonylurea-responsive (KATP) from insulin-dependent (GLIS3/developmental) NDM (PMID: 41769619; PMID: 41614934). Note that monoallelic GLIS3 T2D patients can be sulfonylurea-sensitive (PMID: 38051360) — this does not extend to biallelic NDH.

Surgical/interventional. Liver transplantation for life-limiting biliary cirrhosis (NCIT: C15311 Liver Transplantation); combined multi-organ transplantation (liver ± pancreas ± kidney) has been considered but performed as liver-alone in reported cases (PMID: 36917836). Glaucoma surgery as needed.

"Histology demonstrated predominantly biliary cirrhosis consistent with abnormal bile duct development" — PMID: 36917836

Advanced/experimental therapeutics. No approved gene, cell, or RNA therapy exists for GLIS3-NDH. Because the defect is developmental (failed beta-cell formation in utero), gene replacement faces the challenge that the target cells are largely absent — making stem-cell-derived beta-cell replacement a more plausible future avenue than in-situ gene correction. Human iPSC/hPSC CRISPR models confirm the conserved GLIS3 requirement in human pancreatic differentiation (PMID: 27133796), providing a platform for such work. No NCT-registered GLIS3-specific trials were identified.

Treatment strategy. Genotype-guided precision medicine: confirm GLIS3, commit to insulin (not a therapeutic sulfonylurea trial beyond diagnostic exclusion), replace thyroid hormone early, and institute multidisciplinary surveillance (hepatology, nephrology, ophthalmology, audiology, nutrition).

"necessitating a shift from symptomatic management to precision medicine" — PMID: 41614934

13. Prevention

  • Primary prevention: None possible for the biallelic Mendelian disease (fully genetically determined). Prevention operates at the reproductive/genetic-counseling level.
  • Secondary prevention (early detection): Newborn screening detects congenital hypothyroidism (TSH/T4); prompt recognition of neonatal hyperglycemia enables early insulin and molecular diagnosis. Early levothyroxine prevents irreversible neurodevelopmental injury.
  • Tertiary prevention: Multidisciplinary surveillance and management of hepatic, renal, ophthalmic, and auditory complications to limit disability.
  • Genetic counseling / screening: The key preventive strategy. Autosomal-recessive counseling for consanguineous families, carrier/cascade testing, and options for prenatal diagnosis / preimplantation genetic testing once the familial GLIS3 variant(s) are known (PMID: 42468610; PMID: 41275391).
  • Immunization / public-health / environmental interventions: Not applicable (non-infectious, non-environmental).

14. Other Species / Natural Disease

  • Taxonomy of models/orthologs: Mus musculus (NCBI:txid10090), Oryzias latipes (medaka; NCBI:txid8090). GLIS3 is evolutionarily conserved, and its disease mechanisms are conserved across mouse, fish, and human (PMID: 19609364; PMID: 27133796).
  • Orthologous genes: mouse Glis3, medaka glis3.
  • Natural disease: No well-documented naturally occurring companion-animal (OMIA) equivalent of GLIS3-NDH was identified; the "natural disease" model is the medaka pc mutant, which arose from a transposon insertion in glis3 and models polycystic kidney disease (PMID: 19609364).

"the Gli-similar3 (glis3) gene was identified as the causal gene of the medaka pc mutant, a model of PKD" — PMID: 19609364

  • Comparative biology: Glis3(zf/zf) mice recapitulate the human syndrome (diabetes + PKD), demonstrating strong cross-species conservation of both the beta-cell and ciliary-renal mechanisms.

15. Model Organisms

Model Type Key phenotype / use PMID
Global Glis3−/− mouse knockout, mammalian Severe hyperglycemia; death by P~11; near-absent insulin; >90% Ngn3 reduction in embryos 31340201, 27813676
Glis3(zf/zf) mouse hypomorph/mutant Diabetes + polycystic kidney disease — recapitulates human NDH 19273592
Beta-cell-specific Glis3 KO (RipCre / RosaCreERT2, TAM-inducible) conditional Insulin downregulation → hyperglycemia + beta-cell apoptosis; proves adult maintenance role 23197416
Glis3+/− mouse on high-fat diet heterozygous + environment Diabetes from impaired beta-cell-mass expansion via Ccnd2 23197416
Thyroid-specific Glis3 KO mouse conditional Dysregulated thyroid gene expression; GLIS3 protein from E15.5 37461635
Medaka pc mutant (glis3 transposon insertion) fish Polycystic kidney disease from shortened renal cilia, reduced urine flow 19609364
Human iPSC/hPSC CRISPR/TALEN (GLIS3 among 8 TFs) in vitro/cellular Confirms conserved GLIS3 requirement in human pancreatic differentiation 27133796
INS-1E, primary rat/human islets (GLIS3 KD) cellular Beta-cell apoptosis via SRp55/Bim splicing 23737756

"These mice display abnormalities very similar to those of patients with neonatal diabetes and hypothyroidism syndrome, including the development of diabetes and polycystic kidney disease" — PMID: 19273592

Model characteristics / limitations. Mouse and medaka models faithfully reproduce the diabetes and renal-cystic components; conditional models successfully dissect organ-specific roles. Limitations: the ocular (high hyperopia/glaucoma) and biliary-cirrhosis phenotypes are less fully modeled, and species differences (e.g., a "potentially divergent role of NGN3 in humans and mice," PMID: 27133796) mean human iPSC systems are important complements. Resources: MGI, IMPC, ZFIN/medaka stocks; human iPSC lines from CRISPR studies.

Mechanistic Model / Interpretation

The entire NDH phenotype is best understood as the pleiotropic failure of a single developmental transcription factor deployed in parallel organ programs. GLIS3 is not a metabolic enzyme or an ion channel — it is an upstream builder. Where KATP-channel neonatal diabetes reflects a functional secretory defect in otherwise-formed beta cells (and is therefore drug-reversible with sulfonylureas), GLIS3-NDH reflects a structural/developmental deficit: the beta cells are never adequately specified (Ngn3 collapse) and the few that form are hypofunctional and apoptosis-prone (SRp55→BimS). This is the mechanistic reason the two disorders diverge so completely in treatment — a distinction that molecular diagnosis makes actionable (F005, F014).

The same logic explains the multi-organ reach. Because GLIS3 operates both as a nuclear transactivator and as a cilium-associated / WWTR1-TAZ-coupled factor, its loss simultaneously derails endocrine-pancreas development, thyroid follicular maturation, and cilium-dependent morphogenesis of kidney, biliary tree, and eye. The disorder is thus a "developmental transcription-factor syndrome" whose organ list is essentially the intersection of GLIS3's expression domains and its two molecular modes of action.

            GLIS3 (single TF, two modes)
     ┌──────────────┴───────────────┐
       NUCLEAR TRANSACTIVATION          PRIMARY CILIUM + WWTR1/TAZ
       (Ngn3, Ins2, Glut2, MafA)        (P/LPXY motif; ciliary signaling)
     │                                    │
   Beta-cell + thyroid programs         Kidney / bile-duct / eye programs
     │                                    │
   Neonatal diabetes + CH               PKD + biliary cirrhosis + glaucoma

Evidence Base

PMID Study type Contribution
16715098 Human gene discovery Establishes biallelic GLIS3 LOF as cause; defines core syndrome
26259131 Human case series (n=12) Phenotypic spectrum, frequencies, variability
27813676 Mouse/gene-dosage GLIS3→Ngn3; GWAS T1D/T2D link
31340201 Mouse/ChIP-seq Direct binding to Ins2/Glut2/MafA; lethal global KO
23197416 Mouse conditional Adult beta-cell maintenance; Ccnd2/diet interaction
23737756 In vitro/islets Beta-cell apoptosis via SRp55/BimS
29246973 In vitro SRp55 splicing network in beta cells
37461635 Mouse thyroid KO GLIS3 in thyroid development/CH
19273592 Mouse Cilium localization; WWTR1/TAZ; PKD
19609364 Medaka glis3/cilia/urine-flow renal-cyst mechanism
36917836 Human explant pathology Biliary cirrhosis/bile-duct paucity; transplant
40583116 Human siblings Congenital glaucoma + high hyperopia; large deletion
38051360 Human resequencing + functional Allelic dosage; ACMG functional assays; monoallelic T2D
41769619 / 37251668 Human NDM series/case Molecular diagnosis dictates SU vs insulin
41614934 Review NDM classification; precision medicine
38752501 Human cohort NDM incidence ~1:90,000
37897565 / 42468610 / 41275391 Consanguineous cohorts Recessive burden, consanguinity
27133796 hPSC editing Conserved human GLIS3 requirement
28523428 Review GLIS3 structure/function; disease associations

Evidence source types span human clinical (gene discovery, case series, cohorts, explant pathology), model organism (mouse conditional/global KO, medaka), and in vitro (INS-1E, primary/human islets, iPSC), giving convergent, cross-validated support for the developmental-transcription-factor model.

Limitations and Knowledge Gaps

  1. Small n / publication bias. Only ~20 families are reported; frequency estimates for individual organ features (glaucoma, deafness, EPI) are imprecise and likely biased toward severe, published cases.
  2. No formal natural-history or survival data. Life expectancy, mortality rates, and validated QoL instruments have not been systematically measured for GLIS3-NDH.
  3. Genotype–phenotype correlation is incomplete. Why some patients lack congenital hypothyroidism or have milder hepatic/renal disease (variable expressivity) is not mechanistically resolved; no proven modifier genes.
  4. Under-modeled phenotypes. The ocular (high hyperopia) and biliary-cirrhosis components are not fully recapitulated in existing animal models.
  5. No disease-specific therapeutics. No gene/cell/RNA therapy exists; stem-cell beta-cell replacement remains conceptual.
  6. Ontology mapping provided here (HPO/GO/CL/UBERON/NCIT) is expert-suggested and should be curator-verified.

Proposed Follow-up Experiments / Actions

  1. Curate an international GLIS3-NDH registry to define organ-feature frequencies, natural history, survival, and genotype–phenotype correlations with adequate power.
  2. Systematic ACMG re-classification of all reported GLIS3 variants using the INS-promoter functional assay (PS3) framework (PMID: 38051360), including CNV/deletion detection to avoid missed large deletions.
  3. Human iPSC-derived multi-lineage models (beta cell, thyroid follicular, cholangiocyte, kidney organoid) from patient GLIS3 genotypes to model the ocular/biliary phenotypes currently missing in mice (PMID: 27133796).
  4. Test whether SRp55/Bim-axis modulation protects GLIS3-deficient human beta cells from apoptosis as a proof-of-concept therapeutic target (PMID: 23737756).
  5. Explore stem-cell-derived beta-cell replacement as a rational strategy given the developmental (cell-absent) nature of the defect.
  6. Formalize a diagnostic algorithm ensuring GLIS3 is on all neonatal-diabetes NGS panels and that neonatal diabetes + congenital hypothyroidism triggers GLIS3 deletion analysis, avoiding futile sulfonylurea trials.

Report compiled from 14 confirmed findings and 32 reviewed publications across a 5-iteration autonomous investigation. Evidence types: human clinical, model organism, in vitro, computational.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.3.0rc1.

Outcome Count
References checked 25
Resolved 25
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 25
Quoted claims found in source 25
Quoted claims not found in source 0
References weighed for topical relevance 25
On topic 21
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 38
Resolved 36
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 2
Terms whose name was checked 22
Terms named correctly 14
Terms named as a different term 4
Terms whose name is worth a second look 4

Terms the report names something else

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

  • HP:0000851 (1 mention) - the report calls it "Highly frequent (one compound-het patient lacked it)"; HP calls it Congenital hypothyroidism
  • HP:0008007 (1 mention) - the report calls it "Frequent"; HP calls it Primary congenital glaucoma
  • CL:1000454 (2 mentions) - the report calls it "kidney collecting-duct epithelial cell", "Renal tubular epithelium — shortened cilia, cyst formation"; CL calls it kidney collecting duct epithelial cell**
  • GO:0005634 (1 mention) - the report calls it "GLIS3 transactivation"; GO calls it nucleus

Terms whose name is worth a second look

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

  • MONDO:0012436 (2 mentions) - the report calls it "MONDO"; MONDO calls it neonatal diabetes mellitus with congenital hypothyroidism, and lists "NDH" among its other names
  • CL:0000169 (2 mentions) - the report calls it "type B pancreatic/beta cell", "beta cells", "Pancreatic beta cells"; CL calls it type B pancreatic cell**
  • CL:0000068 (1 mention) - the report calls it "duct epithelial cell / cholangiocyte"; CL calls it duct epithelial cell
  • GO:0005929 (1 mention) - the report calls it "primary cilium"; GO calls it cilium, and lists "primary cilium" among its other names

Terms named inconsistently

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

  • CL:0000169 - called "type B pancreatic/beta cell", "beta cells", "Pancreatic **beta cells"
  • CL:0002258 - called "thyroid follicular cell", "Thyroid follicular cells"
  • CL:1000454 - called "kidney collecting-duct epithelial cell", "Renal tubular epithelium** — shortened cilia, cyst formation"

Prefixes with no resolver

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