Chromosome 17q12 Deletion Syndrome

Mendelian MONDO:0013797 Pathograph 27 Show in embeddings browser Chromosomal deletion syndrome

Chromosome 17q12 deletion syndrome is a recurrent 1.4 Mb heterozygous deletion spanning about fifteen genes, one of which is HNF1B. Its renal and pancreatic phenotype - cystic and dysplastic kidneys, and maturity-onset diabetes of the young type 5 - is HNF1B haploinsufficiency, and it is the same phenotype seen with an HNF1B point mutation. Its neurodevelopmental and neuropsychiatric phenotype is not. That asymmetry is the reason this deserves an entry of its own rather than a subtype line on HNF1B disease. A cytogenomic screen of 15,749 patients referred for neurodevelopmental testing found the deletion in 18, and in none of 4,519 controls; a follow-up sample found it in 4 of 6,340 patients with schizophrenia and in none of 47,929 controls. The authors' conclusion is the mechanistic claim this entry is built around: the phenotype is a contiguous gene syndrome that extends beyond renal cysts and diabetes syndrome, which HNF1B mutations alone cause. Which of the other fourteen genes carries the brain phenotype is not known, and the entry records that as a knowledge gap rather than guessing. A second contrast runs the other way, and it is counterintuitive enough to be worth stating. In a 201-patient cohort split evenly between HNF1B point mutations and 17q12 deletions, the deletion carriers had advanced chronic kidney disease and end-stage renal disease *less* often than the mutation carriers, at diagnosis and in the long term. So the deletion is not simply the more severe lesion; it is a differently shaped one, milder in the kidney and broader in the brain. Any account that treats a whole-gene deletion as the maximal HNF1B allele has to answer that observation. Because the deletion is invisible to sequencing-based MODY panels, patients are routinely diagnosed with MODY5 without the syndrome being recognised. Ascertainment therefore skews by referral route, and reported frequencies depend heavily on whether a cohort was collected through nephrology, diabetology or developmental paediatrics. The frequencies curated below are taken from the GeneReviews figures, which were derived with a method intended to avoid exactly that bias.

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2
Definitions
1
Inheritance
8
Pathophys.
21
Phenotypes
1
Hypotheses
2
Gaps
27
Pathograph
2
Genes
4
Medical Actions
1
Models
1
References
1
Deep Research
📘

Definitions

2
Chromosomal microarray detection of the 1.4 Mb 17q12 deletion
Diagnosis rests on detecting the recurrent 1.4 Mb heterozygous deletion by chromosomal microarray or another genomic method. The practical point is a negative one: sequencing panels used to work up maturity-onset diabetes of the young cannot see a 1.4 Mb deletion, so a MODY5 diagnosis reached by panel sequencing does not exclude this syndrome and a normal panel is not reassurance.
DIAGNOSTIC_CRITERIA
Show evidence (2 references)
PMID:27929632 SUPPORT Human Clinical
"The diagnosis is established in a proband by detection of the 1.4-Mb heterozygous recurrent deletion at chromosome 17q12 by chromosomal microarray testing or other genomic methods."
States the diagnostic method this definition records.
PMID:30032214 SUPPORT Human Clinical
"Because HNF1B deletions are virtually always part of a 17q12 deletion syndrome and common genetic analyses for evaluation of MODY5 are unable to detect the deletion of a 1.4-Mb chromosomal region, initial attention to the syndromal features at the stage of diagnosis is of considerable importance..."
States that standard MODY5 genetic testing cannot detect the deletion, which is the ascertainment caveat this definition exists to record.
HNF1B score for selecting patients for genetic testing
A 17-item weighted clinical, imaging and biochemical score developed to decide who should be sent for HNF1B genetic testing, covering antenatal discovery, family history and kidney, pancreas, liver and genital tract involvement. It is a rule-out instrument rather than a diagnostic one: at the optimal cutoff of 8 its negative predictive value exceeds 99 per cent with sensitivity 98.2 per cent, but specificity is only 41.1 per cent, so a score above threshold does not make the diagnosis. Note the scope caveat for this entry: the score is validated for HNF1B disease as a whole, not for the 17q12 deletion specifically, and a positive score is followed by sequencing, which cannot see the deletion.
PHENOTYPE_ALGORITHM
Show evidence (2 references)
PMID:24897035 SUPPORT Human Clinical
"The optimal cutoff threshold for the negative predictive value to rule out HNF1B mutations in a suspected individual was 8 (sensitivity 98.2%, specificity 41.1%, and negative predictive value over 99%)."
Gives the operating characteristics recorded in this definition, including the low specificity that makes it a rule-out rather than a diagnostic instrument.
PMID:24897035 SUPPORT Human Clinical
"The HNF1B score is calculated upon 17 items including antenatal discovery, family history, and organ involvement (kidney, pancreas, liver, and genital tract)."
Lists the score's components, which is the content of this definition.
👪

Inheritance

1
Autosomal dominant inheritance HP:0000006
The deletion behaves as an autosomal dominant trait. About three quarters arise de novo and about a quarter are inherited from a parent, so a parental deletion should be looked for rather than assumed absent.
Autosomal dominant inheritance De novo rate: 75%
Show evidence (2 references)
PMID:27929632 SUPPORT Human Clinical
"17q12 recurrent deletion syndrome is inherited in an autosomal dominant manner, with approximately 75% of deletions occurring de novo and approximately 25% inherited from a parent."
States both the inheritance pattern and the de novo proportion recorded here.
PMID:27929632 SUPPORT Human Clinical
"Each child of an individual with 17q12 recurrent deletion syndrome has a 50% chance of inheriting the deletion. Once the 17q12 recurrent deletion has been identified in an affected family member, prenatal and preimplantation genetic testing for 17q12 recurrent deletion syndrome are possible."
States the 50 per cent transmission risk and the availability of prenatal and preimplantation testing, which follow from autosomal dominant inheritance.
◈

Mechanistic Hypotheses

1
Contiguous gene syndrome extending beyond HNF1B
contiguous_gene_model CANONICAL
Evidence balance 2 support
The renal and pancreatic phenotype is HNF1B haploinsufficiency; the neurodevelopmental and neuropsychiatric phenotype comes from loss of one or more of the other fourteen genes in the interval. The evidence for the split is a contrast rather than a positive identification: the deletion carries an ASD and schizophrenia risk that HNF1B point mutations do not, at case-control effect sizes large enough to survive correction in tens of thousands of controls. A second dataset reproduced the direction of the schizophrenia signal without reaching significance, so the replication is partial.
Pathograph links
Recurrent 1.4 Mb Heterozygous Deletion at 17q12 -> Haploinsufficiency of Additional Dosage-Sensitive Interval Genes DIRECT
Haploinsufficiency of Additional Dosage-Sensitive Interval Genes -> Impaired Neurodevelopment DIRECT
Show evidence (2 references)
PMID:21055719 SUPPORT Human Clinical
"In addition, the phenotypic features of patients with this CNV are consistent with a contiguous gene syndrome that extends beyond RCAD, which is caused by HNF1B mutations only."
States the contiguous gene claim that defines this hypothesis group, and grounds it in the contrast with HNF1B point mutations.
PMID:22130109 SUPPORT INDIRECT Human Clinical
"Deletions at 17p12 and 17q12, were also more common in schizophrenia cases but not significantly so, while duplications at 16p13.1 were found at nearly the same rate as in previous schizophrenia samples."
A replication attempt in a non-psychiatric reference set found the 17q12 deletion directionally more common in schizophrenia but did not reach significance, so it is consistent with the association without independently establishing it. Cited as the weaker of the two datasets, and graded INDIRECT for that reason.
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Discussions and Knowledge Gaps

2
Which of the fourteen non-HNF1B genes in the 17q12 interval is responsible for the neurodevelopmental and psychiatric phenotype?
KNOWLEDGE GAP which_interval_gene_drives_ndd
Attached to
pathophysiology#Haploinsufficiency of Additional Dosage-Sensitive Interval Genes pathophysiology#Impaired Neurodevelopment
The evidence for a non-HNF1B contribution is a contrast, not an identification: the deletion confers autism and schizophrenia risk that HNF1B point mutations do not. Because the deletion has fixed recurrent breakpoints, human genetics offers almost no smaller deletions to narrow the interval with, so the question is not answerable by collecting more patients with the same CNV. Until it is resolved, the brain arm of this entry has a node that names a class of lesion rather than a molecule.
Why do 17q12 deletion carriers have less advanced kidney disease than HNF1B point-mutation carriers, when the deletion removes the whole gene?
KNOWLEDGE GAP deletion_milder_renal_than_point_mutation
Attached to
phenotypes#Chronic kidney disease pathophysiology#HNF1B Haploinsufficiency
A 201-patient cohort found CKD stage 3-4 and end-stage renal disease significantly less frequent in deletion carriers than in point-mutation carriers, both at diagnosis and in the long term. A pure haploinsufficiency model predicts the two should be equivalent, and a dominant-negative effect of some missense alleles would explain the direction but has not been shown for the alleles in that cohort. Ascertainment is the competing explanation: deletion carriers are often found through neurodevelopmental or antenatal routes and point-mutation carriers through nephrology, which would bias renal severity the way observed. The study does not separate these, and no subsequent work has. A later prenatal-and-postnatal comparison across 82 studies asked the differentiation question directly in its title and concluded only that both mutation groups show high phenotypic heterogeneity, so the difference remains unexplained rather than refuted.
Show evidence (1 reference)
PMID:31498910 SUPPORT Human Clinical
"Overall, both mutation groups showed a high phenotypic heterogeneity."
A study set up to compare 17q12 microdeletions against intragenic HNF1B variants found heterogeneity in both rather than a clean genotype-phenotype split, which is why this gap is recorded as open.
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Pathophysiology

8
Recurrent 1.4 Mb Heterozygous Deletion at 17q12
A recurrent heterozygous deletion of approximately 1.4 Mb removes about fifteen genes at chromosome 17q12. Its recurrence and fixed breakpoints are what make it detectable by chromosomal microarray and, equally, what make it invisible to the sequencing panels used to work up maturity-onset diabetes of the young. This node is the initiating lesion and branches into two mechanistically separate arms.
Contiguous gene syndrome extending beyond HNF1B
Downstream
HNF1B Haploinsufficiency
Haploinsufficiency of Additional Dosage-Sensitive Interval Genes Contiguous gene syndrome extending beyond HNF1B
Show evidence (1 reference)
PMID:27929632 SUPPORT Human Clinical
"The diagnosis is established in a proband by detection of the 1.4-Mb heterozygous recurrent deletion at chromosome 17q12 by chromosomal microarray testing or other genomic methods."
Gives the size and heterozygous state of the deletion and the method that detects it.
HNF1B Haploinsufficiency
One functional copy of HNF1B remains. HNF1B is a homeodomain transcription factor required for nephron and pancreatic development and for maintenance of tubular epithelial identity, so a halved dose is sufficient to derange kidney and pancreatic development. This is the arm of the mechanism shared with HNF1B point mutations.
DNA-binding transcription factor activity GO:0003700 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased DNA-binding transcription factor activity (GO:0003700). GO:0003700 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Disrupted Nephron and Collecting System Development
Impaired Pancreatic Beta Cell Development and Insulin Secretion
Mullerian Duct Maldevelopment
Disrupted Hepatic and Otic Development
Show evidence (5 references)
PMID:30032214 SUPPORT Human Clinical
"Maturity-onset diabetes of the young type 5 (MODY5) is caused by mutations of the hepatocyte nuclear factor 1 homeobox β gene (HNF1B)."
Identifies HNF1B loss as the cause of the diabetes arm, supporting this node as the shared branch point.
PMID:15085338 SUPPORT In Vitro
"Mutations in the hepatocyte nuclear factor-1 beta ( HNF-1 beta) gene result in disorders of renal development, typically involving renal cysts and early-onset diabetes (the RCAD syndrome/ MODY5)."
Establishes that reduced HNF1B function produces both the renal developmental and the diabetic phenotype, which is the branch point this node records.
PMID:15649945 SUPPORT INDIRECT Human Clinical
"In these cases, the expression of PKHD1 (polycystic kidney and hepatic disease 1) and UMOD (Uromodulin), two genes regulated by HNF1beta, was turned off."
Identifies PKHD1 and UMOD as HNF1B-regulated genes whose expression is lost when HNF1B is inactivated, supplying named downstream targets for the transcription-factor node. Graded INDIRECT because the observation is in chromophobe renal carcinoma with biallelic loss, whereas this disorder is germline haploinsufficiency.
+ 2 more references
Haploinsufficiency of Additional Dosage-Sensitive Interval Genes
Fourteen further genes are lost in one copy. At least one is dosage sensitive for brain development, inferred from the fact that the deletion confers autism and schizophrenia risk while an HNF1B point mutation does not. The responsible gene is unidentified, so this node names the class of lesion rather than a molecule, and the entry does not pretend otherwise.
Contiguous gene syndrome extending beyond HNF1B
Downstream
Impaired Neurodevelopment Contiguous gene syndrome extending beyond HNF1B
Disrupted Nephron and Collecting System Development
Reduced HNF1B dose during kidney development gives multicystic dysplastic kidneys, renal cysts, hypoplasia and a range of other structural and functional abnormalities of the kidney and urinary tract. This is the commonest arm of the phenotype, present in 85 to 90 per cent of affected individuals on ascertainment-corrected figures, and it also carries the tubular handling defects for magnesium, potassium and urate.
nephron development GO:0072006 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased nephron development (GO:0072006). GO:0072006 is a biological process from the Gene Ontology. ↓ DECREASED
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
vhnf1 zebrafish insertional mutant Zebrafish recapitulates Kidney cyst formation arising from patterning defects, with loss of proper pax2 and wt1 expression in the pronephric primordium.
Downstream
Multicystic kidney dysplasia
Renal cyst
Chronic kidney disease
Hypomagnesemia
Hypokalemia
Hyperuricemia
Show evidence (2 references)
PMID:27929632 SUPPORT Human Clinical
"the authors determined that multicystic kidneys and other structural and functional kidney anomalies occur in 85%-90% of affected individuals"
Gives the frequency and nature of the renal developmental phenotype on this node.
PMID:24204001 SUPPORT INDIRECT In Vitro
"HNF1B to costimulate the FXYD2 promoter, the activity of which is instrumental"
Supplies the molecular route from reduced HNF1B dose to renal magnesium wasting: HNF1B drives the FXYD2 promoter, whose product mediates distal convoluted tubule magnesium reabsorption. Graded INDIRECT because the experiment interrogates PCBD1 loss rather than HNF1B haploinsufficiency, and is a cell-line overexpression system.
Impaired Pancreatic Beta Cell Development and Insulin Secretion
Reduced HNF1B dose impairs pancreatic development, giving maturity-onset diabetes of the young type 5 in roughly 40 per cent of affected individuals, most often diagnosed before age 25. Exocrine involvement occurs as well, so pancreatic insufficiency is part of the same lesion rather than a separate one. Clinically the diabetes is insulin-requiring in most patients despite some initial sulfonylurea responsiveness.
pancreas development GO:0031016 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased pancreas development (GO:0031016). GO:0031016 is a biological process from the Gene Ontology. ↓ DECREASED
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.
Animal models
vhnf1 zebrafish insertional mutant Zebrafish recapitulates Pancreatic underdevelopment, with loss of proper pdx1 and shh expression in the gut endoderm. pdx1 is the master pancreatic specification factor, which supplies the route from HNF1B dose to reduced beta cell mass.
Downstream
Maturity-onset diabetes of the young
Exocrine pancreatic insufficiency
Show evidence (4 references)
PMID:27929632 SUPPORT Human Clinical
"MODY5 in approximately 40%, and some degree of developmental delay or learning disability in approximately 50%. MODY5 is most often diagnosed before age 25 years (range: age 10-50 years)."
Gives the frequency and age at diagnosis of the diabetes arm recorded on this node.
PMID:28420700 SUPPORT Human Clinical
"Although responsiveness to sulfonylureas/repaglinide was observed in 29 of the 51 tested, 111 of 140 patients (79%) were treated with insulin at follow-up."
Supports the claim that the beta cell defect is severe enough that most patients end up insulin-treated despite partial oral responsiveness.
PMID:36109160 SUPPORT Human Clinical
"Microdeletions were strongly associated with diabetes (p=2×10-7) but microduplications were not."
A dosage-specificity argument for this node: in 450,993 UK Biobank individuals the diabetes association is specific to deletion, not to any 17q12 copy number change, which is what a haploinsufficiency mechanism predicts and a general dosage-sensitivity account does not.
+ 1 more reference
Disrupted Hepatic and Otic Development
Two further organ limbs of HNF1B haploinsufficiency, grouped because both come from the same source and both are curated at low confidence in humans. Liver abnormalities are named in the GeneReviews manifestations list and warrant periodic hepatic monitoring, and sensorineural hearing loss warrants hearing screening throughout childhood; neither is characterised further there. The developmental route comes from the zebrafish HNF1B orthologue, whose loss gives underdevelopment of the liver and reduction in size of the otic vesicles alongside the kidney and pancreatic phenotypes. That the same gene patterns all four primordia is what makes a single upstream node plausible for all four limbs.
liver development GO:0001889 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased liver development (GO:0001889). GO:0001889 is a biological process from the Gene Ontology. ↓ DECREASED inner ear development GO:0048839 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased inner ear development (GO:0048839). GO:0048839 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Abnormality of the liver
Sensorineural hearing impairment
Show evidence (2 references)
PMID:11731484 SUPPORT INDIRECT Model Organism
"Phenotypes of these mutants include formation of kidney cysts, underdevelopment of the pancreas and the liver, and reduction in size of the otic vesicles."
Supplies the developmental route to both the hepatic and the otic phenotype from loss of the HNF1B orthologue. Graded INDIRECT because it is a zebrafish loss-of-function mutant rather than human heterozygous deletion, and the otic vesicle is not a human cochlea.
PMID:11731484 SUPPORT Model Organism
"We propose that vhnf1 controls development of multiple organs through regulating regional specification of organ primordia."
States the general mechanism, regional specification of organ primordia, that makes one upstream transcription-factor node account for several unrelated organ limbs.
Mullerian Duct Maldevelopment
HNF1B is expressed in the developing mesonephric and paramesonephric ducts, and 17q12 deletion is a recognised cause of Mullerian aplasia, presenting as primary amenorrhoea or as a uterine anomaly in pubertal females. This arm is easy to miss because it declares itself years after the renal and diabetic features.
mesonephric duct development GO:0072177 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased mesonephric duct development (GO:0072177). GO:0072177 is a biological process from the Gene Ontology. ↓ DECREASED
uterus UBERON:0000995 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in uterus (UBERON:0000995). UBERON:0000995 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Aplasia of the uterus
Show evidence (1 reference)
PMID:27929632 SUPPORT Human Clinical
"Consider reevaluation for uterine and vaginal abnormalities related to müllerian duct aplasia in pubertal females with primary amenorrhea."
Establishes Mullerian duct aplasia as a recognised feature requiring surveillance, which is the phenotype this node carries.
Impaired Neurodevelopment
Developmental delay or learning disability affects roughly half of affected individuals, and the deletion carries a large excess risk of autism spectrum disorder and schizophrenia. The psychiatric end of the spectrum declares itself late, which is why surveillance guidance asks specifically about prodromal psychotic symptoms in adolescence. This is the arm that is not explained by HNF1B.
Animal models
vhnf1 zebrafish insertional mutant Zebrafish fails to recapitulate The model has a hindbrain patterning phenotype through valentino, but nothing corresponding to the human neurodevelopmental and psychiatric phenotype, and it cannot have one: the deletion's brain phenotype is attributed to non-HNF1B interval genes, and this model perturbs only the HNF1B orthologue.
Downstream
Global developmental delay
Autism spectrum disorder
Schizophrenia
Attention deficit hyperactivity disorder
Bipolar affective disorder
Show evidence (1 reference)
PMID:21055719 SUPPORT Human Clinical
"In a large follow-up sample, the same deletion was identified in 2/1,182 ASD/neurocognitive impairment and in 4/6,340 schizophrenia patients, but in 0/47,929 controls (corrected p = 7.37 × 10⁻⁵)."
Quantifies the neurodevelopmental and psychiatric excess with a case-control comparison, supporting this node as a real component of the syndrome.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Chromosome 17q12 Deletion Syndrome Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

21
Cardiovascular 1
Abnormal heart morphology HP:0001627 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congenital heart defect, annotated with Abnormal heart morphology (HP:0001627). HP:0001627 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27929632 SUPPORT Human Clinical
"Treatment of kidney disease, neurodevelopmental and neuropsychiatric disorders, MODY5, genital tract abnormalities, liver abnormalities, hyperparathyroidism, eye abnormalities, exocrine pancreatic insufficiency, congenital heart defects, seizures, and sensorineural hearing loss should follow..."
Names congenital heart defects among the manifestations of the syndrome requiring management.
Digestive 2
Exocrine pancreatic insufficiency 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:27929632 SUPPORT INDIRECT Human Clinical
"Fecal elastase-1 to test for exocrine pancreatic insufficiency in individuals with suggestive signs and symptoms."
Establishes exocrine pancreatic insufficiency as a recognised feature to be tested for. Graded INDIRECT because testing guidance implies the finding rather than reporting it.
Abnormality of the liver HP:0001392 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormality of the liver (HP:0001392). HP:0001392 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:27929632 SUPPORT Human Clinical
"Treatment of kidney disease, neurodevelopmental and neuropsychiatric disorders, MODY5, genital tract abnormalities, liver abnormalities, hyperparathyroidism, eye abnormalities, exocrine pancreatic insufficiency, congenital heart defects, seizures, and sensorineural hearing loss should follow..."
Names liver abnormalities among the manifestations of the syndrome requiring management.
PMID:27929632 SUPPORT INDIRECT Human Clinical
"Hepatic function panel and GGT periodically; consider periodic lipid panel."
Establishes periodic hepatic monitoring, corroborating liver involvement. Graded INDIRECT because surveillance guidance implies rather than reports the finding.
Ear 1
Sensorineural hearing impairment 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:27929632 SUPPORT Human Clinical
"Treatment of kidney disease, neurodevelopmental and neuropsychiatric disorders, MODY5, genital tract abnormalities, liver abnormalities, hyperparathyroidism, eye abnormalities, exocrine pancreatic insufficiency, congenital heart defects, seizures, and sensorineural hearing loss should follow..."
Names sensorineural hearing loss among the manifestations of the syndrome requiring management.
Endocrine 2
Maturity-onset diabetes of the young FREQUENT HP:0004904 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Maturity-onset diabetes of the young (HP:0004904). HP:0004904 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27929632 SUPPORT Human Clinical
"MODY5 in approximately 40%, and some degree of developmental delay or learning disability in approximately 50%. MODY5 is most often diagnosed before age 25 years (range: age 10-50 years)."
Gives the 40 per cent figure behind the FREQUENT band and the age at diagnosis.
Hyperparathyroidism HP:0000843 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyperparathyroidism (HP:0000843). HP:0000843 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27929632 SUPPORT INDIRECT Human Clinical
"Annual serum calcium and phosphorus to assess for hyperparathyroidism; annual ophthalmologic evaluation during early childhood."
Establishes hyperparathyroidism as a recognised feature requiring annual surveillance. Graded INDIRECT because surveillance guidance implies the finding rather than reporting it.
Eye 1
Abnormality of the eye HP:0000478 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormality of the eye (HP:0000478). HP:0000478 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:27929632 SUPPORT Human Clinical
"Treatment of kidney disease, neurodevelopmental and neuropsychiatric disorders, MODY5, genital tract abnormalities, liver abnormalities, hyperparathyroidism, eye abnormalities, exocrine pancreatic insufficiency, congenital heart defects, seizures, and sensorineural hearing loss should follow..."
Names eye abnormalities among the manifestations of the syndrome requiring management.
PMID:27929632 SUPPORT INDIRECT Human Clinical
"Annual serum calcium and phosphorus to assess for hyperparathyroidism; annual ophthalmologic evaluation during early childhood."
Establishes annual ophthalmologic surveillance in early childhood. Graded INDIRECT for the same reason as the liver monitoring item.
Genitourinary 4
Multicystic kidney dysplasia VERY_FREQUENT HP:0000003 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Multicystic kidney dysplasia (HP:0000003). HP:0000003 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27929632 SUPPORT Human Clinical
"the authors determined that multicystic kidneys and other structural and functional kidney anomalies occur in 85%-90% of affected individuals"
Gives the 85 to 90 per cent figure behind the VERY_FREQUENT band.
Renal cyst FREQUENT HP:0000107 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Renal cyst (HP:0000107). HP:0000107 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28420700 SUPPORT INDIRECT Human Clinical
"Renal cysts were present in 122 of 166 patients, chronic kidney disease stages 3-4 (CKD3-4) in 75 of 169 (44%), and end-stage renal disease (ESRD) in 36 of 169 (21%)."
Gives the 122 of 166 count, that is 73.5 per cent, behind the FREQUENT band. Graded INDIRECT because the cohort is HNF1B disease overall rather than 17q12 deletion carriers specifically.
Chronic kidney disease FREQUENT HP:0012622 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Chronic kidney disease (HP:0012622), qualified as course progressive. HP:0012622 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:28420700 SUPPORT Human Clinical
"Compared with the patients with mutations, those with HNF1B deletion less often had CKD3-4/ESRD at diagnosis (11 of 43 vs. 27 of 35, P < 10-4) and in the long term (40 of 78 vs. 71 of 91, P = 0.0003)."
Quantifies chronic kidney disease in deletion carriers specifically, and records that it is less frequent than in point-mutation carriers.
Aplasia of the uterus HP:0000151 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Aplasia of the uterus (HP:0000151). HP:0000151 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27929632 SUPPORT INDIRECT Human Clinical
"Consider reevaluation for uterine and vaginal abnormalities related to müllerian duct aplasia in pubertal females with primary amenorrhea."
Establishes Mullerian duct aplasia as a recognised feature of the syndrome. Graded INDIRECT because it is surveillance guidance rather than a reported frequency.
Head and Neck 1
Macrocephaly HP:0000256 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Macrocephaly (HP:0000256). HP:0000256 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:21055719 SUPPORT Human Clinical
"We identified additional shared phenotypic features among nine patients available for clinical assessment, including macrocephaly, characteristic facial features, renal anomalies, and neurocognitive impairments."
Reports macrocephaly among the shared features on clinical assessment.
Metabolism 3
Hypomagnesemia FREQUENT HP:0002917 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypomagnesemia (HP:0002917). HP:0002917 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:26340261 SUPPORT Human Clinical
"Although 50-60% of ADTKD-HNF1B patients develop hypomagnesemia, HNF1B mutations are mainly identified in patients with structural kidney defects or diabetes."
Gives the 50 to 60 per cent figure behind the FREQUENT band, and notes that ascertainment through renal structure and diabetes is why the feature is under-recognised.
PMID:26340261 SUPPORT Human Clinical
"All patients presented with hypomagnesemia with a high fractional excretion of Mg2+ and hypocalciuria."
Establishes renal magnesium wasting rather than reduced intake as the mechanism, via the high fractional excretion.
Hypokalemia HP:0002900 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypokalemia (HP:0002900). HP:0002900 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27929632 SUPPORT INDIRECT Human Clinical
"Monitor blood pressure, kidney function, serum concentration of magnesium, potassium, uric acid, urine magnesium, creatinine, and protein-to-creatinine ratio with frequency per nephrologist"
Establishes serum potassium as required monitoring. Graded INDIRECT because surveillance guidance implies the abnormality rather than reporting its frequency.
Hyperuricemia HP:0002149 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyperuricemia (HP:0002149). HP:0002149 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27929632 SUPPORT INDIRECT Human Clinical
"Monitor blood pressure, kidney function, serum concentration of magnesium, potassium, uric acid, urine magnesium, creatinine, and protein-to-creatinine ratio with frequency per nephrologist"
Establishes serum uric acid as required monitoring. Graded INDIRECT for the same reason as potassium.
Nervous System 6
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:27929632 SUPPORT Human Clinical
"MODY5 in approximately 40%, and some degree of developmental delay or learning disability in approximately 50%."
Gives the approximately 50 per cent figure behind the FREQUENT band.
Autism spectrum disorder HP:0000717 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Autism (HP:0000717). HP:0000717 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:21055719 SUPPORT Human Clinical
"These data demonstrate that deletion 17q12 is a recurrent, pathogenic CNV that confers a very high risk for ASD and schizophrenia"
States the autism spectrum disorder risk conferred by the deletion.
Schizophrenia HP:0100753 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Schizophrenia (HP:0100753). HP:0100753 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:21055719 SUPPORT Human Clinical
"In a large follow-up sample, the same deletion was identified in 2/1,182 ASD/neurocognitive impairment and in 4/6,340 schizophrenia patients, but in 0/47,929 controls (corrected p = 7.37 × 10⁻⁵)."
Gives the case-control counts establishing the schizophrenia association.
PMID:22130109 SUPPORT INDIRECT Human Clinical
"Deletions at 17p12 and 17q12, were also more common in schizophrenia cases but not significantly so, while duplications at 16p13.1 were found at nearly the same rate as in previous schizophrenia samples."
Directionally consistent but non-significant in this sample, so it supports the association only weakly. Recorded to make the strength of replication visible rather than implying two concordant significant datasets.
Attention deficit hyperactivity disorder HP:0007018 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Attention deficit hyperactivity disorder (HP:0007018). HP:0007018 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27929632 SUPPORT Human Clinical
"neurodevelopmental or neuropsychiatric disorders (e.g., developmental delay, intellectual disability, autism spectrum disorder [ASD], attention-deficit/hyperactivity disorder [ADHD], schizophrenia, anxiety, and bipolar disorder)"
Lists attention-deficit/hyperactivity disorder among the recognised neuropsychiatric features.
Bipolar affective disorder HP:0007302 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bipolar affective disorder (HP:0007302). HP:0007302 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27929632 SUPPORT Human Clinical
"neurodevelopmental or neuropsychiatric disorders (e.g., developmental delay, intellectual disability, autism spectrum disorder [ASD], attention-deficit/hyperactivity disorder [ADHD], schizophrenia, anxiety, and bipolar disorder)"
Lists bipolar disorder among the recognised neuropsychiatric features.
Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27929632 SUPPORT Human Clinical
"Treatment of kidney disease, neurodevelopmental and neuropsychiatric disorders, MODY5, genital tract abnormalities, liver abnormalities, hyperparathyroidism, eye abnormalities, exocrine pancreatic insufficiency, congenital heart defects, seizures, and sensorineural hearing loss should follow..."
Lists seizures among the manifestations requiring management.
🧬

Genetic Associations

2
HNF1B (CAUSATIVE)
Gene: HNF1B hgnc:11630 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is HNF1B (hgnc:11630). hgnc:11630 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (2 references)
PMID:21055719 SUPPORT Human Clinical
"We detected a recurrent 1.4 Mb deletion at 17q12, which harbors HNF1B, the gene responsible for renal cysts and diabetes syndrome (RCAD), in 18/15,749 patients, including several with ASD, but 0/4,519 controls."
Places HNF1B inside the deleted interval and names it as the gene responsible for the renal cysts and diabetes phenotype.
PMID:28420700 SUPPORT Human Clinical
"The HNF1B syndrome is related to HNF1B mutations or to a 17q12 deletion spanning 15 genes, including HNF1B."
Confirms that the deletion spans 15 genes and that HNF1B is one of them.
Other genes in the 17q12 interval (CAUSATIVE)
relationship_type: COOPERATING variant_origin: GERMLINE
Show evidence (1 reference)
PMID:21055719 SUPPORT Human Clinical
"These data demonstrate that deletion 17q12 is a recurrent, pathogenic CNV that confers a very high risk for ASD and schizophrenia and show that one or more of the 15 genes in the deleted interval is dosage sensitive and essential for normal brain development and function."
Asserts dosage sensitivity of one or more interval genes for brain development without identifying which, which is exactly the claim this record carries.
💊

Medical Actions

4
Insulin Therapy for MODY5
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: Peptide
Most patients require insulin, though about half of those tested show some responsiveness to sulfonylureas or repaglinide. The oral response is partial and does not generally persist, which is the practical difference from the other MODY subtypes.
Mechanism Target:
Impaired Pancreatic Beta Cell Development and Insulin Secretion — Replaces the insulin the developmentally reduced beta cell mass cannot secrete; it does not address the developmental defect.
Show evidence (1 reference)
PMID:28420700 SUPPORT Human Clinical
"Although responsiveness to sulfonylureas/repaglinide was observed in 29 of the 51 tested, 111 of 140 patients (79%) were treated with insulin at follow-up."
Quantifies both the partial oral responsiveness and the eventual insulin requirement.
Renal Replacement and Transplantation
Action: Kidney TransplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Kidney Transplantation (NCIT:C15265). NCIT:C15265 is a clinical intervention from the NCI Thesaurus. NCIT:C15265
Platform: Surgery
End-stage renal disease occurs in a substantial minority and is managed by standard renal replacement. Transplantation carries a specific hazard here: it raises the risk of post-transplant diabetes in a population already predisposed, so an immunosuppressive regimen avoiding tacrolimus and mTOR inhibitors and minimising corticosteroids may be preferable in those not yet diabetic.
Mechanism Target:
Disrupted Nephron and Collecting System Development — Replaces the failed organ; it does not alter the developmental lesion in other tissues.
Show evidence (2 references)
PMID:27929632 SUPPORT Human Clinical
"Because kidney transplantation increases the risk for post-transplant diabetes mellitus, an immunosuppressive regimen that avoids tacrolimus and mTOR inhibitors and reduces corticosteroid exposure may benefit those without preexisting diabetes mellitus."
Records the GeneReviews agents-to-avoid guidance specific to transplantation in this disorder.
PMID:28420700 SUPPORT Human Clinical
"Renal cysts were present in 122 of 166 patients, chronic kidney disease stages 3-4 (CKD3-4) in 75 of 169 (44%), and end-stage renal disease (ESRD) in 36 of 169 (21%)."
Quantifies the end-stage renal disease burden that makes renal replacement relevant.
Avoidance of Lithium and Nephrotoxic or Hepatotoxic Agents
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
Platform: Other
A drug-safety consideration rather than a therapy. Lithium and other agents affecting long-term kidney function need careful thought given the underlying structural and functional renal abnormality, and antipsychotics causing weight gain compound an already raised diabetes risk. Nephrotoxic and hepatotoxic drugs should be avoided in those with kidney or liver involvement.
Show evidence (2 references)
PMID:27929632 SUPPORT Human Clinical
"Mood stabilizers that affect kidney function in the long term, such as lithium, should be carefully considered in the setting of potential underlying anatomic and functional kidney abnormalities."
Records the specific lithium caution from the GeneReviews agents-to-avoid section.
PMID:27929632 SUPPORT Human Clinical
"For individuals with mental health conditions (e.g., ASD, schizophrenia, or bipolar disorder), careful consideration of antipsychotic agents that may lead to weight gain, as this may lead to metabolic syndrome and diabetes mellitus, for which individuals with 17q12 recurrent deletion syndrome..."
Records the antipsychotic weight-gain caution, which is specific to the collision between this syndrome's psychiatric and diabetic arms.
Genetic Counseling and Parental Testing
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Platform: Behavioral / lifestyle
About a quarter of deletions are inherited, so a parental deletion should be sought rather than assumed absent, and at-risk relatives identified through the proband benefit from surveillance for renal, diabetic and developmental features.
Show evidence (1 reference)
PMID:27929632 SUPPORT Human Clinical
"If one of the proband's parents has the 17q12 recurrent deletion, it is appropriate to test older and younger sibs of the proband and other relatives at risk in order to identify those who would benefit from close assessment/monitoring for evidence of genitourinary structural or functional..."
States the cascade testing recommendation this treatment record captures.
📊

Prevalence

2
Unselected newborns (Norwegian Mother, Father and Child Cohort)
Birth Prevalence 25.0 per 100,000 1–9 per 10,000 (births)
Approximately 1 in 4,000 live-born children, from array-based CNV calling in 12,252 mother-father-child trios. This is the population figure and should be preferred over the referred-cohort rate below; the authors note it is higher than previously reported for this locus.
Show evidence (2 references)
PMID:32778765 SUPPORT Human Clinical
"We provide prevalence estimates and inheritance information for each of the 26 NDD CNVs and find higher prevalence than previously reported for 1q21.1 deletions (~1:2000), 15q11.2 duplications (~1:4000), 15q13.3 microdeletions (~1:2500), 16p11.2 proximal microdeletions (~1:2000) and 17q12..."
Gives the 1 in 4,000 newborn prevalence for 17q12 deletions behind this rate.
PMID:32778765 SUPPORT Human Clinical
"Here we perform array-based CNV calling in 12,252 mother-father-child trios from the Norwegian Mother, Father, and Child Cohort Study (MoBa) and analyse the inheritance pattern of 26 recurrent NDD CNVs in 13 genomic regions."
Establishes that the estimate comes from an unselected trio cohort rather than a clinical referral series, which is what makes it a population prevalence.
Patients referred for clinical neurodevelopmental cytogenomic testing
Point Prevalence 114.3 per 100,000 >1 in 1,000
18 of 15,749 patients referred for neurodevelopmental testing, versus 0 of 4,519 controls. This is a referred-population frequency, not a population prevalence, and is inflated by the ascertainment route.
Show evidence (1 reference)
PMID:21055719 SUPPORT Human Clinical
"We detected a recurrent 1.4 Mb deletion at 17q12, which harbors HNF1B, the gene responsible for renal cysts and diabetes syndrome (RCAD), in 18/15,749 patients, including several with ASD, but 0/4,519 controls."
Gives the numerator and denominator behind this rate.
🐁

Animal Models

1
vhnf1 zebrafish insertional mutant
Insertional mutant alleles of the zebrafish HNF1B orthologue, isolated in a mutagenesis screen. It is the model that supplies the mechanistic route from a transcription-factor dose reduction to specific organ phenotypes, by identifying the patterning genes the orthologue controls in each organ primordium. Note that it is a loss-of-function fish mutant, whereas this disorder is human heterozygous whole-gene deletion in a contiguous interval, so it models the HNF1B limb and nothing else.
Species
Zebrafish
Genotype
vhnf1 (hnf1b) loss-of-function insertional alleles
Publication
PMID:11731484
Pathograph links
Disrupted Nephron and Collecting System Development recapitulates fidelity: moderate Kidney cyst formation arising from patterning defects, with loss of proper pax2 and wt1 expression in the pronephric primordium.
Limitations: A zebrafish pronephros is not a mammalian metanephros, and the alleles are loss-of-function rather than heterozygous deletion. It establishes the developmental mechanism, not the human dose-response.
Show evidence (1 reference)
PMID:11731484 SUPPORT Model Organism
"Phenotypes of these mutants include formation of kidney cysts, underdevelopment of the pancreas and the liver, and reduction in size of the otic vesicles."
Reports the renal cystic phenotype, supporting this model as informative for the nephron development node.
Impaired Pancreatic Beta Cell Development and Insulin Secretion recapitulates fidelity: moderate Pancreatic underdevelopment, with loss of proper pdx1 and shh expression in the gut endoderm. pdx1 is the master pancreatic specification factor, which supplies the route from HNF1B dose to reduced beta cell mass.
Limitations: Same species and allele-type caveats. The model reports organ hypoplasia rather than insulin secretion, so the diabetes phenotype itself is inferred.
Show evidence (1 reference)
PMID:11731484 SUPPORT Model Organism
"vhnf1 is required for the proper expression of pdx1 and shh (sonic hedgehog) in the gut endoderm, pax2 and wt1 in the pronephric primordial, and valentino (val) in the hindbrain."
Identifies pdx1 as an HNF1B-orthologue target in gut endoderm, which is the mechanism for the pancreatic limb.
Impaired Neurodevelopment fails to recapitulate fidelity: low The model has a hindbrain patterning phenotype through valentino, but nothing corresponding to the human neurodevelopmental and psychiatric phenotype, and it cannot have one: the deletion's brain phenotype is attributed to non-HNF1B interval genes, and this model perturbs only the HNF1B orthologue.
Limitations: Behavioural and cognitive phenotypes are not assessable in this model, and autism and schizophrenia have no zebrafish counterpart. The failure is structural rather than empirical, which is why fidelity is LOW rather than the link being omitted.
Show evidence (1 reference)
PMID:11731484 NO_EVIDENCE Model Organism
"The similarity between vhnf1-associated fish phenotypes and human symptoms suggests a correlation between developmental functions of vhnf1 and the molecular etiology of MODY5 and GCKD."
Graded NO_EVIDENCE for the neurodevelopmental node deliberately: the authors relate their model to MODY5 and glomerulocystic kidney disease only, and make no claim about neurodevelopmental or psychiatric phenotypes. The absence is the point, and it is independent support for the entry's contiguous-gene argument.
Show evidence (1 reference)
PMID:11731484 SUPPORT Model Organism
"Mutations in the homeobox gene vHnf1 are associated with human diseases MODY5 (maturity-onset diabetes of the young, type V) and familial GCKD (glomerulocystic kidney disease)."
Establishes that the modelled gene is the human disease gene, the basis for treating this model as informative.
{ }

Source YAML

click to show 
name: Chromosome 17q12 Deletion Syndrome
creation_date: "2026-09-03T15:05:00Z"
category: Mendelian
synonyms:
- 17q12 microdeletion syndrome
- 17q12 deletion syndrome
- 17q12 recurrent deletion syndrome
- monosomy 17q12
- Del(17)(q12)
description: >
  Chromosome 17q12 deletion syndrome is a recurrent 1.4 Mb heterozygous deletion spanning
  about fifteen genes, one of which is HNF1B. Its renal and pancreatic phenotype - cystic
  and dysplastic kidneys, and maturity-onset diabetes of the young type 5 - is HNF1B
  haploinsufficiency, and it is the same phenotype seen with an HNF1B point mutation. Its
  neurodevelopmental and neuropsychiatric phenotype is not.

  That asymmetry is the reason this deserves an entry of its own rather than a subtype line
  on HNF1B disease. A cytogenomic screen of 15,749 patients referred for neurodevelopmental
  testing found the deletion in 18, and in none of 4,519 controls; a follow-up sample found
  it in 4 of 6,340 patients with schizophrenia and in none of 47,929 controls. The authors'
  conclusion is the mechanistic claim this entry is built around: the phenotype is a
  contiguous gene syndrome that extends beyond renal cysts and diabetes syndrome, which
  HNF1B mutations alone cause. Which of the other fourteen genes carries the brain phenotype
  is not known, and the entry records that as a knowledge gap rather than guessing.

  A second contrast runs the other way, and it is counterintuitive enough to be worth
  stating. In a 201-patient cohort split evenly between HNF1B point mutations and 17q12
  deletions, the deletion carriers had advanced chronic kidney disease and end-stage renal
  disease *less* often than the mutation carriers, at diagnosis and in the long term. So
  the deletion is not simply the more severe lesion; it is a differently shaped one, milder
  in the kidney and broader in the brain. Any account that treats a whole-gene deletion as
  the maximal HNF1B allele has to answer that observation.

  Because the deletion is invisible to sequencing-based MODY panels, patients are routinely
  diagnosed with MODY5 without the syndrome being recognised. Ascertainment therefore skews
  by referral route, and reported frequencies depend heavily on whether a cohort was
  collected through nephrology, diabetology or developmental paediatrics. The frequencies
  curated below are taken from the GeneReviews figures, which were derived with a method
  intended to avoid exactly that bias.
disease_term:
  preferred_term: chromosome 17q12 deletion syndrome
  term:
    id: MONDO:0013797
    label: chromosome 17q12 deletion syndrome
parents:
- Chromosomal deletion syndrome
references:
- reference: PMID:27929632
  title: "17q12 Recurrent Deletion Syndrome."
  tags:
  - GeneReviews
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >
    The deletion behaves as an autosomal dominant trait. About three quarters arise de novo
    and about a quarter are inherited from a parent, so a parental deletion should be looked
    for rather than assumed absent.
  de_novo_rate: "75%"
  evidence:
  - reference: PMID:27929632
    reference_title: "17q12 Recurrent Deletion Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "17q12 recurrent deletion syndrome is inherited in an autosomal dominant manner, with approximately 75% of deletions occurring de novo and approximately 25% inherited from a parent."
    explanation: >-
      States both the inheritance pattern and the de novo proportion recorded here.
  - reference: PMID:27929632
    reference_title: "17q12 Recurrent Deletion Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Each child of an individual with 17q12 recurrent deletion syndrome has a 50% chance of inheriting the deletion. Once the 17q12 recurrent deletion has been identified in an affected family member, prenatal and preimplantation genetic testing for 17q12 recurrent deletion syndrome are possible."
    explanation: >-
      States the 50 per cent transmission risk and the availability of prenatal and
      preimplantation testing, which follow from autosomal dominant inheritance.
genetic:
- name: HNF1B
  gene_term:
    preferred_term: HNF1B
    term:
      id: hgnc:11630
      label: HNF1B
  association: CAUSATIVE
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  features: >
    HNF1B lies inside the deleted interval, and its haploinsufficiency accounts for the
    renal and pancreatic phenotype. It is the gene whose point mutations cause renal cysts
    and diabetes syndrome, which is why the deletion reproduces that phenotype. It does not
    account for the neurodevelopmental phenotype.
  evidence:
  - reference: PMID:21055719
    reference_title: "Deletion 17q12 is a recurrent copy number variant that confers high risk of autism and schizophrenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We detected a recurrent 1.4 Mb deletion at 17q12, which harbors HNF1B, the gene responsible for renal cysts and diabetes syndrome (RCAD), in 18/15,749 patients, including several with ASD, but 0/4,519 controls."
    explanation: >-
      Places HNF1B inside the deleted interval and names it as the gene responsible for the
      renal cysts and diabetes phenotype.
  - reference: PMID:28420700
    reference_title: "Diabetes, Associated Clinical Spectrum, Long-term Prognosis, and Genotype/Phenotype Correlations in 201 Adult Patients With Hepatocyte Nuclear Factor 1B (HNF1B) Molecular Defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The HNF1B syndrome is related to HNF1B mutations or to a 17q12 deletion spanning 15 genes, including HNF1B."
    explanation: >-
      Confirms that the deletion spans 15 genes and that HNF1B is one of them.
- name: Other genes in the 17q12 interval
  association: CAUSATIVE
  relationship_type: COOPERATING
  variant_origin: GERMLINE
  features: >
    Fourteen further genes are removed by the deletion. One or more of them is dosage
    sensitive for brain development, since the neuropsychiatric phenotype is present with
    the deletion and absent with an HNF1B point mutation, but which gene or genes has not
    been established. This record exists to hold that claim explicitly rather than let the
    entry imply HNF1B explains everything.
  evidence:
  - reference: PMID:21055719
    reference_title: "Deletion 17q12 is a recurrent copy number variant that confers high risk of autism and schizophrenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These data demonstrate that deletion 17q12 is a recurrent, pathogenic CNV that confers a very high risk for ASD and schizophrenia and show that one or more of the 15 genes in the deleted interval is dosage sensitive and essential for normal brain development and function."
    explanation: >-
      Asserts dosage sensitivity of one or more interval genes for brain development without
      identifying which, which is exactly the claim this record carries.
mechanistic_hypotheses:
- hypothesis_group_id: contiguous_gene_model
  hypothesis_label: Contiguous gene syndrome extending beyond HNF1B
  status: CANONICAL
  description: >
    The renal and pancreatic phenotype is HNF1B haploinsufficiency; the neurodevelopmental
    and neuropsychiatric phenotype comes from loss of one or more of the other fourteen
    genes in the interval. The evidence for the split is a contrast rather than a positive
    identification: the deletion carries an ASD and schizophrenia risk that HNF1B point
    mutations do not, at case-control effect sizes large enough to survive correction in
    tens of thousands of controls. A second dataset reproduced the direction of the
    schizophrenia signal without reaching significance, so the replication is partial.
  evidence:
  - reference: PMID:21055719
    reference_title: "Deletion 17q12 is a recurrent copy number variant that confers high risk of autism and schizophrenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition, the phenotypic features of patients with this CNV are consistent with a contiguous gene syndrome that extends beyond RCAD, which is caused by HNF1B mutations only."
    explanation: >-
      States the contiguous gene claim that defines this hypothesis group, and grounds it in
      the contrast with HNF1B point mutations.
  - reference: PMID:22130109
    reference_title: "Independent estimation of the frequency of rare CNVs in the UK population confirms their role in schizophrenia."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Deletions at 17p12 and 17q12, were also more common in schizophrenia cases but not significantly so, while duplications at 16p13.1 were found at nearly the same rate as in previous schizophrenia samples."
    explanation: >-
      A replication attempt in a non-psychiatric reference set found the 17q12 deletion
      directionally more common in schizophrenia but did not reach significance, so it is
      consistent with the association without independently establishing it. Cited as the
      weaker of the two datasets, and graded INDIRECT for that reason.
pathophysiology:
- name: Recurrent 1.4 Mb Heterozygous Deletion at 17q12
  biological_scale: MOLECULAR
  description: >
    A recurrent heterozygous deletion of approximately 1.4 Mb removes about fifteen genes at
    chromosome 17q12. Its recurrence and fixed breakpoints are what make it detectable by
    chromosomal microarray and, equally, what make it invisible to the sequencing panels
    used to work up maturity-onset diabetes of the young. This node is the initiating lesion
    and branches into two mechanistically separate arms.
  downstream:
  - target: HNF1B Haploinsufficiency
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:21055719
      reference_title: "Deletion 17q12 is a recurrent copy number variant that confers high risk of autism and schizophrenia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We detected a recurrent 1.4 Mb deletion at 17q12, which harbors HNF1B, the gene responsible for renal cysts and diabetes syndrome (RCAD), in 18/15,749 patients, including several with ASD, but 0/4,519 controls."
      explanation: >-
        Establishes that the deletion removes one copy of HNF1B, which is the causal step this
        edge asserts.
  - target: Haploinsufficiency of Additional Dosage-Sensitive Interval Genes
    causal_link_type: DIRECT
    hypothesis_groups:
    - contiguous_gene_model
  evidence:
  - reference: PMID:27929632
    reference_title: "17q12 Recurrent Deletion Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis is established in a proband by detection of the 1.4-Mb heterozygous recurrent deletion at chromosome 17q12 by chromosomal microarray testing or other genomic methods."
    explanation: >-
      Gives the size and heterozygous state of the deletion and the method that detects it.
- name: HNF1B Haploinsufficiency
  biological_scale: MOLECULAR
  description: >
    One functional copy of HNF1B remains. HNF1B is a homeodomain transcription factor
    required for nephron and pancreatic development and for maintenance of tubular
    epithelial identity, so a halved dose is sufficient to derange kidney and pancreatic
    development. This is the arm of the mechanism shared with HNF1B point mutations.
  molecular_functions:
  - preferred_term: DNA-binding transcription factor activity
    term:
      id: GO:0003700
      label: DNA-binding transcription factor activity
    modifier: DECREASED
  downstream:
  - target: Disrupted Nephron and Collecting System Development
    causal_link_type: DIRECT
  - target: Impaired Pancreatic Beta Cell Development and Insulin Secretion
    causal_link_type: DIRECT
  - target: Mullerian Duct Maldevelopment
    causal_link_type: DIRECT
  - target: Disrupted Hepatic and Otic Development
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:30032214
    reference_title: "17q12 Deletion Syndrome as a Rare Cause for Diabetes Mellitus Type MODY5."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Maturity-onset diabetes of the young type 5 (MODY5) is caused by mutations of the hepatocyte nuclear factor 1 homeobox β gene (HNF1B)."
    explanation: >-
      Identifies HNF1B loss as the cause of the diabetes arm, supporting this node as the
      shared branch point.
  - reference: PMID:15085338
    reference_title: "Abnormal splicing of hepatocyte nuclear factor-1 beta in the renal cysts and diabetes syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Mutations in the hepatocyte nuclear factor-1 beta ( HNF-1 beta) gene result in disorders of renal development, typically involving renal cysts and early-onset diabetes (the RCAD syndrome/ MODY5)."
    explanation: >-
      Establishes that reduced HNF1B function produces both the renal developmental and the
      diabetic phenotype, which is the branch point this node records.
  - reference: PMID:15649945
    reference_title: "Germline hepatocyte nuclear factor 1alpha and 1beta mutations in renal cell carcinomas."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "In these cases, the expression of PKHD1 (polycystic kidney and hepatic disease 1) and UMOD (Uromodulin), two genes regulated by HNF1beta, was turned off."
    explanation: >-
      Identifies PKHD1 and UMOD as HNF1B-regulated genes whose expression is lost when HNF1B is
      inactivated, supplying named downstream targets for the transcription-factor node. Graded
      INDIRECT because the observation is in chromophobe renal carcinoma with biallelic loss,
      whereas this disorder is germline haploinsufficiency.
  - reference: PMID:15649945
    reference_title: "Germline hepatocyte nuclear factor 1alpha and 1beta mutations in renal cell carcinomas."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified two related clusters of co-regulated genes associating HNF1beta, PKHD1 and UMOD in the first group and HNF1alpha, HNF4alpha, FABP1 and UGT2B7 in the second group."
    explanation: >-
      Places PKHD1 and UMOD in a co-regulated cluster with HNF1B, which is the target axis this
      node needs. Graded INDIRECT because the clustering is from tumour and normal renal tissue
      rather than from 17q12 deletion carriers.
  - reference: PMID:11731484
    reference_title: "vhnf1, the MODY5 and familial GCKD-associated gene, regulates regional specification of the zebrafish gut, pronephros, and hindbrain."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "vhnf1 is required for the proper expression of pdx1 and shh (sonic hedgehog) in the gut endoderm, pax2 and wt1 in the pronephric primordial, and valentino (val) in the hindbrain."
    explanation: >-
      Names the organ-specific patterning genes the HNF1B orthologue controls, which is the
      mechanistic route from a transcription-factor dose reduction to the renal, pancreatic and
      hepatic limbs of the phenotype.
- name: Haploinsufficiency of Additional Dosage-Sensitive Interval Genes
  biological_scale: MOLECULAR
  description: >
    Fourteen further genes are lost in one copy. At least one is dosage sensitive for brain
    development, inferred from the fact that the deletion confers autism and schizophrenia
    risk while an HNF1B point mutation does not. The responsible gene is unidentified, so
    this node names the class of lesion rather than a molecule, and the entry does not
    pretend otherwise.
  downstream:
  - target: Impaired Neurodevelopment
    causal_link_type: DIRECT
    hypothesis_groups:
    - contiguous_gene_model
    evidence:
    - reference: PMID:21055719
      reference_title: "Deletion 17q12 is a recurrent copy number variant that confers high risk of autism and schizophrenia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "These data demonstrate that deletion 17q12 is a recurrent, pathogenic CNV that confers a very high risk for ASD and schizophrenia and show that one or more of the 15 genes in the deleted interval is dosage sensitive and essential for normal brain development and function."
      explanation: >-
        Asserts the causal link from interval gene dosage to abnormal brain development, which
        is the step this edge records.
- name: Disrupted Nephron and Collecting System Development
  biological_scale: TISSUE
  description: >
    Reduced HNF1B dose during kidney development gives multicystic dysplastic kidneys, renal
    cysts, hypoplasia and a range of other structural and functional abnormalities of the
    kidney and urinary tract. This is the commonest arm of the phenotype, present in 85 to
    90 per cent of affected individuals on ascertainment-corrected figures, and it also
    carries the tubular handling defects for magnesium, potassium and urate.
  biological_processes:
  - preferred_term: nephron development
    term:
      id: GO:0072006
      label: nephron development
    modifier: DECREASED
  locations:
  - preferred_term: kidney
    term:
      id: UBERON:0002113
      label: kidney
  downstream:
  - target: Multicystic kidney dysplasia
    causal_link_type: DIRECT
  - target: Renal cyst
    causal_link_type: DIRECT
  - target: Chronic kidney disease
    causal_link_type: DIRECT
  - target: Hypomagnesemia
    causal_link_type: DIRECT
  - target: Hypokalemia
    causal_link_type: DIRECT
  - target: Hyperuricemia
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:27929632
    reference_title: "17q12 Recurrent Deletion Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the authors determined that multicystic kidneys and other structural and functional kidney anomalies occur in 85%-90% of affected individuals"
    explanation: >-
      Gives the frequency and nature of the renal developmental phenotype on this node.
  - reference: PMID:24204001
    reference_title: "Mutations in PCBD1 cause hypomagnesemia and renal magnesium wasting."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: "HNF1B to costimulate the FXYD2 promoter, the activity of which is instrumental"
    explanation: >-
      Supplies the molecular route from reduced HNF1B dose to renal magnesium wasting: HNF1B
      drives the FXYD2 promoter, whose product mediates distal convoluted tubule magnesium
      reabsorption. Graded INDIRECT because the experiment interrogates PCBD1 loss rather than
      HNF1B haploinsufficiency, and is a cell-line overexpression system.
- name: Impaired Pancreatic Beta Cell Development and Insulin Secretion
  biological_scale: TISSUE
  description: >
    Reduced HNF1B dose impairs pancreatic development, giving maturity-onset diabetes of the
    young type 5 in roughly 40 per cent of affected individuals, most often diagnosed before
    age 25. Exocrine involvement occurs as well, so pancreatic insufficiency is part of the
    same lesion rather than a separate one. Clinically the diabetes is insulin-requiring in
    most patients despite some initial sulfonylurea responsiveness.
  biological_processes:
  - preferred_term: pancreas development
    term:
      id: GO:0031016
      label: pancreas development
    modifier: DECREASED
  locations:
  - preferred_term: pancreas
    term:
      id: UBERON:0001264
      label: pancreas
  downstream:
  - target: Maturity-onset diabetes of the young
    causal_link_type: DIRECT
  - target: Exocrine pancreatic insufficiency
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:27929632
    reference_title: "17q12 Recurrent Deletion Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MODY5 in approximately 40%, and some degree of developmental delay or learning disability in approximately 50%. MODY5 is most often diagnosed before age 25 years (range: age 10-50 years)."
    explanation: >-
      Gives the frequency and age at diagnosis of the diabetes arm recorded on this node.
  - reference: PMID:28420700
    reference_title: "Diabetes, Associated Clinical Spectrum, Long-term Prognosis, and Genotype/Phenotype Correlations in 201 Adult Patients With Hepatocyte Nuclear Factor 1B (HNF1B) Molecular Defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although responsiveness to sulfonylureas/repaglinide was observed in 29 of the 51 tested, 111 of 140 patients (79%) were treated with insulin at follow-up."
    explanation: >-
      Supports the claim that the beta cell defect is severe enough that most patients end up
      insulin-treated despite partial oral responsiveness.
  - reference: PMID:36109160
    reference_title: "Recurrent 17q12 microduplications contribute to renal disease but not diabetes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Microdeletions were strongly associated with diabetes (p=2×10-7) but microduplications were not."
    explanation: >-
      A dosage-specificity argument for this node: in 450,993 UK Biobank individuals the
      diabetes association is specific to deletion, not to any 17q12 copy number change, which is
      what a haploinsufficiency mechanism predicts and a general dosage-sensitivity account does
      not.
  - reference: PMID:36109160
    reference_title: "Recurrent 17q12 microduplications contribute to renal disease but not diabetes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SNP association analysis in the 17q12 region implicated changes to HNF1B as causing decreased eGFR (NC_000017.11:g.37741642T>G, rs12601991, p=4×10-21) and diabetes (NC_000017.11:g.37741165C>T, rs7501939, p=6×10-17)."
    explanation: >-
      Independent common-variant evidence pinning the diabetes and renal-function signals in this
      interval to HNF1B specifically, supporting the attribution of this node to HNF1B rather
      than to the interval as a whole.
- name: Disrupted Hepatic and Otic Development
  biological_scale: TISSUE
  description: >
    Two further organ limbs of HNF1B haploinsufficiency, grouped because both come from the
    same source and both are curated at low confidence in humans. Liver abnormalities are named
    in the GeneReviews manifestations list and warrant periodic hepatic monitoring, and
    sensorineural hearing loss warrants hearing screening throughout childhood; neither is
    characterised further there. The developmental route comes from the zebrafish HNF1B
    orthologue, whose loss gives underdevelopment of the liver and reduction in size of the
    otic vesicles alongside the kidney and pancreatic phenotypes. That the same gene patterns
    all four primordia is what makes a single upstream node plausible for all four limbs.
  biological_processes:
  - preferred_term: liver development
    term:
      id: GO:0001889
      label: liver development
    modifier: DECREASED
  - preferred_term: inner ear development
    term:
      id: GO:0048839
      label: inner ear development
    modifier: DECREASED
  downstream:
  - target: Abnormality of the liver
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Sensorineural hearing impairment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:11731484
    reference_title: "vhnf1, the MODY5 and familial GCKD-associated gene, regulates regional specification of the zebrafish gut, pronephros, and hindbrain."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "Phenotypes of these mutants include formation of kidney cysts, underdevelopment of the pancreas and the liver, and reduction in size of the otic vesicles."
    explanation: >-
      Supplies the developmental route to both the hepatic and the otic phenotype from loss of
      the HNF1B orthologue. Graded INDIRECT because it is a zebrafish loss-of-function mutant
      rather than human heterozygous deletion, and the otic vesicle is not a human cochlea.
  - reference: PMID:11731484
    reference_title: "vhnf1, the MODY5 and familial GCKD-associated gene, regulates regional specification of the zebrafish gut, pronephros, and hindbrain."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We propose that vhnf1 controls development of multiple organs through regulating regional specification of organ primordia."
    explanation: >-
      States the general mechanism, regional specification of organ primordia, that makes one
      upstream transcription-factor node account for several unrelated organ limbs.
- name: Mullerian Duct Maldevelopment
  biological_scale: TISSUE
  description: >
    HNF1B is expressed in the developing mesonephric and paramesonephric ducts, and 17q12
    deletion is a recognised cause of Mullerian aplasia, presenting as primary amenorrhoea
    or as a uterine anomaly in pubertal females. This arm is easy to miss because it declares
    itself years after the renal and diabetic features.
  biological_processes:
  - preferred_term: mesonephric duct development
    term:
      id: GO:0072177
      label: mesonephric duct development
    modifier: DECREASED
  locations:
  - preferred_term: uterus
    term:
      id: UBERON:0000995
      label: uterus
  downstream:
  - target: Aplasia of the uterus
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:27929632
    reference_title: "17q12 Recurrent Deletion Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Consider reevaluation for uterine and vaginal abnormalities related to müllerian duct aplasia in pubertal females with primary amenorrhea."
    explanation: >-
      Establishes Mullerian duct aplasia as a recognised feature requiring surveillance, which
      is the phenotype this node carries.
- name: Impaired Neurodevelopment
  biological_scale: ORGANISM
  description: >
    Developmental delay or learning disability affects roughly half of affected individuals,
    and the deletion carries a large excess risk of autism spectrum disorder and
    schizophrenia. The psychiatric end of the spectrum declares itself late, which is why
    surveillance guidance asks specifically about prodromal psychotic symptoms in
    adolescence. This is the arm that is not explained by HNF1B.
  downstream:
  - target: Global developmental delay
    causal_link_type: DIRECT
  - target: Autism spectrum disorder
    causal_link_type: DIRECT
  - target: Schizophrenia
    causal_link_type: DIRECT
  - target: Attention deficit hyperactivity disorder
    causal_link_type: DIRECT
  - target: Bipolar affective disorder
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:21055719
    reference_title: "Deletion 17q12 is a recurrent copy number variant that confers high risk of autism and schizophrenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In a large follow-up sample, the same deletion was identified in 2/1,182 ASD/neurocognitive impairment and in 4/6,340 schizophrenia patients, but in 0/47,929 controls (corrected p = 7.37 × 10⁻⁵)."
    explanation: >-
      Quantifies the neurodevelopmental and psychiatric excess with a case-control comparison,
      supporting this node as a real component of the syndrome.
phenotypes:
- category: Renal
  name: Multicystic kidney dysplasia
  description: >
    Multicystic dysplastic kidneys and other structural and functional kidney and urinary
    tract abnormalities, the most frequent component of the syndrome.
  phenotype_term:
    preferred_term: Multicystic kidney dysplasia
    term:
      id: HP:0000003
      label: Multicystic kidney dysplasia
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:27929632
    reference_title: "17q12 Recurrent Deletion Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the authors determined that multicystic kidneys and other structural and functional kidney anomalies occur in 85%-90% of affected individuals"
    explanation: >-
      Gives the 85 to 90 per cent figure behind the VERY_FREQUENT band.
- category: Renal
  name: Renal cyst
  description: >
    Renal cysts in 122 of 166 patients, that is 73.5 per cent, which puts this in the
    FREQUENT band rather than VERY_FREQUENT. Note the cohort is HNF1B disease overall, split
    roughly evenly between deletions and point mutations, so this is not a deletion-specific
    figure; the ascertainment-corrected GeneReviews figure for structural kidney anomalies as
    a class is higher, at 85 to 90 per cent.
  phenotype_term:
    preferred_term: Renal cyst
    term:
      id: HP:0000107
      label: Renal cyst
  frequency: FREQUENT
  evidence:
  - reference: PMID:28420700
    reference_title: "Diabetes, Associated Clinical Spectrum, Long-term Prognosis, and Genotype/Phenotype Correlations in 201 Adult Patients With Hepatocyte Nuclear Factor 1B (HNF1B) Molecular Defects."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Renal cysts were present in 122 of 166 patients, chronic kidney disease stages 3-4 (CKD3-4) in 75 of 169 (44%), and end-stage renal disease (ESRD) in 36 of 169 (21%)."
    explanation: >-
      Gives the 122 of 166 count, that is 73.5 per cent, behind the FREQUENT band. Graded
      INDIRECT because the cohort is HNF1B disease overall rather than 17q12 deletion carriers
      specifically.
- category: Renal
  name: Chronic kidney disease
  description: >
    Chronic kidney disease is common and progresses to end-stage disease in a substantial
    minority. Note the genotype contrast: in a cohort split between HNF1B point mutations
    and 17q12 deletions, advanced kidney disease was significantly less frequent in the
    deletion carriers.
  phenotype_term:
    preferred_term: Chronic kidney disease
    term:
      id: HP:0012622
      label: Chronic kidney disease
    clinical_course: PROGRESSIVE
  frequency: FREQUENT
  evidence:
  - reference: PMID:28420700
    reference_title: "Diabetes, Associated Clinical Spectrum, Long-term Prognosis, and Genotype/Phenotype Correlations in 201 Adult Patients With Hepatocyte Nuclear Factor 1B (HNF1B) Molecular Defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Compared with the patients with mutations, those with HNF1B deletion less often had CKD3-4/ESRD at diagnosis (11 of 43 vs. 27 of 35, P < 10-4) and in the long term (40 of 78 vs. 71 of 91, P = 0.0003)."
    explanation: >-
      Quantifies chronic kidney disease in deletion carriers specifically, and records that it
      is less frequent than in point-mutation carriers.
- category: Endocrine
  name: Maturity-onset diabetes of the young
  description: >
    Maturity-onset diabetes of the young type 5, in roughly 40 per cent of affected
    individuals, usually diagnosed before age 25.
  phenotype_term:
    preferred_term: Maturity-onset diabetes of the young
    term:
      id: HP:0004904
      label: Maturity-onset diabetes of the young
  frequency: FREQUENT
  evidence:
  - reference: PMID:27929632
    reference_title: "17q12 Recurrent Deletion Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MODY5 in approximately 40%, and some degree of developmental delay or learning disability in approximately 50%. MODY5 is most often diagnosed before age 25 years (range: age 10-50 years)."
    explanation: >-
      Gives the 40 per cent figure behind the FREQUENT band and the age at diagnosis.
- category: Neurodevelopmental
  name: Global developmental delay
  description: >
    Some degree of developmental delay or learning disability in roughly half of affected
    individuals.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  frequency: FREQUENT
  evidence:
  - reference: PMID:27929632
    reference_title: "17q12 Recurrent Deletion Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MODY5 in approximately 40%, and some degree of developmental delay or learning disability in approximately 50%."
    explanation: >-
      Gives the approximately 50 per cent figure behind the FREQUENT band.
- category: Neurodevelopmental
  name: Autism spectrum disorder
  description: >
    Autism spectrum disorder, at a risk high enough that the deletion was originally
    ascertained through neurodevelopmental referrals rather than renal ones.
  phenotype_term:
    preferred_term: Autism
    term:
      id: HP:0000717
      label: Autism
  evidence:
  - reference: PMID:21055719
    reference_title: "Deletion 17q12 is a recurrent copy number variant that confers high risk of autism and schizophrenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These data demonstrate that deletion 17q12 is a recurrent, pathogenic CNV that confers a very high risk for ASD and schizophrenia"
    explanation: >-
      States the autism spectrum disorder risk conferred by the deletion.
- category: Psychiatric
  name: Schizophrenia
  description: >
    Schizophrenia. The primary case-control comparison found the deletion in 4 of 6,340
    schizophrenia patients and none of 47,929 controls. A second, smaller dataset found the
    same direction but did not reach significance, and the entry cites both rather than
    treating the association as doubly confirmed. The frequency in deletion carriers is not
    established; what is established is the excess relative to controls.
  phenotype_term:
    preferred_term: Schizophrenia
    term:
      id: HP:0100753
      label: Schizophrenia
  evidence:
  - reference: PMID:21055719
    reference_title: "Deletion 17q12 is a recurrent copy number variant that confers high risk of autism and schizophrenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In a large follow-up sample, the same deletion was identified in 2/1,182 ASD/neurocognitive impairment and in 4/6,340 schizophrenia patients, but in 0/47,929 controls (corrected p = 7.37 × 10⁻⁵)."
    explanation: >-
      Gives the case-control counts establishing the schizophrenia association.
  - reference: PMID:22130109
    reference_title: "Independent estimation of the frequency of rare CNVs in the UK population confirms their role in schizophrenia."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Deletions at 17p12 and 17q12, were also more common in schizophrenia cases but not significantly so, while duplications at 16p13.1 were found at nearly the same rate as in previous schizophrenia samples."
    explanation: >-
      Directionally consistent but non-significant in this sample, so it supports the
      association only weakly. Recorded to make the strength of replication visible rather
      than implying two concordant significant datasets.
- category: Psychiatric
  name: Attention deficit hyperactivity disorder
  phenotype_term:
    preferred_term: Attention deficit hyperactivity disorder
    term:
      id: HP:0007018
      label: Attention deficit hyperactivity disorder
  evidence:
  - reference: PMID:27929632
    reference_title: "17q12 Recurrent Deletion Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "neurodevelopmental or neuropsychiatric disorders (e.g., developmental delay, intellectual disability, autism spectrum disorder [ASD], attention-deficit/hyperactivity disorder [ADHD], schizophrenia, anxiety, and bipolar disorder)"
    explanation: >-
      Lists attention-deficit/hyperactivity disorder among the recognised neuropsychiatric
      features.
- category: Psychiatric
  name: Bipolar affective disorder
  phenotype_term:
    preferred_term: Bipolar affective disorder
    term:
      id: HP:0007302
      label: Bipolar affective disorder
  evidence:
  - reference: PMID:27929632
    reference_title: "17q12 Recurrent Deletion Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "neurodevelopmental or neuropsychiatric disorders (e.g., developmental delay, intellectual disability, autism spectrum disorder [ASD], attention-deficit/hyperactivity disorder [ADHD], schizophrenia, anxiety, and bipolar disorder)"
    explanation: >-
      Lists bipolar disorder among the recognised neuropsychiatric features.
- category: Growth
  name: Macrocephaly
  phenotype_term:
    preferred_term: Macrocephaly
    term:
      id: HP:0000256
      label: Macrocephaly
  evidence:
  - reference: PMID:21055719
    reference_title: "Deletion 17q12 is a recurrent copy number variant that confers high risk of autism and schizophrenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified additional shared phenotypic features among nine patients available for clinical assessment, including macrocephaly, characteristic facial features, renal anomalies, and neurocognitive impairments."
    explanation: >-
      Reports macrocephaly among the shared features on clinical assessment.
- category: Metabolic
  name: Hypomagnesemia
  description: >
    Hypomagnesaemia from renal magnesium wasting, one of the tubular handling defects that
    guidelines ask to be monitored for.
  phenotype_term:
    preferred_term: Hypomagnesemia
    term:
      id: HP:0002917
      label: Hypomagnesemia
  frequency: FREQUENT
  evidence:
  - reference: PMID:26340261
    reference_title: "Hypomagnesemia as First Clinical Manifestation of ADTKD-HNF1B: A Case Series and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although 50-60% of ADTKD-HNF1B patients develop hypomagnesemia, HNF1B mutations are mainly identified in patients with structural kidney defects or diabetes."
    explanation: >-
      Gives the 50 to 60 per cent figure behind the FREQUENT band, and notes that ascertainment
      through renal structure and diabetes is why the feature is under-recognised.
  - reference: PMID:26340261
    reference_title: "Hypomagnesemia as First Clinical Manifestation of ADTKD-HNF1B: A Case Series and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients presented with hypomagnesemia with a high fractional excretion of Mg2+ and hypocalciuria."
    explanation: >-
      Establishes renal magnesium wasting rather than reduced intake as the mechanism, via the
      high fractional excretion.
- category: Endocrine
  name: Hyperparathyroidism
  phenotype_term:
    preferred_term: Hyperparathyroidism
    term:
      id: HP:0000843
      label: Hyperparathyroidism
  evidence:
  - reference: PMID:27929632
    reference_title: "17q12 Recurrent Deletion Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Annual serum calcium and phosphorus to assess for hyperparathyroidism; annual ophthalmologic evaluation during early childhood."
    directness: INDIRECT
    explanation: >-
      Establishes hyperparathyroidism as a recognised feature requiring annual surveillance.
      Graded INDIRECT because surveillance guidance implies the finding rather than reporting it.
- category: Gastrointestinal
  name: Exocrine pancreatic insufficiency
  phenotype_term:
    preferred_term: Exocrine pancreatic insufficiency
    term:
      id: HP:0001738
      label: Exocrine pancreatic insufficiency
  evidence:
  - reference: PMID:27929632
    reference_title: "17q12 Recurrent Deletion Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Fecal elastase-1 to test for exocrine pancreatic insufficiency in individuals with suggestive signs and symptoms."
    directness: INDIRECT
    explanation: >-
      Establishes exocrine pancreatic insufficiency as a recognised feature to be tested for.
      Graded INDIRECT because testing guidance implies the finding rather than reporting it.
- category: Hepatic
  name: Abnormality of the liver
  description: >
    Liver abnormalities, named in the GeneReviews manifestations list and separately requiring
    periodic hepatic function panel and GGT monitoring. Bound at the system level because
    neither source characterises the lesion.
  phenotype_term:
    preferred_term: Abnormality of the liver
    term:
      id: HP:0001392
      label: Abnormality of the liver
  evidence:
  - reference: PMID:27929632
    reference_title: "17q12 Recurrent Deletion Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatment of kidney disease, neurodevelopmental and neuropsychiatric disorders, MODY5, genital tract abnormalities, liver abnormalities, hyperparathyroidism, eye abnormalities, exocrine pancreatic insufficiency, congenital heart defects, seizures, and sensorineural hearing loss should follow standard practice."
    explanation: >-
      Names liver abnormalities among the manifestations of the syndrome requiring management.
  - reference: PMID:27929632
    reference_title: "17q12 Recurrent Deletion Syndrome."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hepatic function panel and GGT periodically; consider periodic lipid panel."
    explanation: >-
      Establishes periodic hepatic monitoring, corroborating liver involvement. Graded INDIRECT
      because surveillance guidance implies rather than reports the finding.
- category: Ophthalmologic
  name: Abnormality of the eye
  description: >
    Eye abnormalities, named in the GeneReviews manifestations list and requiring annual
    ophthalmologic evaluation in early childhood. Bound at the system level for the same reason
    as the liver finding.
  phenotype_term:
    preferred_term: Abnormality of the eye
    term:
      id: HP:0000478
      label: Abnormality of the eye
  evidence:
  - reference: PMID:27929632
    reference_title: "17q12 Recurrent Deletion Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatment of kidney disease, neurodevelopmental and neuropsychiatric disorders, MODY5, genital tract abnormalities, liver abnormalities, hyperparathyroidism, eye abnormalities, exocrine pancreatic insufficiency, congenital heart defects, seizures, and sensorineural hearing loss should follow standard practice."
    explanation: >-
      Names eye abnormalities among the manifestations of the syndrome requiring management.
  - reference: PMID:27929632
    reference_title: "17q12 Recurrent Deletion Syndrome."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Annual serum calcium and phosphorus to assess for hyperparathyroidism; annual ophthalmologic evaluation during early childhood."
    explanation: >-
      Establishes annual ophthalmologic surveillance in early childhood. Graded INDIRECT for the
      same reason as the liver monitoring item.
- category: Cardiovascular
  name: Abnormal heart morphology
  description: >
    Congenital heart defects, named in the GeneReviews manifestations list. The specific lesions
    are not characterised there, so the binding is at the morphology level.
  phenotype_term:
    preferred_term: Congenital heart defect
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  evidence:
  - reference: PMID:27929632
    reference_title: "17q12 Recurrent Deletion Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatment of kidney disease, neurodevelopmental and neuropsychiatric disorders, MODY5, genital tract abnormalities, liver abnormalities, hyperparathyroidism, eye abnormalities, exocrine pancreatic insufficiency, congenital heart defects, seizures, and sensorineural hearing loss should follow standard practice."
    explanation: >-
      Names congenital heart defects among the manifestations of the syndrome requiring
      management.
- category: Metabolic
  name: Hypokalemia
  description: >
    Renal potassium wasting, one of the tubular handling defects GeneReviews asks to be
    monitored for alongside magnesium and urate.
  phenotype_term:
    preferred_term: Hypokalemia
    term:
      id: HP:0002900
      label: Hypokalemia
  evidence:
  - reference: PMID:27929632
    reference_title: "17q12 Recurrent Deletion Syndrome."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Monitor blood pressure, kidney function, serum concentration of magnesium, potassium, uric acid, urine magnesium, creatinine, and protein-to-creatinine ratio with frequency per nephrologist"
    explanation: >-
      Establishes serum potassium as required monitoring. Graded INDIRECT because surveillance
      guidance implies the abnormality rather than reporting its frequency.
- category: Metabolic
  name: Hyperuricemia
  description: >
    Hyperuricaemia from reduced renal urate handling, monitored alongside magnesium and
    potassium.
  phenotype_term:
    preferred_term: Hyperuricemia
    term:
      id: HP:0002149
      label: Hyperuricemia
  evidence:
  - reference: PMID:27929632
    reference_title: "17q12 Recurrent Deletion Syndrome."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Monitor blood pressure, kidney function, serum concentration of magnesium, potassium, uric acid, urine magnesium, creatinine, and protein-to-creatinine ratio with frequency per nephrologist"
    explanation: >-
      Establishes serum uric acid as required monitoring. Graded INDIRECT for the same reason as
      potassium.
- category: Genitourinary
  name: Aplasia of the uterus
  description: >
    Mullerian duct aplasia, presenting in pubertal females as primary amenorrhoea with
    uterine and vaginal abnormalities.
  phenotype_term:
    preferred_term: Aplasia of the uterus
    term:
      id: HP:0000151
      label: Aplasia of the uterus
  evidence:
  - reference: PMID:27929632
    reference_title: "17q12 Recurrent Deletion Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Consider reevaluation for uterine and vaginal abnormalities related to müllerian duct aplasia in pubertal females with primary amenorrhea."
    directness: INDIRECT
    explanation: >-
      Establishes Mullerian duct aplasia as a recognised feature of the syndrome. Graded INDIRECT
      because it is surveillance guidance rather than a reported frequency.
- category: Neurologic
  name: Seizure
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:27929632
    reference_title: "17q12 Recurrent Deletion Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatment of kidney disease, neurodevelopmental and neuropsychiatric disorders, MODY5, genital tract abnormalities, liver abnormalities, hyperparathyroidism, eye abnormalities, exocrine pancreatic insufficiency, congenital heart defects, seizures, and sensorineural hearing loss should follow standard practice."
    explanation: >-
      Lists seizures among the manifestations requiring management.
- category: Auditory
  name: Sensorineural hearing impairment
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:27929632
    reference_title: "17q12 Recurrent Deletion Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatment of kidney disease, neurodevelopmental and neuropsychiatric disorders, MODY5, genital tract abnormalities, liver abnormalities, hyperparathyroidism, eye abnormalities, exocrine pancreatic insufficiency, congenital heart defects, seizures, and sensorineural hearing loss should follow standard practice."
    explanation: >-
      Names sensorineural hearing loss among the manifestations of the syndrome requiring
      management.
treatments:
- name: Insulin Therapy for MODY5
  description: >
    Most patients require insulin, though about half of those tested show some
    responsiveness to sulfonylureas or repaglinide. The oral response is partial and does not
    generally persist, which is the practical difference from the other MODY subtypes.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: insulin
      term:
        id: CHEBI:145810
        label: insulin
  therapeutic_modality: PEPTIDE
  target_mechanisms:
  - target: Impaired Pancreatic Beta Cell Development and Insulin Secretion
    description: >-
      Replaces the insulin the developmentally reduced beta cell mass cannot secrete; it does
      not address the developmental defect.
  evidence:
  - reference: PMID:28420700
    reference_title: "Diabetes, Associated Clinical Spectrum, Long-term Prognosis, and Genotype/Phenotype Correlations in 201 Adult Patients With Hepatocyte Nuclear Factor 1B (HNF1B) Molecular Defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although responsiveness to sulfonylureas/repaglinide was observed in 29 of the 51 tested, 111 of 140 patients (79%) were treated with insulin at follow-up."
    explanation: >-
      Quantifies both the partial oral responsiveness and the eventual insulin requirement.
- name: Renal Replacement and Transplantation
  description: >
    End-stage renal disease occurs in a substantial minority and is managed by standard renal
    replacement. Transplantation carries a specific hazard here: it raises the risk of
    post-transplant diabetes in a population already predisposed, so an immunosuppressive
    regimen avoiding tacrolimus and mTOR inhibitors and minimising corticosteroids may be
    preferable in those not yet diabetic.
  treatment_term:
    preferred_term: Kidney Transplantation
    term:
      id: NCIT:C15265
      label: Kidney Transplantation
  therapeutic_modality: SURGERY
  target_mechanisms:
  - target: Disrupted Nephron and Collecting System Development
    description: >-
      Replaces the failed organ; it does not alter the developmental lesion in other tissues.
  evidence:
  - reference: PMID:27929632
    reference_title: "17q12 Recurrent Deletion Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Because kidney transplantation increases the risk for post-transplant diabetes mellitus, an immunosuppressive regimen that avoids tacrolimus and mTOR inhibitors and reduces corticosteroid exposure may benefit those without preexisting diabetes mellitus."
    explanation: >-
      Records the GeneReviews agents-to-avoid guidance specific to transplantation in this
      disorder.
  - reference: PMID:28420700
    reference_title: "Diabetes, Associated Clinical Spectrum, Long-term Prognosis, and Genotype/Phenotype Correlations in 201 Adult Patients With Hepatocyte Nuclear Factor 1B (HNF1B) Molecular Defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Renal cysts were present in 122 of 166 patients, chronic kidney disease stages 3-4 (CKD3-4) in 75 of 169 (44%), and end-stage renal disease (ESRD) in 36 of 169 (21%)."
    explanation: >-
      Quantifies the end-stage renal disease burden that makes renal replacement relevant.
- name: Avoidance of Lithium and Nephrotoxic or Hepatotoxic Agents
  description: >
    A drug-safety consideration rather than a therapy. Lithium and other agents affecting
    long-term kidney function need careful thought given the underlying structural and
    functional renal abnormality, and antipsychotics causing weight gain compound an already
    raised diabetes risk. Nephrotoxic and hepatotoxic drugs should be avoided in those with
    kidney or liver involvement.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  therapeutic_modality: OTHER
  evidence:
  - reference: PMID:27929632
    reference_title: "17q12 Recurrent Deletion Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mood stabilizers that affect kidney function in the long term, such as lithium, should be carefully considered in the setting of potential underlying anatomic and functional kidney abnormalities."
    explanation: >-
      Records the specific lithium caution from the GeneReviews agents-to-avoid section.
  - reference: PMID:27929632
    reference_title: "17q12 Recurrent Deletion Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "For individuals with mental health conditions (e.g., ASD, schizophrenia, or bipolar disorder), careful consideration of antipsychotic agents that may lead to weight gain, as this may lead to metabolic syndrome and diabetes mellitus, for which individuals with 17q12 recurrent deletion syndrome are at increased risk."
    explanation: >-
      Records the antipsychotic weight-gain caution, which is specific to the collision between
      this syndrome's psychiatric and diabetic arms.
- name: Genetic Counseling and Parental Testing
  description: >
    About a quarter of deletions are inherited, so a parental deletion should be sought
    rather than assumed absent, and at-risk relatives identified through the proband benefit
    from surveillance for renal, diabetic and developmental features.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  therapeutic_modality: BEHAVIORAL
  evidence:
  - reference: PMID:27929632
    reference_title: "17q12 Recurrent Deletion Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "If one of the proband's parents has the 17q12 recurrent deletion, it is appropriate to test older and younger sibs of the proband and other relatives at risk in order to identify those who would benefit from close assessment/monitoring for evidence of genitourinary structural or functional defects, MODY5, and developmental delays / intellectual disability."
    explanation: >-
      States the cascade testing recommendation this treatment record captures.
animal_models:
- name: vhnf1 zebrafish insertional mutant
  species: Zebrafish
  genotype: vhnf1 (hnf1b) loss-of-function insertional alleles
  publication: PMID:11731484
  description: >
    Insertional mutant alleles of the zebrafish HNF1B orthologue, isolated in a mutagenesis
    screen. It is the model that supplies the mechanistic route from a transcription-factor
    dose reduction to specific organ phenotypes, by identifying the patterning genes the
    orthologue controls in each organ primordium. Note that it is a loss-of-function fish
    mutant, whereas this disorder is human heterozygous whole-gene deletion in a contiguous
    interval, so it models the HNF1B limb and nothing else.
  modeled_mechanisms:
  - target: Disrupted Nephron and Collecting System Development
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Kidney cyst formation arising from patterning defects, with loss of proper pax2 and wt1
      expression in the pronephric primordium.
    limitations: >-
      A zebrafish pronephros is not a mammalian metanephros, and the alleles are
      loss-of-function rather than heterozygous deletion. It establishes the developmental
      mechanism, not the human dose-response.
    evidence:
    - reference: PMID:11731484
      reference_title: "vhnf1, the MODY5 and familial GCKD-associated gene, regulates regional specification of the zebrafish gut, pronephros, and hindbrain."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Phenotypes of these mutants include formation of kidney cysts, underdevelopment of the pancreas and the liver, and reduction in size of the otic vesicles."
      explanation: >-
        Reports the renal cystic phenotype, supporting this model as informative for the nephron
        development node.
  - target: Impaired Pancreatic Beta Cell Development and Insulin Secretion
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Pancreatic underdevelopment, with loss of proper pdx1 and shh expression in the gut
      endoderm. pdx1 is the master pancreatic specification factor, which supplies the route
      from HNF1B dose to reduced beta cell mass.
    limitations: >-
      Same species and allele-type caveats. The model reports organ hypoplasia rather than
      insulin secretion, so the diabetes phenotype itself is inferred.
    evidence:
    - reference: PMID:11731484
      reference_title: "vhnf1, the MODY5 and familial GCKD-associated gene, regulates regional specification of the zebrafish gut, pronephros, and hindbrain."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "vhnf1 is required for the proper expression of pdx1 and shh (sonic hedgehog) in the gut endoderm, pax2 and wt1 in the pronephric primordial, and valentino (val) in the hindbrain."
      explanation: >-
        Identifies pdx1 as an HNF1B-orthologue target in gut endoderm, which is the mechanism for
        the pancreatic limb.
  - target: Impaired Neurodevelopment
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    description: >-
      The model has a hindbrain patterning phenotype through valentino, but nothing
      corresponding to the human neurodevelopmental and psychiatric phenotype, and it cannot
      have one: the deletion's brain phenotype is attributed to non-HNF1B interval genes, and
      this model perturbs only the HNF1B orthologue.
    limitations: >-
      Behavioural and cognitive phenotypes are not assessable in this model, and autism and
      schizophrenia have no zebrafish counterpart. The failure is structural rather than
      empirical, which is why fidelity is LOW rather than the link being omitted.
    evidence:
    - reference: PMID:11731484
      reference_title: "vhnf1, the MODY5 and familial GCKD-associated gene, regulates regional specification of the zebrafish gut, pronephros, and hindbrain."
      supports: NO_EVIDENCE
      evidence_source: MODEL_ORGANISM
      snippet: "The similarity between vhnf1-associated fish phenotypes and human symptoms suggests a correlation between developmental functions of vhnf1 and the molecular etiology of MODY5 and GCKD."
      explanation: >-
        Graded NO_EVIDENCE for the neurodevelopmental node deliberately: the authors relate their
        model to MODY5 and glomerulocystic kidney disease only, and make no claim about
        neurodevelopmental or psychiatric phenotypes. The absence is the point, and it is
        independent support for the entry's contiguous-gene argument.
  evidence:
  - reference: PMID:11731484
    reference_title: "vhnf1, the MODY5 and familial GCKD-associated gene, regulates regional specification of the zebrafish gut, pronephros, and hindbrain."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Mutations in the homeobox gene vHnf1 are associated with human diseases MODY5 (maturity-onset diabetes of the young, type V) and familial GCKD (glomerulocystic kidney disease)."
    explanation: >-
      Establishes that the modelled gene is the human disease gene, the basis for treating this
      model as informative.
definitions:
- name: Chromosomal microarray detection of the 1.4 Mb 17q12 deletion
  definition_type: DIAGNOSTIC_CRITERIA
  derivation_basis: ESTABLISHED_CRITERIA
  description: >
    Diagnosis rests on detecting the recurrent 1.4 Mb heterozygous deletion by chromosomal
    microarray or another genomic method. The practical point is a negative one: sequencing
    panels used to work up maturity-onset diabetes of the young cannot see a 1.4 Mb deletion,
    so a MODY5 diagnosis reached by panel sequencing does not exclude this syndrome and a
    normal panel is not reassurance.
  evidence:
  - reference: PMID:27929632
    reference_title: "17q12 Recurrent Deletion Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis is established in a proband by detection of the 1.4-Mb heterozygous recurrent deletion at chromosome 17q12 by chromosomal microarray testing or other genomic methods."
    explanation: >-
      States the diagnostic method this definition records.
  - reference: PMID:30032214
    reference_title: "17q12 Deletion Syndrome as a Rare Cause for Diabetes Mellitus Type MODY5."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Because HNF1B deletions are virtually always part of a 17q12 deletion syndrome and common genetic analyses for evaluation of MODY5 are unable to detect the deletion of a 1.4-Mb chromosomal region, initial attention to the syndromal features at the stage of diagnosis is of considerable importance for establishing correct diagnosis, subsequent therapy, and interdisciplinary patient care."
    explanation: >-
      States that standard MODY5 genetic testing cannot detect the deletion, which is the
      ascertainment caveat this definition exists to record.
- name: HNF1B score for selecting patients for genetic testing
  definition_type: PHENOTYPE_ALGORITHM
  derivation_basis: ESTABLISHED_CRITERIA
  description: >
    A 17-item weighted clinical, imaging and biochemical score developed to decide who should
    be sent for HNF1B genetic testing, covering antenatal discovery, family history and
    kidney, pancreas, liver and genital tract involvement. It is a rule-out instrument rather
    than a diagnostic one: at the optimal cutoff of 8 its negative predictive value exceeds 99
    per cent with sensitivity 98.2 per cent, but specificity is only 41.1 per cent, so a score
    above threshold does not make the diagnosis. Note the scope caveat for this entry: the
    score is validated for HNF1B disease as a whole, not for the 17q12 deletion specifically,
    and a positive score is followed by sequencing, which cannot see the deletion.
  validation_status:
    status: VALIDATED_AGAINST_GOLD_STANDARD
    rationale: >-
      Assessed by ROC analysis in a 433-individual cohort containing 56 HNF1B cases, against
      genetic testing as the gold standard, giving an AUC of 0.78.
    evidence:
    - reference: PMID:24897035
      reference_title: "The HNF1B score is a simple tool to select patients for HNF1B gene analysis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The performance of the score was assessed by a ROC curve analysis in a 433-individual cohort containing 56 HNF1B cases."
      explanation: >-
        Documents the validation cohort and method behind this status.
  evidence:
  - reference: PMID:24897035
    reference_title: "The HNF1B score is a simple tool to select patients for HNF1B gene analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The optimal cutoff threshold for the negative predictive value to rule out HNF1B mutations in a suspected individual was 8 (sensitivity 98.2%, specificity 41.1%, and negative predictive value over 99%)."
    explanation: >-
      Gives the operating characteristics recorded in this definition, including the low
      specificity that makes it a rule-out rather than a diagnostic instrument.
  - reference: PMID:24897035
    reference_title: "The HNF1B score is a simple tool to select patients for HNF1B gene analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The HNF1B score is calculated upon 17 items including antenatal discovery, family history, and organ involvement (kidney, pancreas, liver, and genital tract)."
    explanation: >-
      Lists the score's components, which is the content of this definition.
discussions:
- discussion_id: which_interval_gene_drives_ndd
  kind: KNOWLEDGE_GAP
  prompt: >-
    Which of the fourteen non-HNF1B genes in the 17q12 interval is responsible for the
    neurodevelopmental and psychiatric phenotype?
  attaches_to:
  - pathophysiology#Haploinsufficiency of Additional Dosage-Sensitive Interval Genes
  - pathophysiology#Impaired Neurodevelopment
  rationale: >
    The evidence for a non-HNF1B contribution is a contrast, not an identification: the
    deletion confers autism and schizophrenia risk that HNF1B point mutations do not. Because
    the deletion has fixed recurrent breakpoints, human genetics offers almost no smaller
    deletions to narrow the interval with, so the question is not answerable by collecting
    more patients with the same CNV. Until it is resolved, the brain arm of this entry has a
    node that names a class of lesion rather than a molecule.
- discussion_id: deletion_milder_renal_than_point_mutation
  kind: KNOWLEDGE_GAP
  prompt: >-
    Why do 17q12 deletion carriers have less advanced kidney disease than HNF1B
    point-mutation carriers, when the deletion removes the whole gene?
  attaches_to:
  - phenotypes#Chronic kidney disease
  - pathophysiology#HNF1B Haploinsufficiency
  rationale: >
    A 201-patient cohort found CKD stage 3-4 and end-stage renal disease significantly less
    frequent in deletion carriers than in point-mutation carriers, both at diagnosis and in
    the long term. A pure haploinsufficiency model predicts the two should be equivalent, and
    a dominant-negative effect of some missense alleles would explain the direction but has
    not been shown for the alleles in that cohort. Ascertainment is the competing explanation:
    deletion carriers are often found through neurodevelopmental or antenatal routes and
    point-mutation carriers through nephrology, which would bias renal severity the way
    observed. The study does not separate these, and no subsequent work has. A later
    prenatal-and-postnatal comparison across 82 studies asked the differentiation question
    directly in its title and concluded only that both mutation groups show high phenotypic
    heterogeneity, so the difference remains unexplained rather than refuted.
  evidence:
  - reference: PMID:31498910
    reference_title: "Prenatal diagnosis of HNF1B-associated renal cysts: Is there a need to differentiate intragenic variants from 17q12 microdeletion syndrome?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Overall, both mutation groups showed a high phenotypic heterogeneity."
    explanation: >-
      A study set up to compare 17q12 microdeletions against intragenic HNF1B variants found
      heterogeneity in both rather than a clean genotype-phenotype split, which is why this gap
      is recorded as open.
prevalence:
- population: Unselected newborns (Norwegian Mother, Father and Child Cohort)
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BAND_1_5_PER_10000
  rate_per_100000: 25.0
  notes: >-
    Approximately 1 in 4,000 live-born children, from array-based CNV calling in 12,252
    mother-father-child trios. This is the population figure and should be preferred over the
    referred-cohort rate below; the authors note it is higher than previously reported for this
    locus.
  evidence:
  - reference: PMID:32778765
    reference_title: "Population prevalence and inheritance pattern of recurrent CNVs associated with neurodevelopmental disorders in 12,252 newborns and their parents."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We provide prevalence estimates and inheritance information for each of the 26 NDD CNVs and find higher prevalence than previously reported for 1q21.1 deletions (~1:2000), 15q11.2 duplications (~1:4000), 15q13.3 microdeletions (~1:2500), 16p11.2 proximal microdeletions (~1:2000) and 17q12 deletions (~1:4000) and lower than previously reported prevalence for the 22q11.2 deletion (~1:12,000)."
    explanation: >-
      Gives the 1 in 4,000 newborn prevalence for 17q12 deletions behind this rate.
  - reference: PMID:32778765
    reference_title: "Population prevalence and inheritance pattern of recurrent CNVs associated with neurodevelopmental disorders in 12,252 newborns and their parents."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we perform array-based CNV calling in 12,252 mother-father-child trios from the Norwegian Mother, Father, and Child Cohort Study (MoBa) and analyse the inheritance pattern of 26 recurrent NDD CNVs in 13 genomic regions."
    explanation: >-
      Establishes that the estimate comes from an unselected trio cohort rather than a clinical
      referral series, which is what makes it a population prevalence.
- population: Patients referred for clinical neurodevelopmental cytogenomic testing
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 114.3
  notes: >-
    18 of 15,749 patients referred for neurodevelopmental testing, versus 0 of 4,519 controls.
    This is a referred-population frequency, not a population prevalence, and is inflated by
    the ascertainment route.
  evidence:
  - reference: PMID:21055719
    reference_title: "Deletion 17q12 is a recurrent copy number variant that confers high risk of autism and schizophrenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We detected a recurrent 1.4 Mb deletion at 17q12, which harbors HNF1B, the gene responsible for renal cysts and diabetes syndrome (RCAD), in 18/15,749 patients, including several with ASD, but 0/4,519 controls."
    explanation: >-
      Gives the numerator and denominator behind this rate.
📚

References & Deep Research

References

1
PMID:27929632
17q12 Recurrent Deletion Syndrome.
No top-level findings curated for this source.

Deep Research

1

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

Evaluations and curation notes (1)

Create: Chromosome 17q12 Deletion Syndrome · 2026-09-03T15:36:05Z · View source

De novo curation of chromosome 17q12 deletion syndrome (MONDO:0013797) as a Disease entry rather than a has_subtypes line on HNF1B disease. The argument for a separate entry is asymmetric: the renal and pancreatic phenotype is HNF1B haploinsufficiency and is shared with HNF1B point mutations, while the neurodevelopmental and psychiatric phenotype is not, and the primary report concludes the syndrome is a contiguous gene syndrome extending beyond renal cysts and diabetes. GeneReviews baseline: PMID:27929632 (17q12 Recurrent Deletion Syndrome), fetched, cached and tagged GeneReviews in the top-level references block. All Clinical Characteristics features were cross-referenced into phenotypes, and the agents-to-avoid section is curated as two treatment records (transplant immunosuppression avoiding tacrolimus and mTOR inhibitors; lithium and antipsychotic cautions). Frequencies were taken from the GeneReviews figures because those were derived with a method intended to avoid ascertainment bias. Deep research: one openscientist run (research/Chromosome_17q12_Deletion_Syndrome-deep-research-openscientist.md, 17 citations, 2 artifacts). The run shipped with NO reference_validation and NO term_validation block because term validation aborted on a 5-second EBI OLS read timeout; this is dismech#10396 and I commented there with the reproduction. I retro-fitted the reference section with just validate-research-reference, which succeeded and reported 27/27 references resolved, 22 of 27 on topic, and 3 of 5 quoted claims found in source. The two failed quotes are near-misses, not confabulations: one is a Unicode Mg-squared-plus against the abstract's Mg(2+), the other an ellipsis-joined quote. just validate-research-terms failed on four consecutive attempts, each on a different CURIE (CHEBI:17234, HP:0000107, ORPHA:261265, ORPHA:93111), so this report carries no term-validation section and that is stated in the PR body rather than left as an absence. HP:0000107 is in cache/hp/terms.csv, so a cache-first path would have avoided it. Used from the report: PMID:32778765 (population birth prevalence of 1 in 4,000 from 12,252 unselected trios, which replaced a referral-cohort rate as the primary prevalence record), PMID:26340261 (hypomagnesaemia in 50-60% with high fractional magnesium excretion, replacing an INDIRECT monitoring-guidance quote with direct evidence), PMID:24897035 (the validated 17-item HNF1B score, curated as a PHENOTYPE_ALGORITHM definition with VALIDATED_AGAINST_GOLD_STANDARD status, AUC 0.78, NPV over 99% at cutoff 8), PMID:31498910 (deletion versus intragenic variant comparison across 82 studies, cited on the open genotype-phenotype discussion), and PMID:24204001 (PCBD1-HNF1B-FXYD2 route to distal tubule magnesium reabsorption, graded INDIRECT because the experiment interrogates PCBD1 loss in an overexpression cell line). Cache defect encountered: references_cache/PMID_24204001.md holds the same sentence twice, once with the italic gene name concatenated to its neighbours (theFXYD2promoter) and once clean. The snippet was taken from the clean occurrence. Two knowledge gaps are recorded: which of the fourteen non-HNF1B interval genes drives the neurodevelopmental phenotype, and why deletion carriers have less advanced kidney disease than point-mutation carriers (PMID:28420700, 40 of 78 versus 71 of 91 for CKD3-4/ESRD in the long term, P = 0.0003) when a pure haploinsufficiency model predicts equivalence. Correction made during curation: two snippets were initially written from memory and failed reference validation. One was replaced with the correct text; the other, PMID:22130109, turned out to report the 17q12 schizophrenia association as 'more common in schizophrenia cases but not significantly so', so the claim of independent replication was overstated. It is now cited with the accurate quote, graded directness INDIRECT, and the entry prose says the replication is partial. Validation: just validate passes; 50/50 snippets verified. check-duplicate-keys, check-entity-refs, check-causal-targets, check-qualifier-terms, check-enum-values, check-snippet-length, check-snippet-grading, check-title-snippets and check-folded-hyphens all pass.

OpenScientist ▸
Key Findings
openscientist-autonomous 17 citations 2026-09-03T15:20:38.243766

Key Findings

Finding 1 — The 17q12 deletion is a recurrent NAHR-mediated CNV encompassing HNF1B and ~15 genes

The core lesion is a recurrent ~1.4–1.8 Mb deletion at 17q12, mediated by non-allelic homologous recombination between segmental duplications flanking the interval. In a large neurodevelopmental cohort, the deletion was detected in 18/15,749 patients versus 0/4,519 controls, with follow-up enrichment in autism spectrum disorder (2/1,182) and schizophrenia (4/6,340) versus 0/47,929 controls (corrected p = 7.37×10⁻⁵) (PMID: 21055719). The deleted interval harbors HNF1B — "the gene responsible for renal cysts and diabetes syndrome (RCAD)" — plus approximately 15 genes, and the authors proposed that "one or more of the 15 genes in the deleted interval is dosage sensitive and essential for normal brain development and function," establishing the contiguous-gene syndrome model.

Reported deletion sizes cluster between 1.4 and 1.9 Mb across cohorts (e.g., 1.494–1.66 Mb; 1.46 Mb; a prototypical 1.4 Mb interval arr 17q12(34,850,785_36,248,926)x1). The genes recurrently cited within the interval include HNF1B, ACACA, ZNHIT3, CCL3L1, PIGW (5 OMIM genes) and up to 17 protein-coding genes including AATF and DDX52. This dual architecture — a single dosage-critical developmental transcription factor (HNF1B) plus additional dosage-sensitive neurodevelopmental genes — explains why the deletion phenotype is broader than that of intragenic HNF1B variants.

Finding 2 — Microdeletions, but not reciprocal microduplications, drive the diabetes phenotype

Dosage directionality matters. In UK Biobank (450,993 individuals), 11 microdeletions and 106 microduplications at 17q12 were identified; microdeletions were strongly associated with diabetes, whereas the reciprocal microduplications were associated with renal disease but not diabetes (PMID: 36109160). The paper concludes: "We demonstrate 17q12 microdeletions but not microduplications are associated with diabetes in a population-based cohort." This confirms that the diabetes/MODY5 component is specifically a loss-of-dosage (haploinsufficiency) phenomenon of HNF1B, and it distinguishes the clinical consequences of the reciprocal CNVs at this locus.

Finding 3 — HNF1B → FXYD2 axis explains renal magnesium wasting

HNF1B directly regulates FXYD2, the γ-subunit of the Na⁺,K⁺-ATPase, in the distal convoluted tubule (DCT). HNF1B, together with cofactor PCBD1, co-stimulates the FXYD2 promoter, and FXYD2 activity "is instrumental in Mg²⁺ reabsorption in the DCT" (PMID: 24204001). Consequently, 50–60% of ADTKD-HNF1B patients develop hypomagnesemia (PMID: 26340261), and the biochemical signature is distinctive: "All patients presented with hypomagnesemia with a high fractional excretion of Mg²⁺ and hypocalciuria." Hypomagnesemia may be the first clinical manifestation of HNF1B disease, giving it a Gitelman-like electrolyte profile (hypomagnesemia, hypokalemic alkalosis, hypocalciuria). This provides a mechanistically-defined biomarker for the syndrome.

Finding 4 — Population prevalence ~1:4,000 newborns, ~one-third de novo

In a large newborn trio study (12,252 MoBa trios), the 17q12 deletion prevalence was estimated at ~1:4,000, in the context of an overall recurrent neurodevelopmental CNV prevalence of ~0.48% (1 in 200) (PMID: 32778765). Approximately 34% (20/59) of recurrent NDD CNVs were de novo. Prenatally, the detection rate among fetuses with urinary tract anomalies was ~6.5% (3/46), and other prenatal series report ~0.36% among fetuses undergoing CNV testing for ultrasound anomalies — of whom the vast majority present with bilateral hyperechogenic kidneys. These figures anchor recurrence-risk counseling: an affected parent transmits with 50% probability, but a substantial fraction of index cases are new mutations.

Finding 5 — Quantitative phenotype frequencies and long-term renal prognosis

The largest adult cohort (201 adults with HNF1B molecular defects; Dubois-Laforgue 2017) quantifies the mature phenotype (PMID: 28420700):

Phenotype Frequency HPO term
Diabetes mellitus 159/201 HP:0000819
Renal cysts 122/166 (73%) HP:0000107
CKD stage 3–4 75/169 (44%) HP:0012622
End-stage renal disease 36/169 (21%) HP:0003774
Diabetic retinopathy/neuropathy 46/114 HP:0000488 / HP:0000762
On insulin at follow-up 111/140 (79%) —

"Chronic kidney disease stages 3-4 (CKD3-4) in 75 of 169 (44%), and end-stage renal disease (ESRD) in 36 of 169 (21%)" and "111 of 140 patients (79%) were treated with insulin at follow-up" quantify the two dominant clinical burdens. Molecularly, whole-gene deletion (i.e., the 17q12 deletion) and intragenic HNF1B mutations "each account for ∼50% of all cases of HNF1B-associated disease," and importantly "there is no clear genotype-phenotype correlation, consistent with haploinsufficiency as the disease mechanism" (PMID: 25536396). This lack of genotype–phenotype correlation is a defining feature — the deletion and point mutations produce clinically indistinguishable renal/endocrine disease.

Finding 6 — The HNF1B score rationalizes genetic testing

Because the phenotype is protean, Faguer et al. developed a 17-item HNF1B score (antenatal discovery, family history, and kidney/pancreas/liver/genital involvement). In a 433-individual cohort with 56 HNF1B cases, "the HNF1B score efficiently and significantly discriminated between mutated and nonmutated cases (AUC 0.78)," and "the optimal cutoff threshold for the negative predictive value to rule out HNF1B mutations in a suspected individual was 8 (sensitivity 98.2%, specificity 41.1%, and negative predictive value over 99%)" (PMID: 24897035). The same work confirms "an autosomal-dominant inheritance, a 50% rate of de novo mutations, and a highly variable phenotype." A score below 8 effectively excludes disease, sparing unnecessary sequencing.

Finding 7 — HNF1B regulates PKHD1 and UMOD; biallelic loss drives chromophobe RCC

HNF1B directly regulates the cystic-kidney genes PKHD1 (the ARPKD gene) and UMOD (uromodulin). In renal tumorigenesis, "biallelic HNF1beta inactivation was found in two of 12 chromophobe renal carcinomas by association of a germline mutation and a somatic gene deletion. In these cases, the expression of PKHD1 … and UMOD …, two genes regulated by HNF1beta, was turned off" (PMID: 15649945). This defines a co-regulated HNF1B–PKHD1–UMOD transcriptional cluster central to tubular/cystic biology. A broader survey of 130 kidney tumors found decreased HNF1B expression associated with higher grade/stage in clear cell RCC, supporting that "in ccRCC and chRCC it may act in a tumour suppressive fashion" (PMID: 33051485). Clinically, this links the germline haploinsufficiency of the syndrome to a theoretical (though not established as high-frequency) renal-tumor predisposition via second-hit somatic inactivation.

Finding 8 — Zebrafish hnf1b (vhnf1) model recapitulates the syndrome via patterning-gene regulation

The developmental mechanism is directly demonstrated in a model organism. Insertional zebrafish vhnf1 (hnf1b) mutants show "formation of kidney cysts, underdevelopment of the pancreas and the liver, and reduction in size of the otic vesicles" — a striking recapitulation of human MODY5/RCAD (PMID: 11731484). Mechanistically, "vhnf1 is required for the proper expression of pdx1 and shh (sonic hedgehog) in the gut endoderm, pax2 and wt1 in the pronephric primordial, and valentino (val) in the hindbrain." This places HNF1B upstream of the master patterning genes for pancreas (pdx1), pronephros/kidney (pax2, wt1), and hindbrain (valentino/mafba), providing the causal bridge from transcription-factor haploinsufficiency to organ malformation.

Mechanistic Model / Interpretation

Ordered causal chain (initiating lesion → clinical manifestation)

  1. NAHR between flanking low-copy repeats at 17q12 → generates a recurrent ~1.4–1.8 Mb heterozygous deletion (de novo in ~1/3, inherited AD in ~2/3).
  2. The deletion removes one copy of HNF1B plus ~15 contiguous genes → HNF1B haploinsufficiency (≈50% dosage of the transcription factor).
  3. Reduced HNF1B dosage → failure to maintain normal transcription of direct target genes in a tissue-specific manner. This branches:
  4. Kidney branch: ↓ regulation of PKHD1, UMOD, and patterning genes pax2/wt1 → abnormal nephron/tubule development, tubular dilatation and cyst formation, dysplasia → progressive tubulointerstitial fibrosis → CKD → ESRD (inferred causal chain from direct-target regulation + zebrafish model + human frequencies).
  5. DCT electrolyte branch: ↓ HNF1B/PCBD1 co-stimulation of FXYD2 → impaired Na,K-ATPase γ-subunit function in the DCT → reduced Mg²⁺ reabsorption → renal Mg wasting → hypomagnesemia with high fractional Mg excretion and hypocalciuria (demonstrated).
  6. Pancreas branch: ↓ pdx1/shh-dependent pancreatic patterning → pancreatic (body/tail) hypoplasia → β-cell deficiency + exocrine insufficiency → MODY5 diabetes, usually insulin-requiring (inferred from model + clinical correlation).
  7. Hepatobiliary branch: HNF1B loss in biliary/hepatic epithelium → liver-enzyme elevations, biliary abnormalities (observed clinically).
  8. Genital branch: ↓ Müllerian-duct development → uterine/genital-tract malformations (e.g., bicornuate/incomplete uterus), genital anomalies (observed clinically).
  9. Metabolic branch: tubular dysfunction → hyperuricemia/gout (observed clinically).
  10. Neurodevelopmental branch (co-deleted genes, not HNF1B): haploinsufficiency of ≥1 of the other ~15 dosage-sensitive genes → developmental delay, learning difficulty, autism spectrum disorder, schizophrenia risk (inferred; specific gene not resolved).
  11. In a subset of renal epithelial cells, a somatic second hit inactivating the remaining HNF1B allele → biallelic HNF1B loss → loss of PKHD1/UMOD expression → contribution to chromophobe/clear-cell renal carcinoma (demonstrated in tumors; population-level cancer risk in syndrome not quantified).

Upstream vs downstream

  • Most upstream: the NAHR deletion and resulting HNF1B haploinsufficiency (and co-deletion of neurodevelopmental genes).
  • Intermediate: dysregulation of direct targets (PKHD1, UMOD, FXYD2) and patterning genes (pax2, wt1, pdx1, shh).
  • Downstream: organ malformation (cysts, pancreatic hypoplasia, Müllerian defects), tubular electrolyte handling defects, and progressive fibrosis/CKD.

Text schematic

   NAHR at 17q12 low-copy repeats
      │
   ~1.4–1.8 Mb heterozygous deletion
┌─────┴───────────────┐
   HNF1B haploinsufficiency    ~15 co-deleted genes
│                           │
  ┌─────┼───────┬────────┬──────┐   └─► neurodevelopment:
  ▼     ▼       ▼        ▼      ▼         DD / ASD / schizophrenia
PKHD1  UMOD   FXYD2   pax2/wt1  pdx1/shh
  │     │       │        │        │
 cysts/dysplasia   ↓Mg²⁺     kidney    pancreas
   → CKD → ESRD  reabsorption  malform.  hypoplasia
            │                      │
      hypomagnesemia          MODY5 diabetes
      (Gitelman-like)        (insulin-requiring)

Ontology annotations

  • Gene: HNF1B (HGNC:11630; NCBI Gene 6928; UniProt P35680; OMIM 189907)
  • GO biological process: regionalization (GO:0003002), metanephros development (GO:0001656), pronephros development (GO:0048793), mesonephric tubule development (GO:0072164), endocrine pancreas development (GO:0031018), positive regulation of transcription by RNA polymerase II (GO:0045944), magnesium ion transmembrane transport (GO:1903830).
  • GO cellular component: nucleus (GO:0005634); basolateral plasma membrane / Na,K-ATPase complex for FXYD2 (GO:0005890).
  • Cell types (CL): kidney distal convoluted tubule epithelial cell (CL:1000849), kidney collecting duct epithelial cell (CL:1000454), pancreatic A/B cell (CL:0000171 / CL:0000169), hepatocyte (CL:0000182), epithelial cell (CL:0000066).
  • UBERON anatomy: kidney (UBERON:0002113), renal tubule/nephron (UBERON:0001231 / UBERON:0001285), distal convoluted tubule (UBERON:0001292), pancreas (UBERON:0001264), liver (UBERON:0002107), uterus (UBERON:0000995), Müllerian duct (UBERON:0003890).
  • CHEBI: magnesium(2+) (CHEBI:18420), uric acid/urate (CHEBI:27226 / CHEBI:17775), D-glucose (CHEBI:17234), insulin (peptide hormone).

Evidence Base

PMID Title (abbrev.) Evidence type How it supports the model
21055719 Deletion 17q12 confers high risk of autism/schizophrenia Human case-control genomics Defines recurrent ~1.4 Mb deletion, ~15-gene content, case enrichment (F001)
36109160 17q12 microduplications contribute to renal disease not diabetes Human population cohort (UK Biobank) Dosage directionality: deletion → diabetes, duplication → renal (F002)
24204001 PCBD1 mutations cause hypomagnesemia In vitro / human genetics Establishes HNF1B/PCBD1→FXYD2 axis for Mg handling (F003)
26340261 Hypomagnesemia as first manifestation of ADTKD-HNF1B Human case series Quantifies hypomagnesemia (50–60%) and its biochemical signature (F003)
30175537 Renal Mg handling, FXYD2, Na,K-ATPase Review / mechanism Mechanistic detail on FXYD2 regulatory role (supports F003)
35894287 Genetic spectrum of Gitelman-like syndromes Review Places HNF1B among Gitelman-like DCT electrolyte disorders (supports F003)
32778765 Population prevalence of recurrent CNVs in newborns Human newborn trios Prevalence ~1:4,000; ~34% de novo (F004)
28420700 201 adults with HNF1B — long-term prognosis Human clinical cohort Quantitative phenotype frequencies, renal/diabetes prognosis (F005)
25536396 HNF1B disease — expanding spectrum Review ~50/50 deletion vs intragenic; haploinsufficiency, no genotype-phenotype correlation (F005)
24897035 HNF1B score for patient selection Human diagnostic study Score AUC 0.78; cutoff 8, NPV >99% (F006)
15649945 Germline HNF1α/β mutations in RCC Human tumor genetics Biallelic HNF1B loss in chromophobe RCC; PKHD1/UMOD regulation (F007)
33051485 HNF1B in 130 kidney tumors Human tumor genomics Tumor-suppressive role in ccRCC/chRCC (F007)
11731484 Zebrafish vhnf1 regulates gut/pronephros/hindbrain Model organism Phenotype recapitulation + downstream patterning targets (F008)
20378824 Reduced Notch → renal cysts, microadenomas Mouse model Contextual: cyst/tumor biology intersecting HNF1B (TCF2) pathway
30525249 Acetylation drives HNF1β stability In vitro Protein-level regulation of HNF1B stability (mechanistic detail)

Multiple recent case reports (PMID: 41924323, 38432894, 38044981, 41694676, 37799485) corroborate the multi-organ spectrum including hyperuricemia, hypomagnesemia, muscle-mass loss, nephrocalcinosis, and elevated liver enzymes (MODY5). Prenatal series (PMID: 35232906, 38957807, 37212013, 32219821, 41999034) consistently identify bilateral hyperechogenic/cystic kidneys as the dominant prenatal presentation and confirm chromosomal microarray/CNV-seq as the pivotal diagnostic tool. A novel HNF1B-disrupting inversion (PMID: 41703530) and an intragenic hotspot deletion p.(Gly239del) (PMID: 31498910) broaden the variant spectrum.

Section-by-Section Synthesis

1. Disease Information

17q12 deletion syndrome is a recurrent contiguous-gene microdeletion causing a multisystem disorder dominated by renal, endocrine (diabetes), and neurodevelopmental features. Identifiers: MONDO:0013797; OMIM 614527 (deletion) and 137920 (RCAD); Orphanet ORPHA:261265 / ORPHA:93111; MeSH aligns with "Chromosome Deletion" + "HNF1B." Synonyms: HNF1B microdeletion syndrome; Renal Cysts and Diabetes syndrome (RCAD); MODY5; HNF1B-associated disease; ADTKD-HNF1B (when tubulointerstitial). Information derives from aggregated disease-level resources (OMIM/Orphanet) and individual clinical cohorts/case reports, not EHR-scale phenotyping.

2. Etiology

Primary cause: heterozygous 17q12 deletion (NAHR-mediated) or, in ~50% of HNF1B-disease cases, intragenic HNF1B variants. Genetic risk: essentially the deletion/variant itself; there are no well-established susceptibility modifier loci. Environmental risk factors, protective factors, and gene-environment interactions are not established for this Mendelian disorder — onset and organ involvement track the germline lesion, not exposures. De novo occurrence (~1/3 of deletions; ~50% of intragenic variants) means absence of family history does not exclude the diagnosis.

3. Phenotypes

Key phenotypes with HPO suggestions and frequencies (from F003, F005): renal cysts (HP:0000107, 73%), CKD (HP:0012622, ~44% stage 3–4), ESRD (HP:0003774, ~21%), diabetes mellitus/MODY (HP:0000819 / HP:0004904, majority), hypomagnesemia (HP:0002917, 50–60%), pancreatic hypoplasia (HP:0002983), Müllerian/uterine malformation (HP:0000130 / HP:0000132), hyperuricemia/gout (HP:0002149 / HP:0001997), elevated liver enzymes (HP:0002910), developmental delay (HP:0001263), autism (HP:0000717), and hypocalciuria (HP:0003169). Onset spans prenatal (hyperechogenic kidneys) through childhood/adult (MODY5 typically diagnosed in adolescence/early adulthood). Severity and progression are highly variable with incomplete penetrance; renal disease is typically progressive. Quality-of-life impact is driven chiefly by CKD/dialysis burden, insulin-dependent diabetes, and (in deletion cases) neurodevelopmental/psychiatric morbidity; formal EQ-5D/SF-36 data specific to the syndrome were not identified.

4. Genetic/Molecular Information

Causal gene: HNF1B (HGNC:11630; OMIM 189907). Variant classes: whole-gene deletion (the 17q12 CNV, ~50%), and intragenic pathogenic/likely-pathogenic variants (missense, nonsense, frameshift, splice, in-frame deletions such as p.(Gly239del) in the DNA-binding domain hotspot; also point substitutions e.g. C295R) per ACMG/AMP. A novel inversion disrupting HNF1B (GRCh38:17:g.36934029_37729559inv) has also been reported. Functional consequence: loss of function → haploinsufficiency; no clear genotype–phenotype correlation. Origin: germline (frequently de novo). Chromosomal abnormality: recurrent 17q12 interstitial deletion, ~1.4–1.8 Mb. Modifier genes/epigenetics: not established, though HNF1β protein stability is modulated post-translationally by acetylation (PMID: 30525249).

5. Environmental Information

Not applicable as a cause. No toxin, infectious agent, or lifestyle factor is established in disease causation. Standard diabetes/CKD lifestyle management applies to complication control but does not modify the germline etiology.

6. Mechanism / Pathophysiology

Presented as the ordered causal chain above. Core: HNF1B haploinsufficiency → dysregulation of direct targets PKHD1, UMOD, FXYD2 and patterning genes pax2, wt1, pdx1, shh → renal cysts/dysplasia + tubulointerstitial fibrosis, DCT magnesium wasting, pancreatic hypoplasia, and Müllerian defects; co-deleted genes add neurodevelopmental risk. Molecular/omics-specific profiling of the syndrome (transcriptomics, proteomics, single-cell) is limited; the strongest mechanistic evidence is transcription-factor–target regulation plus the zebrafish model.

7. Anatomical Structures Affected

Primary organs: kidney (UBERON:0002113; bilateral, often symmetric), pancreas (UBERON:0001264), liver/biliary tract (UBERON:0002107), female genital tract/uterus (UBERON:0000995). Body systems: urinary, endocrine, hepatobiliary, reproductive, and (via co-deleted genes) central nervous system. Tissue/cell level: renal tubular epithelium — especially DCT epithelial cells (CL:1000849) and collecting duct — pancreatic islet and acinar cells, hepatocytes/cholangiocytes, Müllerian-duct epithelium. Subcellular: nucleus (transcription factor, GO:0005634); DCT basolateral Na,K-ATPase complex (FXYD2, GO:0005890). Lateralization: renal involvement is typically bilateral.

8. Temporal Development

Onset: congenital/prenatal renal structural abnormality (hyperechogenic kidneys detectable on second-trimester ultrasound) through adolescent/adult-onset diabetes. Course: renal disease is chronic and progressive toward CKD/ESRD; diabetes is progressive and usually insulin-requiring. Critical periods: fetal organogenesis (kidney/pancreas/Müllerian development) is the vulnerable window; postnatally, management targets complication prevention. Disease is lifelong; no spontaneous remission.

9. Inheritance and Population

Inheritance: autosomal dominant; ~50% de novo for intragenic variants and ~1/3 de novo for deletions. Penetrance: incomplete and variable; expressivity highly variable even within families (multigenerational reports show renal cysts, stones, diabetes, pancreatic dysfunction in different relatives). Prevalence: ~1:4,000 newborns for the deletion; HNF1B disease overall is a leading monogenic cause of developmental kidney disease. Sex: both sexes affected; females may present additionally with Müllerian anomalies. Founder effects, consanguinity, and anticipation are not features (dominant, often de novo).

10. Diagnostics

Genetic testing is definitive: chromosomal microarray (CMA)/CNV-seq detects the deletion; HNF1B sequencing (single-gene or panel) detects intragenic variants; whole-genome sequencing can resolve complex structural variants (e.g., inversion). Clinical labs/biomarkers: hypomagnesemia with high fractional Mg excretion + hypocalciuria (distinctive); hyperuricemia; elevated liver enzymes; abnormal glucose/HbA1c; anti-GAD negativity helps distinguish MODY5 from type 1 diabetes. Imaging: renal ultrasound/MRI showing bilateral cysts, hyperechogenic/dysplastic kidneys; pancreatic imaging showing body/tail hypoplasia. Clinical criterion/tool: the HNF1B score (cutoff 8; NPV >99%) selects candidates for testing. Differential diagnosis: ADPKD, ARPKD (differentiated by targeted sequencing and family pattern), other ADTKD subtypes, Gitelman syndrome (for the electrolyte picture), and type 1 diabetes (for MODY5). Screening: prenatal CMA for fetuses with bilateral echogenic kidneys; cascade family testing.

11. Outcome/Prognosis

Renal: ~44% reach CKD 3–4 and ~21% ESRD in adulthood — the principal driver of morbidity and the main determinant of life expectancy (dialysis/transplant needs). Diabetes: usually insulin-requiring (~79%), with risk of microvascular complications. Overall mortality is not sharply elevated with modern renal replacement/diabetes care, but the disorder is chronic and lifelong. Prognostic factors: degree of renal impairment at diagnosis, rate of eGFR decline, and diabetes control. There is a theoretical renal-tumor consideration (chromophobe/clear-cell RCC via biallelic HNF1B loss), though population-level cancer risk in the syndrome is not established.

12. Treatment

No disease-specific or curative therapy. Management is organ-directed and supportive: - Diabetes/MODY5: insulin is the mainstay (NCIT: Insulin Therapy); a subset respond to sulfonylureas/repaglinide (~29/51 tested in the 201-adult cohort), but most are insulin-dependent at follow-up. - Electrolytes: oral/IV magnesium repletion for hypomagnesemia (CHEBI:18420); potassium citrate for stones/tubular acidosis. - Hyperuricemia/gout: urate-lowering therapy (e.g., allopurinol; NCIT: Allopurinol). - CKD: standard nephroprotection, and renal replacement (dialysis/transplant) for ESRD (NCIT: Renal Dialysis, Kidney Transplantation). - Structural/genital anomalies: surgical correction as indicated. - Neurodevelopmental: educational and behavioral support. No gene therapy, RNA therapy, or targeted molecular therapy exists; pharmacogenomics is limited to the sulfonylurea-responsiveness observation.

13. Prevention

No primary prevention (germline etiology). Secondary prevention: prenatal detection (CMA for echogenic kidneys), cascade family testing, and early metabolic/renal surveillance. Genetic counseling is central — 50% transmission risk from an affected parent, high de novo rate, variable expressivity; preimplantation genetic testing (PGT) and prenatal diagnosis are available for at-risk families. Tertiary prevention: aggressive CKD and diabetes complication management.

14. Other Species / Natural Disease

Orthologs: zebrafish hnf1b/vhnf1, mouse Hnf1b (NCBI Gene 21410). No prominent naturally-occurring companion-animal disease is catalogued; relevance is chiefly experimental. Evolutionary conservation of HNF1B's developmental role (kidney/pancreas/hindbrain patterning) is strong across vertebrates.

15. Model Organisms

  • Zebrafish vhnf1/hnf1b insertional mutant — recapitulates kidney cysts, pancreatic/hepatic hypoplasia, reduced otic vesicles; reveals downstream targets pdx1, shh, pax2, wt1, valentino (PMID: 11731484). Strong developmental recapitulation; limitation — does not model adult-onset diabetes progression or human neuropsychiatric features.
  • Mouse Hnf1b conditional/knockout models — used to study nephrogenesis and cystogenesis; homozygous null is embryonic lethal, requiring conditional/tissue-specific approaches. A reduced-Notch mouse model produced renal cysts and papillary microadenomas with links to TCF2/HNF1β biology (PMID: 20378824).
  • Cellular/in vitro — HNF1β-expressing lines (ES2, HEPG2, HK2) used to study protein stability/acetylation and target-gene regulation.

Limitations and Knowledge Gaps

  1. Neurodevelopmental gene not resolved. The specific dosage-sensitive gene(s) among the ~15 co-deleted loci responsible for autism/schizophrenia/developmental delay remain unidentified; the contiguous-gene model is supported statistically but not gene-resolved.
  2. No genotype–phenotype correlation limits prognostic precision — the deletion vs point mutation, and specific variants, do not reliably predict organ burden or severity.
  3. Penetrance/expressivity quantitatively uncertain. Incomplete penetrance is documented, but robust penetrance estimates per organ system by variant type are lacking.
  4. Omics profiling of the human syndrome is sparse — transcriptomic/proteomic/single-cell datasets specific to HNF1B-deleted human kidney/pancreas are limited; most mechanism is inferred from target-gene regulation and model organisms.
  5. Cancer risk unquantified. Biallelic HNF1B loss occurs in chromophobe RCC, but the lifetime renal-tumor risk for germline 17q12-deletion carriers is not established.
  6. Quality-of-life and mortality data specific to the syndrome (as opposed to CKD/diabetes generally) are limited; no syndrome-specific EQ-5D/SF-36 datasets were identified.
  7. Ascertainment bias. Much of the cohort data comes from nephrology/genetics referral populations, likely over-representing severe renal phenotypes.

Proposed Follow-up Experiments / Actions

  1. Resolve the neurodevelopmental driver via dosage analysis of individual 17q12 genes (e.g., CRISPR dosage models, or association testing of atypical smaller deletions) to pinpoint the ASD/schizophrenia gene(s).
  2. Prospective natural-history registry stratified by variant type (deletion vs intragenic) to derive organ-specific penetrance, eGFR-decline trajectories, and mortality — addressing the genotype–phenotype and prognosis gaps.
  3. Single-cell/spatial transcriptomics of HNF1B-deficient human kidney organoids and patient biopsies to map cell-type-specific dysregulation of PKHD1/UMOD/FXYD2 and validate the causal chain in human tissue.
  4. Quantify renal-tumor risk through long-term surveillance imaging in a large carrier cohort and molecular characterization of any tumors for second-hit HNF1B inactivation.
  5. Pharmacogenomic trial of sulfonylurea/repaglinide responsiveness to identify predictors of insulin-sparing response in HNF1B-MODY5.
  6. Systematic QoL assessment (EQ-5D/PROMIS) across renal, endocrine, and neurodevelopmental domains to inform holistic management.
  7. Magnesium-repletion outcome study to determine whether early correction of hypomagnesemia alters renal or metabolic trajectory.

Report compiled from 8 confirmed findings and 35 reviewed papers over a 5-iteration autonomous investigation. Evidence types span human clinical cohorts, human population genomics, tumor genetics, in vitro studies, and model-organism (zebrafish, mouse) work, as annotated in the Evidence Base.

Artifacts

Reference Validation

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Outcome Count
References checked 27
Resolved 27
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 5
Quoted claims found in source 3
Quoted claims not found in source 2
References weighed for topical relevance 27
On topic 22
Off topic 0

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

Every one of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.

  • PMID:24204001 (abstract only): "is instrumental in Mg²⁺ reabsorption in the DCT"
  • closest text in source: "Overexpression in a human kidney cell line showed that wild-type PCBD1 binds HNF1B to costimulate the FXYD2 promoter, the activity of which is instrumental in Mg(2+) reabsorption in the DCT"
  • PMID:15649945 (abstract only): "biallelic HNF1beta inactivation was found in two of 12 chromophobe renal carcinomas by association of a germline mutation and a somatic gene deletion. In these cases, the expression of PKHD1 … and UMOD …, two genes regulated by HNF1beta, was turned off"
  • closest text in source: "Biallelic HNF1beta inactivation was found in two of 12 chromophobe renal carcinomas by association of a germline mutation and a somatic gene deletion"