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Classifications

Harrison's Part

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Mappings

MONDO

MONDO:0060713 deafness, congenital heart defects, and posterior embryotoxon

MONDO:0060713 is the anchor term for this entry. It carries OMIM:617992 as an xref and DCHE as a related synonym, both of which match the curated content here. MONDO records no causal gene (RO:0004003) for this term, so gene identity was anchored manually on the OMIM entry and on the index publication PMID:12022040, which names JAG1 p.Cys234Tyr.

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Inheritance

1

Autosomal dominant HP:0000006

The p.Cys234Tyr allele segregated as an autosomal dominant trait through a large multigenerational kindred, with high penetrance of the triad but variable expressivity of its individual components (the specific cardiac lesion in particular differed between affected relatives). This mirrors the intra-familial variability characteristic of JAG1 disorders generally.

Autosomal dominant inheritance

Show evidence (2 references)

PMID:12022040 SUPPORT Human Clinical

"In the present study, we report a kindred with hearing loss, congenital heart defects, and posterior embryotoxon, segregating as autosomal dominant traits."

Directly establishes autosomal dominant segregation in the index pedigree.

PMID:12022040 SUPPORT Human Clinical

"Our findings revealed a unique phenotype with highly penetrant deafness, posterior embryotoxon, and congenital heart defects but with variable expressivity in a large kindred"

Supports the high-penetrance, variable-expressivity pattern described here.

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Discussions and Knowledge Gaps

4

Is DCHE a discrete disorder, or the liver-sparing tail of the JAG1 (Alagille) phenotypic continuum?

OPEN QUESTION OPEN dche_entity_status

Attached to

pathophysiology#Modifier-Dependent Organ Selectivity of JAG1 Haploinsufficiency

Three facts pull in different directions and none of them settles the question. In favour of a discrete entity: OMIM and MONDO both catalogue it separately; the index report states explicitly that no affected individual met criteria for any previously described syndrome; and highly penetrant, mid-frequency mixed hearing loss is not a cardinal Alagille criterion. In favour of a continuum: the gene, the pathway, and two of the three cardinal features are shared with Alagille syndrome; JAG1 variants are routinely recovered from individuals expressing only one or two Alagille organ systems; and the mechanistic account offered here, complete haploinsufficiency whose organ selectivity is set by unidentified modifiers, is a continuum mechanism rather than a separate-disorder mechanism, since the very same class of null lesion underlies classic Alagille syndrome. The evidence base is also thin enough that the question may not be answerable: one kindred, one allele. dismech curates it as a separate entry because MONDO does and because the hearing phenotype is distinctive, while recording the continuum reading here rather than suppressing it.

Proposed experiments

Audiological and slit-lamp phenotyping of a JAG1 cohort

dche_jag1_cohort_audiology_slitlamp

Systematic audiological and slit-lamp phenotyping of a molecularly defined JAG1 cohort, to establish whether mid-frequency mixed hearing loss segregates with a particular allele class or is a general, under-ascertained feature of JAG1 disease.

Ascertainment of additional EGF-repeat cysteine kindreds

dche_additional_c234y_kindreds

Identification of additional unrelated p.Cys234Tyr (or other EGF-repeat-1 cysteine) kindreds, to test whether the liver-sparing triad is allele-specific or family-specific.

Show evidence (2 references)

PMID:12022040 SUPPORT Human Clinical

"No individual in this family met diagnostic criteria for any previously described clinical syndrome."

The strongest single statement for discrete-entity status.

PMID:21752016 SUPPORT Human Clinical

"Identification of a JAG1 gene mutation is particularly useful for those patients with atypical or mild Alagille syndrome who do not meet classic diagnostic criteria as it provides a definite molecular diagnosis"

Supports the competing continuum reading, in which this kindred is an atypical JAG1 presentation rather than a separate disorder.

If JAG1 p.Cys234Tyr is completely haploinsufficient, what determines that the heart, ears and anterior segment are affected while the liver is spared?

KNOWLEDGE GAP OPEN dche_organ_selectivity_modifiers

Attached to

pathophysiology#Modifier-Dependent Organ Selectivity of JAG1 Haploinsufficiency

This is the central unsolved question of the entry, and it became sharper rather than softer once p.Cys234Tyr was assayed. The intuitive answer - that a partially functional allele leaves enough ligand for the tissues with the lowest requirement - was proposed on the strength of the hypomorphic p.Gly274Asp allele, and then specifically defeated: p.Cys234Tyr is EndoH-sensitive, absent from the cell surface, and unable to activate Notch, yet its carriers still have normal liver function. A functionally null allele and a leaky allele therefore produce the same liver-sparing pattern, which means residual ligand dose cannot be what distinguishes the spared organ from the affected ones. The assaying authors attribute the pattern to unidentified modifying factors. Nothing currently narrows what those are: candidate classes include trans-acting variation at other Notch-pathway loci, tissue-specific differences in the compensating ligand repertoire (JAG2, DLL1/4) or in receptor availability (NOTCH1 vs NOTCH2), and differences in how much developmental time each organ has to recover from a signalling deficit. Until that is resolved, the organ-selectivity node is curated HYPOTHETICAL and this entry does not claim a dose-threshold mechanism.

Proposed experiments

Genome-wide modifier search in discordant JAG1 carriers

dche_modifier_genome_analysis

Whole-genome sequencing of JAG1 carriers concordant for genotype but discordant for hepatic involvement, within and across families, testing for trans-acting modifier variation at Notch-pathway and other loci. This is the study design the assaying authors themselves proposed.

Comparative ligand and receptor repertoire across affected and spared organs

dche_tissue_ligand_receptor_repertoire

Single-cell profiling of Notch ligand and receptor expression in developing bile duct, cardiac outflow tract, cochlea and periocular mesenchyme, to test whether the spared tissue is the one with the greatest redundancy from other ligands.

Allelic series comparison of organ-level thresholds

dche_allelic_series_organ_thresholds

Direct comparison of null, hypomorphic and knock-in p.Cys234Tyr alleles for bile-duct number, outflow-tract anatomy and auditory thresholds, to establish whether any organ phenotype tracks residual ligand dose at all.

Show evidence (4 references)

PMID:20437614 SUPPORT Human Clinical

"What remains unknown is why these cases present with only a cardiac phenotype and not the full clinical features of AGS, particularly hepatic disease."

The assaying authors state this question as unresolved, which is what makes it a knowledge gap rather than a curation shortfall.

PMID:20437614 SUPPORT In Vitro

"the p.C234Y and p.P810L mutations appear to be completely haploinsufficient"

The assay half of the finding: cell-based characterisation establishes that the allele retains no function.

PMID:20437614 SUPPORT Human Clinical

"yet the patients with these mutations do not have the full spectrum of AGS, consistent with the presence of additional modifying factors"

The clinical half of the same finding, split out per the CLAUDE.md rule that a mixed-source sentence should not share one evidence_source: the patients' restricted phenotype is a human observation, and it is what forces the modifier interpretation.

+ 1 more reference

By what developmental route does reduced Jagged1 dose produce posterior embryotoxon?

KNOWLEDGE GAP OPEN anterior_segment_mechanism_gap

Attached to

pathophysiology#Disrupted Anterior Segment Development in Periocular Neural Crest

The auditory and cardiac arms of this entity each rest on a dedicated Jagged1-specific developmental study. The ocular arm does not: no study of Jagged1 in anterior-segment or periocular-mesenchyme morphogenesis was identified during curation. What supports the node is the human phenotype association plus the neural-crest origin of the Schwalbe line, corneal endothelium and trabecular meshwork - which is inference from anatomy, not a demonstrated mechanism. The node is therefore marked HYPOTHETICAL and its incoming edge INDIRECT_UNKNOWN_INTERMEDIATES.

Proposed experiments

Conditional Jag1 deletion in periocular neural crest

jag1_periocular_crest_conditional_deletion

Conditional Jag1 deletion in neural-crest-derived periocular mesenchyme, with anterior-segment morphometry and Schwalbe-line position as readouts.

Notch-reporter mapping of the developing anterior chamber angle

anterior_chamber_notch_reporter_mapping

Notch-reporter mapping of the developing anterior chamber angle to establish where and when Jagged1-Notch signalling is active in that territory.

Show evidence (1 reference)

PMID:12022040 SUPPORT Human Clinical

"Our findings revealed a unique phenotype with highly penetrant deafness, posterior embryotoxon, and congenital heart defects"

Establishes the phenotype whose developmental mechanism is the subject of this gap.

Do the available Jag1 mouse models, none of which carries p.Cys234Tyr, faithfully represent the human DCHE mechanism?

HUMAN MODEL MISMATCH OPEN dche_model_organism_mismatch

Attached to

pathophysiology#Impaired Notch-Dependent Inner Ear Sensory Patterning pathophysiology#Impaired Jagged1-Notch2 Patterning of the Middle Ear Ossicles

All three mouse models curated here are informative for Jagged1-dependent ear development, and none of them models this disorder. Htu is a different missense allele; Jag1 Ndr/Ndr is a homozygous hypomorph; the middle-ear work uses a heterozygous null. The heterozygous null is in fact the closest match on dose, since p.Cys234Tyr was subsequently shown to be functionally null rather than leaky; Htu is a different missense allele of unknown residual activity, and the homozygous hypomorph sits at a lower dose than any human carrier. Additionally, no mouse model reproduces the human triad: the ear models do not address the cardiac or ocular arms, and the cardiac model does not address hearing. Most importantly, no mouse model addresses the feature that actually defines this disorder against Alagille syndrome - whether bile-duct development is spared - so the models can corroborate the ear and heart arms while being silent on the entity's defining negative.

Proposed experiments

Jag1 p.Cys234Tyr knock-in mouse with full triad phenotyping

c234y_knockin_mouse_full_triad_phenotyping

A Jag1 p.Cys234Tyr knock-in mouse, phenotyped for auditory thresholds and configuration, vestibular function, outflow-tract anatomy, anterior-segment morphology, and bile-duct number - the last being the specific test of the liver-sparing claim.

Allelic series comparison of ear, heart and liver phenotypes

jag1_allelic_series_organ_dose_thresholds

Allelic series comparison (null, hypomorphic missense, p.Cys234Tyr knock-in) of ear, heart and liver phenotypes, to establish whether any organ phenotype tracks residual ligand dose at all.

Show evidence (2 references)

PMID:11259677 SUPPORT Model Organism

"a dominant mouse mutant headturner (Htu) contains a missense mutation in the Jag1 gene and displays missing posterior and sometimes anterior ampullae, structures that house the sensory cristae"

A different Jag1 missense allele producing gross ampullar agenesis, more severe than anything reported in the human kindred - the mismatch this discussion records.

PMID:39373109 SUPPORT Model Organism

"Jag1Ndr/Ndr mice exhibited expected vestibular and auditory deficits, a dose-dependent increase in ectopic inner hair cells, and a reduction in outer hair cells."

A homozygous hypomorph, i.e. a different point on the dose-response curve from a heterozygous human missense carrier.

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Pathophysiology

8

JAG1 First EGF-Like Repeat Cysteine Substitution

The disease-initiating lesion is a heterozygous germline JAG1 missense variant, p.Cys234Tyr, that replaces the first cysteine of the first epidermal-growth-factor(EGF)-like repeat of Jagged1. EGF-like repeats are small, disulfide-stapled modules whose fold depends on a fixed pattern of six cysteines; losing one of them leaves an unpaired partner and destabilises the module. Missense variants in JAG1 are non-randomly distributed and cluster in exactly these regions - the amino-terminal region, the DSL domain, and two clusters within the EGF repeats - which is the structural context in which this substitution should be read.

JAG1 hgnc:6188

Genetic context JAG1 hgnc:6188 allele_type: missense variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: LOSS_OF_FUNCTION

Heterozygous germline JAG1 p.Cys234Tyr (C234Y). Classified LOSS_OF_FUNCTION on direct functional assay of this allele: the mutant protein is EndoH-sensitive, absent from the cell surface, and unable to activate Notch signalling, i.e. complete haploinsufficiency. No dominant-negative activity has been demonstrated for the JAG1 missense proteins assayed to date.

Downstream

Misfolding and Endoplasmic-Reticulum Retention of Mutant Jagged1 Loss of a structurally required cysteine prevents correct disulfide-bonded folding of the EGF module, which is what commits the nascent protein to the ER quality-control fate rather than the secretory route.

Show evidence (5 references)

PMID:12022040 SUPPORT Human Clinical

"A candidate-gene approach was undertaken and culminated in the identification of a novel Jagged 1 (JAG1) missense mutation (C234Y) in the first cysteine of the first epidermal-growth-factor-like repeat domain of the protein."

Directly identifies the causal allele and its position in the first EGF-like repeat.

PMID:11157803 SUPPORT In Vitro

"Missense mutations are non-randomly distributed across the protein with clusters at the 5' end of the protein, in the conserved DSL domain, and two clusters within the EGF repeats."

Establishes that pathogenic JAG1 missense variants cluster in the EGF repeats, the structural context of the C234Y substitution.

PMID:20437614 SUPPORT In Vitro

"Residue 234 (p.C234Y) is located in the first EGF repeat, while 664 (p.C664S) is in the eleventh, and 810 (p.P810L) is in the fifteenth"

Independently confirms the position of the substituted residue in the first EGF-like repeat.

+ 2 more references

Misfolding and Endoplasmic-Reticulum Retention of Mutant Jagged1

Improperly folded Jagged1 is recognised by the ER quality-control machinery, is abnormally glycosylated, and accumulates intracellularly instead of transiting to the plasma membrane. For p.Cys234Tyr specifically this has been demonstrated directly and by two independent methods: the protein remains endoglycosidase-H sensitive, meaning its N-glycans were never processed in the Golgi, and immunofluorescence shows no cell-surface staining at all. Across the wider JAG1 missense class, ER-retained mutants bind the lectin chaperones calnexin and calreticulin more avidly than wild-type Jagged1 does, which is the quality-control step that holds them there. Importantly, no dominant-negative activity has been detected for the JAG1 missense proteins assayed to date, so the mutant allele subtracts function rather than poisoning the wild-type product.

protein folding in the endoplasmic reticulum GO:0034975 ⚠ ABNORMAL delivery of Jagged1 to the plasma membrane GO:0072659 ↓ DECREASED

endoplasmic reticulum GO:0005783

Downstream

Loss of Cell-Surface Jagged1 and Failure of Notch Trans-Activation Ligand retained in the ER cannot engage Notch receptors on neighbouring cells. For p.Cys234Tyr the retention is complete rather than partial, so the functional consequence is the absence of mutant ligand from the surface pool, not merely its reduction.

Show evidence (5 references)

PMID:20437614 SUPPORT In Vitro

"The p.C234Y variant displayed no cell surface staining, consistent with its being retained intracellularly, similar to previously reported AGS missense mutants"

Direct immunofluorescence evidence that the C234Y protein is retained intracellularly rather than reaching the plasma membrane.

PMID:20437614 SUPPORT In Vitro

"JAG1 variants p.C234Y and p.P810L are sensitive to EndoH, suggesting they are improperly modified as previously reported for JAG1 mutations associated with AGS"

Independent biochemical confirmation, by glycan processing rather than imaging, that the C234Y protein does not transit the secretory pathway normally.

PMID:11157803 SUPPORT In Vitro

"Neither R184H or L37S is present on the cell surface and both are abnormally glycosylated. Furthermore, these mutations lead to abnormal accumulation of the protein, possibly in the endoplasmic reticulum."

Generalises the abnormal-glycosylation plus ER-accumulation phenotype across pathogenic JAG1 missense alleles. PARTIAL because C234Y itself was not among the alleles assayed in this earlier study.

+ 2 more references

Loss of Cell-Surface Jagged1 and Failure of Notch Trans-Activation

Jagged1 is a membrane-tethered ligand that must be displayed on the surface of the signal-sending cell to activate Notch receptors on the adjacent signal-receiving cell. Because the p.Cys234Tyr product never reaches the surface, it contributes nothing to trans-activation: in a CBF-dependent luciferase reporter it behaves like the known null allele p.Leu37Ser and cannot initiate Notch signalling at all. The carrier is therefore left with only the wild-type allele's ligand on the cell surface - complete haploinsufficiency, not a graded hypomorphic reduction. This distinction is load-bearing for this entry, because a hypomorphic "leaky allele" model was the leading explanation for liver-sparing JAG1 phenotypes until this allele was assayed and found to be null.

Notch signaling pathway GO:0007219 ↓ DECREASED

Downstream

Modifier-Dependent Organ Selectivity of JAG1 Haploinsufficiency Half-dose Jagged1 is uniform across every tissue in the carrier, yet only some organs malform. The step from the uniform molecular deficit to a selective set of malformations is therefore not itself explained by the deficit, and is marked INDIRECT_UNKNOWN_INTERMEDIATES because the factors that make one tissue decompensate and another not are unidentified.

Show evidence (5 references)

PMID:12022040 SUPPORT Human Clinical

"JAG1 is a cell-surface ligand in the Notch signaling pathway."

Establishes the cell-surface-ligand role that makes surface delivery the rate-limiting step for signalling.

PMID:20437614 SUPPORT In Vitro

"Conversely, p.C234Y and p.P810L were unable to activate Notch signaling, similar to the AGS missense mutation p.L37S."

Reporter-assay evidence that the C234Y protein has no residual trans-activating capacity, benchmarked against a known null allele.

PMID:20437614 SUPPORT In Vitro

"The p.C234Y and p.P810L mutations were not present at the cell surface, were not properly post-translationally modified, and could not initiate Notch signaling. We would therefore predict that these mutations lead to JAG1 haploinsufficiency, with only the wild-type allele in carriers of this..."

The assaying authors' own summary: all three assays agree, and the consequence is haploinsufficiency with only wild-type ligand at the surface.

+ 2 more references

Modifier-Dependent Organ Selectivity of JAG1 Haploinsufficiency

This node is the mechanistic hinge that separates this entity from Alagille syndrome, and it is deliberately curated as an unsolved step rather than an explanation. Every cell in a p.Cys234Tyr carrier has the same half-dose of functional Jagged1, yet the heart, inner ear, middle ear and anterior ocular segment malform while the intrahepatic biliary tree does not. The obvious candidate explanation - that the allele is hypomorphic and leaves enough ligand for the less demanding tissues - was proposed for the leaky p.Gly274Asp allele and then specifically ruled out for p.Cys234Tyr, which is functionally null and still spares the liver. What remains is that unidentified modifying factors, not residual ligand, determine the organ set. The clinical corollary is unchanged and important: the absence of cholestasis does not exclude a JAG1 disorder, and JAG1 variants are recovered from individuals presenting with only one or two of the Alagille organ systems.

Notch signaling pathway GO:0007219 ↓ DECREASED

Downstream

Impaired Notch-Dependent Inner Ear Sensory Patterning Reduced Jagged1 dose in the developing otic epithelium is the route to the sensorineural and vestibular arm of the phenotype.

Impaired Jagged1-Notch2 Patterning of the Middle Ear Ossicles Reduced Jagged1 dose in pharyngeal-arch neural crest is the route to the conductive component of the combined hearing loss.

Disrupted Second Heart Field and Cardiac Neural Crest Outflow Tract Development Reduced Jagged1 dose in second heart field tissue is the route to the right-sided outflow-tract lesions seen in this kindred.

Disrupted Anterior Segment Development in Periocular Neural Crest Reduced Jagged1 dose in neural-crest-derived periocular mesenchyme is the presumed route to posterior embryotoxon. The step is marked INDIRECT_UNKNOWN_INTERMEDIATES because, unlike the ear and heart arms, no Jagged1-specific anterior-segment developmental study was identified.

Show evidence (6 references)

PMID:20437614 SUPPORT In Vitro

"The missense mutants displayed heterogeneous behavior in these assays, some with complete haploinsufficiency, suggesting that there are additional modifiers leading to organ specific features."

Directly states the organ-specificity-plus-modifiers interpretation that this node encodes.

PMID:20437614 SUPPORT Human Clinical

"What remains unknown is why these cases present with only a cardiac phenotype and not the full clinical features of AGS, particularly hepatic disease."

The assaying authors' explicit statement that this step is unexplained, which is why the node carries mechanism_confidence HYPOTHETICAL.

PMID:20437614 REFUTE In Vitro

"We hypothesized at the time that the peculiar nature of these mutations could result in hypomorphic activity and not true haploinsufficiency, and that this increased level of functionality was sufficient to prevent the typical liver manifestations seen in AGS, but the developing heart was too..."

REFUTE against the graded-dose / leaky-allele explanation of liver sparing. The authors state the hypothesis and then report the result that defeats it for this allele. This is the finding that required the mechanism curated here to be reframed from dose thresholds to modifiers.

+ 3 more references

Impaired Notch-Dependent Inner Ear Sensory Patterning

Jagged1 marks the prosensory patches of the developing inner ear well before hair-cell versus supporting-cell fate is settled, and continues to be expressed by supporting cells into adulthood. Reduced Jagged1 therefore has two separable auditory consequences in model systems: an early patterning failure (loss of sensory cristae and their housing ampullae, and altered inner/outer hair-cell specification) that maps onto the vestibular and sensorineural components of the phenotype, and a later maturation failure of inner-hair-cell stereocilia that produces an auditory-neuropathy-like deafness with preserved hair-cell number. Both routes yield a sensorineural deficit without requiring hair-cell death.

cochlear inner hair cell CL:0000589 cochlear outer hair cell CL:0000601 cochlear supporting cell CL:0000630

inner ear development GO:0048839 ⚠ ABNORMAL cochlea development GO:0090102 ⚠ ABNORMAL inner ear receptor cell development GO:0060119 ⚠ ABNORMAL semicircular canal morphogenesis GO:0048752 ⚠ ABNORMAL

Animal models

headturner (Htu) Jag1 missense mouse Mouse partially recapitulates Reproduces the inner-ear sensory arm of the mechanism - loss of vestibular ampullae and reduced outer hair cells - from a heterozygous Jag1 missense allele.

Jag1 Nodder (Jag1 Ndr/Ndr) mouse Mouse partially recapitulates Reproduces dose-dependent cochlear mis-patterning with combined auditory and vestibular deficits.

Show evidence (5 references)

PMID:11259677 SUPPORT Model Organism

"a dominant mouse mutant headturner (Htu) contains a missense mutation in the Jag1 gene and displays missing posterior and sometimes anterior ampullae, structures that house the sensory cristae"

A dominant Jag1 missense allele - the same lesion class as C234Y - disrupts vestibular sensory structures in vivo.

PMID:11259677 SUPPORT Model Organism

"Htu/+ mutants also demonstrate a significant reduction in the numbers of outer hair cells in the organ of Corti."

Shows a cochlear sensory deficit in the heterozygous state, matching the dominant human inheritance.

PMID:39373109 SUPPORT Model Organism

"Jag1Ndr/Ndr mice exhibited expected vestibular and auditory deficits, a dose-dependent increase in ectopic inner hair cells, and a reduction in outer hair cells."

Establishes dose-dependent cochlear mis-patterning with combined auditory and vestibular deficits.

+ 2 more references

Impaired Jagged1-Notch2 Patterning of the Middle Ear Ossicles

The stapes and incus derive from the first two pharyngeal arches and are patterned by Jagged1-Notch2 signalling in arch neural crest cells. Reduced Jagged1 dose malforms the stapes cartilage template early in development, and the resulting ossicular malformation impairs sound conduction across all frequencies. This is the arm of the mechanism that accounts for the conductive component of the combined (mixed) hearing loss recorded in this kindred, and it is why the hearing phenotype here is mixed rather than purely sensorineural.

pharyngeal arch neural crest cell CL:0011012

neural crest cell development in the pharyngeal arches GO:0014032 ⚠ ABNORMAL sensory perception of sound GO:0007605 ↓ DECREASED

middle ear UBERON:0001756

Animal models

Heterozygous Jagged1 knockout mouse (middle ear) Mouse recapitulates Reproduces ossicular malformation from a heterozygous reduction in Jagged1 dose, matching the dominant human inheritance.

Show evidence (2 references)

PMID:28566723 SUPPORT Model Organism

"We find that Jagged1-Notch2 signaling functions early to pattern the stapes cartilage template, with stapes malformations correlating with hearing loss across all frequencies."

Establishes the ossicular patterning mechanism and its audiological consequence.

PMID:28566723 SUPPORT Human Clinical

"We observe similar stapes defects and hearing loss in one patient with heterozygous JAGGED1 loss, and a diversity of conductive and sensorineural hearing loss in nearly half of AGS patients, many of which carry JAGGED1 mutations."

Confirms in humans that heterozygous JAG1 loss yields ossicular defects and a mixture of conductive and sensorineural hearing loss - the combined pattern reported in this kindred.

Disrupted Second Heart Field and Cardiac Neural Crest Outflow Tract Development

Jagged1-Notch signalling in second heart field progenitors sustains Fgf8 and Bmp4 expression, and through them coordinates two neighbouring tissues: migrating cardiac neural crest and the endothelial-to-mesenchymal transition that populates the outflow-tract endocardial cushions. Loss of that signal produces aortic arch artery and outflow-tract anomalies of exactly the right-sided class seen in this kindred - tetralogy of Fallot, ventricular septal defect, and peripheral pulmonic stenosis. In the peripheral pulmonary arteries the corresponding structural lesion in JAG1 disease is a tunica media depleted of smooth muscle cells and thickened by collagen and elastic fibres.

cardiac neural crest cell CL:0011012 pulmonary artery smooth muscle cell CL:0002591 ↓ DECREASED

outflow tract morphogenesis GO:0003151 ⚠ ABNORMAL neural crest cell migration involved in heart formation GO:0003147 ↓ DECREASED

cardiac outflow tract UBERON:0004145

Show evidence (3 references)

PMID:19509466 SUPPORT Model Organism

"faulty migration of cardiac neural crest cells and defective endothelial-mesenchymal transition within the outflow tract endocardial cushions were observed"

Identifies the two tissue-level failures that link reduced Jagged1/Notch signalling to outflow-tract malformation.

PMID:19509466 SUPPORT Model Organism

"In mid-gestation, these mutants displayed decreased Fgf8 and Bmp4 expression."

Supplies the intermediate signalling step (Fgf8/Bmp4) between Jagged1 loss and the tissue phenotype.

PMID:39069193 SUPPORT Human Clinical

"Histological examination of the pulmonary artery walls showed a decrease in smooth muscle cells in the tunica media and an increase in collagen and elastic fibers, although the intrapulmonary arteries were intact."

Gives the vessel-wall correlate of peripheral pulmonary artery stenosis in JAG1 disease. PARTIAL because it is a single autopsy case in Alagille syndrome, not in a DCHE kindred.

Disrupted Anterior Segment Development in Periocular Neural Crest

The trabecular meshwork, corneal endothelium and Schwalbe line derive from neural-crest-derived periocular mesenchyme. Posterior embryotoxon - an anteriorly displaced, prominent Schwalbe line visible at the slit lamp - is a recognised consequence of reduced JAG1/NOTCH2 signalling in humans and is one of the two features this entity shares with Alagille syndrome. The developmental step is curated as HYPOTHETICAL rather than established: no Jagged1-specific study of anterior-segment morphogenesis was identified, so the tissue-level mechanism is inferred from the neural-crest origin of the affected structures and from the human phenotype association rather than demonstrated.

periocular neural crest cell CL:0011012

eye development GO:0001654 ⚠ ABNORMAL

anterior segment of eyeball UBERON:0001801

Show evidence (2 references)

PMID:12022040 SUPPORT Human Clinical

"Our findings revealed a unique phenotype with highly penetrant deafness, posterior embryotoxon, and congenital heart defects"

Establishes posterior embryotoxon as a highly penetrant feature of the JAG1 p.Cys234Tyr phenotype.

PMID:27418850 SUPPORT Human Clinical

"congenital cardiac defects (with particular involvement of the pulmonary arteries), posterior embryotoxon in the eye, characteristic facial features, and butterfly vertebrae"

Confirms posterior embryotoxon as a recognised ocular consequence of JAG1/NOTCH2 pathway disruption. PARTIAL - it documents the association in Alagille syndrome, not the developmental mechanism.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

8

Cardiovascular 2

Congenital heart defect VERY_FREQUENT Abnormal heart morphology HP:0001627

Show evidence (1 reference)

PMID:12022040 SUPPORT Human Clinical

"All patients had congenital heart defects, including tetralogy of Fallot, ventricular septal defect, or isolated peripheral pulmonic stenosis."

"All patients" in the index kindred supports the VERY_FREQUENT band for congenital heart disease as a class.

Ventricular septal defect HP:0001629

Show evidence (1 reference)

PMID:12022040 SUPPORT Human Clinical

"All patients had congenital heart defects, including tetralogy of Fallot, ventricular septal defect, or isolated peripheral pulmonic stenosis."

Names ventricular septal defect among the cardiac lesions in this kindred.

Eye 1

Posterior embryotoxon VERY_FREQUENT HP:0000627

Show evidence (1 reference)

PMID:12022040 SUPPORT Human Clinical

"Our findings revealed a unique phenotype with highly penetrant deafness, posterior embryotoxon, and congenital heart defects but with variable expressivity in a large kindred"

The index report describes posterior embryotoxon as highly penetrant in this kindred. Per docs/frequency-evidence-guidelines.md that qualitative wording maps to the VERY_FREQUENT band (80-100%); no numerator and denominator were published for this feature, so the band rests on the authors' penetrance wording rather than on a count.

Other 5

Mixed hearing impairment VERY_FREQUENT HP:0000410

Show evidence (2 references)

PMID:12022040 SUPPORT Human Clinical

"Six of seven available affected patients manifested mild-to-severe combined hearing loss, predominantly affecting middle frequencies."

Directly documents combined (mixed) hearing loss, and the 6/7 count (86%) is what supports the VERY_FREQUENT band.

PMID:28566723 SUPPORT Human Clinical

"We observe similar stapes defects and hearing loss in one patient with heterozygous JAGGED1 loss, and a diversity of conductive and sensorineural hearing loss in nearly half of AGS patients, many of which carry JAGGED1 mutations."

Independently supports a mixed conductive-plus-sensorineural pattern as the expected audiological consequence of heterozygous JAG1 loss.

Mid-frequency hearing loss HP:0012781

Show evidence (1 reference)

PMID:12022040 SUPPORT Human Clinical

"Six of seven available affected patients manifested mild-to-severe combined hearing loss, predominantly affecting middle frequencies."

Directly documents the mid-frequency-predominant audiometric configuration.

Abnormal vestibular function OCCASIONAL HP:0001751

Show evidence (2 references)

PMID:12022040 SUPPORT Human Clinical

"Two patients were diagnosed with vestibular pathology."

Documents vestibular involvement; 2 of the 7 available affected patients (29%) is what supports the OCCASIONAL band.

PMID:39373109 SUPPORT Model Organism

"Jag1Ndr/Ndr mice exhibited expected vestibular and auditory deficits, a dose-dependent increase in ectopic inner hair cells, and a reduction in outer hair cells."

Model-organism support that reduced Jag1 dose produces vestibular as well as auditory deficits.

Tetralogy of Fallot HP:0001636

Show evidence (2 references)

PMID:12022040 SUPPORT Human Clinical

"All patients had congenital heart defects, including tetralogy of Fallot, ventricular septal defect, or isolated peripheral pulmonic stenosis."

Names tetralogy of Fallot among the cardiac lesions in this kindred.

PMID:20437614 SUPPORT Human Clinical

"We identified functionally significant mutations in 2% (2/94) of TOF patients and 4% (2/50) of PS/PPS/PA patients."

Independently links JAG1 lesions to tetralogy of Fallot outside classic Alagille syndrome.

Peripheral pulmonary artery stenosis HP:0004969

Show evidence (2 references)

PMID:12022040 SUPPORT Human Clinical

"All patients had congenital heart defects, including tetralogy of Fallot, ventricular septal defect, or isolated peripheral pulmonic stenosis."

Names isolated peripheral pulmonic stenosis among the cardiac lesions in this kindred.

PMID:39069193 SUPPORT Human Clinical

"Alagille syndrome is caused by mutations in genes involved in NOTCH signaling, specifically JAG1 and NOTCH2, and is associated with a high rate of peripheral pulmonary artery stenosis."

Supports peripheral pulmonary artery stenosis as a characteristic consequence of JAG1-pathway disruption. PARTIAL because the cohort is Alagille syndrome rather than this entity.

🧬

Genetic Associations

1

JAG1 (Causal heterozygous missense variant p.Cys234Tyr in the first EGF-like repeat)

Gene: JAG1 hgnc:6188 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (3 references)

PMID:12022040 SUPPORT Human Clinical

"A candidate-gene approach was undertaken and culminated in the identification of a novel Jagged 1 (JAG1) missense mutation (C234Y) in the first cysteine of the first epidermal-growth-factor-like repeat domain of the protein."

Establishes JAG1 p.Cys234Tyr as the causal allele in the index kindred.

PMID:31343788 SUPPORT Human Clinical

"The majority of JAG1 variants result in loss of function, however disease has also been attributed to lesser understood missense variants."

Places this missense allele in its variant-class context and flags the interpretive difficulty that attends JAG1 missense variants.

PMID:31343788 SUPPORT Human Clinical

"Using this data set, we developed new guidance to help with the classification of JAG1 missense variants."

Supports the statement that dedicated classification guidance was needed for JAG1 missense variants.

💊

Medical Actions

4

Genetic counselling

Category: Counseling / Informational Action: Genetic Counseling NCIT:C15240

Autosomal dominant transmission with high penetrance of the triad but marked variability in which lesion an individual carrier expresses. Counselling must convey a 50% transmission risk together with the point that the cardiac lesion in an affected child cannot be predicted from the parent's lesion, and should include cascade evaluation of at-risk relatives with audiometry and slit-lamp examination as well as echocardiography.

Show evidence (2 references)

PMID:12022040 SUPPORT Human Clinical

"In the present study, we report a kindred with hearing loss, congenital heart defects, and posterior embryotoxon, segregating as autosomal dominant traits."

Establishes the autosomal dominant transmission pattern that determines the recurrence risk conveyed in counselling.

PMID:12022040 SUPPORT Human Clinical

"Our findings revealed a unique phenotype with highly penetrant deafness, posterior embryotoxon, and congenital heart defects but with variable expressivity in a large kindred"

Supports the counselling message that penetrance is high but expressivity varies between carriers of the same allele.

Surgical repair of the congenital heart defect

Category: Therapeutic Action: Cardiac Surgery NCIT:C157806

Management of the cardiac component follows standard congenital-cardiac practice for the specific lesion; there is no DCHE-specific cardiac protocol. Tetralogy of Fallot requires operative repair, whereas isolated peripheral pulmonic stenosis may need only surveillance - so the same allele in two relatives can imply completely different cardiac management, which is the practical consequence of the variable expressivity recorded here.

Target Phenotypes: Tetralogy of Fallot HP:0001636 Ventricular septal defect HP:0001629

Show evidence (1 reference)

PMID:12022040 SUPPORT Human Clinical

"All patients had congenital heart defects, including tetralogy of Fallot, ventricular septal defect, or isolated peripheral pulmonic stenosis."

Establishes the surgically relevant lesion set. PARTIAL - it documents the lesions requiring management, not an outcome of surgery in this disorder, for which no evidence exists.

Audiological assessment and hearing rehabilitation

Category: Therapeutic Action: audiological support and hearing amplification Ontology label: Supportive Care NCIT:C15747

Because the hearing loss is mixed and mid-frequency-predominant, it is not reliably caught by a screen tuned to high-frequency sensorineural loss, and full audiometry (with tympanometry to characterise the conductive component) is warranted in any carrier or at-risk relative. Amplification and language-development support follow standard paediatric audiology practice; no DCHE-specific rehabilitation evidence exists.

Target Phenotypes: Combined (mixed) hearing loss HP:0000410

Show evidence (1 reference)

PMID:12022040 SUPPORT Human Clinical

"Six of seven available affected patients manifested mild-to-severe combined hearing loss, predominantly affecting middle frequencies."

Establishes the mixed, mid-frequency character of the loss that dictates the audiological assessment described here. PARTIAL - it documents the deficit, not the effect of any intervention.

Ophthalmic surveillance

Category: Monitoring Action: ophthalmic surveillance Ontology label: Supportive Care NCIT:C15747

Posterior embryotoxon is itself usually visually silent and needs no treatment; what warrants follow-up is what may accompany it. Anterior-segment dysgenesis and glaucoma are the findings that determine visual outcome, and the overlap between JAG1 disease and the Axenfeld-Rieger spectrum, in which glaucoma is a principal concern, is close enough that periodic slit-lamp examination with intraocular pressure measurement is prudent in a carrier. Note the evidence base here is the wider JAG1 and anterior-segment literature: no glaucoma was reported in the index kindred, and no surveillance interval has been studied in this entity.

Show evidence (2 references)

PMID:37895297 SUPPORT Human Clinical

"The identification of JAG1 variants, linked with Alagille syndrome, in three separate families with a clinical diagnosis of ARA/ARS highlights the overlapping features and high variability of these two phenotypes."

Establishes the overlap with a spectrum in which glaucoma is a recognised threat to vision, which is the rationale for surveillance. PARTIAL: it documents the phenotypic overlap, not the value of any surveillance interval, which has not been studied in this entity.

PMID:12022040 SUPPORT Human Clinical

"Our findings revealed a unique phenotype with highly penetrant deafness, posterior embryotoxon, and congenital heart defects"

Establishes the near-universal ocular involvement that puts every carrier in scope for ophthalmic follow-up. PARTIAL: it documents the finding, not an outcome of surveillance.

🔬

Diagnosis

7

Formal audiometry with tympanometry

The audiological assessment is the diagnostically decisive test in this entity, and a screen is not sufficient for two independent reasons. First, the loss is mid-frequency predominant, so a protocol weighted toward the high frequencies where most acquired and hereditary sensorineural loss appears can return a reassuring result. Second, the loss is mixed, so tympanometry and air-bone gap measurement are required to demonstrate the conductive component that reflects the underlying ossicular malformation. Auditory brainstem response and otoacoustic emissions extend the same assessment to infants and to the auditory-neuropathy pattern that Jag1 loss produces in the mouse cochlea.

audiometric assessment with tympanometry NCIT:C38036

Markers: Air and bone conduction thresholds, air-bone gap, tympanogram

Results: Mild-to-severe mixed hearing loss with a mid-frequency predominant configuration; the air-bone gap identifies the conductive component attributable to ossicular malformation.

Show evidence (2 references)

PMID:12022040 SUPPORT Human Clinical

"Six of seven available affected patients manifested mild-to-severe combined hearing loss, predominantly affecting middle frequencies."

Establishes both features that dictate the protocol: the loss is combined (so the conductive component must be measured) and mid-frequency predominant (so the configuration must be characterised across frequency).

PMID:28566723 SUPPORT Human Clinical

"We observe similar stapes defects and hearing loss in one patient with heterozygous JAGGED1 loss, and a diversity of conductive and sensorineural hearing loss in nearly half of AGS patients, many of which carry JAGGED1 mutations."

Supports expecting a conductive component of ossicular origin alongside the sensorineural one, which is what tympanometry is there to detect.

Auditory brainstem response testing

Extends audiological assessment to infants, to individuals who cannot give reliable behavioural thresholds, and to the auditory-neuropathy pattern. Relevant here because Jag1 loss during cochlear maturation produces, in the mouse, a deafness clinically similar to auditory neuropathy, in which otoacoustic emissions can be preserved while the brainstem response is not.

auditory brainstem response NCIT:C184949

Show evidence (1 reference)

PMID:36400760 SUPPORT Model Organism

"we show that deletion of JAG1 during cochlear maturation disrupts the inner hair cell pathway and leads to a type of deafness clinically similar to auditory neuropathy"

Motivates brainstem-response testing rather than emissions alone. PARTIAL: this is a mouse result, and the auditory-neuropathy pattern has not been documented in a DCHE carrier.

Echocardiography

Every affected member of the index kindred had a congenital heart defect, so cardiac imaging is indicated in any individual with a molecular diagnosis and in at-risk relatives during cascade evaluation. The lesion set is right sided, spanning tetralogy of Fallot, ventricular septal defect and isolated peripheral pulmonic stenosis, and it differs between relatives carrying the same allele, so a normal study in a parent does not predict the child.

echocardiography NCIT:C16525

Markers: Outflow tract and branch pulmonary artery anatomy, ventricular septum

Results: Right-sided lesions: tetralogy of Fallot, ventricular septal defect, or isolated peripheral pulmonic stenosis.

Show evidence (1 reference)

PMID:12022040 SUPPORT Human Clinical

"All patients had congenital heart defects, including tetralogy of Fallot, ventricular septal defect, or isolated peripheral pulmonic stenosis."

Universal cardiac involvement, across a lesion range wide enough to require imaging rather than auscultation, is what makes echocardiography a required element of the workup.

Slit-lamp examination for posterior embryotoxon

Posterior embryotoxon is an anteriorly displaced, prominent Schwalbe line and is visible only on slit-lamp examination, not on routine visual assessment. It is usually visually silent in itself, so its value here is almost entirely diagnostic, and it is the element of the triad most likely to be missed because nothing prompts the patient to report it. Intraocular pressure measurement belongs in the same visit: it is the associated anterior-segment dysgenesis and glaucoma, rather than the embryotoxon, that threatens vision.

ophthalmic examination with slit-lamp biomicroscopy NCIT:C20989

Markers: Schwalbe line position, iridocorneal angle, intraocular pressure

Results: Posterior embryotoxon, seen as an anteriorly displaced and prominent Schwalbe line.

Show evidence (2 references)

PMID:37895297 SUPPORT Human Clinical

"a specific type of anterior segment disorder characterized by the triad of posterior embryotoxon"

Places posterior embryotoxon among the anterior-segment findings assessed at the slit lamp, which is the examination this entry recommends.

PMID:12022040 SUPPORT Human Clinical

"Our findings revealed a unique phenotype with highly penetrant deafness, posterior embryotoxon, and congenital heart defects"

Establishes posterior embryotoxon as a highly penetrant feature, so its detection materially changes the diagnostic probability.

JAG1 sequencing

Molecular confirmation is by sequencing of the JAG1 coding exons. Because this entity is defined by a missense substitution, exon sequencing rather than deletion analysis is the first-line test that finds it. In Alagille syndrome, the disorder for which JAG1 testing strategy has actually been quantified, sequencing all JAG1 exons identifies approximately 85% of pathogenic variants.

JAG1 gene sequencing NCIT:C15709

Show evidence (2 references)

PMID:31343788 SUPPORT Human Clinical

"The current standard is to sequence all exons in JAG1, which should identify approximately 85% of ALGS pathogenic variants."

Supplies the first-tier yield figure. PARTIAL because the denominator is an Alagille syndrome cohort; no equivalent figure exists for this entity, and the number must not be read as a DCHE detection rate.

PMID:12022040 SUPPORT Human Clinical

"A candidate-gene approach was undertaken and culminated in the identification of a novel Jagged 1 (JAG1) missense mutation (C234Y) in the first cysteine of the first epidermal-growth-factor-like repeat domain of the protein."

The causal variant is an intragenic missense change, which is what makes exon sequencing rather than dosage analysis the test that detects it.

JAG1 copy number analysis

Second-tier testing when sequencing is negative but the phenotype still suggests a JAG1 disorder. Large JAG1 deletions are a recognised cause of JAG1-related disease and are invisible to exon sequencing, so a negative sequencing result does not close the question. Note this test would not have found the variant in the index kindred, which is a point substitution; it is included because a clinician working from the phenotype, not the known genotype, cannot assume that in advance.

copy number variant analysis NCIT:C18084

Show evidence (1 reference)

PMID:31343788 SUPPORT Human Clinical

"second tier diagnostics involves large deletion/duplication analysis through either multiplex ligation-dependent probe amplification (MLPA), chromosomal microarray (CMA), or fluorescence in situ hybridization (FISH), which should identify an additional 9% of pathogenic variants"

Supplies the second-tier method and its incremental yield. PARTIAL for the same reason as the sequencing figure: the denominator is an Alagille syndrome cohort.

Interpretation of a JAG1 missense variant

A caveat rather than a test. The causal allele here is missense, and JAG1 missense variants are the class that resists confident classification, which is why dedicated interpretation guidance had to be developed for them. A missense variant of uncertain significance in JAG1 should therefore not be dismissed on in-silico grounds alone in an individual with this phenotype; segregation and, where available, functional data carry the weight.

variant classification NCIT:C15220

Show evidence (2 references)

PMID:31343788 SUPPORT Human Clinical

"The majority of JAG1 variants result in loss of function, however disease has also been attributed to lesser understood missense variants."

States that JAG1 missense variants are the poorly understood minority, which is the interpretive difficulty this entry flags.

PMID:31343788 SUPPORT Human Clinical

"Using this data set, we developed new guidance to help with the classification of JAG1 missense variants."

Confirms that dedicated classification guidance was required, supporting the caution recorded here.

📊

Prevalence

1

Worldwide

Cases In Literature Ultra Rare

The entity rests on a single reported kindred, in which seven affected individuals were available for study. No population-based prevalence estimate exists, and Alagille syndrome prevalence figures must not be transferred to this entry.

Show evidence (1 reference)

PMID:12022040 SUPPORT Human Clinical

"Six of seven available affected patients manifested mild-to-severe combined hearing loss, predominantly affecting middle frequencies."

Fixes the size of the only reported series (seven available affected individuals in one kindred), which is the basis for the ULTRA_RARE class.

🔀

Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from Deafness, Congenital Heart Defects, and Posterior Embryotoxon:

Alagille syndrome MONDO:0007318

Overlapping Features The single most important differential, and an allelic disorder: Alagille syndrome is caused by heterozygous variants in the same gene (JAG1, and less often NOTCH2), and shares two of this entity's three cardinal features (congenital heart defects with pulmonary-artery predilection, and posterior embryotoxon). This entity is curated separately from kb/disorders/Alagille_syndrome.yaml, and the two must not be merged on the strength of shared gene identity alone.

Distinguishing Features

Present in Alagille syndrome and absent in the index kindred of this entity: cholestasis with paucity of interlobular bile ducts on liver biopsy (the defining Alagille criterion), butterfly vertebrae, and the characteristic facies.
Present here and NOT an Alagille diagnostic criterion: highly penetrant mixed hearing loss with a mid-frequency configuration. Hearing loss does occur in Alagille syndrome, but as an associated finding rather than a cardinal criterion.
Decisive statement from the index report: no individual in this kindred met diagnostic criteria for any previously described clinical syndrome.
The dissociation is NOT explained by a milder molecular lesion. JAG1 p.Cys234Tyr is completely haploinsufficient, being EndoH sensitive, absent from the cell surface, and unable to activate Notch, so the difference from Alagille syndrome is neither gene, nor pathway, nor allele severity. The organ selectivity is attributed to unidentified modifying factors and is recorded here as an open knowledge gap. The superficially attractive graded-dose account, in which the developing heart tolerates reduced JAG1 dose less well than the developing liver does, derives from the DIFFERENT and genuinely leaky p.Gly274Asp allele, and was specifically tested and ruled out for this one.

Show evidence (5 references)

PMID:12022040 SUPPORT Human Clinical

"No individual in this family met diagnostic criteria for any previously described clinical syndrome."

The index report's own explicit statement that this kindred is not Alagille syndrome (or any other described syndrome) - the primary basis for curating a separate entry.

PMID:20437614 SUPPORT Human Clinical

"The p.C234Y variant is a familial mutation segregating with cardiac defects, deafness, and posterior embryotoxon, yet all carriers have normal liver function"

Independent confirmation, by a different group, of the liver sparing that separates this entity from Alagille syndrome - stated for this exact allele and kindred.

PMID:20437614 SUPPORT Human Clinical

"although the lack of any liver dysfunction in the nine family members studied by Le Caignec et al. is unusual"

Records both the size of the assessed group (nine family members) and that experts in Alagille syndrome regard the complete absence of liver dysfunction as atypical for a JAG1 disorder.

+ 2 more references

Axenfeld-Rieger anomaly and syndrome spectrum

Overlapping Features Posterior embryotoxon is also the leading element of the Axenfeld-Rieger anomaly triad, so an individual with this entity who comes to attention through an ophthalmologist can be labelled Axenfeld-Rieger rather than referred for JAG1 testing. This is not hypothetical: a 2023 cohort of Axenfeld-Rieger cases left unsolved after PITX2 and FOXC1 testing found JAG1 variants in three separate families, one of whom - referred with Axenfeld-Rieger anomaly, bilateral sensorineural hearing loss and dysmorphism - is phenotypically close to this entity. The practical consequence is that JAG1 belongs on the differential of anterior-segment dysgenesis with syndromic features, particularly when hearing loss or a congenital heart defect accompanies it.

Distinguishing Features

Axenfeld-Rieger anomaly requires iridocorneal adhesions and iris anomalies (hypoplasia, corectopia, polycoria) in addition to posterior embryotoxon; the index kindred of this entity was reported with posterior embryotoxon alone, without the rest of the triad.
Classic Axenfeld-Rieger syndrome is caused by PITX2 (type 1, with dental and umbilical features) or FOXC1 (type 3), which together explain roughly 70% of cases; this entity is caused by JAG1. Note that FOXC1-associated disease can itself include hearing loss and congenital heart defects, so the clinical overlap with this entity is genuine and gene testing, not phenotype, settles it.
Glaucoma is a major concern in Axenfeld-Rieger anomaly and was not reported in the index kindred here; conversely the mid-frequency mixed hearing loss characteristic of this entity is not an Axenfeld-Rieger feature.

Show evidence (4 references)

PMID:37895297 SUPPORT Human Clinical

"The identification of JAG1 variants, linked with Alagille syndrome, in three separate families with a clinical diagnosis of ARA/ARS highlights the overlapping features and high variability of these two phenotypes."

Directly documents JAG1 presenting under an Axenfeld-Rieger clinical label, which is what makes this a real rather than theoretical differential.

PMID:37895297 SUPPORT Human Clinical

"a specific type of anterior segment disorder characterized by the triad of posterior embryotoxon"

Establishes posterior embryotoxon as an Axenfeld-Rieger triad element, which is the shared feature that creates the diagnostic confusion.

PMID:37895297 SUPPORT Human Clinical

"referred with diagnosis of ARS based on ARA, bilateral sensorineural hearing loss, midface hypoplasia, hypertelorism, and dental crowding"

A JAG1-positive individual carrying anterior-segment disease together with sensorineural hearing loss - the feature combination that defines this entity - reached the clinic under an Axenfeld-Rieger label.

+ 1 more reference

Atypical or oligosymptomatic Alagille syndrome

Overlapping Features Individuals carrying a JAG1 variant who manifest only one or two of the Alagille organ systems. This entity may ultimately prove to be a member of that continuum rather than a discrete disorder - see the open discussion on entity status recorded below.

Distinguishing Features

Distinguished by the presence here of a highly penetrant, mid-frequency mixed hearing loss segregating with the cardiac and ocular features in a single large pedigree, and by the explicit statement in the index report that no affected individual met criteria for a previously described syndrome.

Show evidence (1 reference)

PMID:21752016 SUPPORT Human Clinical

"The highest mutation detection rates were observed in patients with the most frequent presenting features of Alagille syndrome; ranging from 20% (one system) to 86% (five systems)."

Quantifies the oligosymptomatic JAG1 presentation that forms the boundary of this entity.

🐁

Animal Models

3

headturner (Htu) Jag1 missense mouse

A dominant, ENU-derived Jag1 missense allele - the same lesion class as the human p.Cys234Tyr - assessed in the heterozygous state, matching the dominant human inheritance. Its value here is that it links a heterozygous Jag1 missense change to both vestibular and cochlear sensory deficits.

Species

Mouse

Genotype

Jag1 Htu/+ (dominant missense allele)

Publication

PMID:11259677

Pathograph links

Impaired Notch-Dependent Inner Ear Sensory Patterning partially recapitulates fidelity: moderate Reproduces the inner-ear sensory arm of the mechanism - loss of vestibular ampullae and reduced outer hair cells - from a heterozygous Jag1 missense allele.

Limitations: The Htu allele is not p.Cys234Tyr and lies in a different part of the protein; the mouse was not reported to model the cardiac or ocular arms of the human phenotype, and gross ampullar agenesis is more severe than anything documented in the human kindred.

Show evidence (1 reference)

PMID:11259677 SUPPORT Model Organism

"a dominant mouse mutant headturner (Htu) contains a missense mutation in the Jag1 gene and displays missing posterior and sometimes anterior ampullae, structures that house the sensory cristae"

Supports treating this model as informative for Jagged1-dependent inner ear sensory patterning.

Show evidence (1 reference)

PMID:11259677 SUPPORT Model Organism

"Htu/+ mutants also demonstrate a significant reduction in the numbers of outer hair cells in the organ of Corti."

Establishes the model as informative for this disorder: a heterozygous Jag1 missense allele - the lesion class of the human p.Cys234Tyr variant - produces a cochlear sensory deficit.

Jag1 Nodder (Jag1 Ndr/Ndr) mouse

A hypomorphic Jag1 mouse used as an Alagille syndrome model, with cochlear morphology plus single-cell RNA sequencing of the organ of Corti. It establishes that the cochlear phenotype is Jag1 dose dependent, which is what makes a heterozygous human loss-of-function allele a sufficient explanation for hearing loss. This speaks to the ear arm only: it is not support for a graded-dose account of the organ selectivity, which was tested and ruled out for p.Cys234Tyr.

Species

Mouse

Genotype

Jag1 Ndr/Ndr (hypomorphic Alagille syndrome model)

Publication

PMID:39373109

Pathograph links

Impaired Notch-Dependent Inner Ear Sensory Patterning partially recapitulates fidelity: moderate Reproduces dose-dependent cochlear mis-patterning with combined auditory and vestibular deficits.

Limitations: A homozygous hypomorph rather than a heterozygous missense carrier, and not the p.Cys234Tyr allele; the cardiac and ocular arms of the human phenotype are not addressed by this study.

Show evidence (1 reference)

PMID:39373109 SUPPORT Model Organism

"Jag1Ndr/Ndr mice exhibited expected vestibular and auditory deficits, a dose-dependent increase in ectopic inner hair cells, and a reduction in outer hair cells."

Supports treating this model as informative for dose-dependent cochlear patterning failure.

Show evidence (1 reference)

PMID:39373109 SUPPORT Model Organism

"Notch signaling patterns the cochlear organ of Corti, and individuals with the JAG1/NOTCH2-related genetic disorder Alagille syndrome can thus experience hearing loss."

Establishes the model as informative for the human JAG1 hearing phenotype that this entity shares with the wider JAG1 disease spectrum.

Heterozygous Jagged1 knockout mouse (middle ear)

The heterozygous Jag1 null mouse, used as an Alagille syndrome model, carries the conductive arm of the mechanism: it malforms the stapes and incus, and the stapes malformation tracks with hearing loss across all frequencies.

Species

Mouse

Genotype

Jag1 +/- heterozygous null

Publication

PMID:28566723

Pathograph links

Impaired Jagged1-Notch2 Patterning of the Middle Ear Ossicles recapitulates fidelity: moderate Reproduces ossicular malformation from a heterozygous reduction in Jagged1 dose, matching the dominant human inheritance.

Limitations: A null allele rather than the human missense allele, so the ligand reduction is a clean 50%. That is now known to be the right dose for p.Cys234Tyr, which is functionally null, so the mismatch here is one of allele mechanism and species rather than of dose; the audiological correlate is still inferred from mouse thresholds rather than measured in a DCHE carrier.

Show evidence (1 reference)

PMID:28566723 SUPPORT Model Organism

"Heterozygous Jagged1 knockout mice, a model for Alagille Syndrome (AGS), also display stapes and incus defects."

Supports treating this model as informative for Jagged1-dependent ossicular patterning.

Show evidence (1 reference)

PMID:28566723 SUPPORT Human Clinical

"We observe similar stapes defects and hearing loss in one patient with heterozygous JAGGED1 loss, and a diversity of conductive and sensorineural hearing loss in nearly half of AGS patients, many of which carry JAGGED1 mutations."

Establishes the model as informative for humans: the mouse ossicular defect is mirrored in a person with heterozygous JAG1 loss, and the resulting mixed conductive-sensorineural pattern matches this entity's phenotype.

{ }

Source YAML

click to show

name: Deafness, Congenital Heart Defects, and Posterior Embryotoxon
creation_date: "2026-08-19T00:00:00Z"
category: Mendelian
disease_term:
  preferred_term: deafness, congenital heart defects, and posterior embryotoxon
  term:
    id: MONDO:0060713
    label: deafness, congenital heart defects, and posterior embryotoxon
synonyms:
- DCHE
- JAG1-related deafness-congenital heart defects-posterior embryotoxon syndrome
description: >-
  Deafness, congenital heart defects, and posterior embryotoxon (DCHE, OMIM
  617992) is an ultra-rare autosomal dominant Notch-ligand disorder delineated in
  a single large French kindred carrying the heterozygous JAG1 missense variant
  p.Cys234Tyr (C234Y), which substitutes the first cysteine of the first
  epidermal-growth-factor-like repeat of Jagged1. Affected individuals show a
  highly penetrant triad of mild-to-severe combined (mixed) hearing loss with a
  mid-frequency emphasis, congenital heart defects drawn from the right-sided
  outflow-tract spectrum (tetralogy of Fallot, ventricular septal defect,
  isolated peripheral pulmonic stenosis), and posterior embryotoxon, with
  vestibular involvement in a subset.

  DCHE is allelic to Alagille syndrome - the same gene, the same signalling
  pathway, two of the same cardinal features - but is a clinically separable
  presentation: no individual in the index kindred met diagnostic criteria for
  Alagille syndrome or any other described syndrome, all carriers had normal
  liver function, and the defining hepatic feature of Alagille syndrome
  (cholestasis with paucity of interlobular bile ducts) is absent, as are
  butterfly vertebrae and the characteristic facies.

  The mechanism of that dissociation is NOT a milder molecular lesion. p.Cys234Tyr
  has been assayed directly: the mutant protein is EndoH-sensitive (improperly
  post-translationally modified), is absent from the cell surface by both trypsin
  shaving and immunofluorescence, and cannot activate Notch signalling - it is,
  in the assaying authors' words, completely haploinsufficient. That result
  specifically defeats the attractive "leaky allele" explanation: the same group
  had proposed, on the strength of the hypomorphic JAG1 p.Gly274Asp allele, that
  residual ligand dose was what spared the liver in cardiac-only JAG1 families,
  and then found that a completely null allele produces the same liver sparing.
  The organ selectivity of this disorder is therefore attributed to additional
  modifying factors, still unidentified, rather than to residual Jagged1
  activity. This entry deliberately does NOT import Alagille syndrome cohort
  frequencies, and curates hearing loss - which is not a cardinal Alagille
  criterion - as the feature that names this entity.
parents:
- hereditary disease
- Syndromic hearing loss
- Congenital heart defect
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0060713
      label: deafness, congenital heart defects, and posterior embryotoxon
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      MONDO:0060713 is the anchor term for this entry. It carries OMIM:617992 as
      an xref and DCHE as a related synonym, both of which match the curated
      content here. MONDO records no causal gene (RO:0004003) for this term, so
      gene identity was anchored manually on the OMIM entry and on the index
      publication PMID:12022040, which names JAG1 p.Cys234Tyr.

classifications:
  harrisons_chapter:
  - classification_value: DISORDER_OF_EAR
    notes: >-
      Hearing loss is the feature that names and distinguishes this entity from
      its allelic neighbour Alagille syndrome, in which hearing loss is not a
      cardinal diagnostic criterion.
    evidence:
    - reference: PMID:12022040
      reference_title: >-
        Familial deafness, congenital heart defects, and posterior embryotoxon
        caused by cysteine substitution in the first epidermal-growth-factor-like
        domain of jagged 1.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Our findings revealed a unique phenotype with highly penetrant deafness,
        posterior embryotoxon, and congenital heart defects but with variable
        expressivity in a large kindred, which demonstrates that mutation in JAG1
        can cause hearing loss.
      explanation: >-
        Establishes deafness as a highly penetrant, defining feature of this
        entity, which is what places it in the ear-disorder chapter.
  - classification_value: CARDIOVASCULAR
    notes: >-
      Congenital heart disease was present in every affected member of the index
      kindred and is the principal source of structural morbidity.
    evidence:
    - reference: PMID:12022040
      reference_title: >-
        Familial deafness, congenital heart defects, and posterior embryotoxon
        caused by cysteine substitution in the first epidermal-growth-factor-like
        domain of jagged 1.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        All patients had congenital heart defects, including tetralogy of Fallot,
        ventricular septal defect, or isolated peripheral pulmonic stenosis.
      explanation: >-
        Universal congenital heart disease in the index kindred motivates the
        cardiovascular chapter assignment.
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    notes: >-
      A single-gene autosomal dominant disorder delineated by segregation
      analysis and a candidate-gene approach in one multigenerational pedigree.
    evidence:
    - reference: PMID:12022040
      reference_title: >-
        Familial deafness, congenital heart defects, and posterior embryotoxon
        caused by cysteine substitution in the first epidermal-growth-factor-like
        domain of jagged 1.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In the present study, we report a kindred with hearing loss, congenital
        heart defects, and posterior embryotoxon, segregating as autosomal
        dominant traits.
      explanation: >-
        A Mendelian dominant trait defined by pedigree segregation, which is what
        places it in the genetics chapter.

inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    The p.Cys234Tyr allele segregated as an autosomal dominant trait through a
    large multigenerational kindred, with high penetrance of the triad but
    variable expressivity of its individual components (the specific cardiac
    lesion in particular differed between affected relatives). This mirrors the
    intra-familial variability characteristic of JAG1 disorders generally.
  evidence:
  - reference: PMID:12022040
    reference_title: >-
      Familial deafness, congenital heart defects, and posterior embryotoxon
      caused by cysteine substitution in the first epidermal-growth-factor-like
      domain of jagged 1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the present study, we report a kindred with hearing loss, congenital
      heart defects, and posterior embryotoxon, segregating as autosomal dominant
      traits.
    explanation: >-
      Directly establishes autosomal dominant segregation in the index pedigree.
  - reference: PMID:12022040
    reference_title: >-
      Familial deafness, congenital heart defects, and posterior embryotoxon
      caused by cysteine substitution in the first epidermal-growth-factor-like
      domain of jagged 1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our findings revealed a unique phenotype with highly penetrant deafness,
      posterior embryotoxon, and congenital heart defects but with variable
      expressivity in a large kindred
    explanation: >-
      Supports the high-penetrance, variable-expressivity pattern described here.

prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    The entity rests on a single reported kindred, in which seven affected
    individuals were available for study. No population-based prevalence estimate
    exists, and Alagille syndrome prevalence figures must not be transferred to
    this entry.
  evidence:
  - reference: PMID:12022040
    reference_title: >-
      Familial deafness, congenital heart defects, and posterior embryotoxon
      caused by cysteine substitution in the first epidermal-growth-factor-like
      domain of jagged 1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Six of seven available affected patients manifested mild-to-severe combined
      hearing loss, predominantly affecting middle frequencies.
    explanation: >-
      Fixes the size of the only reported series (seven available affected
      individuals in one kindred), which is the basis for the ULTRA_RARE class.

pathophysiology:
- name: JAG1 First EGF-Like Repeat Cysteine Substitution
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    The disease-initiating lesion is a heterozygous germline JAG1 missense
    variant, p.Cys234Tyr, that replaces the first cysteine of the first
    epidermal-growth-factor(EGF)-like repeat of Jagged1. EGF-like repeats are
    small, disulfide-stapled modules whose fold depends on a fixed pattern of
    six cysteines; losing one of them leaves an unpaired partner and destabilises
    the module. Missense variants in JAG1 are non-randomly distributed and
    cluster in exactly these regions - the amino-terminal region, the DSL domain,
    and two clusters within the EGF repeats - which is the structural context in
    which this substitution should be read.
  genetic_context:
    gene:
      preferred_term: JAG1
      term:
        id: hgnc:6188
        label: JAG1
    allele_type: missense
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Heterozygous germline JAG1 p.Cys234Tyr (C234Y). Classified LOSS_OF_FUNCTION
      on direct functional assay of this allele: the mutant protein is
      EndoH-sensitive, absent from the cell surface, and unable to activate Notch
      signalling, i.e. complete haploinsufficiency. No dominant-negative activity
      has been demonstrated for the JAG1 missense proteins assayed to date.
  genes:
  - preferred_term: JAG1
    term:
      id: hgnc:6188
      label: JAG1
  evidence:
  - reference: PMID:12022040
    reference_title: >-
      Familial deafness, congenital heart defects, and posterior embryotoxon
      caused by cysteine substitution in the first epidermal-growth-factor-like
      domain of jagged 1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A candidate-gene approach was undertaken and culminated in the
      identification of a novel Jagged 1 (JAG1) missense mutation (C234Y) in the
      first cysteine of the first epidermal-growth-factor-like repeat domain of
      the protein.
    explanation: >-
      Directly identifies the causal allele and its position in the first
      EGF-like repeat.
  - reference: PMID:11157803
    reference_title: >-
      Defective intracellular transport and processing of JAG1 missense mutations
      in Alagille syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Missense mutations are non-randomly distributed across the protein with
      clusters at the 5' end of the protein, in the conserved DSL domain, and two
      clusters within the EGF repeats.
    explanation: >-
      Establishes that pathogenic JAG1 missense variants cluster in the EGF
      repeats, the structural context of the C234Y substitution.
  - reference: PMID:20437614
    reference_title: >-
      Jagged1 (JAG1) mutations in patients with tetralogy of Fallot or pulmonic
      stenosis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Residue 234 (p.C234Y) is located in the first EGF repeat, while 664
      (p.C664S) is in the eleventh, and 810 (p.P810L) is in the fifteenth
    explanation: >-
      Independently confirms the position of the substituted residue in the first
      EGF-like repeat.
  - reference: PMID:20437614
    reference_title: >-
      Jagged1 (JAG1) mutations in patients with tetralogy of Fallot or pulmonic
      stenosis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Cysteine residues are required for proper folding of EGF repeats due to
      their role in the formation of disulfide bridges.
    explanation: >-
      Supplies the structural reason a cysteine substitution in an EGF repeat is
      destabilising, which is the first step of the mechanism chain.
  - reference: PMID:20437614
    reference_title: >-
      Jagged1 (JAG1) mutations in patients with tetralogy of Fallot or pulmonic
      stenosis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Residue 234 lies in the first EGF repeat within this critical region,
      suggesting that loss of this cysteine residue would have deleterious
      effects on Notch signaling.
    explanation: >-
      Places residue 234 inside the crystallographically defined
      receptor-ligand-interaction region, explaining why its loss is pathogenic.
  downstream:
  - target: Misfolding and Endoplasmic-Reticulum Retention of Mutant Jagged1
    causal_link_type: DIRECT
    description: >-
      Loss of a structurally required cysteine prevents correct disulfide-bonded
      folding of the EGF module, which is what commits the nascent protein to the
      ER quality-control fate rather than the secretory route.
    evidence:
    - reference: PMID:20437614
      reference_title: >-
        Jagged1 (JAG1) mutations in patients with tetralogy of Fallot or pulmonic
        stenosis.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        JAG1 variants p.C234Y and p.P810L are sensitive to EndoH, suggesting they
        are improperly modified
      explanation: >-
        Direct assay of the C234Y protein: EndoH sensitivity is the signature of
        a glycoprotein that never left the endoplasmic reticulum for Golgi
        processing.
    - reference: PMID:22487239
      reference_title: >-
        Functional analysis of the Notch ligand Jagged1 missense mutant proteins
        underlying Alagille syndrome.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        These mutant proteins localized mainly to the endoplasmic reticulum (ER),
        suggesting that the mutations induced improper protein folding.
      explanation: >-
        Generalises misfolding-driven ER localisation across the JAG1 missense
        class. PARTIAL because the assayed alleles were P163L, R184H, G386R and
        C714Y, not C234Y itself.

- name: Misfolding and Endoplasmic-Reticulum Retention of Mutant Jagged1
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Improperly folded Jagged1 is recognised by the ER quality-control machinery,
    is abnormally glycosylated, and accumulates intracellularly instead of
    transiting to the plasma membrane. For p.Cys234Tyr specifically this has been
    demonstrated directly and by two independent methods: the protein remains
    endoglycosidase-H sensitive, meaning its N-glycans were never processed in
    the Golgi, and immunofluorescence shows no cell-surface staining at all.
    Across the wider JAG1 missense class, ER-retained mutants bind the lectin
    chaperones calnexin and calreticulin more avidly than wild-type Jagged1 does,
    which is the quality-control step that holds them there. Importantly, no
    dominant-negative activity has been detected for the JAG1 missense proteins
    assayed to date, so the mutant allele subtracts function rather than
    poisoning the wild-type product.
  biological_processes:
  - preferred_term: protein folding in the endoplasmic reticulum
    term:
      id: GO:0034975
      label: protein folding in endoplasmic reticulum
    modifier: ABNORMAL
  - preferred_term: delivery of Jagged1 to the plasma membrane
    term:
      id: GO:0072659
      label: protein localization to plasma membrane
    modifier: DECREASED
  cellular_components:
  - preferred_term: endoplasmic reticulum
    term:
      id: GO:0005783
      label: endoplasmic reticulum
  evidence:
  - reference: PMID:20437614
    reference_title: >-
      Jagged1 (JAG1) mutations in patients with tetralogy of Fallot or pulmonic
      stenosis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The p.C234Y variant displayed no cell surface staining, consistent with its
      being retained intracellularly, similar to previously reported AGS missense
      mutants
    explanation: >-
      Direct immunofluorescence evidence that the C234Y protein is retained
      intracellularly rather than reaching the plasma membrane.
  - reference: PMID:20437614
    reference_title: >-
      Jagged1 (JAG1) mutations in patients with tetralogy of Fallot or pulmonic
      stenosis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      JAG1 variants p.C234Y and p.P810L are sensitive to EndoH, suggesting they
      are improperly modified as previously reported for JAG1 mutations
      associated with AGS
    explanation: >-
      Independent biochemical confirmation, by glycan processing rather than
      imaging, that the C234Y protein does not transit the secretory pathway
      normally.
  - reference: PMID:11157803
    reference_title: >-
      Defective intracellular transport and processing of JAG1 missense mutations
      in Alagille syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Neither R184H or L37S is present on the cell surface and both are
      abnormally glycosylated. Furthermore, these mutations lead to abnormal
      accumulation of the protein, possibly in the endoplasmic reticulum.
    explanation: >-
      Generalises the abnormal-glycosylation plus ER-accumulation phenotype
      across pathogenic JAG1 missense alleles. PARTIAL because C234Y itself was
      not among the alleles assayed in this earlier study.
  - reference: PMID:22487239
    reference_title: >-
      Functional analysis of the Notch ligand Jagged1 missense mutant proteins
      underlying Alagille syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      These results indicate that accumulation in the ER and binding to the
      chaperones correlate with the impaired signal-transduction activities of
      the missense mutant proteins, which may contribute to the pathogenic
      mechanism of ALGS.
    explanation: >-
      Links ER accumulation and chaperone binding causally to impaired
      signalling. PARTIAL: of the four alleles assayed, this held for P163L and
      R184H, whereas G386R behaved like wild type and C714Y was less severe -
      so the correlation is a class-level statement, not a per-allele one.
  - reference: PMID:22487239
    reference_title: >-
      Functional analysis of the Notch ligand Jagged1 missense mutant proteins
      underlying Alagille syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Dominant-negative effects were not detected for any mutant protein.
    explanation: >-
      Supports subtractive loss of function rather than a dominant-negative
      mechanism, which is why the downstream node is framed as loss of ligand
      rather than interference with the wild-type product. Scope: four alleles
      were assayed (P163L, R184H, G386R, C714Y), so this is "not detected in the
      proteins assayed to date", not a universal negative.
  downstream:
  - target: Loss of Cell-Surface Jagged1 and Failure of Notch Trans-Activation
    causal_link_type: DIRECT
    description: >-
      Ligand retained in the ER cannot engage Notch receptors on neighbouring
      cells. For p.Cys234Tyr the retention is complete rather than partial, so
      the functional consequence is the absence of mutant ligand from the surface
      pool, not merely its reduction.
    evidence:
    - reference: PMID:20437614
      reference_title: >-
        Jagged1 (JAG1) mutations in patients with tetralogy of Fallot or pulmonic
        stenosis.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        The p.C234Y and p.P810L JAG1 proteins did not demonstrate any changes in
        size with increasing exposure, suggesting they are not accessible to
        trypsin degradation and therefore not present on the cell surface.
      explanation: >-
        Trypsin-shaving evidence that the retained C234Y protein is entirely
        absent from the cell surface, which is what makes the retention
        functionally complete.

- name: Loss of Cell-Surface Jagged1 and Failure of Notch Trans-Activation
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Jagged1 is a membrane-tethered ligand that must be displayed on the surface
    of the signal-sending cell to activate Notch receptors on the adjacent
    signal-receiving cell. Because the p.Cys234Tyr product never reaches the
    surface, it contributes nothing to trans-activation: in a CBF-dependent
    luciferase reporter it behaves like the known null allele p.Leu37Ser and
    cannot initiate Notch signalling at all. The carrier is therefore left with
    only the wild-type allele's ligand on the cell surface - complete
    haploinsufficiency, not a graded hypomorphic reduction. This distinction is
    load-bearing for this entry, because a hypomorphic "leaky allele" model was
    the leading explanation for liver-sparing JAG1 phenotypes until this allele
    was assayed and found to be null.
  biological_processes:
  - preferred_term: Notch signaling pathway
    term:
      id: GO:0007219
      label: Notch signaling pathway
    modifier: DECREASED
  evidence:
  - reference: PMID:12022040
    reference_title: >-
      Familial deafness, congenital heart defects, and posterior embryotoxon
      caused by cysteine substitution in the first epidermal-growth-factor-like
      domain of jagged 1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      JAG1 is a cell-surface ligand in the Notch signaling pathway.
    explanation: >-
      Establishes the cell-surface-ligand role that makes surface delivery the
      rate-limiting step for signalling.
  - reference: PMID:20437614
    reference_title: >-
      Jagged1 (JAG1) mutations in patients with tetralogy of Fallot or pulmonic
      stenosis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Conversely, p.C234Y and p.P810L were unable to activate Notch signaling,
      similar to the AGS missense mutation p.L37S.
    explanation: >-
      Reporter-assay evidence that the C234Y protein has no residual
      trans-activating capacity, benchmarked against a known null allele.
  - reference: PMID:20437614
    reference_title: >-
      Jagged1 (JAG1) mutations in patients with tetralogy of Fallot or pulmonic
      stenosis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The p.C234Y and p.P810L mutations were not present at the cell surface,
      were not properly post-translationally modified, and could not initiate
      Notch signaling. We would therefore predict that these mutations lead to
      JAG1 haploinsufficiency, with only the wild-type allele in carriers of this
      dominant mutation appearing on the cell surface.
    explanation: >-
      The assaying authors' own summary: all three assays agree, and the
      consequence is haploinsufficiency with only wild-type ligand at the
      surface.
  - reference: PMID:12649809
    reference_title: >-
      Conditional JAG1 mutation shows the developing heart is more sensitive than
      developing liver to JAG1 dosage.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Carriers of this mutation therefore have >50% but <100% of the normal
      concentration of JAG1 molecules on the cell surface.
    explanation: >-
      Cited here as the CONTRASTING leaky-allele model, not as a description of
      this disorder. It quantifies the graded reduction produced by the
      hypomorphic p.Gly274Asp allele; p.Cys234Tyr was subsequently shown NOT to
      behave this way, which is why this entry does not use a graded-dose
      mechanism.
  - reference: PMID:38194749
    reference_title: >-
      Jagged-mediated development and disease: Mechanistic insights and
      therapeutic implications for Alagille syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Alagille syndrome is usually caused by a single mutation in the jagged
      canonical Notch ligand 1 (JAG1), and manifests with liver disease and
      cardiovascular symptoms that are a direct consequence of JAG1
      haploinsufficiency.
    explanation: >-
      Establishes reduced JAG1 dose (haploinsufficiency) as the accepted
      mechanism class for JAG1 disorders generally.
  downstream:
  - target: Modifier-Dependent Organ Selectivity of JAG1 Haploinsufficiency
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Half-dose Jagged1 is uniform across every tissue in the carrier, yet only
      some organs malform. The step from the uniform molecular deficit to a
      selective set of malformations is therefore not itself explained by the
      deficit, and is marked INDIRECT_UNKNOWN_INTERMEDIATES because the factors
      that make one tissue decompensate and another not are unidentified.
    evidence:
    - reference: PMID:20437614
      reference_title: >-
        Jagged1 (JAG1) mutations in patients with tetralogy of Fallot or pulmonic
        stenosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        However, the p.C234Y and p.P810L mutations appear to be completely
        haploinsufficient, yet the patients with these mutations do not have the
        full spectrum of AGS, consistent with the presence of additional
        modifying factors.
      explanation: >-
        States exactly this step: complete haploinsufficiency does not by itself
        determine which organs are affected, so modifiers must intervene.

- name: Modifier-Dependent Organ Selectivity of JAG1 Haploinsufficiency
  biological_scale: TISSUE
  mechanism_confidence: HYPOTHETICAL
  description: >-
    This node is the mechanistic hinge that separates this entity from Alagille
    syndrome, and it is deliberately curated as an unsolved step rather than an
    explanation. Every cell in a p.Cys234Tyr carrier has the same half-dose of
    functional Jagged1, yet the heart, inner ear, middle ear and anterior ocular
    segment malform while the intrahepatic biliary tree does not. The obvious
    candidate explanation - that the allele is hypomorphic and leaves enough
    ligand for the less demanding tissues - was proposed for the leaky
    p.Gly274Asp allele and then specifically ruled out for p.Cys234Tyr, which is
    functionally null and still spares the liver. What remains is that
    unidentified modifying factors, not residual ligand, determine the organ set.
    The clinical corollary is unchanged and important: the absence of cholestasis
    does not exclude a JAG1 disorder, and JAG1 variants are recovered from
    individuals presenting with only one or two of the Alagille organ systems.
  biological_processes:
  - preferred_term: Notch signaling pathway
    term:
      id: GO:0007219
      label: Notch signaling pathway
    modifier: DECREASED
  evidence:
  - reference: PMID:20437614
    reference_title: >-
      Jagged1 (JAG1) mutations in patients with tetralogy of Fallot or pulmonic
      stenosis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The missense mutants displayed heterogeneous behavior in these assays, some
      with complete haploinsufficiency, suggesting that there are additional
      modifiers leading to organ specific features.
    explanation: >-
      Directly states the organ-specificity-plus-modifiers interpretation that
      this node encodes.
  - reference: PMID:20437614
    reference_title: >-
      Jagged1 (JAG1) mutations in patients with tetralogy of Fallot or pulmonic
      stenosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      What remains unknown is why these cases present with only a cardiac
      phenotype and not the full clinical features of AGS, particularly hepatic
      disease.
    explanation: >-
      The assaying authors' explicit statement that this step is unexplained,
      which is why the node carries mechanism_confidence HYPOTHETICAL.
  - reference: PMID:20437614
    reference_title: >-
      Jagged1 (JAG1) mutations in patients with tetralogy of Fallot or pulmonic
      stenosis.
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: >-
      We hypothesized at the time that the peculiar nature of these mutations
      could result in hypomorphic activity and not true haploinsufficiency, and
      that this increased level of functionality was sufficient to prevent the
      typical liver manifestations seen in AGS, but the developing heart was too
      sensitive to slightly decreased Notch signaling and was still affected.
      However, the p.C234Y and p.P810L mutations appear to be completely
      haploinsufficient
    explanation: >-
      REFUTE against the graded-dose / leaky-allele explanation of liver sparing.
      The authors state the hypothesis and then report the result that defeats it
      for this allele. This is the finding that required the mechanism curated
      here to be reframed from dose thresholds to modifiers.
  - reference: PMID:20437614
    reference_title: >-
      Jagged1 (JAG1) mutations in patients with tetralogy of Fallot or pulmonic
      stenosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations in the Notch pathway ligand Jagged1 (JAG1) cause Alagille
      syndrome (AGS), as well as cardiac defects in seemingly nonsyndromic
      individuals.
    explanation: >-
      Establishes that JAG1 lesions produce organ-restricted, non-Alagille
      presentations - the class this entity belongs to.
  - reference: PMID:20437614
    reference_title: >-
      Jagged1 (JAG1) mutations in patients with tetralogy of Fallot or pulmonic
      stenosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The p.C234Y variant is a familial mutation segregating with cardiac
      defects, deafness, and posterior embryotoxon, yet all carriers have normal
      liver function
    explanation: >-
      The liver-sparing observation stated for this exact allele and kindred -
      the phenotypic fact this node has to explain.
  - reference: PMID:21752016
    reference_title: >-
      JAG1 mutations are found in approximately one third of patients presenting
      with only one or two clinical features of Alagille syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Identification of a JAG1 gene mutation is particularly useful for those
      patients with atypical or mild Alagille syndrome who do not meet classic
      diagnostic criteria as it provides a definite molecular diagnosis
    explanation: >-
      Supports the existence and clinical importance of JAG1 phenotypes that fall
      outside classic Alagille criteria, as this kindred does.
  downstream:
  - target: Impaired Notch-Dependent Inner Ear Sensory Patterning
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Reduced Jagged1 dose in the developing otic epithelium is the route to the
      sensorineural and vestibular arm of the phenotype.
    evidence:
    - reference: PMID:39373109
      reference_title: >-
        Jag1 represses Notch activation in lateral supporting cells and inhibits
        an outer hair cell fate in the medial cochlea.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Notch signaling patterns the cochlear organ of Corti, and individuals
        with the JAG1/NOTCH2-related genetic disorder Alagille syndrome can thus
        experience hearing loss.
      explanation: >-
        Connects reduced JAG1/Notch signalling to cochlear patterning failure and
        hearing loss.
  - target: Impaired Jagged1-Notch2 Patterning of the Middle Ear Ossicles
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Reduced Jagged1 dose in pharyngeal-arch neural crest is the route to the
      conductive component of the combined hearing loss.
    evidence:
    - reference: PMID:28566723
      reference_title: >-
        Requirement for Jagged1-Notch2 signaling in patterning the bones of the
        mouse and human middle ear.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Heterozygous Jagged1 knockout mice, a model for Alagille Syndrome (AGS),
        also display stapes and incus defects.
      explanation: >-
        Shows that a heterozygous reduction in Jagged1 dose is sufficient to
        malform the ossicles.
  - target: Disrupted Second Heart Field and Cardiac Neural Crest Outflow Tract
      Development
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Reduced Jagged1 dose in second heart field tissue is the route to the
      right-sided outflow-tract lesions seen in this kindred.
    evidence:
    - reference: PMID:19509466
      reference_title: >-
        Murine Jagged1/Notch signaling in the second heart field orchestrates
        Fgf8 expression and tissue-tissue interactions during outflow tract
        development.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Here we show that either absence of the Notch ligand Jagged1 or
        inhibition of Notch signaling in second heart field tissues results in
        murine aortic arch artery and cardiac anomalies.
      explanation: >-
        Establishes reduced Jagged1/Notch signalling in the second heart field as
        a direct cause of outflow-tract cardiac anomalies.
  - target: Disrupted Anterior Segment Development in Periocular Neural Crest
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Reduced Jagged1 dose in neural-crest-derived periocular mesenchyme is the
      presumed route to posterior embryotoxon. The step is marked
      INDIRECT_UNKNOWN_INTERMEDIATES because, unlike the ear and heart arms, no
      Jagged1-specific anterior-segment developmental study was identified.
    evidence:
    - reference: PMID:20301450
      reference_title: Alagille Syndrome.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        The major clinical manifestations of ALGS are bile duct paucity on liver
        biopsy, cholestasis, congenital cardiac defects (primarily involving the
        pulmonary arteries), butterfly vertebrae, ophthalmologic abnormalities
        (most commonly posterior embryotoxon), and characteristic facial
        features.
      explanation: >-
        Establishes posterior embryotoxon as a recognised consequence of reduced
        JAG1/NOTCH2 signalling in humans. PARTIAL because it documents the
        association rather than the developmental mechanism.

- name: Impaired Notch-Dependent Inner Ear Sensory Patterning
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  description: >-
    Jagged1 marks the prosensory patches of the developing inner ear well before
    hair-cell versus supporting-cell fate is settled, and continues to be
    expressed by supporting cells into adulthood. Reduced Jagged1 therefore has
    two separable auditory consequences in model systems: an early patterning
    failure (loss of sensory cristae and their housing ampullae, and altered
    inner/outer hair-cell specification) that maps onto the vestibular and
    sensorineural components of the phenotype, and a later maturation failure of
    inner-hair-cell stereocilia that produces an auditory-neuropathy-like
    deafness with preserved hair-cell number. Both routes yield a sensorineural
    deficit without requiring hair-cell death.
  cell_types:
  - preferred_term: cochlear inner hair cell
    term:
      id: CL:0000589
      label: cochlear inner hair cell
  - preferred_term: cochlear outer hair cell
    term:
      id: CL:0000601
      label: cochlear outer hair cell
  - preferred_term: cochlear supporting cell
    term:
      id: CL:0000630
      label: supporting cell
  biological_processes:
  - preferred_term: inner ear development
    term:
      id: GO:0048839
      label: inner ear development
    modifier: ABNORMAL
  - preferred_term: cochlea development
    term:
      id: GO:0090102
      label: cochlea development
    modifier: ABNORMAL
  - preferred_term: inner ear receptor cell development
    term:
      id: GO:0060119
      label: inner ear receptor cell development
    modifier: ABNORMAL
  - preferred_term: semicircular canal morphogenesis
    term:
      id: GO:0048752
      label: semicircular canal morphogenesis
    modifier: ABNORMAL
  evidence:
  - reference: PMID:11259677
    reference_title: The Notch ligand Jagged1 is required for inner ear sensory development.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      a dominant mouse mutant headturner (Htu) contains a missense mutation in
      the Jag1 gene and displays missing posterior and sometimes anterior
      ampullae, structures that house the sensory cristae
    explanation: >-
      A dominant Jag1 missense allele - the same lesion class as C234Y - disrupts
      vestibular sensory structures in vivo.
  - reference: PMID:11259677
    reference_title: The Notch ligand Jagged1 is required for inner ear sensory development.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Htu/+ mutants also demonstrate a significant reduction in the numbers of
      outer hair cells in the organ of Corti.
    explanation: >-
      Shows a cochlear sensory deficit in the heterozygous state, matching the
      dominant human inheritance.
  - reference: PMID:39373109
    reference_title: >-
      Jag1 represses Notch activation in lateral supporting cells and inhibits an
      outer hair cell fate in the medial cochlea.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Jag1Ndr/Ndr mice exhibited expected vestibular and auditory deficits, a
      dose-dependent increase in ectopic inner hair cells, and a reduction in
      outer hair cells.
    explanation: >-
      Establishes dose-dependent cochlear mis-patterning with combined auditory
      and vestibular deficits.
  - reference: PMID:36400760
    reference_title: >-
      Deletion of the Notch ligand Jagged1 during cochlear maturation leads to
      inner hair cell defects and hearing loss.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      we show that deletion of JAG1 during cochlear maturation disrupts the inner
      hair cell pathway and leads to a type of deafness clinically similar to
      auditory neuropathy
    explanation: >-
      Adds a post-patterning maturation route from reduced Jagged1 to
      sensorineural deafness.
  - reference: PMID:36400760
    reference_title: >-
      Deletion of the Notch ligand Jagged1 during cochlear maturation leads to
      inner hair cell defects and hearing loss.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      ultrastructural analyses of JAG1-deleted cochleae revealed stereocilia
      defects in inner hair cells, including fused and elongated bundles
    explanation: >-
      Identifies the stereociliary lesion underlying the maturation-stage hearing
      loss.

- name: Impaired Jagged1-Notch2 Patterning of the Middle Ear Ossicles
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  description: >-
    The stapes and incus derive from the first two pharyngeal arches and are
    patterned by Jagged1-Notch2 signalling in arch neural crest cells. Reduced
    Jagged1 dose malforms the stapes cartilage template early in development, and
    the resulting ossicular malformation impairs sound conduction across all
    frequencies. This is the arm of the mechanism that accounts for the
    conductive component of the combined (mixed) hearing loss recorded in this
    kindred, and it is why the hearing phenotype here is mixed rather than purely
    sensorineural.
  cell_types:
  - preferred_term: pharyngeal arch neural crest cell
    term:
      id: CL:0011012
      label: neural crest cell
  biological_processes:
  - preferred_term: neural crest cell development in the pharyngeal arches
    term:
      id: GO:0014032
      label: neural crest cell development
    modifier: ABNORMAL
  - preferred_term: sensory perception of sound
    term:
      id: GO:0007605
      label: sensory perception of sound
    modifier: DECREASED
  locations:
  - preferred_term: middle ear
    term:
      id: UBERON:0001756
      label: middle ear
  evidence:
  - reference: PMID:28566723
    reference_title: >-
      Requirement for Jagged1-Notch2 signaling in patterning the bones of the
      mouse and human middle ear.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We find that Jagged1-Notch2 signaling functions early to pattern the stapes
      cartilage template, with stapes malformations correlating with hearing loss
      across all frequencies.
    explanation: >-
      Establishes the ossicular patterning mechanism and its audiological
      consequence.
  - reference: PMID:28566723
    reference_title: >-
      Requirement for Jagged1-Notch2 signaling in patterning the bones of the
      mouse and human middle ear.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We observe similar stapes defects and hearing loss in one patient with
      heterozygous JAGGED1 loss, and a diversity of conductive and sensorineural
      hearing loss in nearly half of AGS patients, many of which carry JAGGED1
      mutations.
    explanation: >-
      Confirms in humans that heterozygous JAG1 loss yields ossicular defects and
      a mixture of conductive and sensorineural hearing loss - the combined
      pattern reported in this kindred.

- name: Disrupted Second Heart Field and Cardiac Neural Crest Outflow Tract
    Development
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  description: >-
    Jagged1-Notch signalling in second heart field progenitors sustains Fgf8 and
    Bmp4 expression, and through them coordinates two neighbouring tissues:
    migrating cardiac neural crest and the endothelial-to-mesenchymal transition
    that populates the outflow-tract endocardial cushions. Loss of that signal
    produces aortic arch artery and outflow-tract anomalies of exactly the
    right-sided class seen in this kindred - tetralogy of Fallot, ventricular
    septal defect, and peripheral pulmonic stenosis. In the peripheral pulmonary
    arteries the corresponding structural lesion in JAG1 disease is a tunica
    media depleted of smooth muscle cells and thickened by collagen and elastic
    fibres.
  cell_types:
  - preferred_term: cardiac neural crest cell
    term:
      id: CL:0011012
      label: neural crest cell
  - preferred_term: pulmonary artery smooth muscle cell
    term:
      id: CL:0002591
      label: smooth muscle cell of the pulmonary artery
    modifier: DECREASED
  biological_processes:
  - preferred_term: outflow tract morphogenesis
    term:
      id: GO:0003151
      label: outflow tract morphogenesis
    modifier: ABNORMAL
  - preferred_term: neural crest cell migration involved in heart formation
    term:
      id: GO:0003147
      label: neural crest cell migration involved in heart formation
    modifier: DECREASED
  locations:
  - preferred_term: cardiac outflow tract
    term:
      id: UBERON:0004145
      label: outflow tract
  evidence:
  - reference: PMID:19509466
    reference_title: >-
      Murine Jagged1/Notch signaling in the second heart field orchestrates Fgf8
      expression and tissue-tissue interactions during outflow tract development.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      faulty migration of cardiac neural crest cells and defective
      endothelial-mesenchymal transition within the outflow tract endocardial
      cushions were observed
    explanation: >-
      Identifies the two tissue-level failures that link reduced Jagged1/Notch
      signalling to outflow-tract malformation.
  - reference: PMID:19509466
    reference_title: >-
      Murine Jagged1/Notch signaling in the second heart field orchestrates Fgf8
      expression and tissue-tissue interactions during outflow tract development.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In mid-gestation, these mutants displayed decreased Fgf8 and Bmp4
      expression.
    explanation: >-
      Supplies the intermediate signalling step (Fgf8/Bmp4) between Jagged1 loss
      and the tissue phenotype.
  - reference: PMID:39069193
    reference_title: >-
      Decreased smooth muscle cells and fibrous thickening of the tunica media in
      peripheral pulmonary artery stenosis in Alagille syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Histological examination of the pulmonary artery walls showed a decrease in
      smooth muscle cells in the tunica media and an increase in collagen and
      elastic fibers, although the intrapulmonary arteries were intact.
    explanation: >-
      Gives the vessel-wall correlate of peripheral pulmonary artery stenosis in
      JAG1 disease. PARTIAL because it is a single autopsy case in Alagille
      syndrome, not in a DCHE kindred.

- name: Disrupted Anterior Segment Development in Periocular Neural Crest
  biological_scale: TISSUE
  mechanism_confidence: HYPOTHETICAL
  description: >-
    The trabecular meshwork, corneal endothelium and Schwalbe line derive from
    neural-crest-derived periocular mesenchyme. Posterior embryotoxon - an
    anteriorly displaced, prominent Schwalbe line visible at the slit lamp - is a
    recognised consequence of reduced JAG1/NOTCH2 signalling in humans and is one
    of the two features this entity shares with Alagille syndrome. The
    developmental step is curated as HYPOTHETICAL rather than established: no
    Jagged1-specific study of anterior-segment morphogenesis was identified, so
    the tissue-level mechanism is inferred from the neural-crest origin of the
    affected structures and from the human phenotype association rather than
    demonstrated.
  cell_types:
  - preferred_term: periocular neural crest cell
    term:
      id: CL:0011012
      label: neural crest cell
  biological_processes:
  - preferred_term: eye development
    term:
      id: GO:0001654
      label: eye development
    modifier: ABNORMAL
  locations:
  - preferred_term: anterior segment of eyeball
    term:
      id: UBERON:0001801
      label: anterior segment of eyeball
  evidence:
  - reference: PMID:12022040
    reference_title: >-
      Familial deafness, congenital heart defects, and posterior embryotoxon
      caused by cysteine substitution in the first epidermal-growth-factor-like
      domain of jagged 1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our findings revealed a unique phenotype with highly penetrant deafness,
      posterior embryotoxon, and congenital heart defects
    explanation: >-
      Establishes posterior embryotoxon as a highly penetrant feature of the
      JAG1 p.Cys234Tyr phenotype.
  - reference: PMID:27418850
    reference_title: "Alagille syndrome: clinical perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      congenital cardiac defects (with particular involvement of the pulmonary
      arteries), posterior embryotoxon in the eye, characteristic facial
      features, and butterfly vertebrae
    explanation: >-
      Confirms posterior embryotoxon as a recognised ocular consequence of
      JAG1/NOTCH2 pathway disruption. PARTIAL - it documents the association in
      Alagille syndrome, not the developmental mechanism.

phenotypes:
- name: Mixed hearing impairment
  category: Auditory
  diagnostic: true
  frequency: VERY_FREQUENT
  description: >-
    Mild-to-severe combined (mixed) hearing loss - that is, with both conductive
    and sensorineural components - affected six of the seven available affected
    members of the index kindred. This is the feature that names the entity and
    that distinguishes it from Alagille syndrome, in which hearing loss is not a
    cardinal diagnostic criterion. Mechanistically the two components have
    separate substrates: middle-ear ossicular malformation for the conductive
    part and cochlear sensory mis-patterning for the sensorineural part.
  phenotype_term:
    preferred_term: Combined (mixed) hearing loss
    term:
      id: HP:0000410
      label: Mixed hearing impairment
  evidence:
  - reference: PMID:12022040
    reference_title: >-
      Familial deafness, congenital heart defects, and posterior embryotoxon
      caused by cysteine substitution in the first epidermal-growth-factor-like
      domain of jagged 1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Six of seven available affected patients manifested mild-to-severe combined
      hearing loss, predominantly affecting middle frequencies.
    explanation: >-
      Directly documents combined (mixed) hearing loss, and the 6/7 count (86%)
      is what supports the VERY_FREQUENT band.
  - reference: PMID:28566723
    reference_title: >-
      Requirement for Jagged1-Notch2 signaling in patterning the bones of the
      mouse and human middle ear.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We observe similar stapes defects and hearing loss in one patient with
      heterozygous JAGGED1 loss, and a diversity of conductive and sensorineural
      hearing loss in nearly half of AGS patients, many of which carry JAGGED1
      mutations.
    explanation: >-
      Independently supports a mixed conductive-plus-sensorineural pattern as the
      expected audiological consequence of heterozygous JAG1 loss.

- name: Mid-frequency hearing loss
  category: Auditory
  description: >-
    The audiometric configuration in the index kindred was distinctive: the loss
    predominantly affected the middle frequencies, rather than the high-frequency
    downsloping pattern typical of most acquired and many hereditary
    sensorineural losses. A mid-frequency ("cookie-bite") configuration is a
    useful pointer toward this diagnosis in an otherwise unexplained familial
    hearing loss.
  phenotype_term:
    preferred_term: Mid-frequency hearing loss
    term:
      id: HP:0012781
      label: Mid-frequency hearing loss
  evidence:
  - reference: PMID:12022040
    reference_title: >-
      Familial deafness, congenital heart defects, and posterior embryotoxon
      caused by cysteine substitution in the first epidermal-growth-factor-like
      domain of jagged 1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Six of seven available affected patients manifested mild-to-severe combined
      hearing loss, predominantly affecting middle frequencies.
    explanation: >-
      Directly documents the mid-frequency-predominant audiometric configuration.

- name: Abnormal vestibular function
  category: Auditory
  frequency: OCCASIONAL
  description: >-
    Two of the seven available affected patients were diagnosed with vestibular
    pathology, consistent with the fact that Jagged1 patterns the vestibular as
    well as the cochlear sensory territories of the inner ear. In the mouse, a
    dominant Jag1 missense allele deletes the ampullae that house the sensory
    cristae, and a Jag1 hypomorph shows vestibular as well as auditory deficits.
  phenotype_term:
    preferred_term: Vestibular pathology
    term:
      id: HP:0001751
      label: Abnormal vestibular function
  evidence:
  - reference: PMID:12022040
    reference_title: >-
      Familial deafness, congenital heart defects, and posterior embryotoxon
      caused by cysteine substitution in the first epidermal-growth-factor-like
      domain of jagged 1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two patients were diagnosed with vestibular pathology.
    explanation: >-
      Documents vestibular involvement; 2 of the 7 available affected patients
      (29%) is what supports the OCCASIONAL band.
  - reference: PMID:39373109
    reference_title: >-
      Jag1 represses Notch activation in lateral supporting cells and inhibits an
      outer hair cell fate in the medial cochlea.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Jag1Ndr/Ndr mice exhibited expected vestibular and auditory deficits, a
      dose-dependent increase in ectopic inner hair cells, and a reduction in
      outer hair cells.
    explanation: >-
      Model-organism support that reduced Jag1 dose produces vestibular as well
      as auditory deficits.

- name: Congenital heart defect
  category: Cardiovascular
  diagnostic: true
  frequency: VERY_FREQUENT
  description: >-
    Every affected member of the index kindred had a congenital heart defect. The
    lesions were drawn from the right-sided outflow-tract spectrum characteristic
    of JAG1 disease, but differed between relatives carrying the same allele -
    the clearest illustration of the variable expressivity of this disorder.
  phenotype_term:
    preferred_term: Congenital heart defect
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  evidence:
  - reference: PMID:12022040
    reference_title: >-
      Familial deafness, congenital heart defects, and posterior embryotoxon
      caused by cysteine substitution in the first epidermal-growth-factor-like
      domain of jagged 1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients had congenital heart defects, including tetralogy of Fallot,
      ventricular septal defect, or isolated peripheral pulmonic stenosis.
    explanation: >-
      "All patients" in the index kindred supports the VERY_FREQUENT band for
      congenital heart disease as a class.

- name: Tetralogy of Fallot
  category: Cardiovascular
  description: >-
    One of the three cardiac lesions observed in the index kindred. Tetralogy of
    Fallot is also the presentation in which JAG1 variants are found among
    apparently non-syndromic individuals with right-sided congenital heart
    disease, which is the wider phenotype class this entity sits inside.
  phenotype_term:
    preferred_term: Tetralogy of Fallot
    term:
      id: HP:0001636
      label: Tetralogy of Fallot
  evidence:
  - reference: PMID:12022040
    reference_title: >-
      Familial deafness, congenital heart defects, and posterior embryotoxon
      caused by cysteine substitution in the first epidermal-growth-factor-like
      domain of jagged 1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients had congenital heart defects, including tetralogy of Fallot,
      ventricular septal defect, or isolated peripheral pulmonic stenosis.
    explanation: >-
      Names tetralogy of Fallot among the cardiac lesions in this kindred.
  - reference: PMID:20437614
    reference_title: >-
      Jagged1 (JAG1) mutations in patients with tetralogy of Fallot or pulmonic
      stenosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified functionally significant mutations in 2% (2/94) of TOF
      patients and 4% (2/50) of PS/PPS/PA patients.
    explanation: >-
      Independently links JAG1 lesions to tetralogy of Fallot outside classic
      Alagille syndrome.

- name: Ventricular septal defect
  category: Cardiovascular
  description: >-
    One of the three cardiac lesions observed in the index kindred, consistent
    with failure of outflow-tract and endocardial-cushion development downstream
    of reduced Jagged1-Notch signalling.
  phenotype_term:
    preferred_term: Ventricular septal defect
    term:
      id: HP:0001629
      label: Ventricular septal defect
  evidence:
  - reference: PMID:12022040
    reference_title: >-
      Familial deafness, congenital heart defects, and posterior embryotoxon
      caused by cysteine substitution in the first epidermal-growth-factor-like
      domain of jagged 1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients had congenital heart defects, including tetralogy of Fallot,
      ventricular septal defect, or isolated peripheral pulmonic stenosis.
    explanation: >-
      Names ventricular septal defect among the cardiac lesions in this kindred.

- name: Peripheral pulmonary artery stenosis
  category: Cardiovascular
  description: >-
    Isolated peripheral pulmonic stenosis was the mildest of the three cardiac
    presentations in the index kindred. In JAG1 disease the underlying vessel-wall
    lesion is a tunica media depleted of smooth muscle cells and thickened by
    collagen and elastic fibres, with the intrapulmonary arteries spared.
  phenotype_term:
    preferred_term: Isolated peripheral pulmonic stenosis
    term:
      id: HP:0004969
      label: Peripheral pulmonary artery stenosis
  evidence:
  - reference: PMID:12022040
    reference_title: >-
      Familial deafness, congenital heart defects, and posterior embryotoxon
      caused by cysteine substitution in the first epidermal-growth-factor-like
      domain of jagged 1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients had congenital heart defects, including tetralogy of Fallot,
      ventricular septal defect, or isolated peripheral pulmonic stenosis.
    explanation: >-
      Names isolated peripheral pulmonic stenosis among the cardiac lesions in
      this kindred.
  - reference: PMID:39069193
    reference_title: >-
      Decreased smooth muscle cells and fibrous thickening of the tunica media in
      peripheral pulmonary artery stenosis in Alagille syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Alagille syndrome is caused by mutations in genes involved in NOTCH
      signaling, specifically JAG1 and NOTCH2, and is associated with a high rate
      of peripheral pulmonary artery stenosis.
    explanation: >-
      Supports peripheral pulmonary artery stenosis as a characteristic
      consequence of JAG1-pathway disruption. PARTIAL because the cohort is
      Alagille syndrome rather than this entity.

- name: Posterior embryotoxon
  category: Ophthalmic
  diagnostic: true
  frequency: VERY_FREQUENT
  description: >-
    Posterior embryotoxon - an anteriorly displaced and prominent Schwalbe line,
    seen at the slit lamp - is the third element of the defining triad and the
    other feature this entity shares with Alagille syndrome. It is usually
    visually asymptomatic in itself; its value is diagnostic.
  phenotype_term:
    preferred_term: Posterior embryotoxon
    term:
      id: HP:0000627
      label: Posterior embryotoxon
  evidence:
  - reference: PMID:12022040
    reference_title: >-
      Familial deafness, congenital heart defects, and posterior embryotoxon
      caused by cysteine substitution in the first epidermal-growth-factor-like
      domain of jagged 1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our findings revealed a unique phenotype with highly penetrant deafness,
      posterior embryotoxon, and congenital heart defects but with variable
      expressivity in a large kindred
    explanation: >-
      The index report describes posterior embryotoxon as highly penetrant in
      this kindred. Per docs/frequency-evidence-guidelines.md that qualitative
      wording maps to the VERY_FREQUENT band (80-100%); no numerator and
      denominator were published for this feature, so the band rests on the
      authors' penetrance wording rather than on a count.

genetic:
- name: JAG1
  gene_term:
    preferred_term: JAG1
    term:
      id: hgnc:6188
      label: JAG1
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  association: >-
    Causal heterozygous missense variant p.Cys234Tyr in the first EGF-like repeat
  frequency: OBLIGATE
  notes: >-
    JAG1 is the sole reported causal gene for this entity. The single reported
    allele, p.Cys234Tyr, removes a structurally required cysteine from the first
    EGF-like repeat. JAG1 is also the principal Alagille syndrome gene, so the
    gene identity alone does not discriminate between the two disorders; the
    phenotype does. Most pathogenic JAG1 alleles are loss-of-function
    (truncating, splice-disrupting, or whole-gene deletion), and missense alleles
    such as this one are the less well understood minority, for which dedicated
    classification guidance has had to be developed.
  evidence:
  - reference: PMID:12022040
    reference_title: >-
      Familial deafness, congenital heart defects, and posterior embryotoxon
      caused by cysteine substitution in the first epidermal-growth-factor-like
      domain of jagged 1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A candidate-gene approach was undertaken and culminated in the
      identification of a novel Jagged 1 (JAG1) missense mutation (C234Y) in the
      first cysteine of the first epidermal-growth-factor-like repeat domain of
      the protein.
    explanation: >-
      Establishes JAG1 p.Cys234Tyr as the causal allele in the index kindred.
  - reference: PMID:31343788
    reference_title: >-
      Alagille syndrome mutation update: Comprehensive overview of JAG1 and
      NOTCH2 mutation frequencies and insight into missense variant
      classification.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The majority of JAG1 variants result in loss of function, however disease
      has also been attributed to lesser understood missense variants.
    explanation: >-
      Places this missense allele in its variant-class context and flags the
      interpretive difficulty that attends JAG1 missense variants.
  - reference: PMID:31343788
    reference_title: >-
      Alagille syndrome mutation update: Comprehensive overview of JAG1 and
      NOTCH2 mutation frequencies and insight into missense variant
      classification.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Using this data set, we developed new guidance to help with the
      classification of JAG1 missense variants.
    explanation: >-
      Supports the statement that dedicated classification guidance was needed
      for JAG1 missense variants.

diagnosis:
- name: Formal audiometry with tympanometry
  description: >-
    The audiological assessment is the diagnostically decisive test in this
    entity, and a screen is not sufficient for two independent reasons. First,
    the loss is mid-frequency predominant, so a protocol weighted toward the high
    frequencies where most acquired and hereditary sensorineural loss appears can
    return a reassuring result. Second, the loss is mixed, so tympanometry and
    air-bone gap measurement are required to demonstrate the conductive component
    that reflects the underlying ossicular malformation. Auditory brainstem
    response and otoacoustic emissions extend the same assessment to infants and
    to the auditory-neuropathy pattern that Jag1 loss produces in the mouse
    cochlea.
  diagnosis_term:
    preferred_term: audiometric assessment with tympanometry
    term:
      id: NCIT:C38036
      label: Audiometric Test
  markers: Air and bone conduction thresholds, air-bone gap, tympanogram
  results: >-
    Mild-to-severe mixed hearing loss with a mid-frequency predominant
    configuration; the air-bone gap identifies the conductive component
    attributable to ossicular malformation.
  evidence:
  - reference: PMID:12022040
    reference_title: >-
      Familial deafness, congenital heart defects, and posterior embryotoxon
      caused by cysteine substitution in the first epidermal-growth-factor-like
      domain of jagged 1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Six of seven available affected patients manifested mild-to-severe combined
      hearing loss, predominantly affecting middle frequencies.
    explanation: >-
      Establishes both features that dictate the protocol: the loss is combined
      (so the conductive component must be measured) and mid-frequency
      predominant (so the configuration must be characterised across frequency).
  - reference: PMID:28566723
    reference_title: >-
      Requirement for Jagged1-Notch2 signaling in patterning the bones of the
      mouse and human middle ear.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We observe similar stapes defects and hearing loss in one patient with
      heterozygous JAGGED1 loss, and a diversity of conductive and sensorineural
      hearing loss in nearly half of AGS patients, many of which carry JAGGED1
      mutations.
    explanation: >-
      Supports expecting a conductive component of ossicular origin alongside the
      sensorineural one, which is what tympanometry is there to detect.

- name: Auditory brainstem response testing
  description: >-
    Extends audiological assessment to infants, to individuals who cannot give
    reliable behavioural thresholds, and to the auditory-neuropathy pattern.
    Relevant here because Jag1 loss during cochlear maturation produces, in the
    mouse, a deafness clinically similar to auditory neuropathy, in which
    otoacoustic emissions can be preserved while the brainstem response is not.
  diagnosis_term:
    preferred_term: auditory brainstem response
    term:
      id: NCIT:C184949
      label: Auditory Brainstem Response
  evidence:
  - reference: PMID:36400760
    reference_title: >-
      Deletion of the Notch ligand Jagged1 during cochlear maturation leads to
      inner hair cell defects and hearing loss.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      we show that deletion of JAG1 during cochlear maturation disrupts the inner
      hair cell pathway and leads to a type of deafness clinically similar to
      auditory neuropathy
    explanation: >-
      Motivates brainstem-response testing rather than emissions alone. PARTIAL:
      this is a mouse result, and the auditory-neuropathy pattern has not been
      documented in a DCHE carrier.

- name: Echocardiography
  description: >-
    Every affected member of the index kindred had a congenital heart defect, so
    cardiac imaging is indicated in any individual with a molecular diagnosis and
    in at-risk relatives during cascade evaluation. The lesion set is right
    sided, spanning tetralogy of Fallot, ventricular septal defect and isolated
    peripheral pulmonic stenosis, and it differs between relatives carrying the
    same allele, so a normal study in a parent does not predict the child.
  diagnosis_term:
    preferred_term: echocardiography
    term:
      id: NCIT:C16525
      label: Echocardiography Test
  markers: Outflow tract and branch pulmonary artery anatomy, ventricular septum
  results: >-
    Right-sided lesions: tetralogy of Fallot, ventricular septal defect, or
    isolated peripheral pulmonic stenosis.
  evidence:
  - reference: PMID:12022040
    reference_title: >-
      Familial deafness, congenital heart defects, and posterior embryotoxon
      caused by cysteine substitution in the first epidermal-growth-factor-like
      domain of jagged 1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients had congenital heart defects, including tetralogy of Fallot,
      ventricular septal defect, or isolated peripheral pulmonic stenosis.
    explanation: >-
      Universal cardiac involvement, across a lesion range wide enough to require
      imaging rather than auscultation, is what makes echocardiography a required
      element of the workup.

- name: Slit-lamp examination for posterior embryotoxon
  description: >-
    Posterior embryotoxon is an anteriorly displaced, prominent Schwalbe line and
    is visible only on slit-lamp examination, not on routine visual assessment.
    It is usually visually silent in itself, so its value here is almost entirely
    diagnostic, and it is the element of the triad most likely to be missed
    because nothing prompts the patient to report it. Intraocular pressure
    measurement belongs in the same visit: it is the associated anterior-segment
    dysgenesis and glaucoma, rather than the embryotoxon, that threatens vision.
  diagnosis_term:
    preferred_term: ophthalmic examination with slit-lamp biomicroscopy
    term:
      id: NCIT:C20989
      label: Physical Examination
  markers: Schwalbe line position, iridocorneal angle, intraocular pressure
  results: >-
    Posterior embryotoxon, seen as an anteriorly displaced and prominent Schwalbe
    line.
  evidence:
  - reference: PMID:37895297
    reference_title: Alternative Genetic Diagnoses in Axenfeld-Rieger Syndrome Spectrum.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a specific type of anterior segment disorder characterized by the triad of
      posterior embryotoxon
    explanation: >-
      Places posterior embryotoxon among the anterior-segment findings assessed
      at the slit lamp, which is the examination this entry recommends.
  - reference: PMID:12022040
    reference_title: >-
      Familial deafness, congenital heart defects, and posterior embryotoxon
      caused by cysteine substitution in the first epidermal-growth-factor-like
      domain of jagged 1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our findings revealed a unique phenotype with highly penetrant deafness,
      posterior embryotoxon, and congenital heart defects
    explanation: >-
      Establishes posterior embryotoxon as a highly penetrant feature, so its
      detection materially changes the diagnostic probability.

- name: JAG1 sequencing
  description: >-
    Molecular confirmation is by sequencing of the JAG1 coding exons. Because
    this entity is defined by a missense substitution, exon sequencing rather
    than deletion analysis is the first-line test that finds it. In Alagille
    syndrome, the disorder for which JAG1 testing strategy has actually been
    quantified, sequencing all JAG1 exons identifies approximately 85% of
    pathogenic variants.
  diagnosis_term:
    preferred_term: JAG1 gene sequencing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:31343788
    reference_title: >-
      Alagille syndrome mutation update: Comprehensive overview of JAG1 and
      NOTCH2 mutation frequencies and insight into missense variant
      classification.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The current standard is to sequence all exons in JAG1, which should
      identify approximately 85% of ALGS pathogenic variants.
    explanation: >-
      Supplies the first-tier yield figure. PARTIAL because the denominator is an
      Alagille syndrome cohort; no equivalent figure exists for this entity, and
      the number must not be read as a DCHE detection rate.
  - reference: PMID:12022040
    reference_title: >-
      Familial deafness, congenital heart defects, and posterior embryotoxon
      caused by cysteine substitution in the first epidermal-growth-factor-like
      domain of jagged 1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A candidate-gene approach was undertaken and culminated in the
      identification of a novel Jagged 1 (JAG1) missense mutation (C234Y) in the
      first cysteine of the first epidermal-growth-factor-like repeat domain of
      the protein.
    explanation: >-
      The causal variant is an intragenic missense change, which is what makes
      exon sequencing rather than dosage analysis the test that detects it.

- name: JAG1 copy number analysis
  description: >-
    Second-tier testing when sequencing is negative but the phenotype still
    suggests a JAG1 disorder. Large JAG1 deletions are a recognised cause of
    JAG1-related disease and are invisible to exon sequencing, so a negative
    sequencing result does not close the question. Note this test would not have
    found the variant in the index kindred, which is a point substitution; it is
    included because a clinician working from the phenotype, not the known
    genotype, cannot assume that in advance.
  diagnosis_term:
    preferred_term: copy number variant analysis
    term:
      id: NCIT:C18084
      label: Comparative Genomic Hybridization
  evidence:
  - reference: PMID:31343788
    reference_title: >-
      Alagille syndrome mutation update: Comprehensive overview of JAG1 and
      NOTCH2 mutation frequencies and insight into missense variant
      classification.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      second tier diagnostics involves large deletion/duplication analysis
      through either multiplex ligation-dependent probe amplification (MLPA),
      chromosomal microarray (CMA), or fluorescence in situ hybridization (FISH),
      which should identify an additional 9% of pathogenic variants
    explanation: >-
      Supplies the second-tier method and its incremental yield. PARTIAL for the
      same reason as the sequencing figure: the denominator is an Alagille
      syndrome cohort.

- name: Interpretation of a JAG1 missense variant
  description: >-
    A caveat rather than a test. The causal allele here is missense, and JAG1
    missense variants are the class that resists confident classification, which
    is why dedicated interpretation guidance had to be developed for them. A
    missense variant of uncertain significance in JAG1 should therefore not be
    dismissed on in-silico grounds alone in an individual with this phenotype;
    segregation and, where available, functional data carry the weight.
  diagnosis_term:
    preferred_term: variant classification
    term:
      id: NCIT:C15220
      label: Diagnosis Assessment
  evidence:
  - reference: PMID:31343788
    reference_title: >-
      Alagille syndrome mutation update: Comprehensive overview of JAG1 and
      NOTCH2 mutation frequencies and insight into missense variant
      classification.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The majority of JAG1 variants result in loss of function, however disease
      has also been attributed to lesser understood missense variants.
    explanation: >-
      States that JAG1 missense variants are the poorly understood minority,
      which is the interpretive difficulty this entry flags.
  - reference: PMID:31343788
    reference_title: >-
      Alagille syndrome mutation update: Comprehensive overview of JAG1 and
      NOTCH2 mutation frequencies and insight into missense variant
      classification.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Using this data set, we developed new guidance to help with the
      classification of JAG1 missense variants.
    explanation: >-
      Confirms that dedicated classification guidance was required, supporting
      the caution recorded here.

differential_diagnoses:
- name: Alagille syndrome
  disease_term:
    preferred_term: Alagille syndrome
    term:
      id: MONDO:0007318
      label: Alagille syndrome
  description: >-
    The single most important differential, and an allelic disorder: Alagille
    syndrome is caused by heterozygous variants in the same gene (JAG1, and less
    often NOTCH2), and shares two of this entity's three cardinal features
    (congenital heart defects with pulmonary-artery predilection, and posterior
    embryotoxon). This entity is curated separately from
    kb/disorders/Alagille_syndrome.yaml, and the two must not be merged on the
    strength of shared gene identity alone.
  distinguishing_features:
  - >-
    Present in Alagille syndrome and absent in the index kindred of this entity:
    cholestasis with paucity of interlobular bile ducts on liver biopsy (the
    defining Alagille criterion), butterfly vertebrae, and the characteristic
    facies.
  - >-
    Present here and NOT an Alagille diagnostic criterion: highly penetrant mixed
    hearing loss with a mid-frequency configuration. Hearing loss does occur in
    Alagille syndrome, but as an associated finding rather than a cardinal
    criterion.
  - >-
    Decisive statement from the index report: no individual in this kindred met
    diagnostic criteria for any previously described clinical syndrome.
  - >-
    The dissociation is NOT explained by a milder molecular lesion. JAG1
    p.Cys234Tyr is completely haploinsufficient, being EndoH sensitive, absent
    from the cell surface, and unable to activate Notch, so the difference from
    Alagille syndrome is neither gene, nor pathway, nor allele severity. The
    organ selectivity is attributed to unidentified modifying factors and is
    recorded here as an open knowledge gap. The superficially attractive
    graded-dose account, in which the developing heart tolerates reduced JAG1
    dose less well than the developing liver does, derives from the DIFFERENT and
    genuinely leaky p.Gly274Asp allele, and was specifically tested and ruled out
    for this one.
  evidence:
  - reference: PMID:12022040
    reference_title: >-
      Familial deafness, congenital heart defects, and posterior embryotoxon
      caused by cysteine substitution in the first epidermal-growth-factor-like
      domain of jagged 1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      No individual in this family met diagnostic criteria for any previously
      described clinical syndrome.
    explanation: >-
      The index report's own explicit statement that this kindred is not Alagille
      syndrome (or any other described syndrome) - the primary basis for curating
      a separate entry.
  - reference: PMID:20437614
    reference_title: >-
      Jagged1 (JAG1) mutations in patients with tetralogy of Fallot or pulmonic
      stenosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The p.C234Y variant is a familial mutation segregating with cardiac
      defects, deafness, and posterior embryotoxon, yet all carriers have normal
      liver function
    explanation: >-
      Independent confirmation, by a different group, of the liver sparing that
      separates this entity from Alagille syndrome - stated for this exact allele
      and kindred.
  - reference: PMID:20437614
    reference_title: >-
      Jagged1 (JAG1) mutations in patients with tetralogy of Fallot or pulmonic
      stenosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      although the lack of any liver dysfunction in the nine family members
      studied by Le Caignec et al. is unusual
    explanation: >-
      Records both the size of the assessed group (nine family members) and that
      experts in Alagille syndrome regard the complete absence of liver
      dysfunction as atypical for a JAG1 disorder.
  - reference: PMID:27418850
    reference_title: "Alagille syndrome: clinical perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Alagille syndrome is an autosomal dominant, complex multisystem disorder
      characterized by the presence of three out of five major clinical criteria:
      cholestasis with bile duct paucity on liver biopsy, congenital cardiac
      defects (with particular involvement of the pulmonary arteries), posterior
      embryotoxon in the eye, characteristic facial features, and butterfly
      vertebrae.
    explanation: >-
      States the five Alagille criteria, three of which are absent here - which
      is what the differential turns on.
  - reference: PMID:12649809
    reference_title: >-
      Conditional JAG1 mutation shows the developing heart is more sensitive than
      developing liver to JAG1 dosage.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The cardiac-specific phenotype associated with this mutation suggests that
      the developing heart is more sensitive than the developing liver to
      decreased dosage of JAG1.
    explanation: >-
      Cited as the CONTRASTING model, matching how this reference is framed
      everywhere else in this entry. It establishes that a JAG1 allele can spare
      the liver while affecting the heart, which is the dissociation the
      differential turns on, but it attributes that to graded dose from the leaky
      p.Gly274Asp allele. p.Cys234Tyr was subsequently shown to be functionally
      null and still liver sparing, so this reference supports the existence of
      the dissociation without supplying its mechanism here.

- name: Non-syndromic JAG1-related right-sided congenital heart disease
  description: >-
    JAG1 variants are recovered from individuals with tetralogy of Fallot or
    pulmonic/peripheral pulmonary stenosis who carry no other Alagille feature.
    Such individuals overlap this entity in gene and in cardiac lesion, and are
    separated from it by the absence of the auditory and ocular components -
    which is precisely why an audiological and slit-lamp assessment belongs in
    the work-up of any JAG1-positive congenital heart disease.
  distinguishing_features:
  - >-
      Cardiac lesion only, with normal hearing and a normal anterior segment. This
      entity requires the full triad.
  evidence:
  - reference: PMID:20437614
    reference_title: >-
      Jagged1 (JAG1) mutations in patients with tetralogy of Fallot or pulmonic
      stenosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with right-sided cardiac defects should be carefully screened for
      features of AGS or a family history of cardiac defects that might suggest
      the presence of a JAG1 mutation.
    explanation: >-
      Documents the cardiac-only JAG1 presentation and the recommendation to
      screen such patients for additional JAG1-pathway features.

- name: Axenfeld-Rieger anomaly and syndrome spectrum
  description: >-
    Posterior embryotoxon is also the leading element of the Axenfeld-Rieger
    anomaly triad, so an individual with this entity who comes to attention
    through an ophthalmologist can be labelled Axenfeld-Rieger rather than
    referred for JAG1 testing. This is not hypothetical: a 2023 cohort of
    Axenfeld-Rieger cases left unsolved after PITX2 and FOXC1 testing found JAG1
    variants in three separate families, one of whom - referred with
    Axenfeld-Rieger anomaly, bilateral sensorineural hearing loss and dysmorphism - is
    phenotypically close to this entity. The practical consequence is that JAG1
    belongs on the differential of anterior-segment dysgenesis with syndromic
    features, particularly when hearing loss or a congenital heart defect
    accompanies it.
  distinguishing_features:
  - >-
    Axenfeld-Rieger anomaly requires iridocorneal adhesions and iris anomalies
    (hypoplasia, corectopia, polycoria) in addition to posterior embryotoxon;
    the index kindred of this entity was reported with posterior embryotoxon
    alone, without the rest of the triad.
  - >-
    Classic Axenfeld-Rieger syndrome is caused by PITX2 (type 1, with dental and
    umbilical features) or FOXC1 (type 3), which together explain roughly 70% of
    cases; this entity is caused by JAG1. Note that FOXC1-associated disease can
    itself include hearing loss and congenital heart defects, so the clinical
    overlap with this entity is genuine and gene testing, not phenotype, settles
    it.
  - >-
    Glaucoma is a major concern in Axenfeld-Rieger anomaly and was not reported
    in the index kindred here; conversely the mid-frequency mixed hearing loss
    characteristic of this entity is not an Axenfeld-Rieger feature.
  evidence:
  - reference: PMID:37895297
    reference_title: Alternative Genetic Diagnoses in Axenfeld-Rieger Syndrome Spectrum.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The identification of JAG1 variants, linked with Alagille syndrome, in
      three separate families with a clinical diagnosis of ARA/ARS highlights the
      overlapping features and high variability of these two phenotypes.
    explanation: >-
      Directly documents JAG1 presenting under an Axenfeld-Rieger clinical label,
      which is what makes this a real rather than theoretical differential.
  - reference: PMID:37895297
    reference_title: Alternative Genetic Diagnoses in Axenfeld-Rieger Syndrome Spectrum.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a specific type of anterior segment disorder characterized by the triad of
      posterior embryotoxon
    explanation: >-
      Establishes posterior embryotoxon as an Axenfeld-Rieger triad element,
      which is the shared feature that creates the diagnostic confusion.
  - reference: PMID:37895297
    reference_title: Alternative Genetic Diagnoses in Axenfeld-Rieger Syndrome Spectrum.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      referred with diagnosis of ARS based on ARA, bilateral sensorineural
      hearing loss, midface hypoplasia, hypertelorism, and dental crowding
    explanation: >-
      A JAG1-positive individual carrying anterior-segment disease together with
      sensorineural hearing loss - the feature combination that defines this
      entity - reached the clinic under an Axenfeld-Rieger label.
  - reference: PMID:37895297
    reference_title: Alternative Genetic Diagnoses in Axenfeld-Rieger Syndrome Spectrum.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      PITX2 and FOXC1 variants explain the majority of individuals with
      Axenfeld-Rieger syndrome (ARS) but leave ~30% unsolved.
    explanation: >-
      Supports the statement that the classic Axenfeld-Rieger genes account for
      about 70% of cases, leaving room for JAG1 and others.

- name: Atypical or oligosymptomatic Alagille syndrome
  description: >-
    Individuals carrying a JAG1 variant who manifest only one or two of the
    Alagille organ systems. This entity may ultimately prove to be a member of
    that continuum rather than a discrete disorder - see the open discussion on
    entity status recorded below.
  distinguishing_features:
  - >-
      Distinguished by the presence here of a highly penetrant, mid-frequency mixed
      hearing loss segregating with the cardiac and ocular features in a single
      large pedigree, and by the explicit statement in the index report that no
      affected individual met criteria for a previously described syndrome.
  evidence:
  - reference: PMID:21752016
    reference_title: >-
      JAG1 mutations are found in approximately one third of patients presenting
      with only one or two clinical features of Alagille syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The highest mutation detection rates were observed in patients with the
      most frequent presenting features of Alagille syndrome; ranging from 20%
      (one system) to 86% (five systems).
    explanation: >-
      Quantifies the oligosymptomatic JAG1 presentation that forms the boundary
      of this entity.

animal_models:
- name: headturner (Htu) Jag1 missense mouse
  species: Mouse
  genotype: Jag1 Htu/+ (dominant missense allele)
  publication: PMID:11259677
  description: >-
    A dominant, ENU-derived Jag1 missense allele - the same lesion class as the
    human p.Cys234Tyr - assessed in the heterozygous state, matching the dominant
    human inheritance. Its value here is that it links a heterozygous Jag1
    missense change to both vestibular and cochlear sensory deficits.
  modeled_mechanisms:
  - target: Impaired Notch-Dependent Inner Ear Sensory Patterning
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Reproduces the inner-ear sensory arm of the mechanism - loss of vestibular
      ampullae and reduced outer hair cells - from a heterozygous Jag1 missense
      allele.
    limitations: >-
      The Htu allele is not p.Cys234Tyr and lies in a different part of the
      protein; the mouse was not reported to model the cardiac or ocular arms of
      the human phenotype, and gross ampullar agenesis is more severe than
      anything documented in the human kindred.
    evidence:
    - reference: PMID:11259677
      reference_title: The Notch ligand Jagged1 is required for inner ear sensory development.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        a dominant mouse mutant headturner (Htu) contains a missense mutation in
        the Jag1 gene and displays missing posterior and sometimes anterior
        ampullae, structures that house the sensory cristae
      explanation: >-
        Supports treating this model as informative for Jagged1-dependent inner
        ear sensory patterning.
  evidence:
  - reference: PMID:11259677
    reference_title: The Notch ligand Jagged1 is required for inner ear sensory development.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Htu/+ mutants also demonstrate a significant reduction in the numbers of
      outer hair cells in the organ of Corti.
    explanation: >-
      Establishes the model as informative for this disorder: a heterozygous Jag1
      missense allele - the lesion class of the human p.Cys234Tyr variant -
      produces a cochlear sensory deficit.

- name: Jag1 Nodder (Jag1 Ndr/Ndr) mouse
  species: Mouse
  genotype: Jag1 Ndr/Ndr (hypomorphic Alagille syndrome model)
  publication: PMID:39373109
  description: >-
    A hypomorphic Jag1 mouse used as an Alagille syndrome model, with cochlear
    morphology plus single-cell RNA sequencing of the organ of Corti. It
    establishes that the cochlear phenotype is Jag1 dose dependent, which is what
    makes a heterozygous human loss-of-function allele a sufficient explanation
    for hearing loss. This speaks to the ear arm only: it is not support for a
    graded-dose account of the organ selectivity, which was tested and ruled out
    for p.Cys234Tyr.
  modeled_mechanisms:
  - target: Impaired Notch-Dependent Inner Ear Sensory Patterning
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Reproduces dose-dependent cochlear mis-patterning with combined auditory
      and vestibular deficits.
    limitations: >-
      A homozygous hypomorph rather than a heterozygous missense carrier, and not
      the p.Cys234Tyr allele; the cardiac and ocular arms of the human phenotype
      are not addressed by this study.
    evidence:
    - reference: PMID:39373109
      reference_title: >-
        Jag1 represses Notch activation in lateral supporting cells and inhibits
        an outer hair cell fate in the medial cochlea.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Jag1Ndr/Ndr mice exhibited expected vestibular and auditory deficits, a
        dose-dependent increase in ectopic inner hair cells, and a reduction in
        outer hair cells.
      explanation: >-
        Supports treating this model as informative for dose-dependent cochlear
        patterning failure.
  evidence:
  - reference: PMID:39373109
    reference_title: >-
      Jag1 represses Notch activation in lateral supporting cells and inhibits an
      outer hair cell fate in the medial cochlea.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Notch signaling patterns the cochlear organ of Corti, and individuals with
      the JAG1/NOTCH2-related genetic disorder Alagille syndrome can thus
      experience hearing loss.
    explanation: >-
      Establishes the model as informative for the human JAG1 hearing phenotype
      that this entity shares with the wider JAG1 disease spectrum.

- name: Heterozygous Jagged1 knockout mouse (middle ear)
  species: Mouse
  genotype: Jag1 +/- heterozygous null
  publication: PMID:28566723
  description: >-
    The heterozygous Jag1 null mouse, used as an Alagille syndrome model, carries
    the conductive arm of the mechanism: it malforms the stapes and incus, and
    the stapes malformation tracks with hearing loss across all frequencies.
  modeled_mechanisms:
  - target: Impaired Jagged1-Notch2 Patterning of the Middle Ear Ossicles
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Reproduces ossicular malformation from a heterozygous reduction in Jagged1
      dose, matching the dominant human inheritance.
    limitations: >-
      A null allele rather than the human missense allele, so the ligand
      reduction is a clean 50%. That is now known to be the right dose for
      p.Cys234Tyr, which is functionally null, so the mismatch here is one of
      allele mechanism and species rather than of dose; the audiological
      correlate is still inferred from mouse thresholds rather than measured in
      a DCHE carrier.
    evidence:
    - reference: PMID:28566723
      reference_title: >-
        Requirement for Jagged1-Notch2 signaling in patterning the bones of the
        mouse and human middle ear.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Heterozygous Jagged1 knockout mice, a model for Alagille Syndrome (AGS),
        also display stapes and incus defects.
      explanation: >-
        Supports treating this model as informative for Jagged1-dependent
        ossicular patterning.
  evidence:
  - reference: PMID:28566723
    reference_title: >-
      Requirement for Jagged1-Notch2 signaling in patterning the bones of the
      mouse and human middle ear.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We observe similar stapes defects and hearing loss in one patient with
      heterozygous JAGGED1 loss, and a diversity of conductive and sensorineural
      hearing loss in nearly half of AGS patients, many of which carry JAGGED1
      mutations.
    explanation: >-
      Establishes the model as informative for humans: the mouse ossicular defect
      is mirrored in a person with heterozygous JAG1 loss, and the resulting
      mixed conductive-sensorineural pattern matches this entity's phenotype.

treatments:
- name: Genetic counselling
  description: >-
    Autosomal dominant transmission with high penetrance of the triad but marked
    variability in which lesion an individual carrier expresses. Counselling must
    convey a 50% transmission risk together with the point that the cardiac
    lesion in an affected child cannot be predicted from the parent's lesion, and
    should include cascade evaluation of at-risk relatives with audiometry and
    slit-lamp examination as well as echocardiography.
  action_category: COUNSELING_INFORMATIONAL
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:12022040
    reference_title: >-
      Familial deafness, congenital heart defects, and posterior embryotoxon
      caused by cysteine substitution in the first epidermal-growth-factor-like
      domain of jagged 1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the present study, we report a kindred with hearing loss, congenital
      heart defects, and posterior embryotoxon, segregating as autosomal dominant
      traits.
    explanation: >-
      Establishes the autosomal dominant transmission pattern that determines the
      recurrence risk conveyed in counselling.
  - reference: PMID:12022040
    reference_title: >-
      Familial deafness, congenital heart defects, and posterior embryotoxon
      caused by cysteine substitution in the first epidermal-growth-factor-like
      domain of jagged 1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our findings revealed a unique phenotype with highly penetrant deafness,
      posterior embryotoxon, and congenital heart defects but with variable
      expressivity in a large kindred
    explanation: >-
      Supports the counselling message that penetrance is high but expressivity
      varies between carriers of the same allele.

- name: Surgical repair of the congenital heart defect
  description: >-
    Management of the cardiac component follows standard congenital-cardiac
    practice for the specific lesion; there is no DCHE-specific cardiac protocol.
    Tetralogy of Fallot requires operative repair, whereas isolated peripheral
    pulmonic stenosis may need only surveillance - so the same allele in two
    relatives can imply completely different cardiac management, which is the
    practical consequence of the variable expressivity recorded here.
  action_category: THERAPEUTIC
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Cardiac Surgery
    term:
      id: NCIT:C157806
      label: Cardiac Surgery
  target_phenotypes:
  - preferred_term: Tetralogy of Fallot
    term:
      id: HP:0001636
      label: Tetralogy of Fallot
  - preferred_term: Ventricular septal defect
    term:
      id: HP:0001629
      label: Ventricular septal defect
  evidence:
  - reference: PMID:12022040
    reference_title: >-
      Familial deafness, congenital heart defects, and posterior embryotoxon
      caused by cysteine substitution in the first epidermal-growth-factor-like
      domain of jagged 1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients had congenital heart defects, including tetralogy of Fallot,
      ventricular septal defect, or isolated peripheral pulmonic stenosis.
    explanation: >-
      Establishes the surgically relevant lesion set. PARTIAL - it documents the
      lesions requiring management, not an outcome of surgery in this disorder,
      for which no evidence exists.

- name: Audiological assessment and hearing rehabilitation
  description: >-
    Because the hearing loss is mixed and mid-frequency-predominant, it is not
    reliably caught by a screen tuned to high-frequency sensorineural loss, and
    full audiometry (with tympanometry to characterise the conductive component)
    is warranted in any carrier or at-risk relative. Amplification and
    language-development support follow standard paediatric audiology practice;
    no DCHE-specific rehabilitation evidence exists.
  action_category: THERAPEUTIC
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: audiological support and hearing amplification
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Combined (mixed) hearing loss
    term:
      id: HP:0000410
      label: Mixed hearing impairment
  evidence:
  - reference: PMID:12022040
    reference_title: >-
      Familial deafness, congenital heart defects, and posterior embryotoxon
      caused by cysteine substitution in the first epidermal-growth-factor-like
      domain of jagged 1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Six of seven available affected patients manifested mild-to-severe combined
      hearing loss, predominantly affecting middle frequencies.
    explanation: >-
      Establishes the mixed, mid-frequency character of the loss that dictates
      the audiological assessment described here. PARTIAL - it documents the
      deficit, not the effect of any intervention.

- name: Ophthalmic surveillance
  description: >-
    Posterior embryotoxon is itself usually visually silent and needs no
    treatment; what warrants follow-up is what may accompany it. Anterior-segment
    dysgenesis and glaucoma are the findings that determine visual outcome, and
    the overlap between JAG1 disease and the Axenfeld-Rieger spectrum, in which
    glaucoma is a principal concern, is close enough that periodic slit-lamp
    examination with intraocular pressure measurement is prudent in a carrier.
    Note the evidence base here is the wider JAG1 and anterior-segment
    literature: no glaucoma was reported in the index kindred, and no
    surveillance interval has been studied in this entity.
  action_category: MONITORING
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: ophthalmic surveillance
    term:
      id: NCIT:C15747
      label: Supportive Care
  notes: >-
    Deliberately carries no target_phenotypes. Surveillance detects a phenotype
    rather than acting on one, and test_non_therapeutic_actions_do_not_use_
    treatment_targets forbids treatment-style target slots on a MONITORING
    action. The phenotype linkage lives where it belongs, on the slit-lamp entry
    in the diagnosis section.
  evidence:
  - reference: PMID:37895297
    reference_title: Alternative Genetic Diagnoses in Axenfeld-Rieger Syndrome Spectrum.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The identification of JAG1 variants, linked with Alagille syndrome, in
      three separate families with a clinical diagnosis of ARA/ARS highlights the
      overlapping features and high variability of these two phenotypes.
    explanation: >-
      Establishes the overlap with a spectrum in which glaucoma is a recognised
      threat to vision, which is the rationale for surveillance. PARTIAL: it
      documents the phenotypic overlap, not the value of any surveillance
      interval, which has not been studied in this entity.
  - reference: PMID:12022040
    reference_title: >-
      Familial deafness, congenital heart defects, and posterior embryotoxon
      caused by cysteine substitution in the first epidermal-growth-factor-like
      domain of jagged 1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our findings revealed a unique phenotype with highly penetrant deafness,
      posterior embryotoxon, and congenital heart defects
    explanation: >-
      Establishes the near-universal ocular involvement that puts every carrier
      in scope for ophthalmic follow-up. PARTIAL: it documents the finding, not
      an outcome of surveillance.

discussions:
- discussion_id: dche_entity_status
  kind: OPEN_QUESTION
  status: OPEN
  prompt: >-
    Is DCHE a discrete disorder, or the liver-sparing tail of the JAG1
    (Alagille) phenotypic continuum?
  attaches_to:
  - pathophysiology#Modifier-Dependent Organ Selectivity of JAG1
      Haploinsufficiency
  rationale: >-
    Three facts pull in different directions and none of them settles the
    question. In favour of a discrete entity: OMIM and MONDO both catalogue it
    separately; the index report states explicitly that no affected individual
    met criteria for any previously described syndrome; and highly penetrant,
    mid-frequency mixed hearing loss is not a cardinal Alagille criterion. In
    favour of a continuum: the gene, the pathway, and two of the three cardinal
    features are shared with Alagille syndrome; JAG1 variants are routinely
    recovered from individuals expressing only one or two Alagille organ systems;
    and the mechanistic account offered here, complete haploinsufficiency whose
    organ selectivity is set by unidentified modifiers, is a continuum mechanism
    rather than a separate-disorder mechanism, since the very same class of null
    lesion underlies classic Alagille syndrome. The evidence base is also thin enough that the
    question may not be answerable: one kindred, one allele. dismech curates it
    as a separate entry because MONDO does and because the hearing phenotype is
    distinctive, while recording the continuum reading here rather than
    suppressing it.
  proposed_experiments:
  - experiment_id: dche_jag1_cohort_audiology_slitlamp
    name: >-
      Audiological and slit-lamp phenotyping of a JAG1 cohort
    description: >-
      Systematic audiological and slit-lamp phenotyping of a molecularly defined
      JAG1 cohort, to establish whether mid-frequency mixed hearing loss
      segregates with a particular allele class or is a general,
      under-ascertained feature of JAG1 disease.
  - experiment_id: dche_additional_c234y_kindreds
    name: >-
      Ascertainment of additional EGF-repeat cysteine kindreds
    description: >-
      Identification of additional unrelated p.Cys234Tyr (or other EGF-repeat-1
      cysteine) kindreds, to test whether the liver-sparing triad is
      allele-specific or family-specific.
  evidence:
  - reference: PMID:12022040
    reference_title: >-
      Familial deafness, congenital heart defects, and posterior embryotoxon
      caused by cysteine substitution in the first epidermal-growth-factor-like
      domain of jagged 1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      No individual in this family met diagnostic criteria for any previously
      described clinical syndrome.
    explanation: >-
      The strongest single statement for discrete-entity status.
  - reference: PMID:21752016
    reference_title: >-
      JAG1 mutations are found in approximately one third of patients presenting
      with only one or two clinical features of Alagille syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Identification of a JAG1 gene mutation is particularly useful for those
      patients with atypical or mild Alagille syndrome who do not meet classic
      diagnostic criteria as it provides a definite molecular diagnosis
    explanation: >-
      Supports the competing continuum reading, in which this kindred is an
      atypical JAG1 presentation rather than a separate disorder.

- discussion_id: dche_organ_selectivity_modifiers
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    If JAG1 p.Cys234Tyr is completely haploinsufficient, what determines that the
    heart, ears and anterior segment are affected while the liver is spared?
  attaches_to:
  - pathophysiology#Modifier-Dependent Organ Selectivity of JAG1
      Haploinsufficiency
  rationale: >-
    This is the central unsolved question of the entry, and it became sharper
    rather than softer once p.Cys234Tyr was assayed. The intuitive answer -
    that a partially functional allele leaves enough ligand for the tissues with
    the lowest requirement - was proposed on the strength of the hypomorphic
    p.Gly274Asp allele, and then specifically defeated: p.Cys234Tyr is
    EndoH-sensitive, absent from the cell surface, and unable to activate Notch,
    yet its carriers still have normal liver function. A functionally null allele
    and a leaky allele therefore produce the same liver-sparing pattern, which
    means residual ligand dose cannot be what distinguishes the spared organ from
    the affected ones. The assaying authors attribute the pattern to
    unidentified modifying factors. Nothing currently narrows what those are:
    candidate classes include trans-acting variation at other Notch-pathway loci,
    tissue-specific differences in the compensating ligand repertoire (JAG2,
    DLL1/4) or in receptor availability (NOTCH1 vs NOTCH2), and differences in
    how much developmental time each organ has to recover from a signalling
    deficit. Until that is resolved, the organ-selectivity node is curated
    HYPOTHETICAL and this entry does not claim a dose-threshold mechanism.
  proposed_experiments:
  - experiment_id: dche_modifier_genome_analysis
    name: >-
      Genome-wide modifier search in discordant JAG1 carriers
    description: >-
      Whole-genome sequencing of JAG1 carriers concordant for genotype but
      discordant for hepatic involvement, within and across families, testing
      for trans-acting modifier variation at Notch-pathway and other loci. This
      is the study design the assaying authors themselves proposed.
  - experiment_id: dche_tissue_ligand_receptor_repertoire
    name: >-
      Comparative ligand and receptor repertoire across affected and spared organs
    description: >-
      Single-cell profiling of Notch ligand and receptor expression in
      developing bile duct, cardiac outflow tract, cochlea and periocular
      mesenchyme, to test whether the spared tissue is the one with the greatest
      redundancy from other ligands.
  - experiment_id: dche_allelic_series_organ_thresholds
    name: >-
      Allelic series comparison of organ-level thresholds
    description: >-
      Direct comparison of null, hypomorphic and knock-in p.Cys234Tyr alleles
      for bile-duct number, outflow-tract anatomy and auditory thresholds, to
      establish whether any organ phenotype tracks residual ligand dose at all.
  evidence:
  - reference: PMID:20437614
    reference_title: >-
      Jagged1 (JAG1) mutations in patients with tetralogy of Fallot or pulmonic
      stenosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      What remains unknown is why these cases present with only a cardiac
      phenotype and not the full clinical features of AGS, particularly hepatic
      disease.
    explanation: >-
      The assaying authors state this question as unresolved, which is what makes
      it a knowledge gap rather than a curation shortfall.
  - reference: PMID:20437614
    reference_title: >-
      Jagged1 (JAG1) mutations in patients with tetralogy of Fallot or pulmonic
      stenosis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      the p.C234Y and p.P810L mutations appear to be completely
      haploinsufficient
    explanation: >-
      The assay half of the finding: cell-based characterisation establishes that
      the allele retains no function.
  - reference: PMID:20437614
    reference_title: >-
      Jagged1 (JAG1) mutations in patients with tetralogy of Fallot or pulmonic
      stenosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      yet the patients with these mutations do not have the full spectrum of AGS,
      consistent with the presence of additional modifying factors
    explanation: >-
      The clinical half of the same finding, split out per the CLAUDE.md rule
      that a mixed-source sentence should not share one evidence_source: the
      patients' restricted phenotype is a human observation, and it is what
      forces the modifier interpretation.
  - reference: PMID:20437614
    reference_title: >-
      Jagged1 (JAG1) mutations in patients with tetralogy of Fallot or pulmonic
      stenosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In an era of increasing whole genome analysis, future studies may elucidate
      what these modifying factors are and allow for better predictive diagnosis
      in humans with JAG1 mutations.
    explanation: >-
      Supports the genome-wide modifier search recorded as the first proposed
      experiment.

- discussion_id: anterior_segment_mechanism_gap
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    By what developmental route does reduced Jagged1 dose produce posterior
    embryotoxon?
  attaches_to:
  - pathophysiology#Disrupted Anterior Segment Development in Periocular Neural
      Crest
  rationale: >-
    The auditory and cardiac arms of this entity each rest on a dedicated
    Jagged1-specific developmental study. The ocular arm does not: no study of
    Jagged1 in anterior-segment or periocular-mesenchyme morphogenesis was
    identified during curation. What supports the node is the human phenotype
    association plus the neural-crest origin of the Schwalbe line, corneal
    endothelium and trabecular meshwork - which is inference from anatomy, not a
    demonstrated mechanism. The node is therefore marked HYPOTHETICAL and its
    incoming edge INDIRECT_UNKNOWN_INTERMEDIATES.
  proposed_experiments:
  - experiment_id: jag1_periocular_crest_conditional_deletion
    name: >-
      Conditional Jag1 deletion in periocular neural crest
    description: >-
      Conditional Jag1 deletion in neural-crest-derived periocular mesenchyme,
      with anterior-segment morphometry and Schwalbe-line position as readouts.
  - experiment_id: anterior_chamber_notch_reporter_mapping
    name: >-
      Notch-reporter mapping of the developing anterior chamber angle
    description: >-
      Notch-reporter mapping of the developing anterior chamber angle to
      establish where and when Jagged1-Notch signalling is active in that
      territory.
  evidence:
  - reference: PMID:12022040
    reference_title: >-
      Familial deafness, congenital heart defects, and posterior embryotoxon
      caused by cysteine substitution in the first epidermal-growth-factor-like
      domain of jagged 1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our findings revealed a unique phenotype with highly penetrant deafness,
      posterior embryotoxon, and congenital heart defects
    explanation: >-
      Establishes the phenotype whose developmental mechanism is the subject of
      this gap.

- discussion_id: dche_model_organism_mismatch
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Do the available Jag1 mouse models, none of which carries p.Cys234Tyr,
    faithfully represent the human DCHE mechanism?
  attaches_to:
  - pathophysiology#Impaired Notch-Dependent Inner Ear Sensory Patterning
  - pathophysiology#Impaired Jagged1-Notch2 Patterning of the Middle Ear Ossicles
  rationale: >-
    All three mouse models curated here are informative for Jagged1-dependent ear
    development, and none of them models this disorder. Htu is a different
    missense allele; Jag1 Ndr/Ndr is a homozygous hypomorph; the middle-ear work
    uses a heterozygous null. The heterozygous null is in fact the closest match
    on dose, since p.Cys234Tyr was subsequently shown to be functionally null
    rather than leaky; Htu is a different missense allele of unknown residual
    activity, and the homozygous hypomorph sits at a lower dose than any human
    carrier. Additionally, no mouse model reproduces the human triad: the ear
    models do not address the cardiac or ocular arms, and the cardiac model does
    not address hearing. Most importantly, no mouse model addresses the feature
    that actually defines this disorder against Alagille syndrome - whether
    bile-duct development is spared - so the models can corroborate the ear and
    heart arms while being silent on the entity's defining negative.
  proposed_experiments:
  - experiment_id: c234y_knockin_mouse_full_triad_phenotyping
    name: >-
      Jag1 p.Cys234Tyr knock-in mouse with full triad phenotyping
    description: >-
      A Jag1 p.Cys234Tyr knock-in mouse, phenotyped for auditory thresholds and
      configuration, vestibular function, outflow-tract anatomy,
      anterior-segment morphology, and bile-duct number - the last being the specific
      test of the liver-sparing claim.
  - experiment_id: jag1_allelic_series_organ_dose_thresholds
    name: >-
      Allelic series comparison of ear, heart and liver phenotypes
    description: >-
      Allelic series comparison (null, hypomorphic missense, p.Cys234Tyr
      knock-in) of ear, heart and liver phenotypes, to establish whether any
      organ phenotype tracks residual ligand dose at all.
  evidence:
  - reference: PMID:11259677
    reference_title: The Notch ligand Jagged1 is required for inner ear sensory development.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      a dominant mouse mutant headturner (Htu) contains a missense mutation in
      the Jag1 gene and displays missing posterior and sometimes anterior
      ampullae, structures that house the sensory cristae
    explanation: >-
      A different Jag1 missense allele producing gross ampullar agenesis, more
      severe than anything reported in the human kindred - the mismatch this
      discussion records.
  - reference: PMID:39373109
    reference_title: >-
      Jag1 represses Notch activation in lateral supporting cells and inhibits an
      outer hair cell fate in the medial cochlea.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Jag1Ndr/Ndr mice exhibited expected vestibular and auditory deficits, a
      dose-dependent increase in ectopic inner hair cells, and a reduction in
      outer hair cells.
    explanation: >-
      A homozygous hypomorph, i.e. a different point on the dose-response curve
      from a heterozygous human missense carrier.

references:
- reference: PMID:20301450
  title: Alagille Syndrome.
  tags:
  - GeneReviews
- reference: PMID:12022040
  title: >-
    Familial deafness, congenital heart defects, and posterior embryotoxon caused
    by cysteine substitution in the first epidermal-growth-factor-like domain of
    jagged 1.

notes: >-
  NEC (Named Entity Confusion) preflight, recorded because this entity is a
  high-risk case: "posterior embryotoxon plus congenital heart defects" is a
  cardinal Alagille syndrome pairing, kb/disorders/Alagille_syndrome.yaml already
  exists, and the two disorders share a causal gene, so a gene-frequency check
  cannot discriminate between them.

  `just preflight-dr <report> MONDO:0060713` returned SKIP - MONDO records no
  RO:0004003 causal gene for this term - and additionally reported an OMIM
  mismatch (report 118450 versus MONDO xref 617992). The manual OMIM/synonym
  preflight was therefore run, and the mismatch was resolved as a false positive:
  OMIM 118450 appears in the report only inside a correctly labelled contrastive
  paragraph about classic Alagille syndrome, while the report's target entity is
  named as MONDO:0060713 throughout. Identity anchors all agree - MONDO:0060713
  xrefs OMIM:617992 with the related synonym DCHE; the index publication
  PMID:12022040 (fetched directly from PubMed before the deep-research report was
  read) names JAG1 p.Cys234Tyr in the triad kindred; and JAG1 dominates the
  report's gene mentions (61, versus NOTCH2 6). Manual verdict: PASS.

  Independence note: the phenotype and genetic content of this entry was
  anchored on primary literature retrieved directly from PubMed before the falcon
  report was opened.

  Evidence-source note: PMID:20437614 (Bauer 2010) is cached as full text, not
  abstract only, and the allele-level functional evidence for p.Cys234Tyr -
  EndoH sensitivity, absence from the cell surface by trypsin shaving and by
  immunofluorescence, failure to activate a CBF-dependent Notch reporter, and the
  authors' conclusion of complete haploinsufficiency - is quoted from that cached
  body. An earlier draft of this entry wrongly treated that evidence as
  unavailable and built the mechanism on a graded "leaky allele" dose model
  extrapolated from the p.Gly274Asp allele of PMID:12649809. Bauer 2010
  explicitly tested and rejected that model for this allele, so the mechanism
  chain here is haploinsufficiency plus unidentified modifiers, and PMID:12649809
  is retained only as the labelled contrasting hypothesis.

  GeneReviews: no GeneReviews chapter exists for this entity. The Alagille
  syndrome chapter (PMID:20301450) is tagged in `references:` and used only for
  the allelic-disorder differential, not as a phenotype baseline for this entry.

  Datasets: `just discover-datasets` was run and returned no relevant accession.
  Every candidate was a GENE_ONLY match reached through JAG1 - breast cancer
  lymph-node metastasis, glioma, pancreatic islet, embryonic haematopoietic stem
  cell - i.e. whatever JAG1 is famous for, which is exactly the Named Entity
  Confusion pattern the dataset-curation SOP warns about. No cochlear,
  anterior-segment or outflow-tract dataset was found for this gene, and none
  exists for this entity. `datasets:` is therefore deliberately empty rather than
  populated with a resolvable but irrelevant accession.

📚

References & Deep Research

References

2

PMID:20301450

Alagille Syndrome.

No top-level findings curated for this source.

PMID:12022040

Familial deafness, congenital heart defects, and posterior embryotoxon caused by cysteine substitution in the first epidermal-growth-factor-like domain of jagged 1.

No top-level findings curated for this source.

Deep Research

1

Falcon ▸

Disease Characteristics Research Template

Edison Scientific Literature 18 citations 2026-08-19T09:15:35.596350

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

Disease Name: Deafness, Congenital Heart Defects, and Posterior Embryotoxon
MONDO ID: (if available)
Category: Mendelian

Research Objectives

Please provide a comprehensive research report on Deafness, Congenital Heart Defects, and Posterior Embryotoxon covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

What is the disease? Provide a concise overview.
What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
What are the common synonyms and alternative names?
Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
Risk Factors:

Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases
Genetic risk factors (causal variants, susceptibility loci, modifier genes)
Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
Protective Factors:

Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases
Genetic protective factors (protective variants, modifier alleles)
Environmental protective factors (diet, lifestyle, exposures that reduce risk)
Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene
Pathogenic Variants:
Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
Variant type/class (missense, frameshift, nonsense, splice-site, structural)
Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
Functional consequences (loss of function, gain of function, dominant negative)
Modifier Genes: Genes that modify disease severity or expression
Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases
Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

Search first: CDC databases, WHO, PubMed, NHANES
Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc
Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

Search first: Gene Ontology (GO), Reactome, KEGG, PubMed
Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold
Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA
Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

Search first: ImmPort, Immunome Database, IEDB, Gene Ontology
Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

Search first: PubMed, Gene Ontology, Reactome
Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

Search first: BRENDA, UniProt, KEGG, OMIM, PubMed
Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Molecular Profiling (if available):
Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
Advanced Technologies (if applicable):
Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

Organ Level:
Primary organs directly affected
Secondary organ involvement (complications, secondary effects)
Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT
Tissue and Cell Level:
Specific tissue types affected (epithelial, connective, muscle, nervous)
Specific cell populations targeted (with Cell Ontology terms)

Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB
Subcellular Level:
Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas
Localization:
Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

Onset:
Typical age of onset (congenital, pediatric, adult, geriatric)
Onset pattern (acute, subacute, chronic, insidious)

Search first: OMIM, Orphanet, HPO, PubMed
Progression:
Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
Progression rate (rapid, slow, variable)
Disease course pattern (episodic, relapsing-remitting, progressive, stable)
Disease duration (self-limited, chronic lifelong)

Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM
Patterns:
Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

Epidemiology:
Prevalence (cases per 100,000 at given time)
Incidence (new cases per 100,000 per year)

Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries
For Genetic Etiology:
Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
Population Demographics:
Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
Geographic distribution of specific variants
Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

Clinical Tests:
Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
Genetic Testing:

Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen
Overview of recommended genetic testing approach
Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
FISH > Search first: ClinVar, cytogenetics databases, PubMed
Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
Omics-Based Diagnostics (if applicable):
RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
Clinical Criteria:
Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
Screening:
Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

Survival and Mortality:
Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
Morbidity and Function:
Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
Disease Course:
Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
Prediction:
Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

Pharmacotherapy:
Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
Advanced Therapeutics:
Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
Surgical and Interventional:
Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
Supportive and Rehabilitative:
Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
Experimental:
Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
Treatment Outcomes:
Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
Treatment Strategy:
Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest NCIT (NCI Thesaurus) clinical-intervention terms where applicable.

13. Prevention

Prevention Levels:
Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
Immunization: Vaccine strategies (if applicable)

Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database
Screening and Early Detection:
Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
Behavioral Interventions: Lifestyle modifications to reduce risk

Search first: CDC, WHO, behavioral intervention databases, Cochrane Library
Counseling: Genetic counseling (risk assessment, family planning guidance)

Search first: NSGC resources, ACMG guidelines, GeneReviews
Public Health:
Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
Prophylaxis: Preventive medications or procedures

Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

Taxonomy: Species affected (with NCBI Taxon identifiers)

Search first: NCBI Taxonomy
Breed: Specific breeds affected (with VBO identifiers if applicable)

Search first: VBO (Vertebrate Breed Ontology)
Gene: Orthologous genes in other species (with NCBI Gene IDs)

Search first: NCBI Gene
Natural Disease:
Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
Comparative Biology:
Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
Transmission (if applicable):
Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

Model Types:
Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
Genetic Models:
Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
Model Characteristics:
Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
Applications:
Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
Resources:
Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

Cite primary literature (PMID preferred) for all mechanistic and clinical claims
Prioritize recent reviews and landmark papers
Include direct quotes from abstracts where possible to support key statements
Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, NCIT, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (NCIT terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Research report: Deafness, Congenital Heart Defects, and Posterior Embryotoxon

Executive interpretation

Deafness, congenital heart defects, and posterior embryotoxon is an exceptionally rare, autosomal-dominant JAG1-related developmental disorder catalogued as MONDO:0060713. The disease was delineated in one multigenerational family and is best interpreted as a liver-sparing, atypical Alagille-spectrum phenotype, rather than a mechanistically separate disorder. Its defining allele is JAG1 p.Cys234Tyr (p.C234Y), which segregated with cardiac defects, deafness, and posterior embryotoxon; all nine studied family members had normal liver function. Subsequent experiments showed defective protein maturation, absent cell-surface localization, failure to activate Notch, and functional JAG1 haploinsufficiency. The very small evidence base means that syndrome-specific frequencies, penetrance, prognosis, and treatment-response estimates cannot be calculated reliably. (OpenTargets Search: Deafness, congenital heart defects, and posterior embryotoxon, bauer2010jagged1(jag1)mutations pages 9-10)

domain	syndrome-specific finding	evidence level/limitations
Disease identity	MONDO:0060713 corresponds to an ultra-rare JAG1-related disorder named deafness, congenital heart defects, and posterior embryotoxon; currently linked to JAG1 in disease-target resources.	High confidence for identifier/target mapping; disease definition is based on a very small historical literature base rather than large registries. (OpenTargets Search: Deafness, congenital heart defects, and posterior embryotoxon)
Genetic cause	Causal variant reported is JAG1 p.Cys234Tyr (p.C234Y), a missense substitution affecting a conserved cysteine in the first EGF-like repeat.	High confidence from functional/genetic follow-up literature; nucleotide-level HGVS was not available in retrieved context. (bauer2010jagged1(jag1)mutations pages 9-10)
Inheritance / pedigree	The phenotype is described as a familial, autosomal dominant disorder segregating in a nine-member family.	High confidence for dominant familial segregation and studied family size; exact pedigree structure and penetrance values were not available in retrieved context. (bauer2010jagged1(jag1)mutations pages 9-10)
Defining phenotype triad	Core syndrome-defining features are deafness + congenital heart defects + posterior embryotoxon.	High confidence for the triad; retrieved follow-up source does not fully resolve deafness subtype/severity or the full spectrum of cardiac lesions in each relative. (bauer2010jagged1(jag1)mutations pages 9-10)
Liver involvement	In contrast to classic Alagille syndrome, all nine studied family members had normal liver function.	High confidence and clinically important distinction; this does not exclude broader JAG1/Alagille overlap in other families. (bauer2010jagged1(jag1)mutations pages 9-10)
Molecular mechanism	p.Cys234Tyr causes defective post-translational processing, lack of cell-surface expression, failure to activate Notch signaling, and is interpreted as causing JAG1 haploinsufficiency.	High confidence from functional assays in a later study; mechanism is experimentally supported but was not measured directly in the original family report. (bauer2010jagged1(jag1)mutations pages 9-10, bauer2010jagged1(jag1)mutations pages 13-19)
Structural interpretation	The altered cysteine is predicted to disrupt EGF-repeat folding/disulfide bond formation in a region crucial for ligand-receptor interaction.	High confidence mechanistic inference supported by conservation/structure discussion; still partly inferential rather than direct structural biophysics for this exact family. (bauer2010jagged1(jag1)mutations pages 9-10)
Expressivity	The syndrome shows variable expressivity, consistent with other familial JAG1 disorders.	Moderate-high confidence; no syndrome-specific quantitative expressivity or penetrance estimates were available. (bauer2010jagged1(jag1)mutations pages 9-10)
Relation to Alagille spectrum	Best interpreted as a liver-sparing / atypical Alagille-spectrum JAG1 phenotype, not a wholly separate mechanism.	High confidence from gene-level and clinical-overlap evidence; extrapolation beyond the reported family should be done cautiously. (OpenTargets Search: Deafness, congenital heart defects, and posterior embryotoxon, chitayat2016alagillesyndromeclinical pages 1-2, gilbert2019alagillesyndromemutation pages 1-5)
Broader Alagille context	Broader JAG1-related Alagille syndrome is autosomal dominant, often multisystemic, and may occur without overt liver disease; JAG1 accounts for most molecularly confirmed ALGS cases.	Useful contextual evidence only; these data are not syndrome-specific for MONDO:0060713. (chitayat2016alagillesyndromeclinical pages 1-2, chitayat2016alagillesyndromeclinical pages 5-7, gilbert2019alagillesyndromemutation pages 1-5, chitayat2016alagillesyndromeclinical pages 2-4, gilbert2019alagillesyndromemutation pages 20-24, gilbert2019alagillesyndromemutation pages 24-27)
Diagnostics	Current practical diagnosis would rely on clinical recognition of the triad plus JAG1 sequencing/CNV analysis, often within broader congenital heart disease or Alagille/ocular-anomaly testing.	Moderate confidence by extrapolation from JAG1/ALGS diagnostic practice; no syndrome-specific diagnostic guideline was found. (chitayat2016alagillesyndromeclinical pages 5-7, gilbert2019alagillesyndromemutation pages 20-24, gilbert2019alagillesyndromemutation pages 24-27)
Treatment / management	No syndrome-specific therapy was identified; management is phenotype-directed (cardiac care, hearing evaluation/habilitation, ophthalmic assessment) with genetics follow-up.	Moderate confidence because absence of evidence reflects rarity; no syndrome-specific interventional studies or trials were found. (chitayat2016alagillesyndromeclinical pages 1-2, chitayat2016alagillesyndromeclinical pages 5-7)
Epidemiology / natural history	No syndrome-specific prevalence, incidence, or longitudinal natural-history data were identified.	High confidence for evidence gap; available frequency data pertain to broader Alagille syndrome, not MONDO:0060713 specifically. (chitayat2016alagillesyndromeclinical pages 1-2, gilbert2019alagillesyndromemutation pages 1-5)
Recent developments (2023-2024)	Recent work mainly strengthens the broader JAG1/Alagille framework: alternative diagnoses in Axenfeld-Rieger-spectrum testing (2023) and Jag1-dependent cochlear cell-patterning mechanisms in mouse/scRNA-seq studies (2024).	Indirect but relevant; these studies do not add new syndrome-specific human cases for MONDO:0060713. (reis2023alternativegeneticdiagnoses pages 2-4, haan2024jag1repressesnotch pages 1-3)

Table: This table summarizes the most defensible syndrome-specific facts for deafness, congenital heart defects, and posterior embryotoxon, while clearly separating direct evidence from broader JAG1/Alagille-spectrum context. It is useful for knowledge-base curation because it highlights what is known with high confidence and where evidence gaps remain.

1. Disease information

Definition and identifiers

Preferred name: Deafness, congenital heart defects, and posterior embryotoxon.
MONDO: MONDO:0060713.
Causal-gene association: JAG1, Ensembl ENSG00000101384, encoding jagged canonical Notch ligand 1. Open Targets identifies JAG1 as the sole associated target and links the association to PMID 12022040 and PMID 20437614. (OpenTargets Search: Deafness, congenital heart defects, and posterior embryotoxon)
OMIM/Orphanet: No confidently verified, disorder-specific OMIM phenotype number or Orphanet number was recovered. It may be indexed under JAG1/Alagille-spectrum disease rather than as a distinct entry.
ICD-10/ICD-11 and MeSH: No syndrome-specific code or heading was identified. Component findings should be coded separately—congenital cardiac malformation, hearing loss, and anterior-segment anomaly—while documenting the molecular diagnosis.
Synonyms: “Familial deafness, congenital heart defects, and posterior embryotoxon”; “JAG1-related deafness–heart defect–posterior embryotoxon syndrome”; descriptively, “liver-sparing JAG1/Alagille-spectrum disorder.” The latter is an interpretive synonym, not necessarily a formal database label.

The source evidence is patient/family-level, originating from a nine-member pedigree, with subsequent aggregation in disease databases and JAG1/Alagille reviews. It is not derived from EHR-scale cohorts or population registries. (bauer2010jagged1(jag1)mutations pages 9-10)

Relationship to Alagille syndrome

Classic Alagille syndrome (ALGS; MIM 118450) is a variable autosomal-dominant disorder involving cholestasis/bile-duct paucity, pulmonary-artery or other cardiac disease, posterior embryotoxon, characteristic facies, and butterfly vertebrae; renal and vascular abnormalities may also occur. Molecular testing has demonstrated that JAG1/NOTCH2-positive individuals can lack overt liver disease. Thus, absence of cholestasis does not exclude a JAG1 disorder. (chitayat2016alagillesyndromeclinical pages 1-2)

2. Etiology, risk, and protective factors

Causal factor

The established cause is a heterozygous germline JAG1 missense variant, p.Cys234Tyr, in the first epidermal-growth-factor-like repeat. The altered cysteine is evolutionarily conserved and normally participates in disulfide bonding required for EGF-repeat folding. Functional evidence supports a loss-of-function/haploinsufficiency mechanism. (bauer2010jagged1(jag1)mutations pages 9-10)

The exact transcript-level cDNA HGVS nomenclature was not available in the retrieved primary evidence and should not be inferred without checking the original sequence reference. The variant should therefore be stored as JAG1 p.Cys234Tyr, with transcript and genome build left unresolved pending ClinVar/original-paper verification.

Risk factors

Genetic: Carrying the familial pathogenic JAG1 allele is the principal risk factor. Affected individuals have a theoretical 50% transmission probability per pregnancy under autosomal-dominant inheritance. Broader ALGS data indicate that approximately 50–70% of cases are de novo, but this statistic is not specific to this pedigree. (chitayat2016alagillesyndromeclinical pages 5-7)
Family history: A first-degree relative carrying the allele materially increases prior probability, although phenotype cannot be predicted reliably because JAG1 disorders show marked intrafamilial variability. (bauer2010jagged1(jag1)mutations pages 9-10, gilbert2019alagillesyndromemutation pages 1-5)
Environmental, infectious, lifestyle, age, and sex factors: None are established for this Mendelian syndrome.
Modifier genes: No validated modifier was identified for this particular phenotype.
Gene–environment interactions: No syndrome-specific evidence was found.

Protective factors

No genetic or environmental factor is known to prevent penetrance or protect against the cardiac, auditory, or ocular manifestations. Normal liver function in the reported family is a phenotype observation, not evidence of a protective exposure or allele. (bauer2010jagged1(jag1)mutations pages 9-10)

3. Phenotypes

The syndrome-specific literature confirms the triad but does not provide reliable per-feature percentages, complete lesion-level cardiac data, or standardized hearing measurements. Frequencies below should therefore be recorded as unknown, except that all nine studied relatives reportedly had normal liver function. (bauer2010jagged1(jag1)mutations pages 9-10)

Deafness/hearing loss

Type: Clinical symptom/sign; exact conductive versus sensorineural composition in the original family was not recovered.
Onset: Presumed congenital or early developmental from the syndrome definition, but individual ages were unavailable.
Severity/course: Unknown and probably variable; stability versus progression has not been established.
Suggested HPO: Hearing impairment (HP:0000365); use Sensorineural hearing impairment (HP:0000407) or Conductive hearing impairment (HP:0000405) only after audiologic confirmation.
Functional effect: Potential impairment of speech/language development, education, communication, balance, and social participation. No syndrome-specific PROM, EQ-5D, or SF-36 study exists.

Broader JAG1 disease can produce conductive and sensorineural loss through middle-ear ossicular abnormalities or sensory/neural deficits. This is supportive context, not proof of the hearing-loss subtype in the original family. (haan2024jag1repressesnotch pages 1-3)

Congenital heart defects

Type: Congenital structural malformation.
Onset: Prenatal/congenital.
Severity/course: Lesion-dependent and variably expressed; exact defects in each original relative were not recovered.
Suggested HPO: Congenital heart defect (HP:0001627). Add lesion-specific terms after echocardiography; in broader JAG1 disease, pulmonary stenosis/peripheral pulmonary artery stenosis and tetralogy of Fallot are prominent.
Functional effect: May cause cyanosis, exercise intolerance, arrhythmia, heart failure, need for catheterization or surgery, and premature mortality depending on lesion severity.

In broader ALGS cohorts, cardiac involvement has been reported in 90–97%, pulmonic stenosis in approximately 67%, and tetralogy of Fallot in 7–16%; these values must not be assigned to MONDO:0060713 because they come from classic ALGS cohorts. (chitayat2016alagillesyndromeclinical pages 2-4)

Posterior embryotoxon/anterior-segment anomaly

Type: Ophthalmic clinical sign—an anteriorly displaced/prominent Schwalbe line observed by slit-lamp examination.
Onset/course: Congenital and generally stable.
Severity: Often visually asymptomatic by itself; associated anterior-segment dysgenesis or glaucoma determines visual impact.
Suggested HPO: Posterior embryotoxon (HP:0000627); consider Anterior segment dysgenesis (HP:0004328) and Glaucoma (HP:0000501) if documented.
Frequency: Unknown in this family. In broader ALGS, posterior embryotoxon is reported in approximately 78–89%, again not a syndrome-specific estimate. (chitayat2016alagillesyndromeclinical pages 2-4)

Liver phenotype

All nine studied p.Cys234Tyr family members had normal liver function, an unusual but important distinction from classic ALGS. Suggested HPO annotation: Absence of cholestasis as a negated phenotype rather than a positive HPO feature. Normal biochemical tests do not necessarily establish normal bile-duct anatomy. (bauer2010jagged1(jag1)mutations pages 9-10)

4. Genetic and molecular information

Gene: JAG1; HGNC-approved symbol JAG1; protein Jagged-1, a membrane-bound canonical Notch ligand.
Variant: p.Cys234Tyr, heterozygous, germline, missense, first EGF-like repeat.
Classification: The segregation and functional evidence strongly support pathogenicity, although a current ClinVar assertion and ACMG evidence-code set were not directly recovered.
Population frequency: Not available in the retrieved evidence. Contemporary curation should query gnomAD using verified transcript/genomic coordinates; absence should not be asserted from protein nomenclature alone.
Functional class: Loss of function through defective processing/trafficking and inability to initiate Notch signaling—effectively haploinsufficiency rather than gain of function or dominant negative action. (bauer2010jagged1(jag1)mutations pages 9-10, bauer2010jagged1(jag1)mutations pages 13-19)
Chromosomal locus: JAG1 lies on chromosome 20p12; no syndrome-defining deletion, translocation, inversion, mosaicism, or aneuploidy was identified in this family.
Modifiers/epigenetics: No validated modifier gene, methylation signature, histone abnormality, or disease-specific chromatin alteration is known.

Broader ALGS datasets support haploinsufficiency: most pathogenic JAG1 alleles are truncating, splice-disrupting, or deletions. A 27-year series compiled 401 probands and 111 affected relatives, with 694 JAG1 and 19 NOTCH2 variants documented; 94.3% of molecularly characterized ALGS cases had JAG1 variants, 2.5% NOTCH2 variants, and 3.2% remained unresolved. These are ALGS statistics, not prevalence figures for this named syndrome. (gilbert2019alagillesyndromemutation pages 1-5, gilbert2019alagillesyndromemutation pages 20-24, gilbert2019alagillesyndromemutation pages 24-27)

5. Environmental and infectious information

No toxin, radiation exposure, pollution, occupation, diet, smoking, alcohol use, exercise pattern, medication, or infectious agent is known to cause or trigger this disorder. The phenotype results from a developmental germline JAG1 defect. Environmental risk reduction therefore cannot prevent the inherited allele, although ordinary prenatal risk avoidance remains appropriate for general fetal health.

6. Mechanism and pathophysiology

Causal chain

Upstream genetic lesion: p.Cys234Tyr removes a conserved cysteine in JAG1’s first EGF-like repeat.
Protein-level defect: Disulfide-dependent folding and post-translational maturation are disrupted; experimental protein was EndoH-sensitive and localized perinuclearly/within the endoplasmic-reticulum pathway rather than at the plasma membrane. (bauer2010jagged1(jag1)mutations pages 13-19, bauer2010jagged1(jag1)mutations pages 9-10)
Signaling defect: Mutant JAG1 is absent from the cell surface and cannot activate adjacent-cell Notch receptors. Only the wild-type allele supplies functional surface ligand, producing JAG1 haploinsufficiency. (bauer2010jagged1(jag1)mutations pages 9-10)
Developmental consequences: Reduced cell–cell Notch signaling perturbs fate specification and morphogenesis in the cardiovascular outflow/pulmonary vasculature, anterior eye segment, and inner/middle ear.
Clinical manifestations: Abnormal cardiac morphogenesis causes congenital heart defects; altered cochlear/ear patterning causes hearing loss; abnormal anterior-segment development produces posterior embryotoxon.

Suggested ontology annotations

GO biological processes: Notch signaling pathway (GO:0007219); cell-fate commitment (GO:0045165); inner-ear development (GO:0048839); heart development (GO:0007507); eye development (GO:0001654); epithelial cell differentiation (GO:0030855).
GO molecular function: Notch receptor binding (GO:0005112).
GO cellular components: plasma membrane (GO:0005886), endoplasmic reticulum (GO:0005783), extracellular region (GO:0005576).
Candidate cell types: cochlear supporting cell, inner hair cell, outer hair cell, vascular endothelial cell, vascular smooth-muscle cell, cardiac neural-crest-derived cell, and anterior-segment mesenchymal/neural-crest-derived cell. Exact CL identifiers should be validated against the current Cell Ontology release.

Recent mechanistic development, 2024

A 2024 Jag1^Ndr/Ndr mouse study combined cochlear morphology with single-cell RNA sequencing. Its abstract reports “a dose-dependent increase in ectopic inner hair cells, and a reduction in outer hair cells” and “global dysregulation of genes associated with inner ear development and deafness.” Cell-resolved analysis implicated lateral supporting cells and outer-hair-cell specification. This is compelling model-organism evidence for how JAG1 insufficiency can cause auditory dysfunction, but it was not performed in p.Cys234Tyr carriers. DOI: https://doi.org/10.1242/dev.202949; published November 2024. (haan2024jag1repressesnotch pages 1-3)

No syndrome-specific human transcriptomic, proteomic, metabolomic, lipidomic, spatial-transcriptomic, organoid, or CRISPR-screen dataset was identified.

7. Anatomical structures affected

Primary organs/systems: heart and great vessels; auditory system; anterior ocular segment.
Possible broader JAG1 surveillance organs: liver/biliary tree, kidneys, skeleton, and cerebral/systemic vasculature, even though liver function was normal in the defining family. (chitayat2016alagillesyndromeclinical pages 1-2, chitayat2016alagillesyndromeclinical pages 2-4)
Suggested UBERON: heart (UBERON:0000948), inner ear (UBERON:0001846), cochlea (UBERON:0001844), eye (UBERON:0000970), cornea (UBERON:0000964), liver (UBERON:0002107), pulmonary artery (UBERON:0002012).
Tissues/cells: cardiac/outflow-tract mesenchyme and vasculature; organ-of-Corti sensory hair cells and supporting cells; corneal limbal/anterior-chamber structures.
Subcellular localization: ER/perinuclear secretory pathway and plasma membrane. The mutant’s failure to reach the latter is central to pathogenesis. (bauer2010jagged1(jag1)mutations pages 13-19, bauer2010jagged1(jag1)mutations pages 9-10)
Lateralization: Hearing loss may be bilateral, but syndrome-specific laterality was not recovered; posterior embryotoxon should be assessed in both eyes.

8. Temporal development and natural history

The structural lesions originate during embryogenesis; the clinical pattern is therefore congenital, chronic, and lifelong. Posterior embryotoxon is generally stable. Cardiac course depends on lesion anatomy and intervention. Hearing may be detected during newborn screening or later in childhood; progression has not been characterized in this family.

There is no validated staging system, remission pattern, progression rate, or longitudinal natural-history cohort. Critical intervention windows are nevertheless clinically evident: prenatal/early postnatal cardiac assessment, newborn/early-childhood audiologic diagnosis to protect language development, and early ophthalmologic evaluation for associated glaucoma.

9. Inheritance and population

Inheritance: Autosomal dominant; familial segregation supports vertical transmission. (bauer2010jagged1(jag1)mutations pages 9-10)
Penetrance: Not quantifiable from available data. The allele segregated with the named phenotype, but individual-feature penetrance was not recovered.
Expressivity: Variable, consistent with familial JAG1 disorders. In broader JAG1-positive families, relatives with the same variant may range from subclinical findings to severe disease, and 47% of mutation-positive relatives in one ALGS analysis did not meet classic criteria. (bauer2010jagged1(jag1)mutations pages 9-10, chitayat2016alagillesyndromeclinical pages 2-4)
Anticipation: No evidence.
Germline mosaicism: Not reported; low residual recurrence risk after an apparently de novo variant is a general counseling consideration.
Founder effect, consanguinity, carrier frequency: None established; “carrier” is not clinically neutral in a dominant disorder.
Prevalence/incidence: Unknown. The named phenotype is supported principally by one nine-member pedigree. Broader ALGS is estimated at roughly 1:30,000–1:50,000 live births, but that figure must not be assigned to MONDO:0060713. (chitayat2016alagillesyndromeclinical pages 1-2, gilbert2019alagillesyndromemutation pages 1-5)
Sex/ethnicity/geography: No reliable syndrome-specific distribution or sex ratio exists.

10. Diagnostics

Clinical evaluation

A practical diagnostic work-up should include:

Three-generation pedigree and dysmorphology/medical-genetics examination.
Formal audiology: newborn screen where age-appropriate, diagnostic auditory brainstem response, otoacoustic emissions, and behavioral pure-tone audiometry; tympanometry helps distinguish conductive from sensorineural loss.
Echocardiography with ECG; add cardiac MRI/CT or catheterization according to the identified lesion.
Slit-lamp examination for posterior embryotoxon/anterior-segment dysgenesis; measure intraocular pressure and assess optic nerves.
Baseline liver panel—bilirubin fractions, AST/ALT, GGT, alkaline phosphatase, albumin and coagulation—and clinical assessment for cholestasis, despite normal liver function in the original family.
Renal function/urinalysis and renal ultrasound; vertebral imaging when clinically indicated; consider vascular/neurovascular assessment based on symptoms and broader ALGS practice. Multidisciplinary ALGS care commonly involves cardiology, hepatology, nephrology, and ophthalmology. (chitayat2016alagillesyndromeclinical pages 1-2, chitayat2016alagillesyndromeclinical pages 5-7)

No disease-specific serum protein, metabolite, histologic, or circulating biomarker exists.

Genetic testing

First line: A congenital-heart/hearing-loss/anterior-segment or ALGS panel that includes JAG1 and deletion/duplication analysis. Alternatively, sequence JAG1 directly when the phenotype and family variant are known.
Familial testing: Targeted testing for p.Cys234Tyr after laboratory confirmation of transcript/genomic coordinates.
If negative: JAG1 CNV analysis, NOTCH2, and broader exome/genome testing. In 2023, exome analysis of Axenfeld–Rieger-like cases found pathogenic variants across JAG1, USP9X, CDK13, BCOR, and other regions, supporting broad second-tier testing for overlapping phenotypes. DOI: https://doi.org/10.3390/genes14101948; published October 2023. (reis2023alternativegeneticdiagnoses pages 2-4)
Yield in broader ALGS: Sequencing all JAG1 exons identifies about 85% of variants and CNV analysis approximately another 9%; NOTCH2 testing follows when JAG1 is negative. (gilbert2019alagillesyndromemutation pages 20-24)
WES/WGS: Useful in atypical or panel-negative disease, especially to resolve phenocopies and structural variants. RNA sequencing is investigational for splice effects.
CMA: Appropriate when multiple congenital anomalies/developmental delay suggest a chromosome 20p deletion or another CNV.
Karyotype/FISH: Not routine unless a large rearrangement is suspected.
Mitochondrial and repeat-expansion testing: Not indicated by this phenotype.

Differential diagnosis

Important alternatives include classic Alagille syndrome due to JAG1 or NOTCH2; Axenfeld–Rieger syndrome due to PITX2/FOXC1; CHARGE syndrome; terminal 6p deletion/FOXC1-related disease; BCOR-related ocular syndromes; and other syndromic hearing-loss/congenital-heart disorders. Liver/biliary disease, characteristic pulmonary-artery lesions, butterfly vertebrae and JAG1 findings favor ALGS spectrum; prominent Axenfeld–Rieger anomaly, dental/umbilical findings and PITX2/FOXC1 variants favor classic ARS. The substantial overlap justifies broad molecular testing. (reis2023alternativegeneticdiagnoses pages 2-4, chitayat2016alagillesyndromeclinical pages 1-2)

11. Outcome and prognosis

No syndrome-specific survival rate, life expectancy, mortality rate, disability score, or prognostic biomarker is available. Prognosis should be individualized according to:

congenital-heart lesion type and hemodynamic severity;
degree and timing of hearing loss and access to habilitation;
glaucoma or other sight-threatening anterior-segment disease;
emergence of hepatic, renal, or vascular manifestations.

Normal liver function in all reported relatives may imply a more favorable hepatic course than classic ALGS, but the family size and absence of long-term standardized follow-up preclude a firm prognostic conclusion. In broader ALGS, early mortality is driven mainly by severe cardiac or hepatic disease and later mortality by vascular events. (bauer2010jagged1(jag1)mutations pages 9-10, chitayat2016alagillesyndromeclinical pages 1-2)

Long-term morbidity may include communication disability, educational impact, cardiac exercise limitation, repeated interventions, and visual loss if glaucoma develops. No disease-specific quality-of-life instrument or recovery-rate study was found.

12. Treatment and real-world implementation

There is no disease-modifying or genotype-specific therapy for this named syndrome. Treatment is component-directed:

Heart disease: Pediatric cardiology surveillance; medication for heart failure/arrhythmia where indicated; catheter-based dilation/stenting or surgical repair according to anatomy. Suggested NCIt terms: Cardiac Surgery, Cardiac Catheterization, Angioplasty, Stent Placement.
Hearing loss: Hearing aids for aidable loss; bone-conduction devices for selected conductive/mixed loss; cochlear implantation for severe-to-profound sensorineural loss meeting standard criteria; speech-language and educational support. Suggested NCIt terms: Hearing Aid, Cochlear Implantation, Speech Therapy, Audiologic Evaluation.
Eye disease: Observation for isolated posterior embryotoxon; glaucoma medication, laser, or surgery only when glaucoma/anterior-segment complications occur. Suggested NCIt terms: Ophthalmologic Examination, Glaucoma Therapy, Trabeculectomy.
Genetics: Counseling, cascade testing, and coordinated JAG1/ALGS-spectrum surveillance.

No pharmacogenomic rule, approved targeted drug, gene therapy, cell therapy, antisense/siRNA therapy, or immunotherapy applies. No syndrome-specific interventional ClinicalTrials.gov study was identified. Broader ALGS treatments for cholestasis or liver transplantation are not indicated merely because a patient carries JAG1; they are used only for documented hepatic disease. The reported family had normal liver function. (bauer2010jagged1(jag1)mutations pages 9-10, chitayat2016alagillesyndromeclinical pages 5-7)

13. Prevention

Primary prevention: The inherited developmental disorder cannot be prevented by lifestyle modification, vaccination, or prophylactic medication.
Reproductive prevention/options: Genetic counseling; targeted prenatal diagnosis using chorionic-villus sampling or amniocentesis after the familial genomic variant is verified; and IVF with preimplantation genetic testing for monogenic disease. Variable expressivity must be emphasized because genotype does not predict severity reliably. (chitayat2016alagillesyndromeclinical pages 5-7, gilbert2019alagillesyndromemutation pages 1-5)
Secondary prevention: Cascade testing; fetal echocardiography in an at-risk pregnancy; newborn hearing screening followed by definitive audiology; early echocardiography and slit-lamp examination.
Tertiary prevention: Timely cardiac repair, hearing habilitation during language acquisition, glaucoma monitoring, and surveillance for broader JAG1-related liver, renal, and vascular disease.
Immunization/public-health or infectious prophylaxis: No disease-specific measure.

14. Other species and natural disease

No naturally occurring veterinary disorder specifically equivalent to this human triad was identified, and there is no zoonotic or transmissible component. JAG1/Notch developmental functions are evolutionarily conserved across vertebrates. Relevant taxa include Homo sapiens (NCBI Taxon 9606), Mus musculus (10090), and Danio rerio (7955). Breed-specific VBO annotations, natural animal prevalence, and cross-species transmission are not applicable.

15. Model organisms

Mouse

The principal recent model is the Jag1 Nodder (Jag1^Ndr) mouse. Homozygous mice are viable and show auditory/vestibular deficits, increased ectopic inner hair cells, reduced outer hair cells, and supporting-cell abnormalities. Single-cell RNA sequencing demonstrated cell-type-resolved dysregulation of inner-ear-development and deafness genes. This model is valuable for cochlear patterning and JAG1–Notch signaling but does not carry human p.Cys234Tyr and cannot reproduce the exact family’s penetrance or full cardiac/ocular phenotype. (haan2024jag1repressesnotch pages 1-3)

The 2024 abstract’s key statement is: “Jag1-regulated Notch signaling controls cochlear patterning, affecting inner and outer hair cell specification and hearing in Alagille syndrome.” DOI: https://doi.org/10.1242/dev.202949; November 2024. (haan2024jag1repressesnotch pages 1-3)

Cellular models

Transfected-cell assays of p.Cys234Tyr directly tested maturation, localization, and canonical Notch reporter activity. They showed absent surface expression, defective post-translational processing, and inability to initiate Notch signaling. These assays provide strong variant-level functional evidence but do not model multicellular heart, eye, or cochlear development. DOI: https://doi.org/10.1002/humu.21231; published May 2010; PMID 20437614. (bauer2010jagged1(jag1)mutations pages 9-10, bauer2010jagged1(jag1)mutations pages 13-19)

No p.Cys234Tyr knock-in animal, patient-derived iPSC, organoid, zebrafish model, or human single-cell atlas specific to MONDO:0060713 was identified.

Evidence assessment and knowledge-base cautions

The strongest syndrome-specific evidence consists of dominant familial segregation, the p.Cys234Tyr allele, the defining triad, normal liver function in nine studied relatives, and direct loss-of-function assays. Most quantitative clinical statistics come from broader ALGS cohorts and should be stored only as contextual—not disease-specific—evidence. The retrieved literature did not provide exact per-relative cardiac lesions, hearing subtype/severity, age-specific penetrance, allele frequency, standardized outcomes, or treatment-response data. Recent 2023–2024 research advances diagnosis of overlapping anterior-segment disorders and clarifies cochlear JAG1 biology, but it has not expanded the human case series for this particular MONDO entity. (reis2023alternativegeneticdiagnoses pages 2-4, haan2024jag1repressesnotch pages 1-3, bauer2010jagged1(jag1)mutations pages 9-10)

Key publications

Le Caignec C, et al. Familial deafness, congenital heart defects, and posterior embryotoxon caused by cysteine substitution in the first epidermal-growth-factor-like domain of Jagged 1. American Journal of Human Genetics (2002). PMID 12022040. The title itself records the primary human finding; Open Targets links it directly to MONDO:0060713 and JAG1. (OpenTargets Search: Deafness, congenital heart defects, and posterior embryotoxon)
Bauer RC, et al. Jagged1 (JAG1) mutations in patients with tetralogy of Fallot or pulmonic stenosis. Human Mutation 31:594–601; May 2010. DOI: https://doi.org/10.1002/humu.21231; PMID 20437614. This study supplied the decisive p.Cys234Tyr functional evidence. (bauer2010jagged1(jag1)mutations pages 9-10, bauer2010jagged1(jag1)mutations pages 13-19)
Gilbert MA, et al. Alagille syndrome mutation update. Human Mutation 40:2197–2220; August 2019. DOI: https://doi.org/10.1002/humu.23879. This authoritative aggregation supports JAG1 haploinsufficiency, mutation frequencies, and lack of reliable genotype–phenotype prediction. (gilbert2019alagillesyndromemutation pages 1-5, gilbert2019alagillesyndromemutation pages 20-24, gilbert2019alagillesyndromemutation pages 24-27)
Reis LM, et al. Alternative Genetic Diagnoses in Axenfeld–Rieger Syndrome Spectrum. Genes 14:1948; October 2023. DOI: https://doi.org/10.3390/genes14101948. This supports broad sequencing for overlapping ocular-systemic phenotypes. (reis2023alternativegeneticdiagnoses pages 2-4)
de Haan S, et al. Jag1 represses Notch activation in lateral supporting cells and inhibits an outer hair cell fate in the medial cochlea. Development 151; November 2024. DOI: https://doi.org/10.1242/dev.202949. This is the most recent directly relevant mechanistic study. (haan2024jag1repressesnotch pages 1-3)

References

(OpenTargets Search: Deafness, congenital heart defects, and posterior embryotoxon): Open Targets Query (Deafness, congenital heart defects, and posterior embryotoxon, 1 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(bauer2010jagged1(jag1)mutations pages 9-10): Robert C. Bauer, Ayanna O. Laney, Rosemarie Smith, Jennifer Gerfen, Jennifer J.D. Morrissette, Stacy Woyciechowski, Jennifer Garbarini, Kathleen M. Loomes, Ian D. Krantz, Zsolt Urban, Bruce D. Gelb, Elizabeth Goldmuntz, and Nancy B. Spinner. Jagged1 (jag1) mutations in patients with tetralogy of fallot or pulmonic stenosis. Human Mutation, 31:594-601, May 2010. URL: https://doi.org/10.1002/humu.21231, doi:10.1002/humu.21231. This article has 165 citations and is from a domain leading peer-reviewed journal.
(bauer2010jagged1(jag1)mutations pages 13-19): Robert C. Bauer, Ayanna O. Laney, Rosemarie Smith, Jennifer Gerfen, Jennifer J.D. Morrissette, Stacy Woyciechowski, Jennifer Garbarini, Kathleen M. Loomes, Ian D. Krantz, Zsolt Urban, Bruce D. Gelb, Elizabeth Goldmuntz, and Nancy B. Spinner. Jagged1 (jag1) mutations in patients with tetralogy of fallot or pulmonic stenosis. Human Mutation, 31:594-601, May 2010. URL: https://doi.org/10.1002/humu.21231, doi:10.1002/humu.21231. This article has 165 citations and is from a domain leading peer-reviewed journal.
(chitayat2016alagillesyndromeclinical pages 1-2): David Chitayat, Binita Kamath, and Maha Saleh. Alagille syndrome: clinical perspectives. The Application of Clinical Genetics, Volume 9:75-82, Jun 2016. URL: https://doi.org/10.2147/tacg.s86420, doi:10.2147/tacg.s86420. This article has 178 citations.
(gilbert2019alagillesyndromemutation pages 1-5): Melissa A. Gilbert, Robert C. Bauer, Ramakrishnan Rajagopalan, Christopher M. Grochowski, Grace Chao, Deborah McEldrew, James A. Nassur, Elizabeth B. Rand, Bryan L. Krock, Binita M. Kamath, Ian D. Krantz, David A. Piccoli, Kathleen M. Loomes, and Nancy B. Spinner. Alagille syndrome mutation update: comprehensive overview ofjag1andnotch2mutation frequencies and insight into missense variant classification. Human Mutation, 40:2197-2220, Aug 2019. URL: https://doi.org/10.1002/humu.23879, doi:10.1002/humu.23879. This article has 205 citations and is from a domain leading peer-reviewed journal.
(chitayat2016alagillesyndromeclinical pages 5-7): David Chitayat, Binita Kamath, and Maha Saleh. Alagille syndrome: clinical perspectives. The Application of Clinical Genetics, Volume 9:75-82, Jun 2016. URL: https://doi.org/10.2147/tacg.s86420, doi:10.2147/tacg.s86420. This article has 178 citations.
(chitayat2016alagillesyndromeclinical pages 2-4): David Chitayat, Binita Kamath, and Maha Saleh. Alagille syndrome: clinical perspectives. The Application of Clinical Genetics, Volume 9:75-82, Jun 2016. URL: https://doi.org/10.2147/tacg.s86420, doi:10.2147/tacg.s86420. This article has 178 citations.
(gilbert2019alagillesyndromemutation pages 20-24): Melissa A. Gilbert, Robert C. Bauer, Ramakrishnan Rajagopalan, Christopher M. Grochowski, Grace Chao, Deborah McEldrew, James A. Nassur, Elizabeth B. Rand, Bryan L. Krock, Binita M. Kamath, Ian D. Krantz, David A. Piccoli, Kathleen M. Loomes, and Nancy B. Spinner. Alagille syndrome mutation update: comprehensive overview ofjag1andnotch2mutation frequencies and insight into missense variant classification. Human Mutation, 40:2197-2220, Aug 2019. URL: https://doi.org/10.1002/humu.23879, doi:10.1002/humu.23879. This article has 205 citations and is from a domain leading peer-reviewed journal.
(gilbert2019alagillesyndromemutation pages 24-27): Melissa A. Gilbert, Robert C. Bauer, Ramakrishnan Rajagopalan, Christopher M. Grochowski, Grace Chao, Deborah McEldrew, James A. Nassur, Elizabeth B. Rand, Bryan L. Krock, Binita M. Kamath, Ian D. Krantz, David A. Piccoli, Kathleen M. Loomes, and Nancy B. Spinner. Alagille syndrome mutation update: comprehensive overview ofjag1andnotch2mutation frequencies and insight into missense variant classification. Human Mutation, 40:2197-2220, Aug 2019. URL: https://doi.org/10.1002/humu.23879, doi:10.1002/humu.23879. This article has 205 citations and is from a domain leading peer-reviewed journal.
(reis2023alternativegeneticdiagnoses pages 2-4): Linda M. Reis, David J. Amor, Raad A. Haddad, Catherine B. Nowak, Kim M. Keppler-Noreuil, Smith Ann Chisholm, and Elena V. Semina. Alternative genetic diagnoses in axenfeld–rieger syndrome spectrum. Genes, 14:1948, Oct 2023. URL: https://doi.org/10.3390/genes14101948, doi:10.3390/genes14101948. This article has 14 citations.
(haan2024jag1repressesnotch pages 1-3): Sandra de Haan, Agustin A. Corbat, Christopher R. Cederroth, Lisa G. Autrum, Simona Hankeova, Elizabeth C. Driver, Barbara Canlon, Matthew W. Kelley, and Emma R. Andersson. Jag1 represses notch activation in lateral supporting cells and inhibits an outer hair cell fate in the medial cochlea. Development, Nov 2024. URL: https://doi.org/10.1242/dev.202949, doi:10.1242/dev.202949. This article has 4 citations and is from a domain leading peer-reviewed journal.

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Animal Models

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Research Objectives

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

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12. Treatment

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Research report: Deafness, Congenital Heart Defects, and Posterior Embryotoxon

Executive interpretation

1. Disease information

Definition and identifiers

Relationship to Alagille syndrome

2. Etiology, risk, and protective factors

Causal factor

Risk factors

Protective factors

3. Phenotypes

Deafness/hearing loss

Congenital heart defects

Posterior embryotoxon/anterior-segment anomaly

Liver phenotype

4. Genetic and molecular information

5. Environmental and infectious information

6. Mechanism and pathophysiology

Causal chain

Suggested ontology annotations

Recent mechanistic development, 2024

7. Anatomical structures affected

8. Temporal development and natural history

9. Inheritance and population

10. Diagnostics

Clinical evaluation

Genetic testing

Differential diagnosis

11. Outcome and prognosis

12. Treatment and real-world implementation

13. Prevention

14. Other species and natural disease

15. Model organisms

Mouse

Cellular models

Evidence assessment and knowledge-base cautions

Key publications

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