🏷

Classifications

Harrison's Chapter

Mechanistic Nosology

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Inheritance

1

Autosomal dominant HP:0000006

Houge-Janssens syndrome follows autosomal dominant inheritance. Nearly all pathogenic variants arise de novo as heterozygous missense changes.

Autosomal dominant inheritance Penetrance: COMPLETE

Show evidence (1 reference)

PMID:40555839 SUPPORT Human Clinical

"recurrent pathogenic de novo missense variants in several PP2A subunits, some of which are associated with macrocephaly if congenital, or cancer if somatic."

Overview confirms de novo dominant variants across PP2A subunits.

◆

Subtypes

4

Houge-Janssens syndrome type 1 (PPP2R5D)

Most well-characterized subtype, caused by de novo missense variants in PPP2R5D encoding the B56delta regulatory subunit. Features include macrocephaly, developmental delay, intellectual disability, seizures, ASD, and early-onset parkinsonism. Recurrent variants include E198K and E420K.

Show evidence (2 references)

PMID:40555839 SUPPORT Human Clinical

"dominant pathogenic variants in at least two B subunits (PPP2R5D in HJS type 1 and PPP2R5C in HJS type 4), the major scaffolding subunit (PPP2R1A in HJS type 2) and the major catalytic subunit (PPP2CA in HJS type 3) can cause Houge-Janssens syndrome."

Overview paper defining HJS type 1 as PPP2R5D-related.

PMID:39201832 SUPPORT Human Clinical

"NDDs related to the PPP2R5D gene have recently been defined as Houge-Janssens syndrome 1."

Confirms PPP2R5D as the gene causing HJS type 1.

Houge-Janssens syndrome type 2 (PPP2R1A) MONDO:0014605

Caused by de novo missense variants in PPP2R1A encoding the Aalpha scaffolding subunit. Recurrent hotspots include p.Arg182Trp and p.Arg183Gln in HEAT repeats 5-7. Developmental delay and intellectual disability are universal. Epilepsy occurs in ~51% and structural brain abnormalities in ~83%, with corpus callosum abnormalities and ventriculomegaly most frequent.

Show evidence (2 references)

PMID:41465181 SUPPORT Human Clinical

"We identified 16 studies representing 60 patients with PPP2R1A-related disorders. Twenty-six distinct pathogenic variants were identified; these were predominantly de novo heterozygous missense changes clustering within HEAT repeats 5-7."

Systematic review of 60 PPP2R1A patients defining the clinical spectrum of HJS type 2.

PMID:40781915 SUPPORT Human Clinical

"Houge-Janssens syndrome type 2 (HJS2, OMIM 616362) is a rare neurodevelopmental disorder caused by pathogenic variants in PPP2R1A, typically characterized postnatally by hypotonia, developmental delay, intellectual disability, and distinctive craniofacial features."

Case report confirming HJS2 phenotype including prenatal features.

Houge-Janssens syndrome type 3 (PPP2CA) MONDO:0032697

Caused by de novo missense and loss-of-function variants in PPP2CA encoding the Calpha catalytic subunit.

Show evidence (1 reference)

PMID:40555839 SUPPORT Human Clinical

"dominant pathogenic variants in at least two B subunits (PPP2R5D in HJS type 1 and PPP2R5C in HJS type 4), the major scaffolding subunit (PPP2R1A in HJS type 2) and the major catalytic subunit (PPP2CA in HJS type 3) can cause Houge-Janssens syndrome."

Overview defines HJS type 3 as PPP2CA-related.

Houge-Janssens syndrome type 4 (PPP2R5C) MONDO:0978293

Caused by de novo missense variants in PPP2R5C encoding the B56gamma regulatory subunit. Clinical features are within the HJS spectrum with strongest resemblance to HJS type 1. Average intellectual disability is milder than other subtypes. Head circumferences are above average or macrocephalic. Pathogenic mechanism is dominant-negative on substrate dephosphorylation.

Show evidence (1 reference)

PMID:39978342 SUPPORT Human Clinical

"The clinical features were well within the HJS spectrum with strongest resemblance to HJS type 1, caused by B56delta variants. Common features were neurodevelopmental delay and hypotonia, with a high risk of epilepsy, behavioral problems, and mildly dysmorphic facial features."

Defines HJS type 4 clinical spectrum in 26 individuals with PPP2R5C variants.

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Pathophysiology

4

PP2A subunit mutations

De novo dominant missense variants in PP2A subunit genes (PPP2R5D, PPP2R1A, PPP2CA, PPP2R5C) disrupt the structure or function of the affected subunit. In PPP2R5D, variants such as E198K and E420K cause dominant-negative effects rather than loss of function.

PPP2R5D link PPP2R1A link PPP2CA link PPP2R5C link

Show evidence (2 references)

PMID:40555839 SUPPORT Human Clinical

"Houge-Janssens syndrome (HJS) is caused by protein phosphatase type 2A (PP2A) dysfunction."

Overview paper establishing PP2A dysfunction as the unifying cause of HJS.

PMID:39978342 SUPPORT Human Clinical

"a dominant-negative mechanism on substrate dephosphorylation or general PP2A function is the most likely pathogenic mechanism."

Establishes dominant-negative mechanism in PPP2R5C (HJS type 4), generalizable to other subtypes.

Disrupted PP2A holoenzyme assembly and function

Pathogenic variants impair the assembly of the PP2A heterotrimer (A-B-C complex) or disrupt substrate binding by the regulatory B subunit. In PPP2R5D, most pathogenic missense variants cluster in conserved regions and impair holoenzyme assembly. In PPP2R5C, variants affect substrate binding, C-subunit binding, or both. Catalytic activity of the phosphatase is variably affected.

Protein dephosphorylation link ↓ DECREASED

Show evidence (2 references)

PMID:39201832 SUPPORT Human Clinical

"Except for E420K and T536R, other missense variants impaired holoenzyme assembly."

In vitro experiments demonstrate that most PPP2R5D missense variants disrupt PP2A holoenzyme assembly.

PMID:39978342 SUPPORT Human Clinical

"All variants affected either substrate binding (2/19), C-subunit binding (2/19), or both (15/19)."

Structural analysis showing PPP2R5C variants disrupt substrate or C-subunit binding in the PP2A complex.

Overactivation of growth-promoting kinase pathways

PP2A normally opposes the activity of serine/threonine protein kinases of the PIK3CA/AKT/mTOR and RAS/MAPK pathways. Decreased PP2A activity leads to sustained activation of these growth-promoting pathways, converging on mTORC1/p70S6K/RPS6 signaling. Phosphoproteomic analysis of PPP2R5D variant cells shows RPS6 hyperphosphorylation as a shared signaling alteration, with ERK-dependent mTORC1 activation in both E198K and E420K variants, and additional AKT-mediated mTORC1 activation in the E420K variant.

TOR signaling link ↑ INCREASED MAPK cascade link ↑ INCREASED Ras protein signal transduction link ↑ INCREASED

Show evidence (4 references)

PMID:40555839 SUPPORT Human Clinical

"PP2A oppose the activity of serine/threonine protein kinases, including growth promoting kinases of the PIK3CA/AKT/mTOR and RAS/MAPK pathways. Decreased PP2A activity can thus be growth promoting, as evidenced by recurrent pathogenic de novo missense variants in several PP2A subunits, some of..."

Directly links PP2A dysfunction to overactivation of both PI3K/AKT/mTOR and RAS/MAPK growth kinase pathways.

PMID:37572851 SUPPORT In Vitro

"We observed ribosomal protein S6 (RPS6) hyperphosphorylation as a shared signaling alteration, indicative of increased ribosomal protein S6-kinase activity."

Phosphoproteomics of PPP2R5D E198K and E420K cells shows RPS6 hyperphosphorylation as shared convergent signaling alteration.

PMID:37572851 SUPPORT In Vitro

"our data suggests ERK-dependent activation of mTORC1 in both E198K and E420K variant cells, with additional AKT-mediated mTORC1 activation in the E420K variant."

Demonstrates convergence of both ERK/MAPK and AKT pathways on mTORC1 in PPP2R5D variant cells, explaining why multiple growth pathways are co-activated.

+ 1 more reference

Disrupted neuronal development

Patient-derived iPSC neural progenitors are hyper-proliferative, and cortical glutamatergic neurons show increased neurite outgrowth. RNA-seq reveals disruptions in pathways critical for neuronal development, synaptic signaling, and axon guidance. Importantly, these overgrowth phenotypes are not seen in PPP2R5D-null neurons, confirming dominant-negative rather than loss-of-function effects.

Neural progenitor cell link

Nervous system development link ⚠ ABNORMAL

Show evidence (3 references)

PMID:40340253 SUPPORT In Vitro

"Patient-derived neural progenitors were hyper-proliferative, and glutamatergic neurons differentiated from these cells exhibited increased neurite outgrowth."

iPSC study demonstrating neural progenitor hyperproliferation and neuronal overgrowth in PPP2R5D patients.

PMID:40340253 SUPPORT In Vitro

"RNA sequencing (RNA-seq) of glutamatergic neurons derived from patient lines compared to their isogenic controls revealed disruptions in pathways critical for neuronal development, synaptic signaling, and axon guidance."

Transcriptomic evidence of disrupted neurodevelopmental pathways.

PMID:40340253 SUPPORT In Vitro

"neuronal overgrowth phenotypes were not observed in neurons lacking PPP2R5D, suggesting the disorder does not result from loss of function."

Key finding confirming dominant-negative rather than haploinsufficiency 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

14

Cardiovascular 2

Hemangioma OCCASIONAL Hemangioma (HP:0001028)

Show evidence (1 reference)

PMID:39728742 SUPPORT Human Clinical

"Haemangiomas have never been linked to the syndromic phenotype of the PPP2R5D-associated disorder. The close correlation between the PP2A enzyme and the PI3K/AKT signalling pathway suggests the possible correlation between its dysfunction and activation of haemangiogenesis."

First report linking haemangiomas to PPP2R5D-related disorder, with mechanistic rationale via PI3K/AKT signaling.

Abnormal heart morphology OCCASIONAL Abnormal heart morphology (HP:0001627)

Show evidence (1 reference)

PMID:40781915 SUPPORT Human Clinical

"The most common features were ventriculomegaly (92%), agenesis or dysgenesis of the corpus callosum (50%), and congenital heart defects (42%)."

Congenital heart defects reported in 42% of prenatally detected HJS type 2 cases.

Head and Neck 3

Macrocephaly FREQUENT Macrocephaly (HP:0000256)

Show evidence (3 references)

PMID:40555839 SUPPORT Human Clinical

"Decreased PP2A activity can thus be growth promoting, as evidenced by recurrent pathogenic de novo missense variants in several PP2A subunits, some of which are associated with macrocephaly if congenital, or cancer if somatic."

Links macrocephaly to decreased PP2A activity and growth-promoting signaling.

PMID:41465181 SUPPORT Human Clinical

"macrocephaly in 25.9% (15/58)"

Quantifies macrocephaly at ~26% in HJS type 2.

PMID:39201832 SUPPORT Human Clinical

"the macrocephaly phenotype was related to negatively charged residues involved in substrate recruitment."

Links macrocephaly to specific structural features of PPP2R5D variants affecting substrate recruitment.

Microcephaly OCCASIONAL Microcephaly (HP:0000252)

Show evidence (1 reference)

PMID:41465181 SUPPORT Human Clinical

"Microcephaly was reported in 17.2% (10/58)"

Quantifies microcephaly at ~17% in HJS type 2.

Abnormal facial shape FREQUENT Abnormal facial shape (HP:0001999)

Show evidence (2 references)

PMID:41465181 SUPPORT Human Clinical

"dysmorphic features were present in 53.4% (31/58)"

Systematic review quantifies dysmorphic features at ~53% in HJS type 2 patients.

PMID:39978342 SUPPORT Human Clinical

"Common features were neurodevelopmental delay and hypotonia, with a high risk of epilepsy, behavioral problems, and mildly dysmorphic facial features."

Mildly dysmorphic facial features reported in HJS type 4.

Musculoskeletal 1

Hypotonia VERY_FREQUENT Hypotonia (HP:0001252)

Show evidence (2 references)

PMID:40555839 SUPPORT Human Clinical

"The core features are neurodevelopmental delay, especially concerning language, prolonged hypotonia, high risk of seizures, and behavior problems."

Prolonged hypotonia listed as a core feature.

PMID:39978342 SUPPORT Human Clinical

"Common features were neurodevelopmental delay and hypotonia, with a high risk of epilepsy, behavioral problems, and mildly dysmorphic facial features."

Hypotonia confirmed as common in HJS type 4.

Nervous System 8

Global developmental delay VERY_FREQUENT Global developmental delay (HP:0001263)

Show evidence (2 references)

PMID:40555839 SUPPORT Human Clinical

"The core features are neurodevelopmental delay, especially concerning language, prolonged hypotonia, high risk of seizures, and behavior problems."

Overview defines neurodevelopmental delay as a core feature of HJS.

PMID:41465181 SUPPORT Human Clinical

"Developmental delay and intellectual disability were universally present in all patients for whom data were available (100%, 58/58)."

Systematic review of HJS type 2 showing 100% prevalence of DD/ID.

Delayed speech and language development VERY_FREQUENT Delayed speech and language development (HP:0000750)

Show evidence (1 reference)

PMID:40555839 SUPPORT Human Clinical

"The core features are neurodevelopmental delay, especially concerning language, prolonged hypotonia, high risk of seizures, and behavior problems."

Language delay specifically highlighted as a core feature.

Intellectual disability VERY_FREQUENT Intellectual disability (HP:0001249)

Show evidence (2 references)

PMID:41465181 SUPPORT Human Clinical

"Developmental delay and intellectual disability were universally present in all patients for whom data were available (100%, 58/58)."

Universal in HJS type 2 patients.

PMID:39978342 SUPPORT Human Clinical

"The degree of intellectual disability was, on average, milder than in other HJS types."

HJS type 4 shows milder intellectual disability on average.

Seizures FREQUENT Seizure (HP:0001250)

Show evidence (2 references)

PMID:40555839 SUPPORT Human Clinical

"The core features are neurodevelopmental delay, especially concerning language, prolonged hypotonia, high risk of seizures, and behavior problems."

Seizures listed as a core feature with high risk.

PMID:41465181 SUPPORT Human Clinical

"Epilepsy occurred in 50.9% (29/57)"

Quantifies epilepsy prevalence at ~51% in HJS type 2.

Autistic behavior Autistic behavior (HP:0000729)

Show evidence (1 reference)

PMID:40340253 SUPPORT Human Clinical

"Heterozygous missense variants in PPP2R5D cause Houge-Janssens syndrome 1, a rare NDD characterized by macrocephaly, developmental delay, intellectual disability, seizures, autism spectrum disorder, and early-onset Parkinson disease."

ASD listed as a characteristic feature of HJS type 1.

Abnormal corpus callosum morphology FREQUENT Abnormal corpus callosum morphology (HP:0001273)

Show evidence (2 references)

PMID:41465181 SUPPORT Human Clinical

"structural brain abnormalities in 83.1% (49/59), with corpus callosum abnormalities (40.7%, 24/59) and ventriculomegaly (32.2%, 19/59) being most frequent."

Corpus callosum abnormalities in 41% and ventriculomegaly in 32% of HJS type 2 patients.

PMID:40781915 SUPPORT Human Clinical

"The most common features were ventriculomegaly (92%), agenesis or dysgenesis of the corpus callosum (50%), and congenital heart defects (42%)."

Prenatal review showing corpus callosum abnormalities in 50% of prenatally detected HJS type 2 cases.

Ventriculomegaly FREQUENT Ventriculomegaly (HP:0002119)

Show evidence (2 references)

PMID:41465181 SUPPORT Human Clinical

"structural brain abnormalities in 83.1% (49/59), with corpus callosum abnormalities (40.7%, 24/59) and ventriculomegaly (32.2%, 19/59) being most frequent."

Ventriculomegaly in ~32% of HJS type 2 patients.

PMID:40781915 SUPPORT Human Clinical

"The most common features were ventriculomegaly (92%), agenesis or dysgenesis of the corpus callosum (50%), and congenital heart defects (42%)."

Ventriculomegaly in 92% of prenatally detected HJS type 2 cases.

Parkinsonism Parkinsonism (HP:0001300)

Show evidence (1 reference)

PMID:40340253 SUPPORT Human Clinical

"Heterozygous missense variants in PPP2R5D cause Houge-Janssens syndrome 1, a rare NDD characterized by macrocephaly, developmental delay, intellectual disability, seizures, autism spectrum disorder, and early-onset Parkinson disease."

Early-onset Parkinson disease listed as characteristic of HJS type 1.

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Genetic Associations

4

PPP2R5D (Causative)

Show evidence (2 references)

PMID:40340253 SUPPORT In Vitro

"neuronal overgrowth phenotypes were not observed in neurons lacking PPP2R5D, suggesting the disorder does not result from loss of function."

Confirms dominant-negative rather than loss-of-function mechanism.

PMID:39201832 SUPPORT Human Clinical

"Thirteen new patients carrying twelve PPP2R5D gene variants were detected, including five novel missense variants and one novel frameshift variant."

Expands the variant spectrum for PPP2R5D.

PPP2R1A (Causative)

Show evidence (1 reference)

PMID:41465181 SUPPORT Human Clinical

"Recurrent hotspots included p.Arg182Trp (n = 12) and p.Arg183Gln (n = 5)."

Identifies recurrent hotspot variants in PPP2R1A.

PPP2CA (Causative)

Show evidence (1 reference)

PMID:40555839 SUPPORT Human Clinical

"dominant pathogenic variants in at least two B subunits (PPP2R5D in HJS type 1 and PPP2R5C in HJS type 4), the major scaffolding subunit (PPP2R1A in HJS type 2) and the major catalytic subunit (PPP2CA in HJS type 3) can cause Houge-Janssens syndrome."

Overview defining PPP2CA as causative for HJS type 3.

PPP2R5C (Causative)

Show evidence (1 reference)

PMID:39978342 SUPPORT Human Clinical

"PPP2R5C total loss-of-function variants could be inherited from a non-symptomatic parent. This implies that a dominant-negative mechanism on substrate dephosphorylation or general PP2A function is the most likely pathogenic mechanism."

Key mechanistic insight differentiating dominant-negative from haploinsufficiency.

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Treatments

5

Supportive care

Action: supportive care MAXO:0000950

Management is primarily supportive, focusing on speech therapy, physical therapy, occupational therapy, educational support, and behavioral interventions. No disease-modifying therapy is currently available.

Show evidence (1 reference)

PMID:40555839 SUPPORT Human Clinical

"Hypothetically, small molecules that alleviate substrate blockade by affected B subunits or correct misfolding of affected A subunit, could represent treatment options, but these remain to be found."

Notes that disease-modifying treatments are hypothetical and not yet available, so management remains supportive.

Speech therapy

Action: speech therapy MAXO:0000930

Speech and language therapy to address the prominent language delay.

Show evidence (1 reference)

PMID:40555839 SUPPORT Human Clinical

"The core features are neurodevelopmental delay, especially concerning language, prolonged hypotonia, high risk of seizures, and behavior problems."

Language delay is specifically emphasized, warranting speech therapy.

Genetic counseling

Action: genetic counseling MAXO:0000079

Genetic counseling for families. Most variants are de novo with low recurrence risk, though PPP2R5C loss-of-function variants can be inherited.

Show evidence (1 reference)

PMID:41465181 SUPPORT Human Clinical

"Recognition of recurrent hotspot variants and their phenotype associations facilitates diagnosis, prognosis, and genetic counseling."

Review emphasizes the role of genetic counseling based on variant-specific prognostication.

mTOR pathway inhibition (preclinical)

Action: mTOR pathway inhibition Ontology label: pharmacotherapy MAXO:0000058

Rapamycin (mTORC1 inhibitor) and LY2584702 (p70S6K inhibitor) suppress RPS6 hyperphosphorylation and increased cell size in PPP2R5D variant cells. These findings suggest mTOR pathway modulation as a potential mechanism-based therapeutic approach, though clinical trials have not yet been conducted.

Show evidence (2 references)

PMID:33482199 SUPPORT In Vitro

"Rapamycin reduced cell size and dose-dependently reduced RPS6 phosphorylation in E420K-variant cells, suggesting that inhibition of mTOR1 can suppress both the observed RPS6 hyperphosphorylation and increased cell size."

In vitro evidence that rapamycin reverses molecular phenotypes in PPP2R5D E420K variant cells.

PMID:37572851 SUPPORT In Vitro

"We observed ribosomal protein S6 (RPS6) hyperphosphorylation as a shared signaling alteration, indicative of increased ribosomal protein S6-kinase activity."

Shared RPS6 hyperphosphorylation across PPP2R5D variants provides a pharmacologically targetable biomarker.

Allele-specific antisense oligonucleotides (preclinical)

Action: allele-specific antisense oligonucleotide therapy Ontology label: antisense oligonucleotide inhibitor therapy MAXO:0001593

Allele-specific antisense oligonucleotides (ASOs) targeting the PPP2R5D E198K allele reverse neurite outgrowth defects in patient-derived neurons. This represents a potential precision-medicine approach for the most common HJS type 1 variant.

Show evidence (1 reference)

PMID:40340253 SUPPORT In Vitro

"antisense oligonucleotides (ASOs) were designed to selectively knock down the E198K allele, the most common disease-causing missense variant. The most effective ASOs reversed neurite outgrowth defects in patient-derived neurons."

Demonstrates allele-specific ASO approach reverses neuronal phenotypes in patient iPSC-derived neurons.

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Biochemical Markers

2

RPS6 hyperphosphorylation (Elevated)

Context: Ribosomal protein S6 (RPS6) hyperphosphorylation on S235/236 and S240/244 is a shared signaling alteration in PPP2R5D variant cells, indicating mTORC1/p70S6K pathway overactivation. This phosphorylation signature is pharmacologically reversible with rapamycin or p70S6K inhibitors.

Show evidence (1 reference)

PMID:37572851 SUPPORT In Vitro

"We observed ribosomal protein S6 (RPS6) hyperphosphorylation as a shared signaling alteration, indicative of increased ribosomal protein S6-kinase activity."

Phosphoproteomics identifies RPS6 hyperphosphorylation as a shared molecular signature in PPP2R5D E198K and E420K variant cells.

Constitutively active AKT-mTOR signaling (Elevated)

Context: The PPP2R5D E420K variant leads to constitutively active AKT-mTOR signaling, increased cell size, and uncoordinated cellular growth. Rapamycin reduces both cell size and RPS6 phosphorylation.

Show evidence (1 reference)

PMID:33482199 SUPPORT In Vitro

"Rapamycin reduced cell size and dose-dependently reduced RPS6 phosphorylation in E420K-variant cells, suggesting that inhibition of mTOR1 can suppress both the observed RPS6 hyperphosphorylation and increased cell size."

Demonstrates constitutively active AKT-mTOR signaling in PPP2R5D E420K cells and its pharmacological reversibility.

🔀

Differential Diagnoses

5

Conditions with similar clinical presentations that must be differentiated from Houge-Janssens Syndrome:

Noonan syndrome MONDO:0018997

Overlapping Features RASopathies including Noonan syndrome share overlapping clinical features with HJS due to convergence on the RAS/MAPK signaling pathway, which PP2A normally opposes. Shared features include developmental delay, macrocephaly, seizures, hypotonia, and dysmorphic facial features.

Distinguishing Features

Congenital heart defects (especially pulmonary valve stenosis) are hallmark features of Noonan syndrome but not typical of HJS
Short stature is common in Noonan syndrome but not a core feature of HJS
Noonan syndrome is caused by variants in RAS/MAPK pathway genes (PTPN11, SOS1, RAF1, KRAS, BRAF) rather than PP2A subunit genes
HJS typically presents with more severe language delay relative to overall cognitive level

Show evidence (2 references)

PMID:31250618 SUPPORT Human Clinical

"The frequently seen neurological defects are developmental delay, macrocephaly, seizures, neurocognitive deficits, and structural malformations."

RASopathies share neurodevelopmental features with HJS including DD, macrocephaly, and seizures, because both involve dysregulation of the same downstream kinase pathways.

PMID:40555839 SUPPORT Human Clinical

"PP2A oppose the activity of serine/threonine protein kinases, including growth promoting kinases of the PIK3CA/AKT/mTOR and RAS/MAPK pathways."

PP2A directly opposes RAS/MAPK signaling, explaining the phenotypic overlap between HJS and RASopathies.

Megalencephaly-capillary malformation-polymicrogyria syndrome Not Yet Curated MONDO:0011240

Overlapping Features MCAP syndrome, caused by mosaic gain-of-function PIK3CA variants, shares macrocephaly, neurodevelopmental delay, and brain anomalies with HJS. Both conditions involve overactivation of the PI3K/AKT/mTOR pathway. Alpelisib (PI3K inhibitor) is being evaluated for MCAP, highlighting the shared pathway biology.

Distinguishing Features

Capillary malformations and cutaneous vascular anomalies are characteristic of MCAP but absent in HJS
Polymicrogyria is a hallmark brain finding in MCAP but not typical of HJS
MCAP is caused by somatic mosaic PIK3CA variants rather than germline PP2A subunit variants
Somatic overgrowth with body asymmetry occurs in MCAP but not HJS

Show evidence (1 reference)

PMID:39806603 SUPPORT Human Clinical

"The megalencephaly capillary malformation polymicrogyria (MCAP syndrome) results from mosaic gain-of-function PIK3CA variants. The main clinical features are macrocephaly, somatic overgrowth, neurodevelopmental delay and brain anomalies."

MCAP shares macrocephaly and NDD with HJS through the shared PI3K/AKT/mTOR pathway that PP2A opposes.

PTEN hamartoma tumor syndrome Not Yet Curated MONDO:0017623

Overlapping Features PTEN loss-of-function leads to overactivation of the PI3K/AKT/mTOR pathway, the same pathway that PP2A normally opposes. PTEN hamartoma tumor syndrome (including Cowden and Bannayan-Riley-Ruvalcaba syndromes) shares macrocephaly and autism spectrum features with HJS.

Distinguishing Features

Hamartomatous growths (trichilemmomas, intestinal polyps) are characteristic of PTEN syndromes but absent in HJS
Increased cancer risk (breast, thyroid, endometrial) is a major feature of PTEN syndromes but not of HJS
Macrocephaly in PTEN syndromes is typically more pronounced
PTEN mutations are loss-of-function whereas HJS variants act through dominant-negative mechanisms on PP2A

Show evidence (1 reference)

PMID:34625286 SUPPORT Human Clinical

"we review and discuss phenotypic, genomic, and molecular similarities between ASD and CH, and identify the PTEN-PI3K-mTOR (phosphatase and tensin homolog-phosphoinositide 3-kinase-mammalian target of rapamycin) pathway as a common underlying mechanism"

PTEN acts on the same PI3K-mTOR pathway that PP2A opposes, explaining shared macrocephaly and neurodevelopmental features.

Smith-Kingsmore syndrome Not Yet Curated MONDO:0014716

Overlapping Features Smith-Kingsmore syndrome is caused by heterozygous gain-of-function MTOR variants, directly activating the mTOR kinase that PP2A normally opposes. The clinical overlap with HJS includes macrocephaly/megalencephaly, developmental delay, intellectual disability, and seizures.

Distinguishing Features

Caused by direct gain-of-function MTOR variants rather than PP2A subunit mutations
mTOR inhibitors (rapamycin) are being explored as treatment for SKS but not for HJS
Circadian rhythm and sleep-wake disturbances are prominent in SKS
Small thorax may be present in SKS but is not seen in HJS

Show evidence (1 reference)

PMID:39030910 SUPPORT Human Clinical

"Heterozygous de novo or inherited gain-of-function mutations in the MTOR gene cause Smith-Kingsmore syndrome (SKS). SKS is a rare autosomal dominant condition, and individuals with SKS display macrocephaly/megalencephaly, developmental delay, intellectual disability, and seizures."

SKS shares macrocephaly, DD, ID, and seizures with HJS through the shared mTOR pathway that PP2A opposes.

Angelman syndrome MONDO:0007113

Overlapping Features Angelman syndrome shares severe speech delay, seizures, and behavioral features with HJS, potentially leading to diagnostic confusion before molecular testing. Both conditions present with intellectual disability and movement abnormalities.

Distinguishing Features

Severe absence of speech is characteristic of Angelman syndrome, whereas HJS shows delayed but not absent language
Happy demeanor with frequent laughter is a hallmark of Angelman syndrome
Caused by loss of maternal UBE3A expression on chromosome 15, not PP2A subunit mutations
Microcephaly is common in Angelman syndrome, whereas HJS more often shows macrocephaly
Characteristic EEG pattern in Angelman syndrome

Show evidence (1 reference)

PMID:40555839 SUPPORT Human Clinical

"The core features are neurodevelopmental delay, especially concerning language, prolonged hypotonia, high risk of seizures, and behavior problems."

The combination of prominent language delay, seizures, hypotonia, and behavioral problems in HJS overlaps with Angelman syndrome presentation.

📚

Literature Summaries

2

Disorder ▸

Disorder

Name: Houge-Janssens Syndrome
Category: Mendelian
Existing deep-research providers: falcon
Existing evidence reference count in YAML: 67

Key Pathophysiology Nodes

PP2A subunit mutations
Disrupted PP2A holoenzyme assembly and function
Overactivation of growth-promoting kinase pathways
Disrupted neuronal development
Deep research literature mapping

Citation Inventory (for evidence mapping)

DOI:10.1016/j.jbc.2023.105203
DOI:10.1093/hmg/ddy049
DOI:10.1101/2022.11.02.514882
DOI:10.1212/nxg.0000000000200098
DOI:10.3389/fgene.2023.1225832
DOI:10.3390/biomedicines12051092
DOI:10.3390/brainsci14020179

Falcon ▸

Disease Pathophysiology Research Template

Edison Scientific Literature 25 citations 2026-03-07T18:55:08.930403

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 Pathophysiology Research Template

Target Disease

Disease Name: Houge-Janssens Syndrome
MONDO ID: (if available)
Category: Mendelian

Research Objectives

Please provide a comprehensive research report on the pathophysiology of Houge-Janssens Syndrome. Focus on the molecular and cellular mechanisms underlying disease progression.

Required Information

1. Core Pathophysiology

What are the primary pathophysiological mechanisms?
What molecular pathways are dysregulated?
What cellular processes are affected?

2. Key Molecular Players

Genes/Proteins: Which genes are causally involved or implicated?
Chemical Entities: What metabolites, drugs, or small molecules are relevant?
Cell Types: Which cell types are primarily affected?
Anatomical Locations: Which tissues/organs are involved?

3. Biological Processes (for GO annotation)

What biological processes (GO terms) are disrupted?
Consider: signaling pathways, metabolic processes, cellular responses, transport, etc.

4. Cellular Components

Where in the cell do key processes occur?
Consider: organelles, membrane compartments, extracellular space, etc.

5. Disease Progression

What is the sequence of events from initial trigger to clinical manifestation?
Are there distinct stages or phases?

6. Phenotypic Manifestations

What are the key clinical phenotypes?
How do they relate to the underlying mechanisms?

Citation Requirements

Cite primary literature (PMID preferred) for all mechanistic claims
Prioritize recent reviews and landmark papers
Include direct quotes where possible to support key statements

Output Format

Structure your response as a narrative that could be used to populate a disease knowledge base entry with: - Pathophysiology description - Gene/protein annotations with ontology terms (HGNC, GO) - Phenotype associations (HP terms) - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Evidence items with PMIDs

Houge–Janssens Syndrome (HJS) Pathophysiology Report (PP2A-related neurodevelopmental disorders)

0. Scope, disease definition, and identifiers

Houge–Janssens syndrome (HJS) is a spectrum of Mendelian neurodevelopmental disorders caused by monoallelic pathogenic variants in genes encoding subunits of the serine/threonine phosphatase protein phosphatase 2A (PP2A) holoenzyme, most prominently PPP2R5D (HJS type 1; also termed Jordan syndrome), PPP2R1A (HJS type 2), and PPP2CA (HJS type 3), with emerging expansion to PPP2R5C in the “HJS spectrum.” (janssens2024newinsightsinto pages 1-1, verbinnen2025pathogenicdenovo pages 1-3).

Disease ontology mappings captured in this run: MONDO:0957553 (Houge-Janssens syndrome), MONDO:0014605 (Houge-Janssens syndrome 2; OMIM 616362), MONDO:0032697 (Houge-Janssens syndrome 3). (Derived from Open Targets evidence captured during planning; mechanistic/clinical evidence in texts cited above.)

1. Key concepts and definitions (current understanding)

1.1 PP2A holoenzyme architecture

PP2A functions as a heterotrimeric holoenzyme, built from a catalytic C subunit, a scaffolding A subunit, and a regulatory/substrate-specifying B subunit. Variants in different subunits can converge on impaired holoenzyme assembly, altered catalytic activity, and/or altered substrate recruitment/dephosphorylation specificity (verbinnen2025pathogenicdenovo pages 1-3, lee2025clinicalandmolecular pages 1-2).

1.2 Unifying mechanistic concept: “dephosphorylation network disease”

Across HJS subtypes, the central pathophysiologic hypothesis is that PP2A dysfunction alters serine/threonine dephosphorylation programs, particularly in the developing brain, leading to abnormal growth-signaling, cell-cycle/mitotic control, and neuronal circuit development—manifesting clinically as developmental delay/intellectual disability (DD/ID), hypotonia, epilepsy, and variable head-size abnormalities (macrocephaly/microcephaly) (janssens2024newinsightsinto pages 1-1, lee2025clinicalandmolecular pages 1-2).

2. Core pathophysiology (molecular and cellular mechanisms)

2.1 PPP2R5D (HJS1/Jordan syndrome): dysregulated mTORC1–p70S6K–RPS6 signaling with variant-specific upstream wiring

A major recent mechanistic advance is direct quantitative evidence that PPP2R5D pathogenic variants can drive convergent hyperactivation of mTORC1 output, measured as ribosomal protein S6 (RPS6) hyperphosphorylation.

Shared downstream signature: In engineered heterozygous PPP2R5D E198K and E420K cell lines, Smolen et al. report: “We observed ribosomal protein S6 (RPS6) hyperphosphorylation as a shared signaling alteration” (J Biol Chem; 2023-09; https://doi.org/10.1016/j.jbc.2023.105154) (smolen2023quantitativeproteomicsand pages 1-3). The same work reports increased phosphorylation of RPS6 on S235/236 and S240/244 in both variant backgrounds (smolen2023quantitativeproteomicsand pages 11-13).

Variant-specific upstream wiring: The same study concludes ERK-dependent activation of mTORC1 occurs in both E198K and E420K, with additional AKT-mediated mTORC1 activation in E420K (smolen2023quantitativeproteomicsand pages 1-3). Mechanistically, E420K is linked to increased phosphorylation of TSC2 at AKT sites S1130/S1132, consistent with AKT-mediated relief of TSC1/2 inhibition over Rheb–mTORC1 (smolen2023quantitativeproteomicsand pages 11-13).

Quantitative scale of signaling disruption: In Smolen et al., the phosphoproteome is more extensively rewired in E420K than E198K: ~6% of phosphopeptides vs ~2.1% changed by ≥2-fold (smolen2023quantitativeproteomicsand pages 11-13). In the bioRxiv version, the same magnitudes are reported as ~6.1% and 2.1% (2023-03; https://doi.org/10.1101/2023.03.27.534397) (smolen2023quantitativeproteomicsanda pages 13-16).

2.2 PPP2R5D (HJS1): structural autoinhibition and cell-cycle/mitotic defects as a plausible developmental mechanism

Cryo-EM structural work proposes that PP2A–B56δ (PPP2R5D) exists in closed/latent and open/active forms, where long disordered N- and C-terminal arms establish dual autoinhibition of the phosphatase active site and the substrate-binding groove. This extended interface spans >190 Å and contains “nearly all” residues mutated in ID-associated PPP2R5D (bioRxiv; 2023-04; https://doi.org/10.1101/2023.03.09.530109) (wu2023extendedregulationinterface pages 1-5).

Functionally, these PPP2R5D ID mutations are reported to perturb activation phosphorylation rates, and “severe variants” increase mitotic duration and mitotic error rates relative to wild-type (wu2023extendedregulationinterface pages 1-5). This supports a mechanistic bridge from altered PP2A regulation → cell-cycle abnormalities → disrupted neurodevelopment.

2.3 PPP2R5D (HJS1): PP2A holoenzyme assembly defects and substrate recruitment

A 2024 clinical-genetic series that functionally tested variants reports that most PPP2R5D missense variants impair PP2A holoenzyme assembly, while a novel frameshift yields a truncated protein with lower expression (~50 kDa). In vitro, “other missense variants impaired holoenzyme assembly” (except E420K and T536R), supporting a dominant-negative mechanism affecting formation of functional PP2A complexes (Children; 2024-07; https://doi.org/10.3390/children11080897) (jiang2024thirteennewpatients pages 1-2).

2.4 PPP2R5D (HJS1) and vasculature: PI3K/AKT/mTOR links to angiogenesis (emerging phenotype)

A 2024 case report proposes a mechanistic link between PPP2R5D dysfunction and angiogenesis via dysregulated PI3K/AKT and PI3K/AKT/mTOR signaling, motivated by a patient with multiple haemangiomas and a de novo PPP2R5D E198K variant (Pediatric Reports; 2024-12; https://doi.org/10.3390/pediatric16040101) (comisi2024ppp2r5drelatedneurodevelopmentaldisorder pages 2-4). While evidence is currently case-level, it highlights that PP2A–B56δ can intersect with growth/angiogenic pathways.

2.5 PPP2R1A (HJS2): scaffold disruption of PP2A complex formation and brain developmental consequences

PPP2R1A encodes the PP2A Aα scaffolding subunit. Variants cluster in structural HEAT repeats and are summarized as disrupting “holoenzyme stability or subunit binding” (lee2025clinicalandmolecular pages 1-2). A 2024 knock-in mouse model summary reports that Ppp2r1a M180T and R182W mice recapitulate key disease hallmarks, including neurodevelopmental delay and epileptic seizures (R182W), and indicates alterations in neural cell populations and growth-related pathways (verbinnen2024…ofppp2r1a pages 1-1).

2.6 PPP2R5C (HJS spectrum): dominant-negative impairment of substrate and/or C-subunit binding

The latest mechanistic expansion of the HJS spectrum shows PPP2R5C missense variants (B56γ) frequently disrupt substrate binding and/or C-subunit binding, with most tested variants affecting one or both interaction modes. Quantitatively, variant classes were reported as 2/19 substrate-binding only, 2/19 C-binding only, and 15/19 both; catalytic activity was “variably affected,” and the authors argue for dominant-negative disease mechanisms rather than haploinsufficiency (AJHG; 2025-02; https://doi.org/10.1016/j.ajhg.2025.01.021) (verbinnen2025pathogenicdenovo pages 1-3).

3. Recent developments and latest research (prioritize 2023–2024)

3.1 2023 quantitative phosphoproteomics establishes a tractable biomarker axis (RPS6) and pharmacologic reversibility

Smolen et al. (2023-09) provide a quantitative molecular phenotype (RPS6 hyperphosphorylation) shared across PPP2R5D variants, and show it is pharmacologically suppressible using mTORC1 or p70S6K inhibition (smolen2023quantitativeproteomicsand pages 1-3, smolen2023quantitativeproteomicsand pages 11-13).

3.2 2023 cryo-EM and allostery: a mechanistic model for how PPP2R5D missense variants perturb regulation

Wu et al. (2023-04) propose that disease mutations lie within an extended autoinhibitory/allosteric interface, linking variant location to altered activation phosphorylation and downstream mitotic phenotypes (wu2023extendedregulationinterface pages 1-5).

3.3 2024 genotype–phenotype and functional assembly testing for PPP2R5D

Jiang et al. (2024-07) add new patients and provide functional evidence that many variants reduce holoenzyme assembly, helping connect genotype to biochemical defect (jiang2024thirteennewpatients pages 1-2).

3.4 2024 systems-level “expert synthesis” highlights remaining gaps

A 2024 expert perspective emphasizes that while PP2A is a major serine/threonine phosphatase and HJS phenotypes are consistent across subtypes (DD/ID, hypotonia, high epilepsy risk), “precise molecular mechanisms and affected PP2A brain substrates remain to be defined” (as summarized in excerpt) (janssens2024newinsightsinto pages 1-1).

4. Current applications and real-world implementations

4.1 Mechanism-informed candidate therapeutics (preclinical)

Rapamycin (mTORC1 inhibitor) and LY2584702 (p70S6K inhibitor) suppress PPP2R5D-variant–associated RPS6 hyperphosphorylation in cellular models, suggesting a potential route for mechanism-based therapy prioritization and biomarker-driven readouts in translational studies (smolen2023quantitativeproteomicsand pages 1-3, smolen2023quantitativeproteomicsand media 5b277c86).

4.2 Model systems used in practice

Cell models: engineered heterozygous HEK293 variant lines for PPP2R5D E198K/E420K (smolen2023quantitativeproteomicsand pages 1-3, smolen2023quantitativeproteomicsand pages 11-13).
Animal models: Ppp2r1a M180T/R182W knock-in mice for HJS2-like phenotypes (verbinnen2024…ofppp2r1a pages 1-1).

5. Expert opinions and analysis (authoritative perspectives)

1) Convergence with heterogeneity: The PPP2R5D data indicate convergent downstream activation of mTORC1 output (RPS6), while upstream mechanisms differ by allele (AKT-dependent vs AKT-independent), implying that downstream biomarkers may be more generalizable than upstream pathway nodes for stratification (smolen2023quantitativeproteomicsand pages 1-3, smolen2023quantitativeproteomicsand pages 11-13).

2) Allostery and development: The cryo-EM autoinhibition model suggests many PPP2R5D disease residues sit in a regulatory interface, making altered conformational switching and phosphorylation-based activation a plausible upstream lesion that can propagate to cell-cycle errors—consistent with neurodevelopmental phenotypes (wu2023extendedregulationinterface pages 1-5).

3) Unresolved substrate specificity: The 2024 expert synopsis stresses that identifying which PP2A brain substrates are most critical remains a key gap; this has direct implications for therapy design (targeting downstream signaling vs restoring substrate-specific dephosphorylation) (janssens2024newinsightsinto pages 1-1).

6. Relevant statistics and quantitative data (recent)

6.1 PPP2R5D/Jordan syndrome quantitative points

E198K frequency: reported as ~40% of reported cases in the 2023 preprint text (smolen2023quantitativeproteomicsanda pages 1-5).
Phosphoproteome changes: ~6% (E420K) vs ~2.1% (E198K) of phosphopeptides changed ≥2-fold (smolen2023quantitativeproteomicsand pages 11-13).
Incidence estimate for PPP2R5D-related disorder: 2.32–2.87 per 100,000 births, with ~250,000 potentially undiagnosed cases (as estimated in the 2023 bioRxiv excerpt) (wu2023extendedregulationinterface pages 1-5).

6.2 PPP2R1A/HJS2 phenotype frequencies (systematic review)

In a 60-patient systematic review, reported phenotype frequencies include: DD/ID 100% (58/58), epilepsy 50.9% (29/57), structural brain abnormalities 83.1% (49/59), corpus callosum abnormalities 40.7% (24/59), ventriculomegaly 32.2% (19/59), microcephaly 17.2% (10/58), macrocephaly 25.9% (15/58), dysmorphic features 53.4% (31/58) (lee2025clinicalandmolecular pages 1-2).

6.3 PPP2R5D haemangioma case quantitative clinical measures

A 2024 case report provides neonatal glucose values (35→70 mg/dL over 9 hours) and haemangioma sizes (5×4 mm; 14×9 mm), supporting the vascular phenotype description (comisi2024ppp2r5drelatedneurodevelopmentaldisorder pages 2-4).

7. Knowledge-base style annotations

7.1 Causal genes/proteins (HGNC)

PPP2R5D (B56δ regulatory subunit) – HJS1/Jordan syndrome; affects PP2A–B56δ regulation, holoenzyme assembly, and downstream growth signaling (smolen2023quantitativeproteomicsand pages 1-3, wu2023extendedregulationinterface pages 1-5, jiang2024thirteennewpatients pages 1-2).
PPP2R1A (Aα scaffold subunit) – HJS2; affects scaffold-mediated assembly/stability of PP2A holoenzyme (lee2025clinicalandmolecular pages 1-2, verbinnen2024…ofppp2r1a pages 1-1).
PPP2CA (Cα catalytic subunit) – HJS3; catalytic dephosphorylation dysfunction within PP2A system (janssens2024newinsightsinto pages 1-1).
PPP2R5C (B56γ regulatory subunit) – HJS spectrum; dominant-negative disruption of substrate/C-subunit binding (verbinnen2025pathogenicdenovo pages 1-3).

7.2 Biological processes (GO-style; evidence-backed candidates)

Regulation of protein dephosphorylation / serine-threonine phosphatase activity (PP2A-centric) (janssens2024newinsightsinto pages 1-1, verbinnen2025pathogenicdenovo pages 1-3).
mTORC1 signaling, p70S6K activity, RPS6 phosphorylation (smolen2023quantitativeproteomicsand pages 1-3, smolen2023quantitativeproteomicsand pages 11-13).
PI3K/AKT signaling and PI3K/AKT/mTOR axis (comisi2024ppp2r5drelatedneurodevelopmentaldisorder pages 2-4, smolen2023quantitativeproteomicsand pages 11-13).
ERK/MAPK signaling as an input to mTORC1 in PPP2R5D variants (smolen2023quantitativeproteomicsand pages 1-3).
Cell cycle / mitosis (mitotic duration/error rates) and checkpoint signaling (G2/M, DNA damage response) (wu2023extendedregulationinterface pages 1-5).
Angiogenesis / vasculature development (emerging) (comisi2024ppp2r5drelatedneurodevelopmentaldisorder pages 2-4).

7.3 Cellular components (GO-style)

PP2A holoenzyme / heterotrimeric complex (verbinnen2025pathogenicdenovo pages 1-3, smolen2023quantitativeproteomicsanda pages 1-5).
Phosphatase active site and substrate-binding groove in PP2A–B56δ regulatory architecture (wu2023extendedregulationinterface pages 1-5).
Nucleus and cytoplasm (cellular compartments noted for PPP2R5D-related disorder context) (smolen2023quantitativeproteomicsanda pages 25-27).

7.4 Cell types (CL-style; evidence-limited within retrieved texts)

The retrieved 2023–2024 mechanistic sources primarily use mammalian cell lines and infer brain impact from disease phenotypes; explicit CL-level brain cell types are not enumerated in the available excerpts. Evidence does support involvement of neural cell populations (mouse model summary) and vascular cells/vasculature (haemangioma case) (verbinnen2024…ofppp2r1a pages 1-1, comisi2024ppp2r5drelatedneurodevelopmentaldisorder pages 2-4).

7.5 Anatomical locations (UBERON-style)

Brain (global), corpus callosum, ventricles (ventriculomegaly), and neurodevelopmental context (lee2025clinicalandmolecular pages 1-2, janssens2024newinsightsinto pages 1-1).
Vasculature/skin lesions consistent with haemangioma anatomy (comisi2024ppp2r5drelatedneurodevelopmentaldisorder pages 2-4).

7.6 Chemical entities (CHEBI-style) with evidence

Rapamycin (mTORC1 inhibitor): suppresses PPP2R5D variant-associated RPS6 phosphorylation (smolen2023quantitativeproteomicsand pages 1-3, smolen2023quantitativeproteomicsand media 5b277c86).
LY2584702 (p70S6K inhibitor): suppresses PPP2R5D variant-associated RPS6 phosphorylation (smolen2023quantitativeproteomicsand pages 1-3, smolen2023quantitativeproteomicsand media 5b277c86).
Upstream kinases and signaling modulators mentioned mechanistically include PKA, Chk1, ATM, and cAMP (as pathway components rather than therapeutics) (wu2023extendedregulationinterface pages 1-5).

7.7 Phenotypic manifestations (HP-style; evidence-backed)

Core phenotypes across HJS: DD/ID, language delay, hypotonia, epilepsy, macrocephaly and/or microcephaly, brain malformations (corpus callosum abnormalities, ventriculomegaly), behavioral problems/ASD, and in HJS1 an increased risk of parkinsonism; microtia is noted as more specific to HJS2 in the expert summary (janssens2024newinsightsinto pages 1-1, lee2025clinicalandmolecular pages 1-2, smolen2023quantitativeproteomicsanda pages 1-5).

8. Disease progression model (sequence of events)

1) Initiating event: de novo (typically) pathogenic missense variant affecting a PP2A subunit (PPP2R5D/PPP2R1A/PPP2R5C; PPP2CA in HJS3) (janssens2024newinsightsinto pages 1-1, verbinnen2025pathogenicdenovo pages 1-3). 2) Primary molecular defect: PP2A holoenzyme dysregulation via altered autoinhibition/allostery (PPP2R5D), reduced assembly/stability (PPP2R5D/PPP2R1A), or disrupted substrate/C-subunit binding (PPP2R5C) (wu2023extendedregulationinterface pages 1-5, jiang2024thirteennewpatients pages 1-2, lee2025clinicalandmolecular pages 1-2, verbinnen2025pathogenicdenovo pages 1-3). 3) Network-level consequences: altered phosphorylation states across growth-signaling and cell-cycle modules, including mTORC1→p70S6K→RPS6 hyperphosphorylation and mitotic defects (smolen2023quantitativeproteomicsand pages 1-3, wu2023extendedregulationinterface pages 1-5). 4) Cellular/tissue outcomes: abnormal neural development (altered neural cell populations in models), disrupted circuit function and seizure susceptibility; in some contexts, dysregulated angiogenic signaling may contribute to vascular phenotypes (verbinnen2024…ofppp2r1a pages 1-1, comisi2024ppp2r5drelatedneurodevelopmentaldisorder pages 2-4). 5) Clinical manifestation: early-onset developmental delay/ID, hypotonia, epilepsy, structural brain abnormalities and head-size phenotypes, with variable additional features (janssens2024newinsightsinto pages 1-1, lee2025clinicalandmolecular pages 1-2).

9. Evidence table (subtypes, mechanisms, phenotypes)

HJS subtype / gene (HGNC)	Molecular role in PP2A holoenzyme	Key mechanistic findings (2023–2024 prioritized)	Key phenotypes (quantitative where available)	Representative recent references (year; DOI/URL)	Evidence IDs
HJS1 – PPP2R5D (HGNC:9325)	B' (B56δ) regulatory subunit; substrate-specifying/regulatory subunit of PP2A AC core	Patient-like variants (e.g., E198K, E420K) activate mTORC1→p70S6K with RPS6 hyperphosphorylation; pharmacologic suppression by rapamycin or p70S6K inhibitor (variant-specific AKT dependence) (smolen2023quantitativeproteomicsand pages 11-13, smolen2023quantitativeproteomicsand pages 1-3, smolen2023quantitativeproteomicsanda pages 13-16, smolen2023quantitativeproteomicsanda pages 1-5, smolen2023quantitativeproteomicsand media 5b277c86). Structural cryo-EM shows extended autoinhibition/allosteric interface in B56δ with ID mutations altering activation phosphorylation and increasing mitotic duration/errors (wu2023extendedregulationinterface pages 1-5). Multiple missense variants impair PP2A holoenzyme assembly; genotype-phenotype correlations (macrocephaly linked to substrate-binding residues) (jiang2024thirteennewpatients pages 11-12, jiang2024thirteennewpatients pages 1-2). Possible PI3K/AKT dysregulation and novel angiogenesis link (multiple haemangiomas) (comisi2024ppp2r5drelatedneurodevelopmentaldisorder pages 2-4).	Core HJS1 features: developmental delay/ID, hypotonia, seizures, macrocephaly common; variable ASD/behavioral issues; emerging haemangiomas (case-level) (comisi2024ppp2r5drelatedneurodevelopmentaldisorder pages 2-4, jiang2024thirteennewpatients pages 1-2).	Smolen KA et al., J Biol Chem (2023); 10.1016/j.jbc.2023.105154 (smolen2023quantitativeproteomicsand pages 11-13, smolen2023quantitativeproteomicsand pages 1-3). Smolen KA et al., bioRxiv (2023); 10.1101/2023.03.27.534397 (smolen2023quantitativeproteomicsanda pages 13-16, smolen2023quantitativeproteomicsanda pages 1-5). Wu C-G et al., bioRxiv (2023); 10.1101/2023.03.09.530109 (wu2023extendedregulationinterface pages 1-5). Comisi F et al., Pediatr Rep (2024); 10.3390/pediatric16040101 (comisi2024ppp2r5drelatedneurodevelopmentaldisorder pages 2-4). Jiang Y et al., Children (2024); 10.3390/children11080897 (jiang2024thirteennewpatients pages 11-12, jiang2024thirteennewpatients pages 1-2). Figure: RPS6 rescue by rapamycin/LY2584702 (smolen2023quantitativeproteomicsand media 5b277c86).	(smolen2023quantitativeproteomicsand pages 11-13, smolen2023quantitativeproteomicsand pages 1-3, smolen2023quantitativeproteomicsanda pages 13-16, smolen2023quantitativeproteomicsanda pages 1-5, wu2023extendedregulationinterface pages 1-5, comisi2024ppp2r5drelatedneurodevelopmentaldisorder pages 2-4, jiang2024thirteennewpatients pages 11-12, jiang2024thirteennewpatients pages 1-2, smolen2023quantitativeproteomicsand media 5b277c86)
HJS2 – PPP2R1A (HGNC:9322)	Scaffolding Aα subunit; bridges catalytic C subunit with B regulatory subunits	De novo missense variants cluster in HEAT repeats (5–7), disrupt B-subunit binding/holoenzyme stability; genotype–phenotype correlations (HEAT5 p.Arg182Trp/p.Arg183Gln severe) (lee2025clinicalandmolecular pages 1-2, lee2025clinicalandmolecular pages 8-10). Knock-in mice (M180T/R182W) recapitulate neurodevelopmental delay, seizures, behavioral phenotypes (verbinnen2024…ofppp2r1a pages 1-1).	Systematic review (n=60): DD/ID 100% (58/58), structural brain abnorm. 83.1% (49/59) incl. corpus callosum abnorm. 40.7% (24/59), ventriculomegaly 32.2% (19/59), epilepsy 50.9% (29/57), microcephaly 17.2% (10/58), macrocephaly 25.9% (15/58) (lee2025clinicalandmolecular pages 1-2, lee2025clinicalandmolecular pages 8-10).	Lee J et al., Genes (2025); 10.3390/genes16121508 (lee2025clinicalandmolecular pages 1-2, lee2025clinicalandmolecular pages 8-10). Verbinnen I et al., 2024 (mouse model; preprint/unknown journal) (verbinnen2024…ofppp2r1a pages 1-1).	(lee2025clinicalandmolecular pages 1-2, lee2025clinicalandmolecular pages 8-10, verbinnen2024…ofppp2r1a pages 1-1)
HJS3 – PPP2CA (HGNC:9309)	Catalytic Cα subunit; executes Ser/Thr dephosphorylation within PP2A holoenzyme	PP2A catalytic dysfunction within PP2A-related HJS spectrum; overlapping phenotypes with other HJS types; mechanistic axis is impaired dephosphorylation of neuronal substrates; precise substrate/variant landscape still emerging (janssens2024newinsightsinto pages 1-1).	Overlap with HJS spectrum: global DD/ID, hypotonia, epilepsy, structural brain anomalies reported; macro/microcephaly variable (janssens2024newinsightsinto pages 1-1).	Janssens V & Verbinnen I., 2024 (review/insight; unknown journal) (janssens2024newinsightsinto pages 1-1).	(janssens2024newinsightsinto pages 1-1)
HJS spectrum – PPP2R5C (HGNC:9311)	B' (B56γ) regulatory subunit; substrate-specifying/regulatory subunit of PP2A AC core	Dominant-negative missense variants disrupt substrate and/or C-subunit binding; variant classes: impaired substrate binding (2/19), impaired C binding (2/19), both (15/19); catalytic activity variably affected; overall model supports dominant-negative over simple haploinsufficiency (verbinnen2025pathogenicdenovo pages 1-3).	Neurodevelopmental disorder within HJS spectrum: DD/ID (often milder than other HJS), hypotonia, high epilepsy risk, behavioral problems, mild facial dysmorphism; increased head circumference/macrocephaly frequent (verbinnen2025pathogenicdenovo pages 1-3).	Verbinnen I et al., Am J Hum Genet (2025); 10.1016/j.ajhg.2025.01.021 (verbinnen2025pathogenicdenovo pages 1-3).	(verbinnen2025pathogenicdenovo pages 1-3)

Table: Comparative summary of PP2A-subunit Houge-Janssens syndrome subtypes, highlighting molecular roles, 2023–2024 mechanistic advances (e.g., mTORC1→RPS6, cryo-EM autoinhibition, holoenzyme disruption), and key phenotypes with quantitative data where available. Recent references and evidence IDs enable traceability to primary sources.

10. Key figure supporting a translationally actionable mechanism

Smolen et al. show that rapamycin and LY2584702 suppress elevated phospho-RPS6 in PPP2R5D E198K/E420K lines (Figure 7), supporting mTORC1/p70S6K pathway modulation as a mechanism-based intervention concept (smolen2023quantitativeproteomicsand media 5b277c86).

11. Evidence items (PMID-oriented note)

The evidence excerpts available in this run did not consistently include PubMed identifiers (PMIDs). Where available in the retrieved texts, PMIDs should be attached at ingestion time; for this report, DOIs/URLs and publication months/years are included for traceability (e.g., J Biol Chem 2023-09, bioRxiv 2023-03/04, Children 2024-07, Pediatric Reports 2024-12) (smolen2023quantitativeproteomicsand pages 1-3, wu2023extendedregulationinterface pages 1-5, jiang2024thirteennewpatients pages 1-2, comisi2024ppp2r5drelatedneurodevelopmentaldisorder pages 2-4).

References

(janssens2024newinsightsinto pages 1-1): V Janssens and I Verbinnen. New insights into pp2a-related houge-janssens syndrome from model systems and biochemical studies. Unknown journal, 2024.
(verbinnen2025pathogenicdenovo pages 1-3): Iris Verbinnen, Sofia Douzgou Houge, Tzung-Chien Hsieh, Hellen Lesmann, Aron Kirchhoff, David Geneviève, Elise Brimble, Lisa Lenaerts, Dorien Haesen, Rebecca J. Levy, Julien Thevenon, Laurence Faivre, Elysa Marco, Jessica X. Chong, Mike Bamshad, Karynne Patterson, Ghayda M. Mirzaa, Kimberly Foss, William Dobyns, Susan M. White, Lynn Pais, Emily O’Heir, Raphaela Itzikowitz, Kirsten A. Donald, Celia Van der Merwe, Alessandro Mussa, Raffaela Cervini, Elisa Giorgio, Tony Roscioli, Kerith-Rae Dias, Carey-Anne Evans, Natasha J. Brown, Anna Ruiz, Juan Pablo Trujillo Quintero, Rachel Rabin, John Pappas, Hai Yuan, Katherine Lachlan, Simon Thomas, Anita Devlin, Michael Wright, Richard Martin, Joanna Karwowska, Renata Posmyk, Nicolas Chatron, Zornitza Stark, Oliver Heath, Martin Delatycki, Rebecca Buchert, Georg-Christoph Korenke, Keri Ramsey, Vinodh Narayanan, Dorothy K. Grange, Judith L. Weisenberg, Tobias B. Haack, Stephanie Karch, Patricia Kipkemoi, Moses Mangi, Karen G.C.B. Bindels de Heus, Marie-Claire Y. de Wit, Tahsin Stefan Barakat, Derek Lim, Géraldine Van Winckel, Rebecca C. Spillmann, Vandana Shashi, Maureen Jacob, Antonia M. Stehr, Peter Krawitz, Gunnar Douzgos Houge, and Veerle Janssens. Pathogenic de novo variants in ppp2r5c cause a neurodevelopmental disorder within the houge-janssens syndrome spectrum. American journal of human genetics, Feb 2025. URL: https://doi.org/10.1016/j.ajhg.2025.01.021, doi:10.1016/j.ajhg.2025.01.021. This article has 4 citations and is from a highest quality peer-reviewed journal.
(lee2025clinicalandmolecular pages 1-2): Jaewoong Lee, Ari Ahn, Jaeeun Yoo, and Seungok Lee. Clinical and molecular spectrum of ppp2r1a-related neurodevelopmental disorders: a systematic review. Genes, 16:1508, Dec 2025. URL: https://doi.org/10.3390/genes16121508, doi:10.3390/genes16121508. This article has 0 citations.
(smolen2023quantitativeproteomicsand pages 1-3): Kali A. Smolen, Cinta M. Papke, Mark R. Swingle, Alla Musiyenko, Chenchen Li, E. Alan Salter, Ashley D. Camp, Richard E. Honkanen, and Arminja N. Kettenbach. Quantitative proteomics and phosphoproteomics of pp2a-ppp2r5d variants reveal deregulation of rps6 phosphorylation via converging signaling cascades. Journal of Biological Chemistry, 299:105154, Sep 2023. URL: https://doi.org/10.1016/j.jbc.2023.105154, doi:10.1016/j.jbc.2023.105154. This article has 18 citations and is from a domain leading peer-reviewed journal.
(smolen2023quantitativeproteomicsand pages 11-13): Kali A. Smolen, Cinta M. Papke, Mark R. Swingle, Alla Musiyenko, Chenchen Li, E. Alan Salter, Ashley D. Camp, Richard E. Honkanen, and Arminja N. Kettenbach. Quantitative proteomics and phosphoproteomics of pp2a-ppp2r5d variants reveal deregulation of rps6 phosphorylation via converging signaling cascades. Journal of Biological Chemistry, 299:105154, Sep 2023. URL: https://doi.org/10.1016/j.jbc.2023.105154, doi:10.1016/j.jbc.2023.105154. This article has 18 citations and is from a domain leading peer-reviewed journal.
(smolen2023quantitativeproteomicsanda pages 13-16): Katrina Smolen, CM Papke, M. Swingle, A. Musiyenko, Chun Xing Li, A.D. Camp, R. Honkanen, and AN Kettenbach. Quantitative proteomics and phosphoproteomics of ppp2r5d variants reveal deregulation of rps6 phosphorylation through converging signaling cascades. bioRxiv, Mar 2023. URL: https://doi.org/10.1101/2023.03.27.534397, doi:10.1101/2023.03.27.534397. This article has 3 citations.
(wu2023extendedregulationinterface pages 1-5): Cheng-Guo Wu, Vijaya K. Balakrishnan, Pankaj S. Parihar, Kirill Konovolov, Yu-Chia Chen, Ronald A Merrill, Hui Wei, Bridget Carragher, Ramya Sundaresan, Qiang Cui, Brian E. Wadzinski, Mark R. Swingle, Alla Musiyenko, Richard Honkanen, Wendy K. Chung, Aussie Suzuki, Stefan Strack, Xuhui Huang, and Yongna Xing. Extended regulation interface coupled to the allosteric network and disease mutations in the pp2a-b56δ holoenzyme. bioRxiv, Apr 2023. URL: https://doi.org/10.1101/2023.03.09.530109, doi:10.1101/2023.03.09.530109. This article has 0 citations.
(jiang2024thirteennewpatients pages 1-2): Yinmo Jiang, Bingbing Wu, Xi Zhang, Lin Yang, Sujuan Wang, Huiping Li, Shuizhen Zhou, Yanyan Qian, and Huijun Wang. Thirteen new patients of ppp2r5d gene mutation and the fine profile of genotype–phenotype correlation unraveling the pathogenic mechanism underlying macrocephaly phenotype. Children, 11:897, Jul 2024. URL: https://doi.org/10.3390/children11080897, doi:10.3390/children11080897. This article has 1 citations.
(comisi2024ppp2r5drelatedneurodevelopmentaldisorder pages 2-4): Francesco Comisi, Consolata Soddu, Francesco Lai, Monica Marica, Michela Lorrai, Giancarlo Mancuso, Sabrina Giglio, and Salvatore Savasta. Ppp2r5d-related neurodevelopmental disorder and multiple haemangiomas: a novel phenotypic trait? Pediatric Reports, 16:1200-1206, Dec 2024. URL: https://doi.org/10.3390/pediatric16040101, doi:10.3390/pediatric16040101. This article has 0 citations.
(verbinnen2024…ofppp2r1a pages 1-1): I Verbinnen, L Lenaerts, and Z Callaerts-Végh. … of ppp2r1a m180t and r182w variants in mice recapitulates disease hallmarks of houge-janssens syndrome type 2, a pp2a-related neurodevelopmental disorder. Unknown journal, 2024.
(smolen2023quantitativeproteomicsand media 5b277c86): Kali A. Smolen, Cinta M. Papke, Mark R. Swingle, Alla Musiyenko, Chenchen Li, E. Alan Salter, Ashley D. Camp, Richard E. Honkanen, and Arminja N. Kettenbach. Quantitative proteomics and phosphoproteomics of pp2a-ppp2r5d variants reveal deregulation of rps6 phosphorylation via converging signaling cascades. Journal of Biological Chemistry, 299:105154, Sep 2023. URL: https://doi.org/10.1016/j.jbc.2023.105154, doi:10.1016/j.jbc.2023.105154. This article has 18 citations and is from a domain leading peer-reviewed journal.
(smolen2023quantitativeproteomicsanda pages 1-5): Katrina Smolen, CM Papke, M. Swingle, A. Musiyenko, Chun Xing Li, A.D. Camp, R. Honkanen, and AN Kettenbach. Quantitative proteomics and phosphoproteomics of ppp2r5d variants reveal deregulation of rps6 phosphorylation through converging signaling cascades. bioRxiv, Mar 2023. URL: https://doi.org/10.1101/2023.03.27.534397, doi:10.1101/2023.03.27.534397. This article has 3 citations.
(smolen2023quantitativeproteomicsanda pages 25-27): Katrina Smolen, CM Papke, M. Swingle, A. Musiyenko, Chun Xing Li, A.D. Camp, R. Honkanen, and AN Kettenbach. Quantitative proteomics and phosphoproteomics of ppp2r5d variants reveal deregulation of rps6 phosphorylation through converging signaling cascades. bioRxiv, Mar 2023. URL: https://doi.org/10.1101/2023.03.27.534397, doi:10.1101/2023.03.27.534397. This article has 3 citations.
(jiang2024thirteennewpatients pages 11-12): Yinmo Jiang, Bingbing Wu, Xi Zhang, Lin Yang, Sujuan Wang, Huiping Li, Shuizhen Zhou, Yanyan Qian, and Huijun Wang. Thirteen new patients of ppp2r5d gene mutation and the fine profile of genotype–phenotype correlation unraveling the pathogenic mechanism underlying macrocephaly phenotype. Children, 11:897, Jul 2024. URL: https://doi.org/10.3390/children11080897, doi:10.3390/children11080897. This article has 1 citations.
(lee2025clinicalandmolecular pages 8-10): Jaewoong Lee, Ari Ahn, Jaeeun Yoo, and Seungok Lee. Clinical and molecular spectrum of ppp2r1a-related neurodevelopmental disorders: a systematic review. Genes, 16:1508, Dec 2025. URL: https://doi.org/10.3390/genes16121508, doi:10.3390/genes16121508. This article has 0 citations.

{ }

Source YAML

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name: Houge-Janssens Syndrome
creation_date: "2026-02-15T00:00:00Z"
updated_date: "2026-03-07T19:00:00Z"
category: Mendelian
description: >
  Houge-Janssens syndrome (HJS) is a group of neurodevelopmental disorders caused
  by dysfunction of protein phosphatase type 2A (PP2A). PP2A is a heterotrimeric
  serine/threonine phosphatase composed of a catalytic (C), scaffolding (A), and
  regulatory (B) subunit. PP2A opposes the activity of growth-promoting kinases of
  the
  PIK3CA/AKT/mTOR and RAS/MAPK pathways. Core clinical features include neurodevelopmental
  delay (especially affecting language), prolonged hypotonia, high risk of seizures,
  behavioral problems, and variable head circumference abnormalities. Four subtypes
  are
  recognized based on the affected PP2A subunit gene: HJS type 1 (PPP2R5D), HJS type
  2
  (PPP2R1A), HJS type 3 (PPP2CA), and HJS type 4 (PPP2R5C). Most pathogenic variants
  are de novo heterozygous missense changes acting through dominant-negative mechanisms.
disease_term:
  preferred_term: Houge-Janssens syndrome
  term:
    id: MONDO:0957553
    label: Houge-Janssens syndrome
parents:
- Neurodevelopmental disorder
- PP2A-related disorder
synonyms:
- HJS
- PP2A-related neurodevelopmental disorder
- Jordan's Syndrome
- PPP2R5D-related neurodevelopmental disorder
prevalence:
- population: Global
  notes: >
    Houge-Janssens syndrome is rare. No formal prevalence estimates exist.
    The largest reported cohorts include 60 PPP2R1A patients (HJS type 2)
    and 26 PPP2R5C patients (HJS type 4). HJS type 1 (PPP2R5D) is the
    most commonly reported subtype, with multiple case series totaling
    over 50 patients.
  evidence:
  - reference: PMID:41465181
    reference_title: "Clinical and Molecular Spectrum of PPP2R1A-Related Neurodevelopmental Disorders: A Systematic Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified 16 studies representing 60 patients with PPP2R1A-related
      disorders."
    explanation: Systematic review identified 60 PPP2R1A patients across 16
      studies, indicating rarity.
  - reference: PMID:39978342
    reference_title: "Pathogenic de novo variants in PPP2R5C cause a neurodevelopmental disorder within the Houge-Janssens syndrome spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we describe an additional condition in the HJS spectrum in 26 individuals
      with variants in PPP2R5C"
    explanation: 26 individuals reported for the HJS type 4 subtype.
has_subtypes:
- name: Houge-Janssens syndrome type 1 (PPP2R5D)
  description: >
    Most well-characterized subtype, caused by de novo missense variants in PPP2R5D
    encoding the B56delta regulatory subunit. Features include macrocephaly,
    developmental delay, intellectual disability, seizures, ASD, and early-onset
    parkinsonism. Recurrent variants include E198K and E420K.
  evidence:
  - reference: PMID:40555839
    reference_title: "Houge-Janssens syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "dominant pathogenic variants in at least two B subunits (PPP2R5D in
      HJS type 1 and PPP2R5C in HJS type 4), the major scaffolding subunit (PPP2R1A
      in HJS type 2) and the major catalytic subunit (PPP2CA in HJS type 3) can cause
      Houge-Janssens syndrome."
    explanation: Overview paper defining HJS type 1 as PPP2R5D-related.
  - reference: PMID:39201832
    reference_title: "Thirteen New Patients of PPP2R5D Gene Mutation and the Fine Profile of Genotype-Phenotype Correlation Unraveling the Pathogenic Mechanism Underlying Macrocephaly Phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "NDDs related to the PPP2R5D gene have recently been defined as Houge-Janssens
      syndrome 1."
    explanation: Confirms PPP2R5D as the gene causing HJS type 1.
- name: Houge-Janssens syndrome type 2 (PPP2R1A)
  subtype_term:
    preferred_term: Houge-Janssens syndrome 2
    term:
      id: MONDO:0014605
      label: Houge-Janssens syndrome 2
  description: >
    Caused by de novo missense variants in PPP2R1A encoding the Aalpha scaffolding
    subunit.
    Recurrent hotspots include p.Arg182Trp and p.Arg183Gln in HEAT repeats 5-7.
    Developmental delay and intellectual disability are universal. Epilepsy occurs
    in ~51%
    and structural brain abnormalities in ~83%, with corpus callosum abnormalities
    and
    ventriculomegaly most frequent.
  evidence:
  - reference: PMID:41465181
    reference_title: "Clinical and Molecular Spectrum of PPP2R1A-Related Neurodevelopmental Disorders: A Systematic Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified 16 studies representing 60 patients with PPP2R1A-related
      disorders. Twenty-six distinct pathogenic variants were identified; these were
      predominantly de novo heterozygous missense changes clustering within HEAT repeats
      5-7."
    explanation: Systematic review of 60 PPP2R1A patients defining the clinical
      spectrum of HJS type 2.
  - reference: PMID:40781915
    reference_title: "Prenatal Characterization of Houge-Janssens Syndrome Type 2: A Case Report and Systematic Review of Fetal Phenotypes Associated With PPP2R1A Mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Houge-Janssens syndrome type 2 (HJS2, OMIM 616362) is a rare neurodevelopmental
      disorder caused by pathogenic variants in PPP2R1A, typically characterized postnatally
      by hypotonia, developmental delay, intellectual disability, and distinctive
      craniofacial features."
    explanation: Case report confirming HJS2 phenotype including prenatal
      features.
- name: Houge-Janssens syndrome type 3 (PPP2CA)
  subtype_term:
    preferred_term: Houge-Janssens syndrome 3
    term:
      id: MONDO:0032697
      label: Houge-Janssens syndrome 3
  description: >
    Caused by de novo missense and loss-of-function variants in PPP2CA encoding the
    Calpha catalytic subunit.
  evidence:
  - reference: PMID:40555839
    reference_title: "Houge-Janssens syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "dominant pathogenic variants in at least two B subunits (PPP2R5D in
      HJS type 1 and PPP2R5C in HJS type 4), the major scaffolding subunit (PPP2R1A
      in HJS type 2) and the major catalytic subunit (PPP2CA in HJS type 3) can cause
      Houge-Janssens syndrome."
    explanation: Overview defines HJS type 3 as PPP2CA-related.
- name: Houge-Janssens syndrome type 4 (PPP2R5C)
  subtype_term:
    preferred_term: Houge-Janssens syndrome 4
    term:
      id: MONDO:0978293
      label: Houge-Janssens syndrome 4
  description: >
    Caused by de novo missense variants in PPP2R5C encoding the B56gamma regulatory
    subunit. Clinical features are within the HJS spectrum with strongest resemblance
    to HJS type 1. Average intellectual disability is milder than other subtypes.
    Head circumferences are above average or macrocephalic. Pathogenic mechanism is
    dominant-negative on substrate dephosphorylation.
  evidence:
  - reference: PMID:39978342
    reference_title: "Pathogenic de novo variants in PPP2R5C cause a neurodevelopmental disorder within the Houge-Janssens syndrome spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical features were well within the HJS spectrum with strongest
      resemblance to HJS type 1, caused by B56delta variants. Common features were
      neurodevelopmental delay and hypotonia, with a high risk of epilepsy, behavioral
      problems, and mildly dysmorphic facial features."
    explanation: Defines HJS type 4 clinical spectrum in 26 individuals with
      PPP2R5C variants.
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: COMPLETE
  description: >
    Houge-Janssens syndrome follows autosomal dominant inheritance. Nearly all
    pathogenic variants arise de novo as heterozygous missense changes.
  evidence:
  - reference: PMID:40555839
    reference_title: "Houge-Janssens syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "recurrent pathogenic de novo missense variants in several PP2A subunits,
      some of which are associated with macrocephaly if congenital, or cancer if somatic."
    explanation: Overview confirms de novo dominant variants across PP2A
      subunits.
pathophysiology:
- name: PP2A subunit mutations
  description: >
    De novo dominant missense variants in PP2A subunit genes (PPP2R5D, PPP2R1A,
    PPP2CA, PPP2R5C) disrupt the structure or function of the affected subunit.
    In PPP2R5D, variants such as E198K and E420K cause dominant-negative effects
    rather than loss of function.
  genes:
  - preferred_term: PPP2R5D
    term:
      id: hgnc:9312
      label: PPP2R5D
  - preferred_term: PPP2R1A
    term:
      id: hgnc:9302
      label: PPP2R1A
  - preferred_term: PPP2CA
    term:
      id: hgnc:9299
      label: PPP2CA
  - preferred_term: PPP2R5C
    term:
      id: hgnc:9311
      label: PPP2R5C
  downstream:
  - target: Disrupted PP2A holoenzyme assembly and function
    description: Mutant subunits impair holoenzyme assembly or catalytic
      activity through dominant-negative mechanisms.
    evidence:
    - reference: PMID:39201832
      reference_title: "Thirteen New Patients of PPP2R5D Gene Mutation and the Fine Profile of Genotype-Phenotype Correlation Unraveling the Pathogenic Mechanism Underlying Macrocephaly Phenotype."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Except for E420K and T536R, other missense variants impaired holoenzyme
        assembly."
      explanation: Demonstrates that PP2A subunit mutations lead to disrupted
        holoenzyme assembly.
  evidence:
  - reference: PMID:40555839
    reference_title: "Houge-Janssens syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Houge-Janssens syndrome (HJS) is caused by protein phosphatase type
      2A (PP2A) dysfunction."
    explanation: Overview paper establishing PP2A dysfunction as the unifying
      cause of HJS.
  - reference: PMID:39978342
    reference_title: "Pathogenic de novo variants in PPP2R5C cause a neurodevelopmental disorder within the Houge-Janssens syndrome spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a dominant-negative mechanism on substrate dephosphorylation or general
      PP2A function is the most likely pathogenic mechanism."
    explanation: Establishes dominant-negative mechanism in PPP2R5C (HJS type
      4), generalizable to other subtypes.
- name: Disrupted PP2A holoenzyme assembly and function
  description: >
    Pathogenic variants impair the assembly of the PP2A heterotrimer (A-B-C complex)
    or disrupt substrate binding by the regulatory B subunit. In PPP2R5D, most
    pathogenic missense variants cluster in conserved regions and impair holoenzyme
    assembly. In PPP2R5C, variants affect substrate binding, C-subunit binding, or
    both. Catalytic activity of the phosphatase is variably affected.
  notes: >
    The affected molecular function is protein serine/threonine phosphatase activity
    (GO:0004722). PP2A is the major serine/threonine phosphatase opposing growth
    kinase signaling.
  biological_processes:
  - preferred_term: Protein dephosphorylation
    modifier: DECREASED
    term:
      id: GO:0006470
      label: protein dephosphorylation
  downstream:
  - target: Overactivation of growth-promoting kinase pathways
    description: Reduced PP2A dephosphorylation activity leads to sustained
      kinase signaling.
    evidence:
    - reference: PMID:40555839
      reference_title: "Houge-Janssens syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "PP2A oppose the activity of serine/threonine protein kinases, including
        growth promoting kinases of the PIK3CA/AKT/mTOR and RAS/MAPK pathways. Decreased
        PP2A activity can thus be growth promoting, as evidenced by recurrent pathogenic
        de novo missense variants in several PP2A subunits, some of which are associated
        with macrocephaly if congenital, or cancer if somatic."
      explanation: Links disrupted PP2A function to overactivation of growth
        kinase pathways.
  evidence:
  - reference: PMID:39201832
    reference_title: "Thirteen New Patients of PPP2R5D Gene Mutation and the Fine Profile of Genotype-Phenotype Correlation Unraveling the Pathogenic Mechanism Underlying Macrocephaly Phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Except for E420K and T536R, other missense variants impaired holoenzyme
      assembly."
    explanation: In vitro experiments demonstrate that most PPP2R5D missense
      variants disrupt PP2A holoenzyme assembly.
  - reference: PMID:39978342
    reference_title: "Pathogenic de novo variants in PPP2R5C cause a neurodevelopmental disorder within the Houge-Janssens syndrome spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All variants affected either substrate binding (2/19), C-subunit binding
      (2/19), or both (15/19)."
    explanation: Structural analysis showing PPP2R5C variants disrupt substrate
      or C-subunit binding in the PP2A complex.
- name: Overactivation of growth-promoting kinase pathways
  description: >
    PP2A normally opposes the activity of serine/threonine protein kinases of the
    PIK3CA/AKT/mTOR and RAS/MAPK pathways. Decreased PP2A activity leads to
    sustained activation of these growth-promoting pathways, converging on
    mTORC1/p70S6K/RPS6 signaling. Phosphoproteomic analysis of PPP2R5D variant
    cells shows RPS6 hyperphosphorylation as a shared signaling alteration, with
    ERK-dependent mTORC1 activation in both E198K and E420K variants, and
    additional AKT-mediated mTORC1 activation in the E420K variant.
  biological_processes:
  - preferred_term: TOR signaling
    modifier: INCREASED
    term:
      id: GO:0031929
      label: TOR signaling
  - preferred_term: MAPK cascade
    modifier: INCREASED
    term:
      id: GO:0000165
      label: MAPK cascade
  - preferred_term: Ras protein signal transduction
    modifier: INCREASED
    term:
      id: GO:0007265
      label: Ras protein signal transduction
  downstream:
  - target: Disrupted neuronal development
    description: Overactive growth signaling impairs normal neural progenitor
      proliferation and differentiation.
    evidence:
    - reference: PMID:40340253
      reference_title: "Pathogenic PPP2R5D variants disrupt neuronal development and neurite outgrowth in patient-derived neurons that are reversed by allele-specific knockdown."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Patient-derived neural progenitors were hyper-proliferative, and glutamatergic
        neurons differentiated from these cells exhibited increased neurite outgrowth."
      explanation: Demonstrates that overactive growth signaling from PP2A
        dysfunction leads to neuronal overgrowth.
  evidence:
  - reference: PMID:40555839
    reference_title: "Houge-Janssens syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PP2A oppose the activity of serine/threonine protein kinases, including
      growth promoting kinases of the PIK3CA/AKT/mTOR and RAS/MAPK pathways. Decreased
      PP2A activity can thus be growth promoting, as evidenced by recurrent pathogenic
      de novo missense variants in several PP2A subunits, some of which are associated
      with macrocephaly if congenital, or cancer if somatic."
    explanation: Directly links PP2A dysfunction to overactivation of both
      PI3K/AKT/mTOR and RAS/MAPK growth kinase pathways.
  - reference: PMID:37572851
    reference_title: "Quantitative proteomics and phosphoproteomics of PP2A-PPP2R5D variants reveal deregulation of RPS6 phosphorylation via converging signaling cascades."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We observed ribosomal protein S6 (RPS6) hyperphosphorylation as a shared
      signaling alteration, indicative of increased ribosomal protein S6-kinase activity."
    explanation: Phosphoproteomics of PPP2R5D E198K and E420K cells shows RPS6
      hyperphosphorylation as shared convergent signaling alteration.
  - reference: PMID:37572851
    reference_title: "Quantitative proteomics and phosphoproteomics of PP2A-PPP2R5D variants reveal deregulation of RPS6 phosphorylation via converging signaling cascades."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "our data suggests ERK-dependent activation of mTORC1 in both E198K and
      E420K variant cells, with additional AKT-mediated mTORC1 activation in the E420K
      variant."
    explanation: Demonstrates convergence of both ERK/MAPK and AKT pathways on
      mTORC1 in PPP2R5D variant cells, explaining why multiple growth pathways
      are co-activated.
  - reference: PMID:39728742
    reference_title: "PPP2R5D-Related Neurodevelopmental Disorder and Multiple Haemangiomas: A Novel Phenotypic Trait?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There is evidence that the PP2A-PPP2R5D complex is involved in regulating
      the phosphatidylinositol 3-kinase (PI3K)/AKT signalling pathway, which is crucial
      for several cellular processes, including the pathogenesis and progression of
      haemangiomas."
    explanation: Documents PP2A-PPP2R5D regulation of PI3K/AKT signaling.
- name: Disrupted neuronal development
  description: >
    Patient-derived iPSC neural progenitors are hyper-proliferative, and cortical
    glutamatergic neurons show increased neurite outgrowth. RNA-seq reveals
    disruptions in pathways critical for neuronal development, synaptic signaling,
    and axon guidance. Importantly, these overgrowth phenotypes are not seen in
    PPP2R5D-null neurons, confirming dominant-negative rather than loss-of-function
    effects.
  cell_types:
  - preferred_term: Neural progenitor cell
    term:
      id: CL:0011020
      label: neural progenitor cell
  biological_processes:
  - preferred_term: Nervous system development
    modifier: ABNORMAL
    term:
      id: GO:0007399
      label: nervous system development
  evidence:
  - reference: PMID:40340253
    reference_title: "Pathogenic PPP2R5D variants disrupt neuronal development and neurite outgrowth in patient-derived neurons that are reversed by allele-specific knockdown."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Patient-derived neural progenitors were hyper-proliferative, and glutamatergic
      neurons differentiated from these cells exhibited increased neurite outgrowth."
    explanation: iPSC study demonstrating neural progenitor hyperproliferation
      and neuronal overgrowth in PPP2R5D patients.
  - reference: PMID:40340253
    reference_title: "Pathogenic PPP2R5D variants disrupt neuronal development and neurite outgrowth in patient-derived neurons that are reversed by allele-specific knockdown."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "RNA sequencing (RNA-seq) of glutamatergic neurons derived from patient
      lines compared to their isogenic controls revealed disruptions in pathways critical
      for neuronal development, synaptic signaling, and axon guidance."
    explanation: Transcriptomic evidence of disrupted neurodevelopmental
      pathways.
  - reference: PMID:40340253
    reference_title: "Pathogenic PPP2R5D variants disrupt neuronal development and neurite outgrowth in patient-derived neurons that are reversed by allele-specific knockdown."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "neuronal overgrowth phenotypes were not observed in neurons lacking
      PPP2R5D, suggesting the disorder does not result from loss of function."
    explanation: Key finding confirming dominant-negative rather than
      haploinsufficiency mechanism.
phenotypes:
- name: Global developmental delay
  description: >
    Universal feature across all HJS subtypes. Neurodevelopmental delay with
    particular impact on language acquisition.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:40555839
    reference_title: "Houge-Janssens syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The core features are neurodevelopmental delay, especially concerning
      language, prolonged hypotonia, high risk of seizures, and behavior problems."
    explanation: Overview defines neurodevelopmental delay as a core feature of
      HJS.
  - reference: PMID:41465181
    reference_title: "Clinical and Molecular Spectrum of PPP2R1A-Related Neurodevelopmental Disorders: A Systematic Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Developmental delay and intellectual disability were universally present
      in all patients for whom data were available (100%, 58/58)."
    explanation: Systematic review of HJS type 2 showing 100% prevalence of
      DD/ID.
- name: Delayed speech and language development
  description: >
    Language delay is particularly prominent across HJS subtypes and is emphasized
    as a core feature.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:40555839
    reference_title: "Houge-Janssens syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The core features are neurodevelopmental delay, especially concerning
      language, prolonged hypotonia, high risk of seizures, and behavior problems."
    explanation: Language delay specifically highlighted as a core feature.
- name: Intellectual disability
  description: >
    Variable severity across subtypes, from mild (HJS type 4) to severe.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:41465181
    reference_title: "Clinical and Molecular Spectrum of PPP2R1A-Related Neurodevelopmental Disorders: A Systematic Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Developmental delay and intellectual disability were universally present
      in all patients for whom data were available (100%, 58/58)."
    explanation: Universal in HJS type 2 patients.
  - reference: PMID:39978342
    reference_title: "Pathogenic de novo variants in PPP2R5C cause a neurodevelopmental disorder within the Houge-Janssens syndrome spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The degree of intellectual disability was, on average, milder than in
      other HJS types."
    explanation: HJS type 4 shows milder intellectual disability on average.
- name: Hypotonia
  description: >
    Prolonged muscular hypotonia is a core feature across all HJS subtypes.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:40555839
    reference_title: "Houge-Janssens syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The core features are neurodevelopmental delay, especially concerning
      language, prolonged hypotonia, high risk of seizures, and behavior problems."
    explanation: Prolonged hypotonia listed as a core feature.
  - reference: PMID:39978342
    reference_title: "Pathogenic de novo variants in PPP2R5C cause a neurodevelopmental disorder within the Houge-Janssens syndrome spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Common features were neurodevelopmental delay and hypotonia, with a
      high risk of epilepsy, behavioral problems, and mildly dysmorphic facial features."
    explanation: Hypotonia confirmed as common in HJS type 4.
- name: Seizures
  description: >
    High risk of seizures is a core feature of HJS. Epilepsy occurs in approximately
    51% of HJS type 2 patients and is common across all subtypes.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Seizures
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:40555839
    reference_title: "Houge-Janssens syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The core features are neurodevelopmental delay, especially concerning
      language, prolonged hypotonia, high risk of seizures, and behavior problems."
    explanation: Seizures listed as a core feature with high risk.
  - reference: PMID:41465181
    reference_title: "Clinical and Molecular Spectrum of PPP2R1A-Related Neurodevelopmental Disorders: A Systematic Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Epilepsy occurred in 50.9% (29/57)"
    explanation: Quantifies epilepsy prevalence at ~51% in HJS type 2.
- name: Macrocephaly
  description: >
    Head circumference above normal is common, particularly in HJS type 1 (PPP2R5D)
    and type 4 (PPP2R5C). In HJS type 2, macrocephaly occurs in about 26% of patients.
    Related to overactivation of growth-promoting kinase pathways.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Macrocephaly
    term:
      id: HP:0000256
      label: Macrocephaly
  evidence:
  - reference: PMID:40555839
    reference_title: "Houge-Janssens syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Decreased PP2A activity can thus be growth promoting, as evidenced by
      recurrent pathogenic de novo missense variants in several PP2A subunits, some
      of which are associated with macrocephaly if congenital, or cancer if somatic."
    explanation: Links macrocephaly to decreased PP2A activity and
      growth-promoting signaling.
  - reference: PMID:41465181
    reference_title: "Clinical and Molecular Spectrum of PPP2R1A-Related Neurodevelopmental Disorders: A Systematic Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "macrocephaly in 25.9% (15/58)"
    explanation: Quantifies macrocephaly at ~26% in HJS type 2.
  - reference: PMID:39201832
    reference_title: "Thirteen New Patients of PPP2R5D Gene Mutation and the Fine Profile of Genotype-Phenotype Correlation Unraveling the Pathogenic Mechanism Underlying Macrocephaly Phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the macrocephaly phenotype was related to negatively charged residues
      involved in substrate recruitment."
    explanation: Links macrocephaly to specific structural features of PPP2R5D
      variants affecting substrate recruitment.
- name: Microcephaly
  description: >
    Microcephaly can also occur in a subset of HJS patients, particularly HJS type
    2,
    reported in approximately 17% of PPP2R1A patients.
  frequency: OCCASIONAL
  subtype: Houge-Janssens syndrome type 2 (PPP2R1A)
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:41465181
    reference_title: "Clinical and Molecular Spectrum of PPP2R1A-Related Neurodevelopmental Disorders: A Systematic Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Microcephaly was reported in 17.2% (10/58)"
    explanation: Quantifies microcephaly at ~17% in HJS type 2.
- name: Autistic behavior
  description: >
    Behavioral problems including autism spectrum disorder features are common.
  phenotype_term:
    preferred_term: Autistic behavior
    term:
      id: HP:0000729
      label: Autistic behavior
  evidence:
  - reference: PMID:40340253
    reference_title: "Pathogenic PPP2R5D variants disrupt neuronal development and neurite outgrowth in patient-derived neurons that are reversed by allele-specific knockdown."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Heterozygous missense variants in PPP2R5D cause Houge-Janssens syndrome
      1, a rare NDD characterized by macrocephaly, developmental delay, intellectual
      disability, seizures, autism spectrum disorder, and early-onset Parkinson disease."
    explanation: ASD listed as a characteristic feature of HJS type 1.
- name: Abnormal corpus callosum morphology
  description: >
    Corpus callosum abnormalities including agenesis, dysgenesis, or hypoplasia
    are a common structural brain finding, particularly in HJS type 2 (~41%).
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Abnormal corpus callosum morphology
    term:
      id: HP:0001273
      label: Abnormal corpus callosum morphology
  evidence:
  - reference: PMID:41465181
    reference_title: "Clinical and Molecular Spectrum of PPP2R1A-Related Neurodevelopmental Disorders: A Systematic Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "structural brain abnormalities in 83.1% (49/59), with corpus callosum
      abnormalities (40.7%, 24/59) and ventriculomegaly (32.2%, 19/59) being most
      frequent."
    explanation: Corpus callosum abnormalities in 41% and ventriculomegaly in
      32% of HJS type 2 patients.
  - reference: PMID:40781915
    reference_title: "Prenatal Characterization of Houge-Janssens Syndrome Type 2: A Case Report and Systematic Review of Fetal Phenotypes Associated With PPP2R1A Mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most common features were ventriculomegaly (92%), agenesis or dysgenesis
      of the corpus callosum (50%), and congenital heart defects (42%)."
    explanation: Prenatal review showing corpus callosum abnormalities in 50% of
      prenatally detected HJS type 2 cases.
- name: Ventriculomegaly
  description: >
    Enlarged cerebral ventricles are a common structural brain finding.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Ventriculomegaly
    term:
      id: HP:0002119
      label: Ventriculomegaly
  evidence:
  - reference: PMID:41465181
    reference_title: "Clinical and Molecular Spectrum of PPP2R1A-Related Neurodevelopmental Disorders: A Systematic Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "structural brain abnormalities in 83.1% (49/59), with corpus callosum
      abnormalities (40.7%, 24/59) and ventriculomegaly (32.2%, 19/59) being most
      frequent."
    explanation: Ventriculomegaly in ~32% of HJS type 2 patients.
  - reference: PMID:40781915
    reference_title: "Prenatal Characterization of Houge-Janssens Syndrome Type 2: A Case Report and Systematic Review of Fetal Phenotypes Associated With PPP2R1A Mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most common features were ventriculomegaly (92%), agenesis or dysgenesis
      of the corpus callosum (50%), and congenital heart defects (42%)."
    explanation: Ventriculomegaly in 92% of prenatally detected HJS type 2
      cases.
- name: Parkinsonism
  description: >
    Early-onset parkinsonism has been reported as a feature of HJS type 1 (PPP2R5D).
  subtype: Houge-Janssens syndrome type 1 (PPP2R5D)
  phenotype_term:
    preferred_term: Parkinsonism
    term:
      id: HP:0001300
      label: Parkinsonism
  evidence:
  - reference: PMID:40340253
    reference_title: "Pathogenic PPP2R5D variants disrupt neuronal development and neurite outgrowth in patient-derived neurons that are reversed by allele-specific knockdown."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Heterozygous missense variants in PPP2R5D cause Houge-Janssens syndrome
      1, a rare NDD characterized by macrocephaly, developmental delay, intellectual
      disability, seizures, autism spectrum disorder, and early-onset Parkinson disease."
    explanation: Early-onset Parkinson disease listed as characteristic of HJS
      type 1.
- name: Abnormal facial shape
  description: >
    Dysmorphic facial features are common across HJS subtypes. Reported in
    approximately 53% of HJS type 2 patients and described as mildly dysmorphic
    in HJS type 4.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Dysmorphic facial features
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:41465181
    reference_title: "Clinical and Molecular Spectrum of PPP2R1A-Related Neurodevelopmental Disorders: A Systematic Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "dysmorphic features were present in 53.4% (31/58)"
    explanation: Systematic review quantifies dysmorphic features at ~53% in
      HJS type 2 patients.
  - reference: PMID:39978342
    reference_title: "Pathogenic de novo variants in PPP2R5C cause a neurodevelopmental disorder within the Houge-Janssens syndrome spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Common features were neurodevelopmental delay and hypotonia, with a
      high risk of epilepsy, behavioral problems, and mildly dysmorphic facial features."
    explanation: Mildly dysmorphic facial features reported in HJS type 4.
- name: Hemangioma
  description: >
    Multiple haemangiomas have been reported as a possible novel phenotypic
    trait in HJS type 1, potentially linked to PP2A-PPP2R5D regulation of the
    PI3K/AKT signaling pathway involved in angiogenesis.
  frequency: OCCASIONAL
  subtype: Houge-Janssens syndrome type 1 (PPP2R5D)
  phenotype_term:
    preferred_term: Hemangioma
    term:
      id: HP:0001028
      label: Hemangioma
  evidence:
  - reference: PMID:39728742
    reference_title: "PPP2R5D-Related Neurodevelopmental Disorder and Multiple Haemangiomas: A Novel Phenotypic Trait?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Haemangiomas have never been linked to the syndromic phenotype of
      the PPP2R5D-associated disorder. The close correlation between the PP2A enzyme
      and the PI3K/AKT signalling pathway suggests the possible correlation between
      its dysfunction and activation of haemangiogenesis."
    explanation: First report linking haemangiomas to PPP2R5D-related disorder,
      with mechanistic rationale via PI3K/AKT signaling.
- name: Abnormal heart morphology
  description: >
    Congenital heart defects are reported in a subset of HJS patients, particularly
    detected prenatally in HJS type 2 (approximately 42% of prenatally detected cases).
  frequency: OCCASIONAL
  subtype: Houge-Janssens syndrome type 2 (PPP2R1A)
  phenotype_term:
    preferred_term: Congenital heart defect
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  evidence:
  - reference: PMID:40781915
    reference_title: "Prenatal Characterization of Houge-Janssens Syndrome Type 2: A Case Report and Systematic Review of Fetal Phenotypes Associated With PPP2R1A Mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most common features were ventriculomegaly (92%), agenesis or dysgenesis
      of the corpus callosum (50%), and congenital heart defects (42%)."
    explanation: Congenital heart defects reported in 42% of prenatally detected
      HJS type 2 cases.
genetic:
- name: PPP2R5D
  gene_term:
    preferred_term: PPP2R5D
    term:
      id: hgnc:9312
      label: PPP2R5D
  association: Causative
  notes: >
    Encodes the B56delta regulatory subunit of PP2A. De novo heterozygous missense
    variants cause HJS type 1. Most pathogenic variants cluster in three conserved
    regions. Dominant-negative mechanism, not loss of function.
  evidence:
  - reference: PMID:40340253
    reference_title: "Pathogenic PPP2R5D variants disrupt neuronal development and neurite outgrowth in patient-derived neurons that are reversed by allele-specific knockdown."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "neuronal overgrowth phenotypes were not observed in neurons lacking
      PPP2R5D, suggesting the disorder does not result from loss of function."
    explanation: Confirms dominant-negative rather than loss-of-function
      mechanism.
  - reference: PMID:39201832
    reference_title: "Thirteen New Patients of PPP2R5D Gene Mutation and the Fine Profile of Genotype-Phenotype Correlation Unraveling the Pathogenic Mechanism Underlying Macrocephaly Phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thirteen new patients carrying twelve PPP2R5D gene variants were detected,
      including five novel missense variants and one novel frameshift variant."
    explanation: Expands the variant spectrum for PPP2R5D.
  variants:
  - name: E198K
    description: >
      Most common disease-causing missense variant in PPP2R5D. Allele-specific
      antisense oligonucleotides targeting this variant can reverse neuronal
      overgrowth phenotypes in patient-derived neurons.
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:40340253
      reference_title: "Pathogenic PPP2R5D variants disrupt neuronal development and neurite outgrowth in patient-derived neurons that are reversed by allele-specific knockdown."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "antisense oligonucleotides (ASOs) were designed to selectively knock
        down the E198K allele, the most common disease-causing missense variant. The
        most effective ASOs reversed neurite outgrowth defects in patient-derived
        neurons."
      explanation: Demonstrates therapeutic potential of allele-specific
        knockdown for the E198K variant.
- name: PPP2R1A
  gene_term:
    preferred_term: PPP2R1A
    term:
      id: hgnc:9302
      label: PPP2R1A
  association: Causative
  notes: >
    Encodes the Aalpha scaffolding subunit of PP2A. De novo heterozygous missense
    variants cause HJS type 2. Recurrent hotspots include p.Arg182Trp and p.Arg183Gln
    in HEAT repeats 5-7.
  evidence:
  - reference: PMID:41465181
    reference_title: "Clinical and Molecular Spectrum of PPP2R1A-Related Neurodevelopmental Disorders: A Systematic Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Recurrent hotspots included p.Arg182Trp (n = 12) and p.Arg183Gln (n
      = 5)."
    explanation: Identifies recurrent hotspot variants in PPP2R1A.
- name: PPP2CA
  gene_term:
    preferred_term: PPP2CA
    term:
      id: hgnc:9299
      label: PPP2CA
  association: Causative
  notes: >
    Encodes the Calpha catalytic subunit of PP2A. De novo missense and
    loss-of-function variants cause HJS type 3.
  evidence:
  - reference: PMID:40555839
    reference_title: "Houge-Janssens syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "dominant pathogenic variants in at least two B subunits (PPP2R5D in
      HJS type 1 and PPP2R5C in HJS type 4), the major scaffolding subunit (PPP2R1A
      in HJS type 2) and the major catalytic subunit (PPP2CA in HJS type 3) can cause
      Houge-Janssens syndrome."
    explanation: Overview defining PPP2CA as causative for HJS type 3.
- name: PPP2R5C
  gene_term:
    preferred_term: PPP2R5C
    term:
      id: hgnc:9311
      label: PPP2R5C
  association: Causative
  notes: >
    Encodes the B56gamma regulatory subunit of PP2A. De novo missense variants
    cause HJS type 4. Total loss-of-function variants can be inherited from
    non-symptomatic parents, implying a dominant-negative mechanism.
  evidence:
  - reference: PMID:39978342
    reference_title: "Pathogenic de novo variants in PPP2R5C cause a neurodevelopmental disorder within the Houge-Janssens syndrome spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PPP2R5C total loss-of-function variants could be inherited from a non-symptomatic
      parent. This implies that a dominant-negative mechanism on substrate dephosphorylation
      or general PP2A function is the most likely pathogenic mechanism."
    explanation: Key mechanistic insight differentiating dominant-negative from
      haploinsufficiency.
biochemical:
- name: RPS6 hyperphosphorylation
  presence: Elevated
  context: >
    Ribosomal protein S6 (RPS6) hyperphosphorylation on S235/236 and S240/244
    is a shared signaling alteration in PPP2R5D variant cells, indicating
    mTORC1/p70S6K pathway overactivation. This phosphorylation signature is
    pharmacologically reversible with rapamycin or p70S6K inhibitors.
  notes: >
    RPS6 hyperphosphorylation represents a potential biomarker for PP2A
    dysfunction and a readout for therapeutic intervention.
  evidence:
  - reference: PMID:37572851
    reference_title: "Quantitative proteomics and phosphoproteomics of PP2A-PPP2R5D variants reveal deregulation of RPS6 phosphorylation via converging signaling cascades."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We observed ribosomal protein S6 (RPS6) hyperphosphorylation as a shared
      signaling alteration, indicative of increased ribosomal protein S6-kinase activity."
    explanation: Phosphoproteomics identifies RPS6 hyperphosphorylation as a
      shared molecular signature in PPP2R5D E198K and E420K variant cells.
- name: Constitutively active AKT-mTOR signaling
  presence: Elevated
  context: >
    The PPP2R5D E420K variant leads to constitutively active AKT-mTOR signaling,
    increased cell size, and uncoordinated cellular growth. Rapamycin reduces
    both cell size and RPS6 phosphorylation.
  evidence:
  - reference: PMID:33482199
    reference_title: "A disorder-related variant (E420K) of a PP2A-regulatory subunit (PPP2R5D) causes constitutively active AKT-mTOR signaling and uncoordinated cell growth."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Rapamycin reduced cell size and dose-dependently reduced RPS6
      phosphorylation in E420K-variant cells, suggesting that inhibition of mTOR1
      can suppress both the observed RPS6 hyperphosphorylation and increased cell size."
    explanation: Demonstrates constitutively active AKT-mTOR signaling in
      PPP2R5D E420K cells and its pharmacological reversibility.
animal_models:
- species: Mouse
  genotype: Ppp2r1a M180T/+ and R182W/+ knock-in
  description: >
    Knock-in mice carrying Ppp2r1a variants M180T and R182W recapitulate key
    disease hallmarks of HJS type 2, including neurodevelopmental delay and
    epileptic seizures. The R182W variant is associated with more severe
    phenotypes. These models provide in vivo evidence for PP2A scaffold
    dysfunction causing neurodevelopmental abnormalities. Data reported by
    Verbinnen, Lenaerts, and Callaerts-Vegh (2024, preprint/conference
    abstract; not yet indexed in PubMed).
  genes:
  - preferred_term: PPP2R1A
    term:
      id: hgnc:9302
      label: PPP2R1A
  associated_phenotypes:
  - Seizures
  - Developmental delay
  - Behavioral abnormalities
treatments:
- name: Supportive care
  description: >
    Management is primarily supportive, focusing on speech therapy, physical therapy,
    occupational therapy, educational support, and behavioral interventions. No
    disease-modifying therapy is currently available.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  evidence:
  - reference: PMID:40555839
    reference_title: "Houge-Janssens syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hypothetically, small molecules that alleviate substrate blockade by
      affected B subunits or correct misfolding of affected A subunit, could represent
      treatment options, but these remain to be found."
    explanation: Notes that disease-modifying treatments are hypothetical and
      not yet available, so management remains supportive.
- name: Speech therapy
  description: >
    Speech and language therapy to address the prominent language delay.
  treatment_term:
    preferred_term: speech therapy
    term:
      id: MAXO:0000930
      label: speech therapy
  evidence:
  - reference: PMID:40555839
    reference_title: "Houge-Janssens syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The core features are neurodevelopmental delay, especially concerning
      language, prolonged hypotonia, high risk of seizures, and behavior problems."
    explanation: Language delay is specifically emphasized, warranting speech
      therapy.
- name: Genetic counseling
  description: >
    Genetic counseling for families. Most variants are de novo with low recurrence
    risk, though PPP2R5C loss-of-function variants can be inherited.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: MAXO:0000079
      label: genetic counseling
  evidence:
  - reference: PMID:41465181
    reference_title: "Clinical and Molecular Spectrum of PPP2R1A-Related Neurodevelopmental Disorders: A Systematic Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Recognition of recurrent hotspot variants and their phenotype associations
      facilitates diagnosis, prognosis, and genetic counseling."
    explanation: Review emphasizes the role of genetic counseling based on
      variant-specific prognostication.
- name: mTOR pathway inhibition (preclinical)
  description: >
    Rapamycin (mTORC1 inhibitor) and LY2584702 (p70S6K inhibitor) suppress
    RPS6 hyperphosphorylation and increased cell size in PPP2R5D variant cells.
    These findings suggest mTOR pathway modulation as a potential
    mechanism-based therapeutic approach, though clinical trials have not yet
    been conducted.
  treatment_term:
    preferred_term: mTOR pathway inhibition
    term:
      id: MAXO:0000058
      label: pharmacotherapy
  role: Investigational
  notes: >
    Inhibition of mTORC1 or p70S6K suppresses the downstream effects of
    constitutively active AKT-mTOR signaling caused by PP2A dysfunction.
  evidence:
  - reference: PMID:33482199
    reference_title: "A disorder-related variant (E420K) of a PP2A-regulatory subunit (PPP2R5D) causes constitutively active AKT-mTOR signaling and uncoordinated cell growth."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Rapamycin reduced cell size and dose-dependently reduced RPS6
      phosphorylation in E420K-variant cells, suggesting that inhibition of mTOR1
      can suppress both the observed RPS6 hyperphosphorylation and increased cell size."
    explanation: In vitro evidence that rapamycin reverses molecular phenotypes
      in PPP2R5D E420K variant cells.
  - reference: PMID:37572851
    reference_title: "Quantitative proteomics and phosphoproteomics of PP2A-PPP2R5D variants reveal deregulation of RPS6 phosphorylation via converging signaling cascades."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We observed ribosomal protein S6 (RPS6) hyperphosphorylation as a shared
      signaling alteration, indicative of increased ribosomal protein S6-kinase activity."
    explanation: Shared RPS6 hyperphosphorylation across PPP2R5D variants
      provides a pharmacologically targetable biomarker.
- name: Allele-specific antisense oligonucleotides (preclinical)
  description: >
    Allele-specific antisense oligonucleotides (ASOs) targeting the PPP2R5D
    E198K allele reverse neurite outgrowth defects in patient-derived neurons.
    This represents a potential precision-medicine approach for the most common
    HJS type 1 variant.
  treatment_term:
    preferred_term: allele-specific antisense oligonucleotide therapy
    term:
      id: MAXO:0001593
      label: antisense oligonucleotide inhibitor therapy
  role: Investigational
  notes: >
    Selective knockdown of the dominant-negative E198K allele while preserving
    wild-type PPP2R5D expression.
  evidence:
  - reference: PMID:40340253
    reference_title: "Pathogenic PPP2R5D variants disrupt neuronal development and neurite outgrowth in patient-derived neurons that are reversed by allele-specific knockdown."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "antisense oligonucleotides (ASOs) were designed to selectively knock
      down the E198K allele, the most common disease-causing missense variant. The
      most effective ASOs reversed neurite outgrowth defects in patient-derived
      neurons."
    explanation: Demonstrates allele-specific ASO approach reverses neuronal
      phenotypes in patient iPSC-derived neurons.
differential_diagnoses:
- name: Noonan syndrome
  disease_term:
    preferred_term: Noonan syndrome
    term:
      id: MONDO:0018997
      label: Noonan syndrome
  description: >
    RASopathies including Noonan syndrome share overlapping clinical features with
    HJS due to convergence on the RAS/MAPK signaling pathway, which PP2A normally
    opposes. Shared features include developmental delay, macrocephaly, seizures,
    hypotonia, and dysmorphic facial features.
  distinguishing_features:
  - Congenital heart defects (especially pulmonary valve stenosis) are hallmark
    features of Noonan syndrome but not typical of HJS
  - Short stature is common in Noonan syndrome but not a core feature of HJS
  - Noonan syndrome is caused by variants in RAS/MAPK pathway genes (PTPN11,
    SOS1, RAF1, KRAS, BRAF) rather than PP2A subunit genes
  - HJS typically presents with more severe language delay relative to overall
    cognitive level
  evidence:
  - reference: PMID:31250618
    reference_title: "Neurodevelopmental Aspects of RASopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The frequently seen neurological defects are developmental delay, macrocephaly,
      seizures, neurocognitive deficits, and structural malformations."
    explanation: RASopathies share neurodevelopmental features with HJS
      including DD, macrocephaly, and seizures, because both involve
      dysregulation of the same downstream kinase pathways.
  - reference: PMID:40555839
    reference_title: "Houge-Janssens syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PP2A oppose the activity of serine/threonine protein kinases, including
      growth promoting kinases of the PIK3CA/AKT/mTOR and RAS/MAPK pathways."
    explanation: PP2A directly opposes RAS/MAPK signaling, explaining the
      phenotypic overlap between HJS and RASopathies.
- name: Megalencephaly-capillary malformation-polymicrogyria syndrome
  disease_term:
    preferred_term: megalencephaly-capillary malformation-polymicrogyria
      syndrome
    term:
      id: MONDO:0011240
      label: megalencephaly-capillary malformation-polymicrogyria syndrome
  description: >
    MCAP syndrome, caused by mosaic gain-of-function PIK3CA variants, shares macrocephaly,
    neurodevelopmental delay, and brain anomalies with HJS. Both conditions involve
    overactivation of the PI3K/AKT/mTOR pathway. Alpelisib (PI3K inhibitor) is being
    evaluated for MCAP, highlighting the shared pathway biology.
  distinguishing_features:
  - Capillary malformations and cutaneous vascular anomalies are characteristic
    of MCAP but absent in HJS
  - Polymicrogyria is a hallmark brain finding in MCAP but not typical of HJS
  - MCAP is caused by somatic mosaic PIK3CA variants rather than germline PP2A
    subunit variants
  - Somatic overgrowth with body asymmetry occurs in MCAP but not HJS
  evidence:
  - reference: PMID:39806603
    reference_title: "A phase II double-blind multicentre, placebo-controlled trial to assess the efficacy and safety of alpelisib (BYL719) in paediatric and adult patients with Megalencephaly-CApillary malformation Polymicrogyria syndrome (MCAP): the SESAM study protocol."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The megalencephaly capillary malformation polymicrogyria (MCAP syndrome)
      results from mosaic gain-of-function PIK3CA variants. The main clinical features
      are macrocephaly, somatic overgrowth, neurodevelopmental delay and brain anomalies."
    explanation: MCAP shares macrocephaly and NDD with HJS through the shared
      PI3K/AKT/mTOR pathway that PP2A opposes.
- name: PTEN hamartoma tumor syndrome
  disease_term:
    preferred_term: PTEN hamartoma tumor syndrome
    term:
      id: MONDO:0017623
      label: PTEN hamartoma tumor syndrome
  description: >
    PTEN loss-of-function leads to overactivation of the PI3K/AKT/mTOR pathway, the
    same pathway that PP2A normally opposes. PTEN hamartoma tumor syndrome (including
    Cowden and Bannayan-Riley-Ruvalcaba syndromes) shares macrocephaly and autism
    spectrum features with HJS.
  distinguishing_features:
  - Hamartomatous growths (trichilemmomas, intestinal polyps) are characteristic
    of PTEN syndromes but absent in HJS
  - Increased cancer risk (breast, thyroid, endometrial) is a major feature of
    PTEN syndromes but not of HJS
  - Macrocephaly in PTEN syndromes is typically more pronounced
  - PTEN mutations are loss-of-function whereas HJS variants act through
    dominant-negative mechanisms on PP2A
  evidence:
  - reference: PMID:34625286
    reference_title: "PTEN mutations in autism spectrum disorder and congenital hydrocephalus: developmental pleiotropy and therapeutic targets."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we review and discuss phenotypic, genomic, and molecular similarities
      between ASD and CH, and identify the PTEN-PI3K-mTOR (phosphatase and tensin
      homolog-phosphoinositide 3-kinase-mammalian target of rapamycin) pathway as
      a common underlying mechanism"
    explanation: PTEN acts on the same PI3K-mTOR pathway that PP2A opposes,
      explaining shared macrocephaly and neurodevelopmental features.
- name: Smith-Kingsmore syndrome
  disease_term:
    preferred_term: macrocephaly-intellectual disability-neurodevelopmental
      disorder-small thorax syndrome
    term:
      id: MONDO:0014716
      label: macrocephaly-intellectual disability-neurodevelopmental
        disorder-small thorax syndrome
  description: >
    Smith-Kingsmore syndrome is caused by heterozygous gain-of-function MTOR variants,
    directly activating the mTOR kinase that PP2A normally opposes. The clinical
    overlap with HJS includes macrocephaly/megalencephaly, developmental delay,
    intellectual disability, and seizures.
  distinguishing_features:
  - Caused by direct gain-of-function MTOR variants rather than PP2A subunit
    mutations
  - mTOR inhibitors (rapamycin) are being explored as treatment for SKS but not
    for HJS
  - Circadian rhythm and sleep-wake disturbances are prominent in SKS
  - Small thorax may be present in SKS but is not seen in HJS
  evidence:
  - reference: PMID:39030910
    reference_title: "Clinical and functional studies of MTOR variants in Smith-Kingsmore syndrome reveal deficits of circadian rhythm and sleep-wake behavior."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Heterozygous de novo or inherited gain-of-function mutations in the
      MTOR gene cause Smith-Kingsmore syndrome (SKS). SKS is a rare autosomal dominant
      condition, and individuals with SKS display macrocephaly/megalencephaly, developmental
      delay, intellectual disability, and seizures."
    explanation: SKS shares macrocephaly, DD, ID, and seizures with HJS through
      the shared mTOR pathway that PP2A opposes.
- name: Angelman syndrome
  disease_term:
    preferred_term: Angelman syndrome
    term:
      id: MONDO:0007113
      label: Angelman syndrome
  description: >
    Angelman syndrome shares severe speech delay, seizures, and behavioral features
    with HJS, potentially leading to diagnostic confusion before molecular testing.
    Both conditions present with intellectual disability and movement abnormalities.
  distinguishing_features:
  - Severe absence of speech is characteristic of Angelman syndrome, whereas HJS
    shows delayed but not absent language
  - Happy demeanor with frequent laughter is a hallmark of Angelman syndrome
  - Caused by loss of maternal UBE3A expression on chromosome 15, not PP2A
    subunit mutations
  - Microcephaly is common in Angelman syndrome, whereas HJS more often shows
    macrocephaly
  - Characteristic EEG pattern in Angelman syndrome
  evidence:
  - reference: PMID:40555839
    reference_title: "Houge-Janssens syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The core features are neurodevelopmental delay, especially concerning
      language, prolonged hypotonia, high risk of seizures, and behavior problems."
    explanation: The combination of prominent language delay, seizures,
      hypotonia, and behavioral problems in HJS overlaps with Angelman syndrome
      presentation.
notes: >
  Houge-Janssens syndrome represents a PP2A-opathy with potential for targeted
  therapies. Allele-specific antisense oligonucleotides targeting PPP2R5D E198K
  have shown reversal of neuronal overgrowth phenotypes in iPSC-derived neurons
  (PMID:40340253). Hypothetical small-molecule approaches to alleviate substrate
  blockade or correct subunit misfolding have been proposed but not yet realized.
  Some PP2A variants are somatically recurrent in cancer, highlighting the dual
  role of PP2A as both a developmental and tumor-suppressive regulator.
classifications:
  harrisons_chapter:
  - classification_value: nervous system disorder
    evidence:
    - reference: PMID:40555839
      reference_title: "Houge-Janssens syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The core features are neurodevelopmental delay, especially concerning
        language, prolonged hypotonia, high risk of seizures, and behavior problems."
      explanation: Core features are neurological, placing HJS under nervous
        system disorders.
  - classification_value: hereditary disease
    evidence:
    - reference: PMID:40555839
      reference_title: "Houge-Janssens syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "recurrent pathogenic de novo missense variants in several PP2A subunits,
        some of which are associated with macrocephaly if congenital, or cancer if
        somatic."
      explanation: HJS is caused by germline de novo genetic variants,
        classifying it as a hereditary disease.
  mechanistic_category:
  - classification_value: RASopathy
    notes: >
      HJS is not a classical RASopathy but is mechanistically related as a
      PP2A-opathy. PP2A directly opposes the RAS/MAPK and PI3K/AKT/mTOR
      kinase pathways, so loss of PP2A function converges on the same
      downstream signaling as RASopathies. No dedicated PP2A-opathy category
      exists in the current mechanistic nosology.
    evidence:
    - reference: PMID:37572851
      reference_title: "Quantitative proteomics and phosphoproteomics of PP2A-PPP2R5D variants reveal deregulation of RPS6 phosphorylation via converging signaling cascades."
      supports: PARTIAL
      evidence_source: IN_VITRO
      snippet: "our data suggests ERK-dependent activation of mTORC1 in both E198K
        and E420K variant cells, with additional AKT-mediated mTORC1 activation in
        the E420K variant."
      explanation: ERK/MAPK pathway activation in PPP2R5D variant cells supports
        classification as RASopathy-adjacent, though the primary defect is in
        PP2A rather than a RAS/MAPK pathway component.
datasets: