Hyperphosphatasia-intellectual disability syndrome

Summary

Hyperphosphatasia-intellectual disability syndrome (MONDO:0016596) is a disease (an umbrella term covering 6 Mondo subtypes) with 7 cohort genes. The dominant Reactome pathway is Synthesis of glycosylphosphatidylinositol (GPI) (5 cohort genes).

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Umbrella term: 6 Mondo subtypes
• Cohort genes: 7
• ClinVar variants: 5
• Phenotypes (HPO): 62

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		24	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

62 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0000316	Hypertelorism	Very frequent (80-99%)
HP:0001250	Seizure	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0003155	Elevated circulating alkaline phosphatase concentration	Very frequent (80-99%)
HP:0006118	Shortening of all distal phalanges of the fingers	Very frequent (80-99%)
HP:0008947	Floppy infant	Very frequent (80-99%)
HP:0000431	Wide nasal bridge	Frequent (30-79%)
HP:0000637	Long palpebral fissure	Frequent (30-79%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001510	Growth delay	Frequent (30-79%)
HP:0001999	Abnormal facial shape	Frequent (30-79%)
HP:0002069	Bilateral tonic-clonic seizure	Frequent (30-79%)
HP:0002714	Downturned corners of mouth	Frequent (30-79%)
HP:0010804	Tented upper lip vermilion	Frequent (30-79%)
HP:0000126	Hydronephrosis	Occasional (5-29%)
HP:0000193	Bifid uvula	Occasional (5-29%)
HP:0000218	High palate	Occasional (5-29%)
HP:0000248	Brachycephaly	Occasional (5-29%)
HP:0000280	Coarse facial features	Occasional (5-29%)
HP:0000286	Epicanthus	Occasional (5-29%)
HP:0000289	Broad philtrum	Occasional (5-29%)
HP:0000303	Mandibular prognathia	Occasional (5-29%)
HP:0000311	Round face	Occasional (5-29%)
HP:0000322	Short philtrum	Occasional (5-29%)
HP:0000347	Micrognathia	Occasional (5-29%)
HP:0000378	Cupped ear	Occasional (5-29%)
HP:0000391	Thickened helices	Occasional (5-29%)
HP:0000414	Bulbous nose	Occasional (5-29%)
HP:0000426	Prominent nasal bridge	Occasional (5-29%)
HP:0000470	Short neck	Occasional (5-29%)
HP:0000540	Hypermetropia	Occasional (5-29%)
HP:0000565	Esotropia	Occasional (5-29%)
HP:0000582	Upslanted palpebral fissure	Occasional (5-29%)
HP:0000594	Shallow anterior chamber	Occasional (5-29%)
HP:0000657	Oculomotor apraxia	Occasional (5-29%)
HP:0000729	Autistic behavior	Occasional (5-29%)
HP:0000767	Pectus excavatum	Occasional (5-29%)
HP:0001009	Telangiectasia	Occasional (5-29%)
HP:0001195	Single umbilical artery	Occasional (5-29%)
HP:0001251	Ataxia	Occasional (5-29%)
HP:0001288	Gait disturbance	Occasional (5-29%)
HP:0001315	Reduced tendon reflexes	Occasional (5-29%)
HP:0001336	Myoclonus	Occasional (5-29%)
HP:0001357	Plagiocephaly	Occasional (5-29%)
HP:0001385	Hip dysplasia	Occasional (5-29%)
HP:0001545	Anteriorly placed anus	Occasional (5-29%)
HP:0001562	Oligohydramnios	Occasional (5-29%)
HP:0001792	Small nail	Occasional (5-29%)
HP:0002251	Aganglionic megacolon	Occasional (5-29%)
HP:0002342	Intellectual disability, moderate	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hyperphosphatasia-intellectual disability syndrome
Mondo ID	MONDO:0016596
OMIM	239300
Orphanet	247262
DOID	DOID:0070431
SNOMED CT	33982008
UMLS	C1855923
MedGen	383800
GARD	0017188
Is cancer (heuristic)	no

Also known as: HPMR · hyperphosphatasia with intellectual disability syndrome · hyperphosphatasia with mental retardation syndrome · Mabry syndrome

Data availability: 5 ClinVar variants · 7 GenCC gene-disease records.

Disease family

An umbrella term covering 6 Mondo subtypes.

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › developmental anomaly of metabolic origin › hyperphosphatasia-intellectual disability syndrome

Related subtypes (56): Neu-Laxova syndrome, inborn mitochondrial metabolism disorder, Ehlers-Danlos syndrome, spondylodysplastic type, MGAT2-congenital disorder of glycosylation, ALDH18A1-related de Barsy syndrome, classic homocystinuria, Larsen-like syndrome, B3GAT3 type, Nijmegen breakage syndrome, Peters plus syndrome, Wiedemann-Rautenstrauch syndrome, 46,XY disorder of sex development due to 5-alpha-reductase 2 deficiency, SHORT syndrome, mucosulfatidosis, CHIME syndrome, creatine transporter deficiency, multiple congenital anomalies-hypotonia-seizures syndrome 2, SLC35A2-congenital disorder of glycosylation, SSR4-congenital disorder of glycosylation, Fabry disease, occipital horn syndrome, Ehlers-Danlos syndrome, musculocontractural type, temtamy preaxial brachydactyly syndrome, B4GALT1-congenital disorder of glycosylation, AICA-ribosiduria, COG7-congenital disorder of glycosylation, permanent neonatal diabetes mellitus-pancreatic and cerebellar agenesis syndrome, Al-Gazali syndrome, COG1-congenital disorder of glycosylation, RFT1-congenital disorder of glycosylation, Nijmegen breakage syndrome-like disorder, multiple congenital anomalies-hypotonia-seizures syndrome 1, multiple congenital anomalies-hypotonia-seizures syndrome 3, autism spectrum disorder - epilepsy - arthrogryposis syndrome, cutis laxa, autosomal dominant 3, SLC39A8-CDG, transketolase deficiency, mucopolysaccharidosis-plus syndrome, Cockayne syndrome, pontocerebellar hypoplasia type 1, mandibuloacral dysplasia, arthrogryposis-renal dysfunction-cholestasis syndrome, CADDS, XYLT1-congenital disorder of glycosylation, hypophosphatasia, sterol biosynthesis disorder, mucolipidosis, mucopolysaccharidosis, oligosaccharidosis, encephalopathy due to sulfite oxidase deficiency, Fanconi anemia, autosomal recessive cutis laxa type 2, Zellweger spectrum disorders, pseudohypoparathyroidism, developmental and epileptic encephalopathy, 77, glycosylphosphatidylinositol biosynthesis defect 15, progressive hypotonia-intellectual disability-facial dysmorphism syndrome due to FYVE-defective RBSN

Subtypes (6): hyperphosphatasia with intellectual disability syndrome 1, hyperphosphatasia with intellectual disability syndrome 3, hyperphosphatasia with intellectual disability syndrome 2, hyperphosphatasia with intellectual disability syndrome 4, hyperphosphatasia with intellectual disability syndrome 5, hyperphosphatasia with intellectual disability syndrome 6

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

5 retrieved; paginated sample, class counts are floors:

2 pathogenic/likely pathogenic, 2 likely pathogenic, 1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
286126	NM_032634.4(PIGO):c.1810dup (p.Arg604fs)	PIGO	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1284	NM_017837.4(PIGV):c.1022C>A (p.Ala341Glu)	PIGV	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3068561	NM_033419.5(PGAP3):c.43dup (p.Ala15fs)	PGAP3	Likely pathogenic	criteria provided, single submitter
666981	NM_032634.4(PIGO):c.2736dup (p.Pro913fs)	PIGO	Likely pathogenic	criteria provided, single submitter
522896	NM_032634.4(PIGO):c.2431C>T (p.Arg811Trp)	PIGO	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 38 · Orphanet: 9 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
PGAP2	Definitive	Autosomal recessive	hyperphosphatasia with intellectual disability syndrome 3	4
PGAP3	Definitive	Autosomal recessive	hyperphosphatasia with intellectual disability syndrome 4	4
PIGO	Definitive	Autosomal recessive	hyperphosphatasia with intellectual disability syndrome 2	5
PIGV	Definitive	Autosomal recessive	hyperphosphatasia with intellectual disability syndrome 1	6
PIGW	Strong	Autosomal recessive	hyperphosphatasia with intellectual disability syndrome 5	7
PIGY	Strong	Autosomal recessive	hyperphosphatasia with intellectual disability syndrome 6	5
PIGL	Supportive	Autosomal recessive	hyperphosphatasia-intellectual disability syndrome	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PIGO	Orphanet:247262	Hyperphosphatasia-intellectual disability syndrome
PGAP3	Orphanet:247262	Hyperphosphatasia-intellectual disability syndrome
PIGV	Orphanet:247262	Hyperphosphatasia-intellectual disability syndrome
PGAP2	Orphanet:247262	Hyperphosphatasia-intellectual disability syndrome
PIGW	Orphanet:247262	Hyperphosphatasia-intellectual disability syndrome
PIGW	Orphanet:83639	Hypercoagulability syndrome due to glycosylphosphatidylinositol deficiency
PIGY	Orphanet:247262	Hyperphosphatasia-intellectual disability syndrome
PIGL	Orphanet:247262	Hyperphosphatasia-intellectual disability syndrome
PIGL	Orphanet:3474	CHIME syndrome

Cohort genes → proteins

7 cohort genes, 7 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	7

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PIGO	HGNC:23215	ENSG00000165282	Q8TEQ8	GPI ethanolamine phosphate transferase 3, catalytic subunit	gencc,clinvar
PGAP3	HGNC:23719	ENSG00000161395	Q96FM1	GPI-specific phospholipase A2-like PGAP3	gencc,clinvar
PIGV	HGNC:26031	ENSG00000060642	Q9NUD9	GPI alpha-1,6-mannosyltransferase 2	gencc,clinvar
PGAP2	HGNC:17893	ENSG00000148985	Q9UHJ9	Acyltransferase PGAP2	gencc
PIGW	HGNC:23213	ENSG00000277161	Q7Z7B1	Glucosaminyl-phosphatidylinositol-acyltransferase PIGW	gencc
PIGY	HGNC:28213	ENSG00000255072	Q3MUY2	Phosphatidylinositol N-acetylglucosaminyltransferase subunit Y	gencc
PIGL	HGNC:8966	ENSG00000108474	Q9Y2B2	N-acetylglucosaminyl-phosphatidylinositol de-N-acetylase	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PIGO	GPI ethanolamine phosphate transferase 3, catalytic subunit	Catalytic subunit of the ethanolamine phosphate transferase 3 complex that transfers an ethanolamine phosphate (EtNP) from a phosphatidylethanolamine (PE) to the 6-OH position of the third alpha-1,2-linked mannose of the a 2-acyl-6-[alpha-…
PGAP3	GPI-specific phospholipase A2-like PGAP3	Involved in the fatty acid remodeling steps of GPI-anchor maturation where the unsaturated acyl chain at sn-2 of inositol phosphate is replaced by a saturated stearoyl chain.
PIGV	GPI alpha-1,6-mannosyltransferase 2	Alpha-1,6-mannosyltransferase that catalyzes the transfer of the second mannose, via an alpha-1,6 bond, from a dolichol-phosphate-mannose (Dol-P-Man) to a 2-acyl-6-(alpha-D-mannosyl-(1->4)-alpha-D-glucosaminyl)-1-(1-radyl,2-acyl-sn-glycero…
PGAP2	Acyltransferase PGAP2	Involved in the fatty acid remodeling steps of GPI-anchor maturation where the unsaturated acyl chain at sn-2 of inositol phosphate is replaced by a saturated stearoyl chain.
PIGW	Glucosaminyl-phosphatidylinositol-acyltransferase PIGW	Acyltransferase that catalyzes the acyl transfer from an acyl-CoA at the 2-OH position of the inositol ring of a 6-(alpha-D-glucosaminyl)-1-(1,2-diacyl-sn-glycero-3-phospho)-1D-myo-inositol (glucosaminyl phosphatidylinositol, GlcN-PI) to g…
PIGY	Phosphatidylinositol N-acetylglucosaminyltransferase subunit Y	Part of the glycosylphosphatidylinositol-N-acetylglucosaminyltransferase (GPI-GnT) complex that catalyzes the transfer of N-acetylglucosamine from UDP-N-acetylglucosamine to phosphatidylinositol and participates in the first step of GPI bi…
PIGL	N-acetylglucosaminyl-phosphatidylinositol de-N-acetylase	Catalyzes the second step of glycosylphosphatidylinositol (GPI) biosynthesis, which is the de-N-acetylation of N-acetylglucosaminyl-phosphatidylinositol.

Protein-family classification

Druggable: 3 · Difficult: 0 · Unknown: 4 · Druggable fraction: 0.43

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Phosphatase	1	12.0×	0.165
Enzyme (other)	2	3.4×	0.165
Other/Unknown	4	1.0×	0.626

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PIGO	Phosphatase	yes		Phosphodiest/P_Trfase, Alkaline_phosphatase_core_sf, PIG-O_N
PGAP3	Other/Unknown	no		Per1-like
PIGV	Other/Unknown	no		PIG-V/Gpi18
PGAP2	Other/Unknown	no		CWH43_N, PGAP2
PIGW	Other/Unknown	no		PIGW/GWT1
PIGY	Enzyme (other)	yes	2.4.1.198	PIG-Y
PIGL	Enzyme (other)	yes	3.5.1.89	GlcNAc_PI_deacetylase-related, LmbE-like_dom_sf

Expression context

Cohort genes with no expression data: 0.

4 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	7
unknown	0

Top tissues across cohort

Tissue	Cohort genes
islet of Langerhans	2
diaphragm	1
mucosa of transverse colon	1
vena cava	1
left lobe of thyroid gland	1
pancreatic ductal cell	1
right lobe of thyroid gland	1
adult organism	1
male germ cell	1
sperm	1
corpus epididymis	1
lower esophagus mucosa	1
skin of abdomen	1
endometrium	1
gastrocnemius	1
C1 segment of cervical spinal cord	1
smooth muscle tissue	1
mucosa of stomach	1
right uterine tube	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PIGO	264	ubiquitous	yes	mucosa of transverse colon, diaphragm, vena cava
PGAP3	270	ubiquitous	marker	pancreatic ductal cell, left lobe of thyroid gland, right lobe of thyroid gland
PIGV	278	ubiquitous	marker	sperm, male germ cell, adult organism
PGAP2	280	ubiquitous	marker	corpus epididymis, lower esophagus mucosa, skin of abdomen
PIGW	134	ubiquitous	yes	islet of Langerhans, endometrium, gastrocnemius
PIGY	134	ubiquitous	yes	islet of Langerhans, C1 segment of cervical spinal cord, smooth muscle tissue
PIGL	236	ubiquitous	marker	mucosa of stomach, right uterine tube, sural nerve

Protein interactions among cohort

Intra-cohort edges: 21.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PIGW	1,715
PIGO	1,302
PIGL	995
PGAP2	887
PIGV	758
PGAP3	750
PIGY	474

Intra-cohort edges

A	B	Sources
PGAP2	PGAP3	string_interaction
PGAP2	PIGL	string_interaction
PGAP2	PIGO	string_interaction
PGAP2	PIGV	string_interaction
PGAP2	PIGW	string_interaction
PGAP2	PIGY	string_interaction
PGAP3	PIGL	string_interaction
PGAP3	PIGO	string_interaction
PGAP3	PIGV	string_interaction
PGAP3	PIGW	string_interaction
PGAP3	PIGY	string_interaction
PIGL	PIGO	string_interaction
PIGL	PIGV	string_interaction
PIGL	PIGW	string_interaction
PIGL	PIGY	string_interaction
PIGO	PIGV	string_interaction
PIGO	PIGW	string_interaction
PIGO	PIGY	string_interaction
PIGV	PIGW	string_interaction
PIGV	PIGY	string_interaction
PIGW	PIGY	string_interaction

Structural data

PDB: 0 · AlphaFold-only: 7 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PGAP3	Q96FM1	93.17
PIGL	Q9Y2B2	91.66
PIGV	Q9NUD9	90.22
PGAP2	Q9UHJ9	90.00
PIGY	Q3MUY2	89.02
PIGW	Q7Z7B1	87.17
PIGO	Q8TEQ8	82.57

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 7 evidence-associated genes (5 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Synthesis of glycosylphosphatidylinositol (GPI)	5	634.4×	5e-15	PIGO, PIGV, PIGW, PIGY, PIGL

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 7 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
GPI anchor biosynthetic process	7	495.6×	2e-19	PIGO, PGAP3, PIGV, PGAP2, PIGW, PIGY, PIGL
GPI anchor metabolic process	2	1605.0×	7e-07	PGAP3, PIGW
protein localization to plasma membrane	1	15.5×	0.063	PIGW

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 7

Druggability breadth: 2 of 7 evidence-associated genes (29%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PIGO	0	0
PGAP3	0	0
PIGV	0	0
PGAP2	0	0
PIGW	0	0
PIGY	0	0
PIGL	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
PIGO	1	Binding:1
PIGW	1	ADMET:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PIGY	2.4.1.198	phosphatidylinositol N-acetylglucosaminyltransferase
PIGL	3.5.1.89	N-acetylglucosaminylphosphatidylinositol deacetylase

Pharmacogenomics

Cohort genes with a PharmGKB record: 7; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	3	PIGO, PIGY, PIGL
E	Difficult family or no structure, no drug	4	PGAP3, PIGV, PGAP2, PIGW

Undrugged target profiles

7 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
PIGO	1	—
PGAP3	0	—
PIGV	0	—
PGAP2	0	—
PIGW	1	—
PIGY	0	—
PIGL	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.