Prieto syndrome

Summary

Prieto syndrome (MONDO:0010667) is a disease caused by WNK3 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: WNK3 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 12
• Phenotypes (HPO): 23

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		8	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

23 HPO clinical features (Orphanet curated; top 23 by frequency):

HPO ID	Term	Frequency
HP:0000023	Inguinal hernia	Frequent (30-79%)
HP:0000028	Cryptorchidism	Frequent (30-79%)
HP:0000278	Retrognathia	Frequent (30-79%)
HP:0000286	Epicanthus	Frequent (30-79%)
HP:0000316	Hypertelorism	Frequent (30-79%)
HP:0000348	High forehead	Frequent (30-79%)
HP:0000369	Low-set ears	Frequent (30-79%)
HP:0000448	Prominent nose	Frequent (30-79%)
HP:0000486	Strabismus	Frequent (30-79%)
HP:0000508	Ptosis	Frequent (30-79%)
HP:0000639	Nystagmus	Frequent (30-79%)
HP:0000939	Osteoporosis	Frequent (30-79%)
HP:0001098	Abnormal fundus morphology	Frequent (30-79%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001290	Generalized hypotonia	Frequent (30-79%)
HP:0001776	Bilateral talipes equinovarus	Frequent (30-79%)
HP:0002059	Cerebral atrophy	Frequent (30-79%)
HP:0002673	Coxa valga	Frequent (30-79%)
HP:0005815	Supernumerary ribs	Frequent (30-79%)
HP:0010499	Patellar subluxation	Frequent (30-79%)
HP:0010781	Skin dimple	Frequent (30-79%)
HP:0011064	Abnormal number of incisors	Frequent (30-79%)
HP:0040019	Finger clinodactyly	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Prieto syndrome
Mondo ID	MONDO:0010667
MeSH	C535274
OMIM	309610
Orphanet	2958
DOID	DOID:0060805
SNOMED CT	719140001
UMLS	C1839730
MedGen	374294
GARD	0004482
Is cancer (heuristic)	no

Also known as: mental retardation, X-linked, syndromic 2 · mental retardation, X-linked, with Dysmorphism and cerebral atrophy · MRXS2 · Prieto syndrome, X-linked recessive · Prieto X-linked intellectual disability syndrome · Prieto X-linked mental retardation syndrome · Prieto-Badia-Mulas syndrome · PRS · X-linked intellectual disability-dysmorphism-cerebral atrophy syndrome

Data availability: 12 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › neurodevelopmental disorder › intellectual disability › syndromic intellectual disability › X-linked syndromic intellectual disability › Prieto syndrome

Related subtypes (80): X-linked intellectual disability-psychosis-macroorchidism syndrome, X-linked intellectual disability-plagiocephaly syndrome, intellectual disability, X-linked 49, MEHMO syndrome, syndromic X-linked intellectual disability 7, syndromic X-linked intellectual disability Shashi type, syndromic X-linked intellectual disability Lubs type, syndromic X-linked intellectual disability Abidi type, syndromic X-linked intellectual disability Siderius type, X-linked intellectual disability, Cabezas type, X-linked intellectual disability, Stocco dos Santos type, X-linked intellectual disability-cubitus valgus-dysmorphism syndrome, corpus callosum agenesis-intellectual disability-coloboma-micrognathia syndrome, X-linked intellectual disability-cerebellar hypoplasia syndrome, Allan-Herndon-Dudley syndrome, syndromic X-linked intellectual disability Claes-Jensen type, X-linked intellectual disability-retinitis pigmentosa syndrome, syndromic X-linked intellectual disability 14, syndromic X-linked intellectual disability 94, intellectual disability, X-linked syndromic, Turner type, syndromic X-linked intellectual disability Shrimpton type, X-linked intellectual disability-craniofacioskeletal syndrome, syndromic X-linked intellectual disability Raymond type, syndromic X-linked intellectual disability 17, syndromic X-linked intellectual disability Nascimento type, syndromic X-linked intellectual disability Chudley-Schwartz type, X-linked intellectual disability-cardiomegaly-congestive heart failure syndrome, X-linked intellectual disability, Cantagrel type, X-linked intellectual disability-short stature-overweight syndrome, intellectual disability, X-linked, syndromic 33, syndromic X-linked intellectual disability 34, intellectual disability, X-linked 99, syndromic, female-restricted, intellectual disability, X-linked, syndromic, Bain type, Borjeson-Forssman-Lehmann syndrome, Coffin-Lowry syndrome, syndromic X-linked intellectual disability 5, X-linked intellectual disability-seizures-psoriasis syndrome, Renpenning syndrome, Partington syndrome, syndromic X-linked intellectual disability 12, severe X-linked intellectual disability, Gustavson type, syndromic X-linked intellectual disability Snyder type, Wilson-Turner syndrome, skeletal dysplasia-intellectual disability syndrome, X-linked intellectual disability-spastic quadriparesis syndrome, early-onset parkinsonism-intellectual disability syndrome, X-linked intellectual disability, Schimke type, X-linked intellectual disability, Cilliers type, X-linked intellectual disability, van Esch type, X-linked intellectual disability-epilepsy syndrome, ATR-X-related syndrome, X-linked intellectual disability-hypogonadism-ichthyosis-obesity-short stature syndrome, X-linked intellectual disability, Schutz type, X-linked intellectual disability-hypotonia-movement disorder syndrome, X-linked intellectual disability with isolated growth hormone deficiency, X-linked intellectual disability-hypogammaglobulinemia-progressive neurological deterioration syndrome, X-linked intellectual disability-precocious puberty-obesity syndrome, X-linked intellectual disability-epilepsy-progressive joint contractures-dysmorphism syndrome, X-linked intellectual disability-macrocephaly-macroorchidism syndrome, X-linked intellectual disability, Pai type, X-linked intellectual disability, Seemanova type, X-linked intellectual disability, Stevenson type, X-linked intellectual disability, Stoll type, X-linked intellectual disability-acromegaly-hyperactivity syndrome, X-linked intellectual disability-corpus callosum agenesis-spastic quadriparesis syndrome, fried syndrome, X-linked intellectual disability-ataxia-apraxia syndrome, intellectual developmental disorder, X-linked, syndromic, Pilorge type, Paganini-Miozzo syndrome, intellectual developmental disorder, X-linked, syndromic, Hackmann-Di Donato type, intellectual disability, X-linked, syndromic, 35, intellectual disability, X-linked, syndromic, Houge type, MED12-related intellectual disability syndrome, NAA10-related syndrome, ATP6AP2-related disorder, X-linked intellectual disability with hypopituitarism, SOX3-related X-linked pituitary hormone deficiency with or without intellectual developmental disorder, intellectual developmental disorder, X-linked, syndromic, with pigmentary mosaicism and coarse facies, intellectual developmental disorder, X-linked, syndromic 37, CASK-related intellectual disability

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

12 retrieved; paginated sample, class counts are floors:

7 uncertain significance, 5 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1344899	NM_020922.5(WNK3):c.611C>G (p.Pro204Arg)	WNK3	Pathogenic	no assertion criteria provided
1344900	NM_020922.5(WNK3):c.721C>T (p.Arg241Ter)	WNK3	Pathogenic	no assertion criteria provided
1344901	NM_020922.5(WNK3):c.899T>C (p.Leu300Ser)	WNK3	Pathogenic	no assertion criteria provided
1344902	NM_020922.5(WNK3):c.1089+1G>A	WNK3	Pathogenic	no assertion criteria provided
4077050	NM_020922.5(WNK3):c.1228G>T (p.Gly410Ter)	WNK3	Pathogenic	criteria provided, single submitter
3024305	NM_020922.5(WNK3):c.322_323del (p.Gln108fs)	WNK3	Uncertain significance	criteria provided, single submitter
3190672	NM_020922.5(WNK3):c.4064T>C (p.Ile1355Thr)	WNK3	Uncertain significance	criteria provided, multiple submitters, no conflicts
3255092	NM_020922.5(WNK3):c.122A>G (p.Glu41Gly)	WNK3	Uncertain significance	criteria provided, single submitter
3376130	NM_020922.5(WNK3):c.537+5871C>T	WNK3	Uncertain significance	criteria provided, single submitter
3376365	NM_020922.5(WNK3):c.2785C>T (p.Arg929Cys)	WNK3	Uncertain significance	criteria provided, single submitter
3598415	NM_020922.5(WNK3):c.4283C>A (p.Thr1428Asn)	WNK3	Uncertain significance	criteria provided, single submitter
3598416	NM_020922.5(WNK3):c.2993C>G (p.Ala998Gly)	WNK3	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · Orphanet: 0 · 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
WNK3	Strong	X-linked	Prieto syndrome	2

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
WNK3	HGNC:14543	ENSG00000196632	Q9BYP7	Serine/threonine-protein kinase WNK3	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
WNK3	Serine/threonine-protein kinase WNK3	Serine/threonine-protein kinase component of the WNK3-SPAK/OSR1 kinase cascade, which plays an important role in the regulation of electrolyte homeostasis and regulatory volume increase in response to hyperosmotic stress.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Kinase	1	27.7×	0.036

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
WNK3	Kinase	yes		Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
buccal mucosa cell	1
cauda epididymis	1
corpus epididymis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
WNK3	181	broad	marker	corpus epididymis, buccal mucosa cell, cauda epididymis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
WNK3	1,097

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
WNK3	Q9BYP7	9

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Stimuli-sensing channels	1	135.9×	0.007	WNK3

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of sodium ion transmembrane transporter activity	1	8426.0×	0.002	WNK3
negative regulation of pancreatic juice secretion	1	3370.4×	0.002	WNK3
monoatomic ion homeostasis	1	2407.4×	0.002	WNK3
regulation of calcium ion import	1	2106.5×	0.002	WNK3
regulation of monoatomic cation transmembrane transport	1	2106.5×	0.002	WNK3
positive regulation of peptidyl-threonine phosphorylation	1	1872.4×	0.002	WNK3
osmosensory signaling pathway	1	1532.0×	0.002	WNK3
cellular hyperosmotic response	1	1203.7×	0.002	WNK3
membraneless organelle assembly	1	1123.5×	0.002	WNK3
renal sodium ion absorption	1	991.3×	0.002	WNK3
positive regulation of sodium ion transport	1	842.6×	0.002	WNK3
negative regulation of protein localization to plasma membrane	1	624.1×	0.003	WNK3
cell volume homeostasis	1	601.9×	0.003	WNK3
positive regulation of calcium ion transport	1	581.1×	0.003	WNK3
maintenance of blood-brain barrier	1	481.5×	0.003	WNK3
positive regulation of protein localization to plasma membrane	1	271.8×	0.005	WNK3
protein localization to plasma membrane	1	108.7×	0.011	WNK3
protein phosphorylation	1	68.0×	0.017	WNK3
DNA damage response	1	53.5×	0.021	WNK3
intracellular signal transduction	1	38.1×	0.028	WNK3
negative regulation of apoptotic process	1	34.8×	0.029	WNK3

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
WNK3	1	2

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ADAVOSERTIB	2	WNK3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
WNK3	142	Binding:142

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
WNK3	142

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

1 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.

Compound	Max phase	Cohort target (bioactivity)
ADAVOSERTIB	2	WNK3

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	1	WNK3
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.