X-linked intellectual disability, van Esch type

Summary

X-linked intellectual disability, van Esch type (MONDO:0015601) is a disease caused by POLA1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: POLA1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 29
• Phenotypes (HPO): 21

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		7	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

21 HPO clinical features (Orphanet curated; top 21 by frequency):

HPO ID	Term	Frequency
HP:0000026	Male hypogonadism	Very frequent (80-99%)
HP:0000028	Cryptorchidism	Very frequent (80-99%)
HP:0000252	Microcephaly	Very frequent (80-99%)
HP:0000278	Retrognathia	Very frequent (80-99%)
HP:0000815	Hypergonadotropic hypogonadism	Very frequent (80-99%)
HP:0002750	Delayed skeletal maturation	Very frequent (80-99%)
HP:0001256	Intellectual disability, mild	Very frequent (80-99%)
HP:0001508	Failure to thrive	Very frequent (80-99%)
HP:0004322	Short stature	Very frequent (80-99%)
HP:0001511	Intrauterine growth retardation	Very frequent (80-99%)
HP:0005978	Type II diabetes mellitus	Very frequent (80-99%)
HP:0007018	Attention deficit hyperactivity disorder	Very frequent (80-99%)
HP:0008187	Absence of secondary sex characteristics	Very frequent (80-99%)
HP:0008551	Microtia	Very frequent (80-99%)
HP:0008734	Decreased testicular size	Very frequent (80-99%)
HP:0012646	Retractile testis	Very frequent (80-99%)
HP:0012760	Reduced social responsiveness	Very frequent (80-99%)
HP:0000837	Increased circulating gonadotropin level	Frequent (30-79%)
HP:0040171	Decreased serum testosterone concentration	Frequent (30-79%)
HP:0004209	Clinodactyly of the 5th finger	Occasional (5-29%)
HP:0004440	Coronal craniosynostosis	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	X-linked intellectual disability, van Esch type
Mondo ID	MONDO:0015601
OMIM	301030
Orphanet	163976
DOID	DOID:0111840
SNOMED CT	718914002
UMLS	C4305072
MedGen	930741
GARD	0017008
Is cancer (heuristic)	no

Also known as: mental retardation, X-Linked, syndromic, Van Esch-O’Driscoll type · Van Esch-O’Driscoll syndrome · Van Esch-O’Driscoll syndrome, X-linked recessive · VEODS

Data availability: 29 ClinVar variants · 5 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 › X-linked intellectual disability, van Esch type

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, Prieto 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-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

29 retrieved; paginated sample, class counts are floors:

16 uncertain significance, 5 pathogenic, 4 benign/likely benign, 2 conflicting classifications of pathogenicity, 1 likely benign, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
627632	NM_001330360.2(POLA1):c.254T>G (p.Ile85Ser)	POLA1	Pathogenic	no assertion criteria provided
627633	NM_001330360.2(POLA1):c.4160C>T (p.Pro1387Leu)	POLA1	Pathogenic	no assertion criteria provided
627634	NM_001330360.2(POLA1):c.525+1G>A	POLA1	Pathogenic	no assertion criteria provided
627635	NM_016937.3(POLA1):c.445_507del	POLA1	Pathogenic	no assertion criteria provided
627636	NM_001330360.2(POLA1):c.346G>A (p.Gly116Arg)	POLA1	Pathogenic	no assertion criteria provided
807658	NM_001330360.2(POLA1):c.1207G>A (p.Asp403Asn)	POLA1	Likely pathogenic	criteria provided, single submitter
1172688	NM_001330360.2(POLA1):c.463-2A>T	POLA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1669603	NM_001330360.2(POLA1):c.463-9C>T	POLA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1028032	NM_001330360.2(POLA1):c.3050A>G (p.Asn1017Ser)	POLA1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1055272	NM_001330360.2(POLA1):c.3955A>G (p.Ile1319Val)	POLA1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1251955	NM_001330360.2(POLA1):c.3046A>G (p.Thr1016Ala)	POLA1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1333995	NM_001330360.2(POLA1):c.478T>C (p.Ser160Pro)	POLA1	Uncertain significance	criteria provided, single submitter
1384071	NM_001330360.2(POLA1):c.1834-3C>T	POLA1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1440824	NM_001330360.2(POLA1):c.2516G>A (p.Gly839Glu)	POLA1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1696715	NM_001330360.2(POLA1):c.1931A>G (p.Asn644Ser)	POLA1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1706639	NM_001330360.2(POLA1):c.4313A>T (p.Lys1438Ile)	POLA1	Uncertain significance	criteria provided, single submitter
1709808	NM_001330360.2(POLA1):c.3212A>G (p.Asp1071Gly)	POLA1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1805959	NM_001330360.2(POLA1):c.3950G>A (p.Ser1317Asn)	POLA1	Uncertain significance	criteria provided, single submitter
2444023	NM_001330360.2(POLA1):c.4001A>G (p.Asn1334Ser)	POLA1	Uncertain significance	criteria provided, single submitter
3012181	NM_001330360.2(POLA1):c.3736G>C (p.Gly1246Arg)	POLA1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3598250	NM_001330360.2(POLA1):c.4087A>G (p.Thr1363Ala)	POLA1	Uncertain significance	criteria provided, single submitter
4279858	NM_001330360.2(POLA1):c.979G>A (p.Glu327Lys)	POLA1	Uncertain significance	criteria provided, single submitter
4291863	NM_001330360.2(POLA1):c.1987C>G (p.Pro663Ala)	POLA1	Uncertain significance	criteria provided, single submitter
4292860	NM_001330360.2(POLA1):c.2087T>C (p.Ile696Thr)	POLA1	Uncertain significance	criteria provided, single submitter
1166581	NM_001330360.2(POLA1):c.2236T>C (p.Tyr746His)	POLA1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
1168543	NM_001330360.2(POLA1):c.2267A>G (p.Lys756Arg)	POLA1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
1170758	NM_001330360.2(POLA1):c.1687-15C>T	POLA1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
1615797	NM_001330360.2(POLA1):c.4383C>T (p.Phe1461=)	POLA1	Likely benign	criteria provided, multiple submitters, no conflicts
719273	NM_001330360.2(POLA1):c.4356C>T (p.Tyr1452=)	POLA1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 2 · 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
POLA1	Definitive	X-linked	X-linked intellectual disability, van Esch type	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
POLA1	Orphanet:163976	X-linked intellectual disability, Van Esch type
POLA1	Orphanet:85453	X-linked reticulate pigmentary disorder

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
POLA1	HGNC:9173	ENSG00000101868	P09884	DNA polymerase alpha catalytic subunit	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
POLA1	DNA polymerase alpha catalytic subunit	Catalytic subunit of the DNA polymerase alpha complex (also known as the alpha DNA polymerase-primase complex) which plays an essential role in the initiation of DNA synthesis.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.0

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
Transcription factor	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
POLA1	Transcription factor	no	2.7.7.102	DNA-dir_DNA_pol_B_exonuc, DNA-dir_DNA_pol_B_multi_dom, DNA-dir_DNA_pol_B

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
calcaneal tendon	1
sural nerve	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
POLA1	231	ubiquitous	marker	ventricular zone, sural nerve, calcaneal tendon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
POLA1	3,189

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
POLA1	P09884	21

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. 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
DNA replication initiation	1	1427.5×	0.002	POLA1
Processive synthesis on the lagging strand	1	1142.0×	0.002	POLA1
Inhibition of replication initiation of damaged DNA by RB1/E2F1	1	815.7×	0.002	POLA1
Telomere C-strand synthesis initiation	1	815.7×	0.002	POLA1
Polymerase switching	1	815.7×	0.002	POLA1
Removal of the Flap Intermediate	1	815.7×	0.002	POLA1
Polymerase switching on the C-strand of the telomere	1	423.0×	0.003	POLA1
G1/S-Specific Transcription	1	356.9×	0.003	POLA1
Activation of the pre-replicative complex	1	326.3×	0.003	POLA1
Defective pyroptosis	1	156.4×	0.006	POLA1

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
lagging strand elongation	1	5617.3×	1e-03	POLA1
leading strand elongation	1	4213.0×	1e-03	POLA1
DNA replication, synthesis of primer	1	2808.7×	1e-03	POLA1
mitotic DNA replication initiation	1	2808.7×	1e-03	POLA1
DNA strand elongation involved in DNA replication	1	1872.4×	0.001	POLA1
regulation of type I interferon production	1	1685.2×	0.001	POLA1
DNA synthesis involved in DNA repair	1	936.2×	0.002	POLA1
DNA replication initiation	1	624.1×	0.002	POLA1
double-strand break repair via nonhomologous end joining	1	421.3×	0.003	POLA1
DNA replication	1	165.2×	0.007	POLA1
DNA repair	1	63.8×	0.016	POLA1

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · 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).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
POLA1	RUCAPARIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
POLA1	3	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
RUCAPARIB	4	POLA1
ADEFOVIR DIPIVOXIL	4	POLA1
RESVERATROL	3	POLA1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
POLA1	73	Binding:64, ADMET:5, Functional:4

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
POLA1	2.7.7.102	DNA primase AEP

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

3 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)
RUCAPARIB	4	POLA1
ADEFOVIR DIPIVOXIL	4	POLA1
RESVERATROL	3	POLA1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	POLA1
B	Phased (≥1) drug, not yet approved	0
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.