X-linked reticulate pigmentary disorder

Summary

X-linked reticulate pigmentary disorder (MONDO:0010523) is a disease caused by POLA1 (GenCC Strong), with 1 cohort gene and 2 clinical trials.

At a glance

• Prevalence: (Worldwide) [Orphanet-validated]
• Causal gene: POLA1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 13
• Clinical trials: 2

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		6	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Not yet validated

Identifiers

Disease identifiers

Field	Value
Canonical name	X-linked reticulate pigmentary disorder
Mondo ID	MONDO:0010523
MeSH	C564461
OMIM	301220
Orphanet	85453
DOID	DOID:0111834
SNOMED CT	717224002
UMLS	C1845050
MedGen	336844
GARD	0016756
Is cancer (heuristic)	no

Also known as: familial cutaneous amyloidosis · Partington disease · PDR · pigmentary disorder, reticulate, with systemic manifestations · pigmentary disorder, reticulate, with systemic manifestations, X-linked, X-linked recessive · X-linked cutaneous amyloidosis · XLPDR

Data availability: 13 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › hereditary disorder of connective tissue › X-linked reticulate pigmentary disorder

Related subtypes (86): Ewing sarcoma of bone, hereditary multiple osteochondromas, acroosteolysis dominant type, diaphyseal medullary stenosis-bone malignancy syndrome, cherubism, chondrocalcinosis 2, desmoid tumor, familial ossifying fibroma, hyperparathyroidism 1, hyperparathyroidism 2 with jaw tumors, uterine corpus leiomyoma, multiple symmetric lipomatosis, systemic lupus erythematosus, Ollier disease, Peyronie disease, Singleton-Merten dysplasia, Blau syndrome, inherited torticollis, arterial tortuosity syndrome, camptodactyly-arthropathy-coxa vara-pericarditis syndrome, chondrosarcoma, trichohepatoenteric syndrome, brittle cornea syndrome, neonatal severe primary hyperparathyroidism, proteosome-associated autoinflammatory syndrome, chronic recurrent multifocal osteomyelitis, Pelger-Huet-like anomaly and episodic fever with abdominal pain, acquired polycythemia vera, autosomal recessive inherited pseudoxanthoma elasticum, CHILD syndrome, ossification of the posterior longitudinal ligament of the spine, MASS syndrome, pyogenic arthritis-pyoderma gangrenosum-acne syndrome, Spondyloenchondrodysplasia with immune dysregulation, sweet syndrome, chronic myeloid leukemia, hyperparathyroidism 3, bone fragility with contractures, arterial rupture, and deafness, encephalocraniocutaneous lipomatosis, psoriasis 14, pustular, Maffucci syndrome, autoinflammation-PLCG2-associated antibody deficiency-immune dysregulation, deficiency of adenosine deaminase 2, STING-associated vasculopathy with onset in infancy, autoimmune interstitial lung disease-arthritis syndrome, progeroid and marfanoid aspect-lipodystrophy syndrome, thrombocytopenia 6, multiple epiphyseal dysplasia due to collagen 9 anomaly, Ehlers-Danlos syndrome, kyphoscoliotic type 1, juvenile hyaline fibromatosis, IL10-related early-onset inflammatory bowel disease, infantile myofibromatosis, Marfan and Marfan-related disorder, neonatal inflammatory skin and bowel disease, familial isolated pituitary adenoma, inherited acute myeloid leukemia, hereditary periodic fever syndrome, autoinflammatory syndrome with pyogenic bacterial infection and amylopectinosis, aneurysmal bone cyst, familial chilblain lupus, pseudo-TORCH syndrome 2, Aicardi-Goutieres syndrome, jugulotympanic paraganglioma, type 2 collagenopathy, hyperparathyroidism 4, VEXAS syndrome, autoinflammatory syndrome, familial, Behcet-like, congenital progressive bone marrow failure-B-cell immunodeficiency-skeletal dysplasia syndrome, LAMA5-related multisystemic syndrome, EMILIN-1-related connective tissue disease, TREX1-related type 1 interferonopathy, RNASEH2B-related type 1 interferonopathy, RNASEH2C-related type 1 interferonopathy, RNASEH2A-related type 1 interferonopathy, SAMHD1-related type 1 interferonopathy, ADAR-related type 1 interferonopathy, IFIH1-related type 1 interferonopathy, RNU7-1-related type 1 interferonopathy, autoinflammatory disease, X-linked, autoinflammatory syndrome with immunodeficiency, autoinflammatory disease, systemic, with vasculitis, autoinflammatory disease, multisystem, with immune dysregulation, X-linked, arterial tortuosity-bone fragility syndrome, linkeropathy, hypermobility spectrum disorder, Sharpin-related autoinflammatory syndrome

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

13 retrieved; paginated sample, class counts are floors:

7 uncertain significance, 3 benign/likely benign, 1 likely benign, 1 pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
224980	NM_001330360.2(POLA1):c.1393-354A>G	POLA1	Pathogenic	criteria provided, multiple submitters, no conflicts
587618	NM_001330360.2(POLA1):c.3622G>C (p.Asp1208His)	POLA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1055272	NM_001330360.2(POLA1):c.3955A>G (p.Ile1319Val)	POLA1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1173105	NM_001330360.2(POLA1):c.1193G>A (p.Arg398His)	POLA1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1314854	NM_001330360.2(POLA1):c.2468G>A (p.Gly823Glu)	POLA1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2441952	NM_001330360.2(POLA1):c.3806G>T (p.Gly1269Val)	POLA1	Uncertain significance	criteria provided, single submitter
2664168	NM_001330360.2(POLA1):c.2018G>A (p.Arg673Gln)	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
523007	NM_001330360.2(POLA1):c.412A>G (p.Asn138Asp)	POLA1	Uncertain significance	criteria provided, single submitter
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: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE1	1
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01487070	PHASE1	COMPLETED	A Single-Center Trial of Intravitreous Injections of Macugen (Pegaptanib Sodium) Given at Least 7 Days Before Vitrectomy Secondary To Tractional Retinal Detachment in Proliferative Diabetic Retinopathy
NCT03113006	Not specified	COMPLETED	The Individually-Marked Panretinal Laser phoTocoagulation for Proliferative Diabetic Retinopathy Study (TREAT)