Telomere syndrome

Summary

Telomere syndrome (MONDO:0100137) is a disease (an umbrella term covering 7 Mondo subtypes) caused by POLA2 (GenCC Strong), with 5 cohort genes and 2 clinical trials. The dominant Reactome pathway is Telomere Extension By Telomerase (3 cohort genes). Top therapeutic interventions include fludarabine phosphate.

At a glance

• Causal gene: POLA2 (GenCC Strong)
• Umbrella term: 7 Mondo subtypes
• Cohort genes: 5
• ClinVar variants: 12
• Clinical trials: 2

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	telomere syndrome
Mondo ID	MONDO:0100137
NCIT	C152065
UMLS	C4727832
MedGen	1668986
GARD	0026060
Is cancer (heuristic)	no

Also known as: short telomere syndrome · STS

Data availability: 12 ClinVar variants · 3 GenCC gene-disease records.

Disease family

An umbrella term covering 7 Mondo subtypes.

Classification path: disease › human disease › disease by developmental or physiological process › premature aging syndrome › telomere syndrome

Related subtypes (7): Flynn-Aird syndrome, acrogeria, premature aging syndrome, Okamoto type, acroosteolysis-keloid-like lesions-premature aging syndrome, progeroid syndrome, de Barsy syndrome, LMNA-related cardiocutaneous progeria syndrome

Subtypes (7): immunodeficiency-centromeric instability-facial anomalies syndrome, pulmonary fibrosis and/or bone marrow failure, telomere-related, cirrhosis, familial, dyskeratosis congenita, autosomal dominant 1, Coats plus syndrome, nodular regenerative hyperplasia of the liver, ACD-related telomere biology disorder

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:

5 pathogenic, 3 conflicting classifications of pathogenicity, 2 uncertain significance, 1 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2443315	NM_198253.3(TERT):c.258G>C (p.Gln86His)	LOC110806263	Pathogenic	no assertion criteria provided
2443316	NM_001283009.2(RTEL1):c.3628_3629delinsT (p.His1210fs)	RTEL1	Pathogenic	no assertion criteria provided
973866	NM_001283009.2(RTEL1):c.2223del (p.Ile742fs)	RTEL1	Pathogenic	criteria provided, single submitter
2443317	NM_198253.3(TERT):c.289_290delinsG (p.Leu97fs)	TERT	Pathogenic	no assertion criteria provided
29899	NM_198253.3(TERT):c.1892G>A (p.Arg631Gln)	TERT	Pathogenic	criteria provided, multiple submitters, no conflicts
410693	NM_198253.3(TERT):c.2011C>T (p.Arg671Trp)	TERT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1485756	NM_198253.3(TERT):c.3118G>A (p.Ala1040Thr)	TERT	Likely pathogenic	criteria provided, single submitter
983511	NR_001566.3(TERC):n.95G>C	LOC110806306	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
219120	NM_002582.4(PARN):c.1045C>T (p.Arg349Trp)	PARN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
580119	NM_198253.3(TERT):c.2591T>C (p.Leu864Pro)	TERT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1185035	NM_002582.4(PARN):c.39C>G (p.His13Gln)	PARN	Uncertain significance	criteria provided, single submitter
981516	NM_001283009.2(RTEL1):c.2114A>G (p.Tyr705Cys)	RTEL1	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 16 · 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
POLA2	Strong	Autosomal recessive	telomere syndrome	2
NOP10	Moderate	Autosomal recessive	telomere syndrome	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NOP10	Orphanet:1775	Dyskeratosis congenita
TERT	Orphanet:146	Differentiated thyroid carcinoma
TERT	Orphanet:1501	Adrenocortical carcinoma
TERT	Orphanet:1775	Dyskeratosis congenita
TERT	Orphanet:2032	Idiopathic pulmonary fibrosis
TERT	Orphanet:2495	Meningioma
TERT	Orphanet:3322	Hoyeraal-Hreidarsson syndrome
TERT	Orphanet:457246	Clear cell sarcoma of kidney
TERT	Orphanet:618	Familial melanoma
TERT	Orphanet:88	Idiopathic aplastic anemia
RTEL1	Orphanet:1775	Dyskeratosis congenita
RTEL1	Orphanet:2032	Idiopathic pulmonary fibrosis
RTEL1	Orphanet:3322	Hoyeraal-Hreidarsson syndrome
PARN	Orphanet:1775	Dyskeratosis congenita
PARN	Orphanet:2032	Idiopathic pulmonary fibrosis
PARN	Orphanet:3322	Hoyeraal-Hreidarsson syndrome

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NOP10	HGNC:14378	ENSG00000182117	Q9NPE3	H/ACA ribonucleoprotein complex subunit 3	gencc
POLA2	HGNC:30073	ENSG00000014138	Q14181	DNA polymerase alpha subunit B	gencc
TERT	HGNC:11730	ENSG00000164362	O14746	Telomerase reverse transcriptase	clinvar
RTEL1	HGNC:15888	ENSG00000258366	Q9NZ71	Regulator of telomere elongation helicase 1	clinvar
PARN	HGNC:8609	ENSG00000140694	O95453	Poly(A)-specific ribonuclease PARN	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NOP10	H/ACA ribonucleoprotein complex subunit 3	Required for ribosome biogenesis and telomere maintenance.
POLA2	DNA polymerase alpha subunit B	Accessory 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.
TERT	Telomerase reverse transcriptase	Telomerase is a ribonucleoprotein enzyme essential for the replication of chromosome termini in most eukaryotes.
RTEL1	Regulator of telomere elongation helicase 1	A probable ATP-dependent DNA helicase implicated in telomere-length regulation, DNA repair and the maintenance of genomic stability.
PARN	Poly(A)-specific ribonuclease PARN	3’-exoribonuclease that has a preference for poly(A) tails of mRNAs, thereby efficiently degrading poly(A) tails.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 5 · 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
Other/Unknown	5	1.8×	0.054

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NOP10	Other/Unknown	no		H/ACA_rnp_Nop10, H/ACA_rnp_Nop10_sf
POLA2	Other/Unknown	no		DNA_pol_a/d/e_bsu, Pol_alpha_B_N, DNA_pol_alpha_bsu
TERT	Other/Unknown	no		RT_dom, Telomerase_RT, Telomerase_RBD
RTEL1	Other/Unknown	no		Helicase-like_DEXD_c2, ATP-dep_Helicase_C, RAD3-like_helicase_DEAD
PARN	Other/Unknown	no		R3H_dom, RNase_CAF1, RNaseH-like_sf

Expression context

Cohort genes with no expression data: 0.

3 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
leukocyte	1
monocyte	1
rectum	1
embryo	1
lower esophagus muscularis layer	1
ventricular zone	1
olfactory bulb	1
stromal cell of endometrium	1
type B pancreatic cell	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
sural nerve	1
calcaneal tendon	1
corpus callosum	1
male germ line stem cell (sensu Vertebrata) in testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NOP10	286	ubiquitous	marker	monocyte, rectum, leukocyte
POLA2	213	ubiquitous	marker	ventricular zone, embryo, lower esophagus muscularis layer
TERT	105	broad	yes	stromal cell of endometrium, type B pancreatic cell, olfactory bulb
RTEL1	134	ubiquitous	yes	sural nerve, right hemisphere of cerebellum, cerebellar hemisphere
PARN	134	ubiquitous	marker	calcaneal tendon, corpus callosum, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 4.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TERT	5,717
NOP10	2,488
RTEL1	2,324
POLA2	1,984
PARN	1,532

Intra-cohort edges

A	B	Sources
NOP10	RTEL1	string_interaction
NOP10	TERT	string_interaction
PARN	RTEL1	string_interaction
RTEL1	TERT	string_interaction

Structural data

PDB: 5 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TERT	O14746	23
POLA2	Q14181	13
NOP10	Q9NPE3	7
RTEL1	Q9NZ71	3
PARN	O95453	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 35. Enrichment computed across 5 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
Telomere Extension By Telomerase	3	274.1×	3e-06	TERT, NOP10, RTEL1
Extension of Telomeres	2	240.4×	5e-04	TERT, RTEL1
Telomere Maintenance	2	147.3×	8e-04	TERT, RTEL1
Chromosome Maintenance	2	84.6×	0.002	TERT, RTEL1
Regulation of MITF-M-dependent genes involved in DNA replication, damage repair and senescence	1	326.3×	0.018	TERT
DNA replication initiation	1	285.5×	0.018	POLA2
Processive synthesis on the lagging strand	1	228.4×	0.018	POLA2
Inhibition of replication initiation of damaged DNA by RB1/E2F1	1	163.1×	0.018	POLA2
Telomere C-strand synthesis initiation	1	163.1×	0.018	POLA2
Polymerase switching	1	163.1×	0.018	POLA2
Removal of the Flap Intermediate	1	163.1×	0.018	POLA2
Cytosolic iron-sulfur cluster assembly	1	152.3×	0.018	RTEL1
KSRP (KHSRP) binds and destabilizes mRNA	1	126.9×	0.018	PARN
Resolution of D-Loop Structures	1	126.9×	0.018	RTEL1
Cell Cycle	2	14.4×	0.018	TERT, RTEL1
Deadenylation of mRNA	1	87.8×	0.023	PARN
Polymerase switching on the C-strand of the telomere	1	84.6×	0.023	POLA2
ATF4 activates genes in response to endoplasmic reticulum stress	1	81.6×	0.023	PARN
Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)	1	78.8×	0.023	RTEL1
Activation of the pre-replicative complex	1	65.3×	0.026	POLA2
Homology Directed Repair	1	61.7×	0.026	RTEL1
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	1	61.7×	0.026	RTEL1
DNA Double-Strand Break Repair	1	49.6×	0.030	RTEL1
HDR through Homologous Recombination (HRR)	1	38.1×	0.037	RTEL1
rRNA modification in the nucleus and cytosol	1	37.4×	0.037	NOP10
MITF-M-dependent gene expression	1	36.2×	0.037	TERT
Defective pyroptosis	1	31.3×	0.041	POLA2
Formation of the beta-catenin:TCF transactivating complex	1	24.0×	0.050	TERT
TCF dependent signaling in response to WNT	1	23.6×	0.050	TERT
MITF-M-regulated melanocyte development	1	22.8×	0.050	TERT

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
telomere maintenance via telomerase	2	293.1×	0.001	TERT, NOP10
DNA strand displacement	1	3370.4×	0.002	RTEL1
RNA-templated transcription	1	3370.4×	0.002	TERT
DNA strand elongation	1	3370.4×	0.002	TERT
siRNA transcription	1	3370.4×	0.002	TERT
positive regulation of transdifferentiation	1	3370.4×	0.002	TERT
negative regulation of telomere maintenance in response to DNA damage	1	3370.4×	0.002	RTEL1
positive regulation of telomeric loop disassembly	1	3370.4×	0.002	RTEL1
box H/ACA sno(s)RNA 3’-end processing	1	1685.2×	0.002	PARN
RNA-templated DNA biosynthetic process	1	1685.2×	0.002	TERT
RNA modification	1	1685.2×	0.002	PARN
positive regulation of hair cycle	1	1685.2×	0.002	TERT
telomeric loop disassembly	1	1685.2×	0.002	RTEL1
lncRNA processing	1	1685.2×	0.002	PARN
priRNA 3’-end processing	1	1685.2×	0.002	PARN
siRNA 3’-end processing	1	1685.2×	0.002	PARN
telomere maintenance	2	107.0×	0.002	TERT, RTEL1
protein import into nucleus	2	57.6×	0.002	TERT, POLA2
pseudouridine synthesis	1	1123.5×	0.003	NOP10
snRNA pseudouridine synthesis	1	1123.5×	0.003	NOP10
mitotic telomere maintenance via semi-conservative replication	1	1123.5×	0.003	RTEL1
negative regulation of t-circle formation	1	1123.5×	0.003	RTEL1
rRNA pseudouridine synthesis	1	842.6×	0.003	NOP10
telomerase RNA stabilization	1	842.6×	0.003	PARN
regulation of telomerase RNA localization to Cajal body	1	842.6×	0.003	PARN
positive regulation of telomere capping	1	674.1×	0.004	RTEL1
DNA replication, synthesis of primer	1	561.7×	0.004	POLA2
positive regulation of telomere maintenance via telomere lengthening	1	561.7×	0.004	RTEL1
positive regulation of protein localization to nucleolus	1	561.7×	0.004	TERT
telomerase RNA localization to Cajal body	1	481.5×	0.005	NOP10

Therapeutics

Drug target analysis

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

Druggability breadth: 4 of 5 evidence-associated genes (80%) 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
TERT	BERBERINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TERT	10	4
NOP10	0	0
POLA2	0	0
RTEL1	0	0
PARN	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BERBERINE	4	TERT
DOXORUBICIN	4	TERT
RESVERATROL	3	TERT
EPIGALOCATECHIN GALLATE	3	TERT
PERIFOSINE	3	TERT
ISOMETAMIDIUM	2	TERT
HOMIDIUM BROMIDE	2	TERT
ALLICIN	2	TERT
OLEIC ACID	2	TERT
ETHACRIDINE	2	TERT

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
TERT	391	Binding:389, Functional:2
NOP10	1	Binding:1
PARN	1	Binding:1

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
TERT	391

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

10 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)
BERBERINE	4	TERT
DOXORUBICIN	4	TERT
RESVERATROL	3	TERT
EPIGALOCATECHIN GALLATE	3	TERT
PERIFOSINE	3	TERT
ISOMETAMIDIUM	2	TERT
HOMIDIUM BROMIDE	2	TERT
ALLICIN	2	TERT
OLEIC ACID	2	TERT
ETHACRIDINE	2	TERT

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	TERT
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	4	NOP10, POLA2, RTEL1, PARN

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
NOP10	1	TERT
POLA2	0	—
RTEL1	0	—
PARN	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	1
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04232085	PHASE2	RECRUITING	Regenerative Medicine to Restore Hematopoiesis and Immune Function in Immunodeficiencies and Inherited Bone Marrow Failures
NCT05813327	PHASE1	ACTIVE_NOT_RECRUITING	Neoadjuvant ADI-PEG 20 + Ifosfamide + Radiotherapy in Soft Tissue Sarcoma

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
FLUDARABINE PHOSPHATE	4	1