Hoyeraal-Hreidarsson syndrome

Summary

Hoyeraal-Hreidarsson syndrome (MONDO:0018045) is a disease with 8 cohort genes and 3 clinical trials. The dominant Reactome pathway is Telomere Extension By Telomerase (6 cohort genes). Top therapeutic interventions include fludarabine phosphate and doxecitine.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 8
• ClinVar variants: 103
• Phenotypes (HPO): 28
• Clinical trials: 3

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		33	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

28 HPO clinical features (Orphanet curated; top 28 by frequency):

HPO ID	Term	Frequency
HP:0000252	Microcephaly	Very frequent (80-99%)
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0001321	Cerebellar hypoplasia	Very frequent (80-99%)
HP:0001508	Failure to thrive	Very frequent (80-99%)
HP:0001511	Intrauterine growth retardation	Very frequent (80-99%)
HP:0001873	Thrombocytopenia	Very frequent (80-99%)
HP:0002721	Immunodeficiency	Very frequent (80-99%)
HP:0004322	Short stature	Very frequent (80-99%)
HP:0004334	Dermal atrophy	Very frequent (80-99%)
HP:0001276	Hypertonia	Frequent (30-79%)
HP:0001903	Anemia	Frequent (30-79%)
HP:0001928	Abnormality of coagulation	Frequent (30-79%)
HP:0002119	Ventriculomegaly	Frequent (30-79%)
HP:0002120	Cerebral cortical atrophy	Frequent (30-79%)
HP:0002209	Sparse scalp hair	Frequent (30-79%)
HP:0002216	Premature graying of hair	Frequent (30-79%)
HP:0002745	Oral leukoplakia	Frequent (30-79%)
HP:0007392	Excessive wrinkled skin	Frequent (30-79%)
HP:0007440	Generalized hyperpigmentation	Frequent (30-79%)
HP:0008404	Nail dystrophy	Frequent (30-79%)
HP:0011358	Generalized hypopigmentation of hair	Frequent (30-79%)
HP:0001251	Ataxia	Occasional (5-29%)
HP:0001265	Hyporeflexia	Occasional (5-29%)
HP:0001881	Abnormal leukocyte morphology	Occasional (5-29%)
HP:0002514	Cerebral calcification	Occasional (5-29%)
HP:0002664	Neoplasm	Occasional (5-29%)
HP:0005528	Bone marrow hypocellularity	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Hoyeraal-Hreidarsson syndrome
Mondo ID	MONDO:0018045
MeSH	C536068
Orphanet	3322
ICD-11	340127408
SNOMED CT	707276009
UMLS	C1846142
MedGen	337518
GARD	0000346
Is cancer (heuristic)	no

Also known as: Growth retardation prenatal with progressive pancytopenia and cerebellar hypoplasia · Hoyeraal Hreidarsson syndrome · progressive pancytopenia-immunodeficiency-cerebellar hypoplasia syndrome

Data availability: 103 ClinVar variants · 6 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › X-linked disease › dyskeratosis congenita, X-linked › Hoyeraal-Hreidarsson 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

103 retrieved; paginated sample, class counts are floors:

60 uncertain significance, 31 likely benign, 5 conflicting classifications of pathogenicity, 5 benign, 1 pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
11593	NM_001363.5(DKC1):c.113T>C (p.Ile38Thr)	DKC1	Pathogenic	no assertion criteria provided
410693	NM_198253.3(TERT):c.2011C>T (p.Arg671Trp)	TERT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1366071	NM_022836.4(DCLRE1B):c.1184G>A (p.Arg395Gln)	DCLRE1B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
644470	NM_022836.4(DCLRE1B):c.946G>A (p.Val316Met)	DCLRE1B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
11592	NM_001363.5(DKC1):c.361A>G (p.Ser121Gly)	DKC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
541876	NM_015450.3(POT1):c.1294C>T (p.Arg432Ter)	POT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
280299	NM_001099274.3(TINF2):c.936C>A (p.Tyr312Ter)	TINF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1007052	NM_022836.4(DCLRE1B):c.1093C>G (p.Gln365Glu)	DCLRE1B	Uncertain significance	criteria provided, single submitter
1009099	NM_022836.4(DCLRE1B):c.188A>C (p.Gln63Pro)	DCLRE1B	Uncertain significance	criteria provided, single submitter
1010600	NM_022836.4(DCLRE1B):c.1238T>C (p.Val413Ala)	DCLRE1B	Uncertain significance	criteria provided, single submitter
1014253	NM_022836.4(DCLRE1B):c.1597T>C (p.Ter533Arg)	DCLRE1B	Uncertain significance	criteria provided, single submitter
1015208	NM_022836.4(DCLRE1B):c.1277C>T (p.Thr426Met)	DCLRE1B	Uncertain significance	criteria provided, single submitter
1017685	NM_022836.4(DCLRE1B):c.1040C>T (p.Pro347Leu)	DCLRE1B	Uncertain significance	criteria provided, single submitter
1027291	NM_022836.4(DCLRE1B):c.1148C>T (p.Ala383Val)	DCLRE1B	Uncertain significance	criteria provided, multiple submitters, no conflicts
1046505	NM_022836.4(DCLRE1B):c.280C>T (p.Leu94Phe)	DCLRE1B	Uncertain significance	criteria provided, single submitter
1052620	NM_022836.4(DCLRE1B):c.341C>G (p.Thr114Ser)	DCLRE1B	Uncertain significance	criteria provided, single submitter
1053170	NM_022836.4(DCLRE1B):c.178C>G (p.Arg60Gly)	DCLRE1B	Uncertain significance	criteria provided, single submitter
1053302	NM_022836.4(DCLRE1B):c.472C>T (p.Arg158Ter)	DCLRE1B	Uncertain significance	criteria provided, single submitter
1055500	NM_022836.4(DCLRE1B):c.1519A>T (p.Thr507Ser)	DCLRE1B	Uncertain significance	criteria provided, single submitter
1055594	NM_022836.4(DCLRE1B):c.961G>A (p.Asp321Asn)	DCLRE1B	Uncertain significance	criteria provided, single submitter
1056946	NM_022836.4(DCLRE1B):c.226G>C (p.Glu76Gln)	DCLRE1B	Uncertain significance	criteria provided, multiple submitters, no conflicts
1058614	NM_022836.4(DCLRE1B):c.1433G>T (p.Gly478Val)	DCLRE1B	Uncertain significance	criteria provided, single submitter
1419030	NM_022836.4(DCLRE1B):c.1347G>T (p.Glu449Asp)	DCLRE1B	Uncertain significance	criteria provided, multiple submitters, no conflicts
1491459	NM_022836.4(DCLRE1B):c.190-3C>G	DCLRE1B	Uncertain significance	criteria provided, single submitter
465151	NM_022836.4(DCLRE1B):c.77T>G (p.Leu26Arg)	DCLRE1B	Uncertain significance	criteria provided, single submitter
533708	NM_022836.4(DCLRE1B):c.78CTT[2] (p.Phe28del)	DCLRE1B	Uncertain significance	criteria provided, single submitter
533709	NM_022836.4(DCLRE1B):c.218A>C (p.Glu73Ala)	DCLRE1B	Uncertain significance	criteria provided, multiple submitters, no conflicts
533711	NM_022836.4(DCLRE1B):c.1456dup (p.Ser486fs)	DCLRE1B	Uncertain significance	criteria provided, single submitter
569061	NM_022836.4(DCLRE1B):c.137G>T (p.Arg46Leu)	DCLRE1B	Uncertain significance	criteria provided, multiple submitters, no conflicts
570621	NM_022836.4(DCLRE1B):c.10G>A (p.Val4Ile)	DCLRE1B	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 71 · Orphanet: 27 · 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
ACD	Supportive	Autosomal dominant	Hoyeraal-Hreidarsson syndrome	15
DKC1	Supportive	Autosomal dominant	Hoyeraal-Hreidarsson syndrome	5
PARN	Supportive	Autosomal dominant	Hoyeraal-Hreidarsson syndrome	8
RTEL1	Supportive	Autosomal dominant	Hoyeraal-Hreidarsson syndrome	12
TERT	Supportive	Autosomal dominant	Hoyeraal-Hreidarsson syndrome	20
TINF2	Supportive	Autosomal dominant	Hoyeraal-Hreidarsson syndrome	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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
TINF2	Orphanet:1775	Dyskeratosis congenita
TINF2	Orphanet:3088	Revesz syndrome
TINF2	Orphanet:3322	Hoyeraal-Hreidarsson syndrome
DKC1	Orphanet:1775	Dyskeratosis congenita
DKC1	Orphanet:3322	Hoyeraal-Hreidarsson syndrome
RTEL1	Orphanet:1775	Dyskeratosis congenita
RTEL1	Orphanet:2032	Idiopathic pulmonary fibrosis
RTEL1	Orphanet:3322	Hoyeraal-Hreidarsson syndrome
ACD	Orphanet:3322	Hoyeraal-Hreidarsson syndrome
ACD	Orphanet:397692	Hereditary isolated aplastic anemia
ACD	Orphanet:618	Familial melanoma
PARN	Orphanet:1775	Dyskeratosis congenita
PARN	Orphanet:2032	Idiopathic pulmonary fibrosis
PARN	Orphanet:3322	Hoyeraal-Hreidarsson syndrome
POT1	Orphanet:251627	Oligodendroglioma
POT1	Orphanet:251630	Anaplastic oligodendroglioma
POT1	Orphanet:618	Familial melanoma
POT1	Orphanet:67038	B-cell chronic lymphocytic leukemia

Cohort genes → proteins

8 cohort genes, 8 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	8

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TERT	HGNC:11730	ENSG00000164362	O14746	Telomerase reverse transcriptase	gencc,clinvar
TINF2	HGNC:11824	ENSG00000092330	Q9BSI4	TERF1-interacting nuclear factor 2	gencc,clinvar
DKC1	HGNC:2890	ENSG00000130826	O60832	H/ACA ribonucleoprotein complex subunit DKC1	gencc,clinvar
RTEL1	HGNC:15888	ENSG00000258366	Q9NZ71	Regulator of telomere elongation helicase 1	gencc
ACD	HGNC:25070	ENSG00000102977	Q96AP0	Adrenocortical dysplasia protein homolog	gencc
PARN	HGNC:8609	ENSG00000140694	O95453	Poly(A)-specific ribonuclease PARN	gencc
POT1	HGNC:17284	ENSG00000128513	Q9NUX5	Protection of telomeres protein 1	clinvar
DCLRE1B	HGNC:17641	ENSG00000118655	Q9H816	5’ exonuclease Apollo	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TERT	Telomerase reverse transcriptase	Telomerase is a ribonucleoprotein enzyme essential for the replication of chromosome termini in most eukaryotes.
TINF2	TERF1-interacting nuclear factor 2	Component of the shelterin complex (telosome) that is involved in the regulation of telomere length and protection.
DKC1	H/ACA ribonucleoprotein complex subunit DKC1	Catalytic subunit of H/ACA small nucleolar ribonucleoprotein (H/ACA snoRNP) complex, which catalyzes pseudouridylation of rRNA.
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.
ACD	Adrenocortical dysplasia protein homolog	Component of the shelterin complex (telosome) that is involved in the regulation of telomere length and protection.
PARN	Poly(A)-specific ribonuclease PARN	3’-exoribonuclease that has a preference for poly(A) tails of mRNAs, thereby efficiently degrading poly(A) tails.
POT1	Protection of telomeres protein 1	Component of the telomerase ribonucleoprotein (RNP) complex that is essential for the replication of chromosome termini.
DCLRE1B	5’ exonuclease Apollo	5’-3’ exonuclease that plays a central role in telomere maintenance and protection during S-phase.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 8 · 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	8	1.8×	0.009

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TERT	Other/Unknown	no		RT_dom, Telomerase_RT, Telomerase_RBD
TINF2	Other/Unknown	no		TINF2_N, TINF2
DKC1	Other/Unknown	no		PUA, PsdUridine_synth_N, Uncharacterised_CHP00451
RTEL1	Other/Unknown	no		Helicase-like_DEXD_c2, ATP-dep_Helicase_C, RAD3-like_helicase_DEAD
ACD	Other/Unknown	no		TPP1/Est3, ACD
PARN	Other/Unknown	no		R3H_dom, RNase_CAF1, RNaseH-like_sf
POT1	Other/Unknown	no		Telomer_end-bd_POT1/Cdc13, NA-bd_OB-fold, POT1
DCLRE1B	Other/Unknown	no		DRMBL, RibonucZ/Hydroxyglut_hydro

Expression context

Cohort genes with no expression data: 0.

5 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)	8
unknown	0

Top tissues across cohort

Tissue	Cohort genes
secondary oocyte	3
sural nerve	2
cerebellar hemisphere	2
right hemisphere of cerebellum	2
calcaneal tendon	2
olfactory bulb	1
stromal cell of endometrium	1
type B pancreatic cell	1
granulocyte	1
right adrenal gland	1
right adrenal gland cortex	1
gingival epithelium	1
cerebellar cortex	1
corpus callosum	1
male germ line stem cell (sensu Vertebrata) in testis	1
germinal epithelium of ovary	1
oocyte	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TERT	105	broad	yes	stromal cell of endometrium, type B pancreatic cell, olfactory bulb
TINF2	144	ubiquitous	marker	granulocyte, right adrenal gland, right adrenal gland cortex
DKC1	287	ubiquitous	marker	secondary oocyte, sural nerve, gingival epithelium
RTEL1	134	ubiquitous	yes	sural nerve, right hemisphere of cerebellum, cerebellar hemisphere
ACD	282	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
PARN	134	ubiquitous	marker	calcaneal tendon, corpus callosum, male germ line stem cell (sensu Vertebrata) in testis
POT1	279	ubiquitous	marker	secondary oocyte, germinal epithelium of ovary, calcaneal tendon
DCLRE1B	224	ubiquitous	yes	secondary oocyte, primordial germ cell in gonad, oocyte

Protein interactions among cohort

Intra-cohort edges: 16.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TERT	5,717
DKC1	4,882
RTEL1	2,324
POT1	1,842
TINF2	1,769
PARN	1,532
DCLRE1B	1,528
ACD	1,044

Intra-cohort edges

A	B	Sources
ACD	POT1	biogrid_interaction, intact, string_interaction
ACD	TERT	string_interaction
ACD	TINF2	biogrid_interaction, intact, string_interaction
DCLRE1B	POT1	biogrid_interaction, string_interaction
DCLRE1B	TINF2	biogrid_interaction, string_interaction
DKC1	PARN	string_interaction
DKC1	RTEL1	string_interaction
DKC1	TERT	intact, string_interaction
DKC1	TINF2	string_interaction
PARN	RTEL1	string_interaction
PARN	TINF2	string_interaction
POT1	TERT	string_interaction
POT1	TINF2	biogrid_interaction, intact, string_interaction
RTEL1	TERT	string_interaction
RTEL1	TINF2	string_interaction
TERT	TINF2	string_interaction

Structural data

PDB: 8 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TERT	O14746	23
ACD	Q96AP0	19
POT1	Q9NUX5	14
DKC1	O60832	7
DCLRE1B	Q9H816	5
TINF2	Q9BSI4	3
RTEL1	Q9NZ71	3
PARN	O95453	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 49. Enrichment computed across 8 evidence-associated genes (8 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 8 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	6	342.6×	8e-14	TERT, TINF2, DKC1, RTEL1, POT1, ACD
Telomere C-strand synthesis initiation	3	305.9×	1e-06	TINF2, POT1, ACD
Processive synthesis on the C-strand of the telomere	3	285.5×	1e-06	TINF2, POT1, ACD
Telomere C-strand (Lagging Strand) Synthesis	3	285.5×	1e-06	TINF2, POT1, ACD
Removal of the Flap Intermediate from the C-strand	3	237.9×	2e-06	TINF2, POT1, ACD
Extension of Telomeres	3	225.4×	2e-06	TERT, RTEL1, ACD
Polymerase switching on the C-strand of the telomere	3	158.6×	5e-06	TINF2, POT1, ACD
Telomere Maintenance	3	138.2×	6e-06	TERT, RTEL1, ACD
Packaging Of Telomere Ends	3	82.4×	3e-05	TINF2, POT1, ACD
Chromosome Maintenance	3	79.3×	3e-05	TERT, RTEL1, ACD
Recognition and association of DNA glycosylase with site containing an affected purine	3	76.5×	3e-05	TINF2, POT1, ACD
Cleavage of the damaged purine	3	76.5×	3e-05	TINF2, POT1, ACD
Recognition and association of DNA glycosylase with site containing an affected pyrimidine	3	69.1×	3e-05	TINF2, POT1, ACD
Cleavage of the damaged pyrimidine	3	69.1×	3e-05	TINF2, POT1, ACD
Inhibition of DNA recombination at telomere	3	63.0×	4e-05	TINF2, POT1, ACD
DNA Damage/Telomere Stress Induced Senescence	3	61.2×	4e-05	TINF2, POT1, ACD
Meiotic synapsis	3	52.9×	5e-05	TINF2, POT1, ACD
Cell Cycle	3	13.5×	0.003	TERT, RTEL1, ACD
DNA Repair	2	24.6×	0.007	RTEL1, ACD
Depurination	1	203.9×	0.011	ACD
Regulation of MITF-M-dependent genes involved in DNA replication, damage repair and senescence	1	203.9×	0.011	TERT
Depyrimidination	1	119.0×	0.019	ACD
Base-Excision Repair, AP Site Formation	1	109.8×	0.019	ACD
Cytosolic iron-sulfur cluster assembly	1	95.2×	0.021	RTEL1
Base Excision Repair	1	89.2×	0.022	ACD
KSRP (KHSRP) binds and destabilizes mRNA	1	79.3×	0.023	PARN
Resolution of D-Loop Structures	1	79.3×	0.023	RTEL1
Deadenylation of mRNA	1	54.9×	0.032	PARN
ATF4 activates genes in response to endoplasmic reticulum stress	1	51.0×	0.033	PARN
Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)	1	49.2×	0.033	RTEL1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 8 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
telomere capping	4	648.1×	1e-09	TINF2, POT1, DCLRE1B, ACD
telomere maintenance via telomerase	4	366.4×	8e-09	TERT, DKC1, POT1, ACD
telomere assembly	3	1579.9×	9e-09	TINF2, POT1, ACD
positive regulation of telomere maintenance	4	255.3×	2e-08	TINF2, RTEL1, POT1, ACD
establishment of protein localization to telomere	3	789.9×	7e-08	TERT, POT1, ACD
telomere maintenance	4	133.8×	2e-07	TERT, RTEL1, DCLRE1B, ACD
negative regulation of telomere maintenance via telomerase	3	274.8×	1e-06	TINF2, POT1, ACD
positive regulation of telomere maintenance via telomerase	3	274.8×	1e-06	DKC1, POT1, PARN
box H/ACA sno(s)RNA 3’-end processing	2	2106.5×	2e-06	DKC1, PARN
telomerase RNA stabilization	2	1053.2×	1e-05	DKC1, PARN
regulation of telomerase RNA localization to Cajal body	2	1053.2×	1e-05	DKC1, PARN
protection from non-homologous end joining at telomere	2	601.9×	3e-05	DCLRE1B, ACD
protein localization to chromosome, telomeric region	2	383.0×	8e-05	TINF2, ACD
DNA strand displacement	1	2106.5×	0.002	RTEL1
RNA-templated transcription	1	2106.5×	0.002	TERT
DNA strand elongation	1	2106.5×	0.002	TERT
positive regulation of DNA strand elongation	1	2106.5×	0.002	POT1
siRNA transcription	1	2106.5×	0.002	TERT
positive regulation of transdifferentiation	1	2106.5×	0.002	TERT
regulation of telomere maintenance via telomere lengthening	1	2106.5×	0.002	TINF2
negative regulation of telomere maintenance in response to DNA damage	1	2106.5×	0.002	RTEL1
positive regulation of telomeric loop disassembly	1	2106.5×	0.002	RTEL1
positive regulation of telomeric D-loop disassembly	1	2106.5×	0.002	POT1
RNA-templated DNA biosynthetic process	1	1053.2×	0.003	TERT
RNA modification	1	1053.2×	0.003	PARN
telomeric loop formation	1	1053.2×	0.003	DCLRE1B
segmentation	1	1053.2×	0.003	ACD
positive regulation of hair cycle	1	1053.2×	0.003	TERT
telomeric loop disassembly	1	1053.2×	0.003	RTEL1
lncRNA processing	1	1053.2×	0.003	PARN

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 2 · Undrugged: 6

Druggability breadth: 5 of 8 evidence-associated genes (62%) 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
DKC1	1	2
TINF2	0	0
RTEL1	0	0
ACD	0	0
PARN	0	0
POT1	0	0
DCLRE1B	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
MOLIBRESIB	2	DKC1

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
DKC1	8	Binding:8
PARN	1	Binding:1
POT1	1	Binding:1
DCLRE1B	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: 8; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

11 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
MOLIBRESIB	2	DKC1

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	1	DKC1
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	6	TINF2, RTEL1, ACD, PARN, POT1, DCLRE1B

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TINF2	0	—
RTEL1	0	—
ACD	0	—
PARN	1	—
POT1	1	—
DCLRE1B	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 3.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	2
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01659606	PHASE2	ACTIVE_NOT_RECRUITING	Radiation- and Alkylator-free Bone Marrow Transplantation Regimen for Patients With Dyskeratosis Congenita
NCT04232085	PHASE2	RECRUITING	Regenerative Medicine to Restore Hematopoiesis and Immune Function in Immunodeficiencies and Inherited Bone Marrow Failures
NCT06817590	PHASE1	RECRUITING	Nucleoside Therapy in Patients With Telomere Biology Disorders

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
FLUDARABINE PHOSPHATE	4	2
DOXECITINE	2	1