Dyskeratosis congenita

Summary

Dyskeratosis congenita (MONDO:0015780) is a disease (an umbrella term covering 16 Mondo subtypes) caused by variants in CTC1 and NPM1, with 29 cohort genes and 18 clinical trials. The dominant Reactome pathway is Telomere Extension By Telomerase (8 cohort genes). Top therapeutic interventions include fludarabine phosphate, danazol, and alefacept.

At a glance

• Prevalence: 1-9 / 1 000 000 (Europe) [Orphanet-validated]
• Causal genes: CTC1 (GenCC Definitive), NPM1 (GenCC Strong)
• Umbrella term: 16 Mondo subtypes
• Cohort genes: 29
• ClinVar variants: 5,606
• Phenotypes (HPO): 62
• Clinical trials: 18

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000	0.1	Europe	Validated

Signs & symptoms

Clinical features (HPO)

62 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0001034	Hypermelanotic macule	Very frequent (80-99%)
HP:0001231	Abnormal fingernail morphology	Very frequent (80-99%)
HP:0001873	Thrombocytopenia	Very frequent (80-99%)
HP:0001874	Abnormality of neutrophils	Very frequent (80-99%)
HP:0001903	Anemia	Very frequent (80-99%)
HP:0002745	Oral leukoplakia	Very frequent (80-99%)
HP:0008066	Abnormal blistering of the skin	Very frequent (80-99%)
HP:0008404	Nail dystrophy	Very frequent (80-99%)
HP:0012733	Macule	Very frequent (80-99%)
HP:0000008	Abnormal morphology of female internal genitalia	Frequent (30-79%)
HP:0000164	Abnormality of the dentition	Frequent (30-79%)
HP:0000600	Abnormality of the pharynx	Frequent (30-79%)
HP:0000668	Hypodontia	Frequent (30-79%)
HP:0000670	Carious teeth	Frequent (30-79%)
HP:0000679	Taurodontia	Frequent (30-79%)
HP:0000704	Periodontitis	Frequent (30-79%)
HP:0000975	Hyperhidrosis	Frequent (30-79%)
HP:0001053	Hypopigmented skin patches	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001511	Intrauterine growth retardation	Frequent (30-79%)
HP:0001928	Abnormality of coagulation	Frequent (30-79%)
HP:0002024	Malabsorption	Frequent (30-79%)
HP:0002205	Recurrent respiratory infections	Frequent (30-79%)
HP:0002575	Tracheoesophageal fistula	Frequent (30-79%)
HP:0002664	Neoplasm	Frequent (30-79%)
HP:0002757	Recurrent fractures	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0005374	Cellular immunodeficiency	Frequent (30-79%)
HP:0005528	Bone marrow hypocellularity	Frequent (30-79%)
HP:0008065	Aplasia/Hypoplasia of the skin	Frequent (30-79%)
HP:0008070	Sparse hair	Frequent (30-79%)
HP:0008661	Urethral stenosis	Frequent (30-79%)
HP:0010450	Esophageal stenosis	Frequent (30-79%)
HP:0010624	Aplastic/hypoplastic toenail	Frequent (30-79%)
HP:0012732	Anorectal anomaly	Frequent (30-79%)
HP:0100585	Telangiectasia of the skin	Frequent (30-79%)
HP:0100670	Rough bone trabeculation	Frequent (30-79%)
HP:0200042	Skin ulcer	Frequent (30-79%)
HP:0000035	Abnormal testis morphology	Occasional (5-29%)
HP:0000327	Hypoplasia of the maxilla	Occasional (5-29%)
HP:0000365	Hearing impairment	Occasional (5-29%)
HP:0000498	Blepharitis	Occasional (5-29%)
HP:0000499	Abnormal eyelash morphology	Occasional (5-29%)
HP:0000518	Cataract	Occasional (5-29%)
HP:0000534	Abnormal eyebrow morphology	Occasional (5-29%)
HP:0000819	Diabetes mellitus	Occasional (5-29%)
HP:0000939	Osteoporosis	Occasional (5-29%)
HP:0000982	Palmoplantar keratoderma	Occasional (5-29%)
HP:0001394	Cirrhosis	Occasional (5-29%)
HP:0001399	Hepatic failure	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	dyskeratosis congenita
Mondo ID	MONDO:0015780
MeSH	D019871
OMIM	127550
Orphanet	1775
DOID	DOID:2729
ICD-11	1531033936
NCIT	C111802
SNOMED CT	74911008
UMLS	C0265965
MedGen	78580
GARD	0010905
MedDRA	10062759
NORD	1071
Is cancer (heuristic)	no

Also known as: DC · DKC · dyskeratosis congenita · Hoyeraal-Hreidarsson syndrome · Zinsser Cole Engman syndrome · Zinsser-Engman-Cole syndrome

Data availability: 5,606 ClinVar variants · 15 GenCC gene-disease records · 17 cell lines.

Disease family

An umbrella term covering 16 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › hereditary neoplastic syndrome › dyskeratosis congenita

Related subtypes (116): mosaic variegated aneuploidy syndrome, tuberous sclerosis, hereditary breast ovarian cancer syndrome, hereditary multiple osteochondromas, nevoid basal cell carcinoma syndrome, leukemia, chronic lymphocytic, susceptibility to, 2, blue rubber bleb nevus, cherubism, Beckwith-Wiedemann syndrome, multiple self-healing squamous epithelioma, erythroleukemia, familial, susceptibility to, goiter, multinodular 1, with or without Sertoli-Leydig cell tumors, hyperparathyroidism 2 with jaw tumors, Kaposi sarcoma, susceptibility to, hereditary leiomyomatosis and renal cell cancer, susceptibility to uveal melanoma, melanoma and neural system tumor syndrome, nasopharyngeal carcinoma, susceptibility to, 2, WAGR syndrome, neuroblastoma, susceptibility to, 1, Rothmund-Thomson syndrome, mismatch repair cancer syndrome 1, Wiskott-Aldrich syndrome, N syndrome, hereditary thrombocytopenia and hematologic cancer predisposition syndrome, prostate cancer/brain cancer susceptibility, Brooke-Spiegler syndrome, pancreatic cancer, susceptibility to, 1, Carney-Stratakis syndrome, nasopharyngeal carcinoma, susceptibility to, 1, ovarian cancer, susceptibility to, 1, colorectal cancer, susceptibility to, 1, lung cancer susceptibility 1, leukemia, chronic lymphocytic, susceptibility to, 1, Kostmann syndrome, colorectal cancer, susceptibility to, 2, colorectal cancer, susceptibility to, 3, colorectal cancer, susceptibility to, 5, colorectal cancer, susceptibility to, 6, colorectal cancer, susceptibility to, 7, leukemia, chronic lymphocytic, susceptibility to, 3, leukemia, chronic lymphocytic, susceptibility to, 4, leukemia, chronic lymphocytic, susceptibility to, 5, lung cancer susceptibility 3, colorectal cancer, susceptibility to, 8, colorectal cancer, susceptibility to, 9, colorectal cancer, susceptibility to, 10, colorectal cancer, susceptibility to, 11, lung cancer susceptibility 4, neuroblastoma, susceptibility to, 3, neuroblastoma, susceptibility to, 4, neuroblastoma, susceptibility to, 5, neuroblastoma, susceptibility to, 6, leukemia, acute lymphocytic, susceptibility to, 1, leukemia, acute lymphocytic, susceptibility to, 2, lung cancer susceptibility 5, BAP1-related tumor predisposition syndrome, familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome, Maffucci syndrome, basal cell carcinoma, susceptibility to, 7, colorectal cancer, susceptibility to, 12, leukemia, acute lymphoblastic, susceptibility to, 3, cholangiocarcinoma, susceptibility to, progeroid features-hepatocellular carcinoma predisposition syndrome, neuroblastoma, susceptibility to, 7, DDX41-related hematologic malignancy predisposition syndrome, nasopharyngeal carcinoma, susceptibility to, 3, familial isolated hyperparathyroidism, intestinal polyposis syndrome, familial rhabdoid tumor, multiple endocrine neoplasia, hereditary pheochromocytoma-paraganglioma, PTEN hamartoma tumor syndrome, familial multiple fibrofolliculoma, hereditary retinoblastoma, familial atypical multiple mole melanoma syndrome, hereditary nonpolyposis colon cancer, Li-Fraumeni syndrome, Cobb syndrome, neurofibromatosis, susceptibility to familial cutaneous melanoma, pancreatic cancer, susceptibility to, 5, leukemia, acute myeloid, susceptibility to, diffuse gastric and lobular breast cancer syndrome with or without cleft lip and/or palate, glioma susceptibility, hemangioma, capillary infantile, susceptibility to, CDH1-related diffuse gastric and lobular breast cancer syndrome, NTHL1-deficiency tumor predisposition syndrome, SAMD9-related spectrum and myeloid neoplasm risk, neuroblastoma, susceptibility to, 2, BARD1-related cancer predisposition, BRCA1-related cancer predisposition, BRCA2-related cancer predisposition, ATM-related cancer predisposition, CHEK2-related cancer predisposition, PALB2-related cancer predisposition, RAD51C-related cancer predisposition, RAD51D-related cancer predisposition, Li-fraumeni-like syndrome, breast cancer, familial, susceptibility to, 1, breast cancer, familial, susceptibility to, 2, breast cancer, familial, susceptibility to, 3, colorectal cancer, susceptibility to, 4, colorectal cancer, susceptibility to, on chromosome 15, ovarian cancer, familial, susceptibility to, 1, ovarian cancer, familial, susceptibility to, 2, ovarian cancer, familial, susceptibility to, 3, inherited hematologic cancer-predisposing syndrome, mosaic neurofibromatosis/schwannomatosis, tumor predisposition syndrome 2, prostate cancer, hereditary, X-linked 3, follicular lymphoma, susceptibility to, GPR161-related medulloblastoma predisposition, SAMD9L-related spectrum and myeloid neoplasm risk, HAVCR2-related cancer predisposition, EGLN1-related erythrocytosis and pheochromocytoma/paraganglioma predisposition

Subtypes (16): dyskeratosis congenita, autosomal dominant 1, dyskeratosis congenita, autosomal recessive 1, Revesz syndrome, dyskeratosis congenita, autosomal recessive 2, dyskeratosis congenita, autosomal recessive 3, dyskeratosis congenita, autosomal dominant 2, dyskeratosis congenita, autosomal dominant 3, dyskeratosis congenita, autosomal recessive 6, dyskeratosis congenita, autosomal dominant 6, autosomal recessive dyskeratosis congenita 4, dyskeratosis congenita, digenic, DKC1-related disorder, dyskeratosis congenita, autosomal dominant 4, dyskeratosis congenita, autosomal recessive 7, dyskeratosis congenita and related telomere biology disorder, dyskeratosis congenita, autosomal recessive 8

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

600 retrieved; paginated sample, class counts are floors:

297 likely benign, 217 uncertain significance, 49 conflicting classifications of pathogenicity, 9 benign, 8 pathogenic, 8 pathogenic/likely pathogenic, 8 benign/likely benign, 4 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1060669	NM_025099.6(CTC1):c.3538C>T (p.Gln1180Ter)	CTC1	Pathogenic	criteria provided, single submitter
1071034	NM_025099.6(CTC1):c.1668_1671del (p.Glu557fs)	CTC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072838	NM_025099.6(CTC1):c.458G>A (p.Trp153Ter)	CTC1	Pathogenic	criteria provided, single submitter
1073096	NM_025099.6(CTC1):c.1753C>T (p.Gln585Ter)	CTC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076259	NM_025099.6(CTC1):c.591del (p.Val198fs)	CTC1	Pathogenic	criteria provided, single submitter
1322169	NM_025099.6(CTC1):c.150G>A (p.Trp50Ter)	CTC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1322170	NM_025099.6(CTC1):c.2581G>T (p.Glu861Ter)	CTC1	Pathogenic	criteria provided, multiple submitters, no conflicts
1342131	NM_025099.6(CTC1):c.2T>C (p.Met1Thr)	CTC1	Pathogenic	criteria provided, multiple submitters, no conflicts
1342132	NM_025099.6(CTC1):c.2452C>T (p.Arg818Ter)	CTC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11587	NM_001363.5(DKC1):c.1058C>T (p.Ala353Val)	DKC1	Pathogenic	criteria provided, multiple submitters, no conflicts
11591	NM_001363.5(DKC1):c.146C>T (p.Thr49Met)	DKC1	Pathogenic	criteria provided, multiple submitters, no conflicts
1324185	NM_025099.6(CTC1):c.2T>A (p.Met1Lys)	PFAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068424	NM_001283009.2(RTEL1):c.1236_1266+47del	RTEL1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1338484	NM_001283009.2(RTEL1):c.190C>T (p.Arg64Ter)	RTEL1-TNFRSF6B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12736	NM_198253.3(TERT):c.2594G>A (p.Arg865His)	TERT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1338582	NM_198253.3(TERT):c.570_586dup (p.Arg196fs)	TERT	Pathogenic	criteria provided, multiple submitters, no conflicts
1324186	NM_025099.6(CTC1):c.1818+1G>A	CTC1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1324187	NM_025099.6(CTC1):c.3221+1G>A	CTC1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
11583	NM_001363.5(DKC1):c.109_111del (p.Leu37del)	DKC1	Likely pathogenic	criteria provided, single submitter
1067185	NM_001283009.2(RTEL1):c.2265+1G>T	RTEL1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1015509	NM_025099.6(CTC1):c.2783G>T (p.Cys928Phe)	CTC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1066973	NM_025099.6(CTC1):c.1A>C (p.Met1Leu)	CTC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1067575	NM_025099.6(CTC1):c.2385+2T>C	CTC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1082473	NM_025099.6(CTC1):c.648-9C>T	CTC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1337319	NM_025099.6(CTC1):c.485G>A (p.Arg162His)	CTC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1338142	NM_025099.6(CTC1):c.2345G>C (p.Gly782Ala)	CTC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1346136	NM_025099.6(CTC1):c.221A>G (p.Lys74Arg)	CTC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1010558	NM_001363.5(DKC1):c.1471G>A (p.Asp491Asn)	DKC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1014953	NM_001363.5(DKC1):c.41A>G (p.Lys14Arg)	DKC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1016074	NM_001363.5(DKC1):c.487A>G (p.Ile163Val)	DKC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 89 · Orphanet: 69 · 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
CTC1	Definitive	Autosomal recessive	dyskeratosis congenita	6
DKC1	Definitive	X-linked	dyskeratosis congenita, X-linked	5
PARN	Definitive	Autosomal recessive	dyskeratosis congenita, autosomal recessive 6	8
RTEL1	Definitive	Autosomal recessive	dyskeratosis congenita, autosomal recessive 5	12
TERT	Definitive	Autosomal recessive	dyskeratosis congenita, autosomal dominant 2	20
TINF2	Definitive	Autosomal dominant	dyskeratosis congenita, autosomal dominant 3	11
NHP2	Strong	Autosomal recessive	dyskeratosis congenita, autosomal recessive 2	5
NOP10	Strong	Autosomal recessive	dyskeratosis congenita, autosomal recessive 1	8
NPM1	Strong	Autosomal dominant	dyskeratosis congenita	3
WRAP53	Strong	Autosomal recessive	dyskeratosis congenita, autosomal recessive 3	6
USB1	Supportive	Autosomal dominant	dyskeratosis congenita	5

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
NHP2	Orphanet:1775	Dyskeratosis congenita
NOP10	Orphanet:1775	Dyskeratosis congenita
RTEL1	Orphanet:1775	Dyskeratosis congenita
RTEL1	Orphanet:2032	Idiopathic pulmonary fibrosis
RTEL1	Orphanet:3322	Hoyeraal-Hreidarsson syndrome
WRAP53	Orphanet:1775	Dyskeratosis congenita
CTC1	Orphanet:1775	Dyskeratosis congenita
CTC1	Orphanet:313838	Coats plus syndrome
DKC1	Orphanet:1775	Dyskeratosis congenita
DKC1	Orphanet:3322	Hoyeraal-Hreidarsson syndrome
NPM1	Orphanet:1775	Dyskeratosis congenita
NPM1	Orphanet:300865	Primary cutaneous anaplastic large cell lymphoma
NPM1	Orphanet:402026	Acute myeloid leukemia with NPM1 somatic mutations
NPM1	Orphanet:520	Acute promyelocytic leukemia
NPM1	Orphanet:98833	Acute myeloblastic leukemia without maturation
NPM1	Orphanet:98834	Acute myeloblastic leukemia with maturation
NPM1	Orphanet:98842	Lymphomatoid papulosis
PARN	Orphanet:1775	Dyskeratosis congenita
PARN	Orphanet:2032	Idiopathic pulmonary fibrosis
PARN	Orphanet:3322	Hoyeraal-Hreidarsson syndrome
USB1	Orphanet:1775	Dyskeratosis congenita
USB1	Orphanet:221046	Poikiloderma with neutropenia
TGM1	Orphanet:100976	Bathing suit ichthyosis
TGM1	Orphanet:281122	Self-improving collodion baby
TGM1	Orphanet:281127	Acral self-healing collodion baby
TGM1	Orphanet:313	Lamellar ichthyosis
TGM1	Orphanet:79394	Congenital ichthyosiform erythroderma
TP53	Orphanet:1333	Familial pancreatic carcinoma
TP53	Orphanet:145	Hereditary breast and/or ovarian cancer syndrome
TP53	Orphanet:1501	Adrenocortical carcinoma
TP53	Orphanet:210159	Adult hepatocellular carcinoma
TP53	Orphanet:251576	Gliosarcoma
TP53	Orphanet:251579	Giant cell glioblastoma
TP53	Orphanet:251899	Choroid plexus carcinoma
TP53	Orphanet:2807	Papilloma of choroid plexus
TP53	Orphanet:293199	Pleomorphic rhabdomyosarcoma
TP53	Orphanet:3318	Essential thrombocythemia
TP53	Orphanet:524	Li-Fraumeni syndrome

Cohort genes → proteins

29 cohort genes, 24 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	29

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
NHP2	HGNC:14377	ENSG00000145912	Q9NX24	H/ACA ribonucleoprotein complex subunit 2	gencc,clinvar
NOP10	HGNC:14378	ENSG00000182117	Q9NPE3	H/ACA ribonucleoprotein complex subunit 3	gencc,clinvar
RTEL1	HGNC:15888	ENSG00000258366	Q9NZ71	Regulator of telomere elongation helicase 1	gencc,clinvar
WRAP53	HGNC:25522	ENSG00000141499	Q9BUR4	Telomerase Cajal body protein 1	gencc,clinvar
CTC1	HGNC:26169	ENSG00000178971	Q2NKJ3	CST complex subunit CTC1	gencc,clinvar
DKC1	HGNC:2890	ENSG00000130826	O60832	H/ACA ribonucleoprotein complex subunit DKC1	gencc,clinvar
NPM1	HGNC:7910	ENSG00000181163	P06748	Nucleophosmin	gencc,clinvar
PARN	HGNC:8609	ENSG00000140694	O95453	Poly(A)-specific ribonuclease PARN	gencc,clinvar
USB1	HGNC:25792	ENSG00000103005	Q9BQ65	U6 snRNA phosphodiesterase 1	gencc
TGM1	HGNC:11777	ENSG00000092295	P22735	Protein-glutamine gamma-glutamyltransferase K	clinvar
TP53	HGNC:11998	ENSG00000141510	P04637	Cellular tumor antigen p53	clinvar
TRG-GCC2-6	HGNC:12273			tRNA-Gly (anticodon GCC) 2-6	clinvar
TYMS	HGNC:12441	ENSG00000176890	P04818	Thymidylate synthase	clinvar
POT1	HGNC:17284	ENSG00000128513	Q9NUX5	Protection of telomeres protein 1	clinvar
ODF4	HGNC:19056	ENSG00000184650	Q2M2E3	Outer dense fiber protein 4	clinvar
ZCCHC8	HGNC:25265	ENSG00000033030	Q6NZY4	Zinc finger CCHC domain-containing protein 8	clinvar
RMND5B	HGNC:26181	ENSG00000145916	Q96G75	E3 ubiquitin-protein transferase RMND5B	clinvar
ENOSF1	HGNC:30365	ENSG00000132199	Q7L5Y1	Mitochondrial enolase superfamily member 1	clinvar
DUSP9	HGNC:3076	ENSG00000130829	Q99956	Dual specificity protein phosphatase 9	clinvar
TRS-AGA2-6	HGNC:34747			tRNA-Ser (anticodon AGA) 2-6	clinvar
TRT-AGT1-2	HGNC:34785			tRNA-Thr (anticodon AGT) 1-2	clinvar
TRI-AAT4-1	HGNC:34961			tRNA-Ile (anticodon AAT) 4-1	clinvar
GMPR2	HGNC:4377	ENSG00000100938	Q9P2T1	GMP reductase 2	clinvar
RTEL1-TNFRSF6B	HGNC:44095	ENSG00000026036		RTEL1-TNFRSF6B readthrough (NMD candidate)	clinvar
ABCD1	HGNC:61	ENSG00000101986	P33897	ATP-binding cassette sub-family D member 1	clinvar
PFAS	HGNC:8863	ENSG00000178921	O15067	Phosphoribosylformylglycinamidine synthase	clinvar
B4GALT7	HGNC:930	ENSG00000027847	Q9UBV7	Beta-1,4-galactosyltransferase 7	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.
NHP2	H/ACA ribonucleoprotein complex subunit 2	Required for ribosome biogenesis and telomere maintenance.
NOP10	H/ACA ribonucleoprotein complex subunit 3	Required for ribosome biogenesis and telomere maintenance.
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.
WRAP53	Telomerase Cajal body protein 1	RNA chaperone that plays a key role in telomere maintenance and RNA localization to Cajal bodies.
CTC1	CST complex subunit CTC1	Component of the CST complex proposed to act as a specialized replication factor promoting DNA replication under conditions of replication stress or natural replication barriers such as the telomere duplex.
DKC1	H/ACA ribonucleoprotein complex subunit DKC1	Catalytic subunit of H/ACA small nucleolar ribonucleoprotein (H/ACA snoRNP) complex, which catalyzes pseudouridylation of rRNA.
NPM1	Nucleophosmin	Involved in diverse cellular processes such as ribosome biogenesis, centrosome duplication, protein chaperoning, histone assembly, cell proliferation, and regulation of tumor suppressors p53/TP53 and ARF.
PARN	Poly(A)-specific ribonuclease PARN	3’-exoribonuclease that has a preference for poly(A) tails of mRNAs, thereby efficiently degrading poly(A) tails.
USB1	U6 snRNA phosphodiesterase 1	3’-5’ RNA exonuclease that trims the 3’ end of oligo(U) and oligo(A) tracts of the pre-U6 small nuclear RNA (snRNA) molecule, leading to the formation of a mature U6 snRNA 3’ end-terminated with a 2’,3’-cyclic phosphate.
TGM1	Protein-glutamine gamma-glutamyltransferase K	Catalyzes the cross-linking of proteins and the conjugation of polyamines to proteins.
TP53	Cellular tumor antigen p53	Multifunctional transcription factor that induces cell cycle arrest, DNA repair or apoptosis upon binding to its target DNA sequence.
TYMS	Thymidylate synthase	Catalyzes the reductive methylation of 2’-deoxyuridine 5’-monophosphate (dUMP) to thymidine 5’-monophosphate (dTMP), using the cosubstrate, 5,10- methylenetetrahydrofolate (CH2H4folate) as a 1-carbon donor and reductant and contributes to…
POT1	Protection of telomeres protein 1	Component of the telomerase ribonucleoprotein (RNP) complex that is essential for the replication of chromosome termini.
ODF4	Outer dense fiber protein 4	Component of the outer dense fibers (ODF) of spermatozoa which could be involved in sperm tail structure, sperm movement and general organization of cellular cytoskeleton.
ZCCHC8	Zinc finger CCHC domain-containing protein 8	Scaffolding subunit of the trimeric nuclear exosome targeting (NEXT) complex that is involved in the surveillance and turnover of aberrant transcripts and non-coding RNAs.
RMND5B	E3 ubiquitin-protein transferase RMND5B	Core component of the CTLH E3 ubiquitin-protein ligase complex that selectively accepts ubiquitin from UBE2H and mediates ubiquitination and subsequent proteasomal degradation of the transcription factor HBP1.
ENOSF1	Mitochondrial enolase superfamily member 1	Plays a role in the catabolism of L-fucose, a sugar that is part of the carbohydrates that are attached to cellular glycoproteins.
DUSP9	Dual specificity protein phosphatase 9	Inactivates MAP kinases.
GMPR2	GMP reductase 2	Catalyzes the irreversible NADPH-dependent deamination of GMP to IMP.
ABCD1	ATP-binding cassette sub-family D member 1	ATP-dependent transporter of the ATP-binding cassette (ABC) family involved in the transport of very long chain fatty acid (VLCFA)-CoA from the cytosol to the peroxisome lumen.
PFAS	Phosphoribosylformylglycinamidine synthase	Phosphoribosylformylglycinamidine synthase involved in the purines biosynthetic pathway.
B4GALT7	Beta-1,4-galactosyltransferase 7	Required for the biosynthesis of the tetrasaccharide linkage region of proteoglycans, especially for small proteoglycans in skin fibroblasts.

Protein-family classification

Druggable: 7 · Difficult: 4 · Unknown: 18 · Druggable fraction: 0.24

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
Phosphatase	1	2.9×	0.550
Transporter	1	2.7×	0.550
Enzyme (other)	4	1.6×	0.550
Other/Unknown	18	1.1×	0.550
Antibody/Immunoglobulin	1	1.0×	0.816
Transcription factor	3	0.8×	0.816
Scaffold/PPI	1	0.6×	0.823

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
NHP2	Other/Unknown	no		H/ACA_rnp_Nhp2-like, Ribosomal_eL8/eL30/eS12/Gad45, Ribosomal_eL8/Nhp2
NOP10	Other/Unknown	no		H/ACA_rnp_Nop10, H/ACA_rnp_Nop10_sf
RTEL1	Other/Unknown	no		Helicase-like_DEXD_c2, ATP-dep_Helicase_C, RAD3-like_helicase_DEAD
WRAP53	Scaffold/PPI	no		WD40_rpt, WD40/YVTN_repeat-like_dom_sf, WD40_repeat_dom_sf
CTC1	Other/Unknown	no		CTC1, CTC1-like
DKC1	Other/Unknown	no		PUA, PsdUridine_synth_N, Uncharacterised_CHP00451
NPM1	Other/Unknown	no		Nucleoplasmin, Nucleoplasmin_core_dom, NPM1_C
PARN	Other/Unknown	no		R3H_dom, RNase_CAF1, RNaseH-like_sf
USB1	Other/Unknown	no		Usb1
TGM1	Antibody/Immunoglobulin	yes	2.3.2.13	Transglutaminase_N, Transglutaminase-like, Transglutaminase_C
TP53	Transcription factor	no		p53_tumour_suppressor, p53-like_TF_DNA-bd_sf, p53_tetrameristn
TRG-GCC2-6	Other/Unknown	no
TYMS	Enzyme (other)	yes	2.1.1.45	Thymidylate_synthase, Thymidylate_synthase_AS, Thymidate_synth/dCMP_Mease_dom
POT1	Other/Unknown	no		Telomer_end-bd_POT1/Cdc13, NA-bd_OB-fold, POT1
ODF4	Other/Unknown	no
ZCCHC8	Transcription factor	no		Znf_CCHC, PSP_pro-rich, NEXT_complex_subunit_ZCCHC8
RMND5B	Transcription factor	no		LisH, CTLH_C, CRA_dom
ENOSF1	Other/Unknown	no		Mandelate_racemase_N, Mandelate_racemase_C, Mandel_Rmase/mucon_lact_enz_CS
DUSP9	Phosphatase	yes	3.1.3.48	Dual-sp_phosphatase_cat-dom, Tyr_Pase_dom, Rhodanese-like_dom
TRS-AGA2-6	Other/Unknown	no
TRT-AGT1-2	Other/Unknown	no
TRI-AAT4-1	Other/Unknown	no
GMPR2	Enzyme (other)	yes	1.7.1.7	IMP_DH_GMPRt, GMPR, Aldolase_TIM
RTEL1-TNFRSF6B	Other/Unknown	no
ABCD1	Transporter	yes	7.6.2.4	ABC_transporter-like_ATP-bd, AAA+_ATPase, FA_transporter
PFAS	Enzyme (other)	yes	6.3.5.3	PurL_large, PurM-like_C_dom, Class_I_gatase-like
B4GALT7	Enzyme (other)	yes	2.4.1.133	Galactosyl_T, Galactosyl_T_C, Galactosyl_T_N

Expression context

Cohort genes with no expression data: 4.

22 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)	25
unknown	4

Top tissues across cohort

Tissue	Cohort genes
ventricular zone	4
granulocyte	3
right adrenal gland	3
cerebellar hemisphere	3
right hemisphere of cerebellum	3
calcaneal tendon	3
left adrenal gland	3
right adrenal gland cortex	2
esophagus mucosa	2
leukocyte	2
monocyte	2
sural nerve	2
right uterine tube	2
secondary oocyte	2
lower esophagus mucosa	2
ganglionic eminence	2
tendon of biceps brachii	2
embryo	2
left testis	2
right testis	2

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
NHP2	292	ubiquitous	marker	esophagus squamous epithelium, esophagus mucosa, epithelium of esophagus
NOP10	286	ubiquitous	marker	monocyte, rectum, leukocyte
RTEL1	134	ubiquitous	yes	sural nerve, right hemisphere of cerebellum, cerebellar hemisphere
WRAP53	237	ubiquitous	marker	right uterine tube, epithelium of bronchus, bronchus
CTC1	198	ubiquitous	marker	granulocyte, right hemisphere of cerebellum, cerebellar hemisphere
DKC1	287	ubiquitous	marker	secondary oocyte, sural nerve, gingival epithelium
NPM1	276	ubiquitous	marker	calcaneal tendon, left ovary, ventricular zone
PARN	134	ubiquitous	marker	calcaneal tendon, corpus callosum, male germ line stem cell (sensu Vertebrata) in testis
USB1	259	ubiquitous	marker	granulocyte, leukocyte, monocyte
TGM1	135	broad	marker	lower esophagus mucosa, esophagus mucosa, skin of leg
TP53	223	ubiquitous	marker	ventricular zone, ganglionic eminence, tendon of biceps brachii
TRG-GCC2-6
TYMS	262	ubiquitous	marker	ventricular zone, embryo, trabecular bone tissue
POT1	279	ubiquitous	marker	secondary oocyte, germinal epithelium of ovary, calcaneal tendon
ODF4	41	tissue_specific	yes	left testis, sperm, right testis
ZCCHC8	282	ubiquitous	marker	cervix squamous epithelium, sperm, endothelial cell
RMND5B	273	ubiquitous	marker	lower esophagus mucosa, left testis, right testis
ENOSF1	289	ubiquitous	marker	right uterine tube, mucosa of stomach, right lobe of thyroid gland
DUSP9	107	broad	marker	placenta, renal medulla, adult mammalian kidney
TRS-AGA2-6
TRT-AGT1-2
TRI-AAT4-1
GMPR2	134	ubiquitous	marker	right adrenal gland, right adrenal gland cortex, left adrenal gland
RTEL1-TNFRSF6B	135		marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellum
ABCD1	201	ubiquitous	marker	ileal mucosa, left adrenal gland cortex, left adrenal gland
PFAS	264	ubiquitous	marker	ventricular zone, embryo, ganglionic eminence
B4GALT7	259	ubiquitous	marker	tendon of biceps brachii, right adrenal gland, left adrenal gland

Protein interactions among cohort

Intra-cohort edges: 47.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TP53	22,736
NPM1	7,589
TERT	5,717
DKC1	4,882
NHP2	4,751
TYMS	4,628
NOP10	2,488
RTEL1	2,324
GMPR2	2,075
TGM1	1,978

Intra-cohort edges

A	B	Sources
CTC1	DKC1	string_interaction
CTC1	NHP2	string_interaction
CTC1	NOP10	string_interaction
CTC1	PARN	string_interaction
CTC1	POT1	string_interaction
CTC1	RTEL1	string_interaction
CTC1	TERT	string_interaction
CTC1	TINF2	string_interaction
CTC1	USB1	string_interaction
CTC1	WRAP53	string_interaction
DKC1	NHP2	intact, string_interaction
DKC1	NOP10	biogrid_interaction, intact, string_interaction
DKC1	PARN	string_interaction
DKC1	RTEL1	string_interaction
DKC1	TERT	intact, string_interaction
DKC1	TINF2	string_interaction
DKC1	USB1	string_interaction
DKC1	WRAP53	biogrid_interaction, intact, string_interaction
ENOSF1	TYMS	string_interaction
GMPR2	PFAS	string_interaction
NHP2	NOP10	biogrid_interaction, intact, string_interaction
NHP2	RTEL1	string_interaction
NHP2	TERT	string_interaction
NHP2	TINF2	string_interaction
NHP2	USB1	string_interaction
NHP2	WRAP53	string_interaction
NOP10	POT1	string_interaction
NOP10	RTEL1	string_interaction
NOP10	TERT	string_interaction
NOP10	TINF2	string_interaction
NOP10	USB1	string_interaction
NOP10	WRAP53	intact, string_interaction
NPM1	TP53	string_interaction
PARN	RTEL1	string_interaction
PARN	TINF2	string_interaction
PARN	WRAP53	string_interaction
POT1	TERT	string_interaction
POT1	TINF2	biogrid_interaction, intact, string_interaction
RTEL1	TERT	string_interaction
RTEL1	TINF2	string_interaction
RTEL1	USB1	string_interaction
RTEL1	WRAP53	string_interaction
TERT	TINF2	string_interaction
TERT	WRAP53	intact, string_interaction
TINF2	USB1	string_interaction
TINF2	WRAP53	string_interaction
USB1	WRAP53	string_interaction

Structural data

PDB: 22 · AlphaFold-only: 2 · No structure: 5

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TP53	P04637	313
TYMS	P04818	61
TERT	O14746	23
POT1	Q9NUX5	14
ABCD1	P33897	14
NPM1	P06748	8
ZCCHC8	Q6NZY4	8
NHP2	Q9NX24	7
NOP10	Q9NPE3	7
WRAP53	Q9BUR4	7
CTC1	Q2NKJ3	7
DKC1	O60832	7
USB1	Q9BQ65	5
TINF2	Q9BSI4	3
RTEL1	Q9NZ71	3
PARN	O95453	3
GMPR2	Q9P2T1	3
PFAS	O15067	3
DUSP9	Q99956	2
B4GALT7	Q9UBV7	2
TGM1	P22735	1
ENOSF1	Q7L5Y1	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
RMND5B	Q96G75	90.58
ODF4	Q2M2E3	55.59

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 133. Enrichment computed across 29 evidence-associated genes (21 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 21 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	8	174.0×	4e-15	TERT, TINF2, NHP2, NOP10, RTEL1, WRAP53, DKC1, POT1
Telomere C-strand synthesis initiation	3	116.5×	1e-04	TINF2, CTC1, POT1
Extension of Telomeres	3	85.9×	2e-04	TERT, RTEL1, WRAP53
Polymerase switching on the C-strand of the telomere	3	60.4×	5e-04	TINF2, CTC1, POT1
Telomere Maintenance	3	52.6×	6e-04	TERT, RTEL1, WRAP53
Chromosome Maintenance	3	30.2×	0.003	TERT, RTEL1, WRAP53
rRNA modification in the nucleus and cytosol	3	26.7×	0.003	NHP2, NOP10, DKC1
Processive synthesis on the C-strand of the telomere	2	72.5×	0.004	TINF2, POT1
Telomere C-strand (Lagging Strand) Synthesis	2	72.5×	0.004	TINF2, POT1
DNA Damage/Telomere Stress Induced Senescence	3	23.3×	0.004	TINF2, TP53, POT1
Removal of the Flap Intermediate from the C-strand	2	60.4×	0.006	TINF2, POT1
TP53 regulates transcription of additional cell cycle genes whose exact role in the p53 pathway remain uncertain	2	49.4×	0.008	NPM1, TP53
Loss of function of TP53 in cancer due to loss of tetramerization ability	1	543.8×	0.019	TP53
Association of TriC/CCT with target proteins during biosynthesis	2	27.9×	0.022	WRAP53, TP53
Defective ABCD1 causes ALD	1	271.9×	0.031	ABCD1
Regulation of TP53 Expression	1	271.9×	0.031	TP53
Packaging Of Telomere Ends	2	20.9×	0.032	TINF2, POT1
Recognition and association of DNA glycosylase with site containing an affected purine	2	19.4×	0.033	TINF2, POT1
Cleavage of the damaged purine	2	19.4×	0.033	TINF2, POT1
Recognition and association of DNA glycosylase with site containing an affected pyrimidine	2	17.5×	0.036	TINF2, POT1
Cleavage of the damaged pyrimidine	2	17.5×	0.036	TINF2, POT1
Inhibition of DNA recombination at telomere	2	16.0×	0.041	TINF2, POT1
Transcriptional activation of cell cycle inhibitor p21	1	135.9×	0.042	TP53
Signaling by ALK fusions and activated point mutants	2	14.3×	0.047	NPM1, TP53
TFAP2A acts as a transcriptional repressor during retinoic acid induced cell differentiation	1	108.8×	0.047	NPM1
Meiotic synapsis	2	13.4×	0.047	TINF2, POT1
PKR-mediated signaling	2	13.4×	0.047	NPM1, TP53
Activation of NOXA and translocation to mitochondria	1	90.6×	0.050	TP53
alpha-linolenic (omega3) and linoleic (omega6) acid metabolism	1	90.6×	0.050	ABCD1
RUNX3 regulates CDKN1A transcription	1	77.7×	0.053	TP53

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 24 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	6	183.2×	1e-10	TERT, NHP2, NOP10, WRAP53, DKC1, POT1
snRNA pseudouridine synthesis	3	702.2×	4e-07	NHP2, NOP10, DKC1
rRNA pseudouridine synthesis	3	526.6×	1e-06	NHP2, NOP10, DKC1
negative regulation of telomere maintenance via telomerase	4	122.1×	2e-06	TINF2, CTC1, TP53, POT1
positive regulation of telomere maintenance via telomerase	4	122.1×	2e-06	WRAP53, DKC1, PARN, POT1
telomerase RNA localization to Cajal body	3	300.9×	5e-06	NHP2, NOP10, WRAP53
telomere capping	3	162.0×	3e-05	TINF2, CTC1, POT1
box H/ACA sno(s)RNA 3’-end processing	2	702.2×	6e-05	DKC1, PARN
protein localization to Cajal body	2	702.2×	6e-05	WRAP53, DKC1
replicative senescence	3	123.9×	6e-05	TERT, CTC1, TP53
telomere assembly	2	351.1×	3e-04	TINF2, POT1
telomerase RNA stabilization	2	351.1×	3e-04	DKC1, PARN
regulation of telomerase RNA localization to Cajal body	2	351.1×	3e-04	DKC1, PARN
positive regulation of telomere maintenance	3	63.8×	3e-04	TINF2, RTEL1, POT1
scaRNA localization to Cajal body	2	280.9×	4e-04	WRAP53, DKC1
positive regulation of protein localization to nucleolus	2	234.1×	6e-04	TERT, NPM1
regulation of DNA damage response, signal transduction by p53 class mediator	2	175.5×	9e-04	NPM1, TP53
establishment of protein localization to telomere	2	175.5×	9e-04	TERT, POT1
telomere maintenance	3	33.4×	0.002	TERT, RTEL1, CTC1
bone marrow development	2	127.7×	0.002	CTC1, TP53
DNA biosynthetic process	2	66.9×	0.006	TERT, TYMS
protein import into nucleus	3	18.0×	0.008	TERT, NPM1, TP53
DNA strand displacement	1	702.2×	0.011	RTEL1
RNA-templated transcription	1	702.2×	0.011	TERT
DNA strand elongation	1	702.2×	0.011	TERT
telomere formation via telomerase	1	702.2×	0.011	WRAP53
RNA folding	1	702.2×	0.011	WRAP53
negative regulation of helicase activity	1	702.2×	0.011	TP53
positive regulation of DNA strand elongation	1	702.2×	0.011	POT1
regulation of eIF2 alpha phosphorylation by dsRNA	1	702.2×	0.011	NPM1

Therapeutics

Drug target analysis

Approved (phase 4): 4 · Phase ≥3: 4 · Phased (≥1): 6 · Undrugged: 23

Druggability breadth: 14 of 29 evidence-associated genes (48%) 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
NPM1	CERITINIB
TP53	NITROFURANTOIN
TYMS	FOLIC ACID

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TP53	196	4
TERT	10	4
TYMS	9	4
NPM1	5	4
NHP2	1	2
DKC1	1	2
TINF2	0	0
NOP10	0	0
RTEL1	0	0
WRAP53	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BERBERINE	4	TERT
DOXORUBICIN	4	TERT
CERITINIB	4	NPM1
BOSUTINIB	4	NPM1
CRIZOTINIB	4	NPM1
NITROFURANTOIN	4	TP53
DIOSMIN	4	TP53
VERTEPORFIN	4	TP53
CANDESARTAN CILEXETIL	4	TP53
DIENESTROL	4	TP53
CLOTRIMAZOLE	4	TP53
COLCHICINE	4	TP53
NABUMETONE	4	TP53
SALMETEROL XINAFOATE	4	TP53
AMIODARONE HYDROCHLORIDE	4	TP53
FURAZOLIDONE	4	TP53
AMOXAPINE	4	TP53
RALOXIFENE HYDROCHLORIDE	4	TP53
NICARDIPINE HYDROCHLORIDE	4	TP53
SULCONAZOLE NITRATE	4	TP53
PYRITHIONE ZINC	4	TP53
LACTIC ACID	4	TP53
OXYMETHOLONE	4	TP53
CHLOROXINE	4	TP53
PROPIOLACTONE	4	TP53
CLOMIPRAMINE HYDROCHLORIDE	4	TP53
PHENYL AMINOSALICYLATE	4	TP53
THIORIDAZINE HYDROCHLORIDE	4	TP53
AMITRIPTYLINE HYDROCHLORIDE	4	TP53
ETHOPROPAZINE HYDROCHLORIDE	4	TP53

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 7.

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

Symbol	Assays	Type breakdown
TP53	869	Binding:775, ADMET:83, Functional:10, Toxicity:1
TERT	391	Binding:389, Functional:2
TYMS	376	Binding:373, ADMET:2, Functional:1
NPM1	113	Binding:108, Functional:5
TGM1	11	Binding:11
DKC1	8	Binding:8
NHP2	7	Binding:7
WRAP53	2	Binding:2
PFAS	2	Binding:2
NOP10	1	Binding:1
PARN	1	Binding:1
POT1	1	Binding:1
ZCCHC8	1	Binding:1
GMPR2	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TGM1	2.3.2.13	protein-glutamine gamma-glutamyltransferase
TYMS	2.1.1.45	thymidylate synthase
DUSP9	3.1.3.48	protein-tyrosine-phosphatase
GMPR2	1.7.1.7	GMP reductase
ABCD1	7.6.2.4	ABC-type fatty-acyl-CoA transporter
PFAS	6.3.5.3	phosphoribosylformylglycinamidine synthase
B4GALT7	2.4.1.133, 2.4.1.38	xylosylprotein 4-beta-galactosyltransferase, beta-N-acetylglucosaminylglycopeptide beta-1,4-galactosyltransferase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
TERT	391
NPM1	113
TP53	869
TYMS	376

Pharmacogenomics

Cohort genes with a PharmGKB record: 24; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

30 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
CERITINIB	4	NPM1
BOSUTINIB	4	NPM1
CRIZOTINIB	4	NPM1
NITROFURANTOIN	4	TP53
DIOSMIN	4	TP53
VERTEPORFIN	4	TP53
CANDESARTAN CILEXETIL	4	TP53
DIENESTROL	4	TP53
CLOTRIMAZOLE	4	TP53
COLCHICINE	4	TP53
NABUMETONE	4	TP53
SALMETEROL XINAFOATE	4	TP53
AMIODARONE HYDROCHLORIDE	4	TP53
FURAZOLIDONE	4	TP53
AMOXAPINE	4	TP53
RALOXIFENE HYDROCHLORIDE	4	TP53
NICARDIPINE HYDROCHLORIDE	4	TP53
SULCONAZOLE NITRATE	4	TP53
PYRITHIONE ZINC	4	TP53
LACTIC ACID	4	TP53
OXYMETHOLONE	4	TP53
CHLOROXINE	4	TP53
PROPIOLACTONE	4	TP53
CLOMIPRAMINE HYDROCHLORIDE	4	TP53
PHENYL AMINOSALICYLATE	4	TP53
THIORIDAZINE HYDROCHLORIDE	4	TP53
AMITRIPTYLINE HYDROCHLORIDE	4	TP53
ETHOPROPAZINE HYDROCHLORIDE	4	TP53

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	4	TERT, NPM1, TP53, TYMS
B	Phased (≥1) drug, not yet approved	2	NHP2, DKC1
C	Druggable family + PDB, no drug	6	TGM1, DUSP9, GMPR2, ABCD1, PFAS, B4GALT7
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	17	TINF2, NOP10, RTEL1, WRAP53, CTC1, PARN, USB1, TRG-GCC2-6, POT1, ODF4 (+7 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
NOP10	1	NHP2, DKC1, TERT
WRAP53	2	DKC1, NHP2, TERT
CTC1	0	NHP2
USB1	0	NHP2
ENOSF1	0	TYMS
TINF2	0	—
RTEL1	0	—
PARN	1	—
TGM1	11	—
TRG-GCC2-6	0	—
POT1	1	—
ODF4	0	—
ZCCHC8	1	—
RMND5B	0	—
DUSP9	0	—
TRS-AGA2-6	0	—
TRT-AGT1-2	0	—
TRI-AAT4-1	0	—
GMPR2	1	—
RTEL1-TNFRSF6B	0	—
ABCD1	0	—
PFAS	2	—
B4GALT7	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 18.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	8
PHASE2	5
PHASE1	3
PHASE2/PHASE3	1
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00455312	PHASE2/PHASE3	COMPLETED	Stem Cell Transplant (SCT) for Dyskeratosis Congenita or SAA
NCT01659606	PHASE2	ACTIVE_NOT_RECRUITING	Radiation- and Alkylator-free Bone Marrow Transplantation Regimen for Patients With Dyskeratosis Congenita
NCT03579875	PHASE2	RECRUITING	Alpha/Beta TCD HCT in Patients With Inherited BMF Disorders
NCT04232085	PHASE2	RECRUITING	Regenerative Medicine to Restore Hematopoiesis and Immune Function in Immunodeficiencies and Inherited Bone Marrow Failures
NCT00004787	PHASE2	COMPLETED	Phase II Pilot Study of Granulocyte Colony-Stimulating Factor for Inherited Bone Marrow Failure Syndromes
NCT01001598	PHASE1/PHASE2	TERMINATED	Safety and Efficacy Trial of Danazol in Patients With Fanconi Anemia or Dyskeratosis Congenita
NCT04638517	PHASE2	TERMINATED	The TELO-SCOPE Study: Attenuating Telomere Attrition With Danazol. Is There Scope to Dramatically Improve Health Outcomes for Adults and Children With Pulmonary Fibrosis
NCT06477614	PHASE1	RECRUITING	Anti-cancer DC Cell Vaccination to Treat Solid Tumors
NCT06817590	PHASE1	RECRUITING	Nucleoside Therapy in Patients With Telomere Biology Disorders
NCT01917708	PHASE1	COMPLETED	Bone Marrow Transplant With Abatacept for Non-Malignant Diseases
NCT00027274	Not specified	RECRUITING	Cancer in Inherited Bone Marrow Failure Syndromes
NCT02720679	Not specified	RECRUITING	Investigation of the Genetics of Hematologic Diseases
NCT03050268	Not specified	RECRUITING	Familial Investigations of Childhood Cancer Predisposition
NCT06731036	Not specified	AVAILABLE	Expanded Access to CD34+ Selection Utilizing Miltenyi CliniMACS Prodigy® for Patients Receiving Peripheral Blood Stem Cell Transplantations and Stem Cell Boosts
NCT00499070	Not specified	COMPLETED	Assessing Immune Function in Young Patients With Cytopenia That Did Not Respond to Treatment
NCT01319851	Not specified	TERMINATED	Alefacept and Allogeneic Hematopoietic Stem Cell Transplantation
NCT02162420	Not specified	COMPLETED	Hematopoietic Stem Cell Transplant for Dyskeratosis Congenita or Severe Aplastic Anemia
NCT04959188	Not specified	COMPLETED	Needs Assessment for Individuals and Families Affected by Dyskeratosis Congenita (DC) and Related Telomere Biology Disorders (TBD)

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
FLUDARABINE PHOSPHATE	4	5
DANAZOL	4	2
ALEFACEPT	4	1
FLUDARABINE	3	1
DOXECITINE	2	1
CHEMBL290077	0	1