Autosomal recessive dyskeratosis congenita 4

Summary

Autosomal recessive dyskeratosis congenita 4 (MONDO:0027353) is a disease with 1 cohort gene.

At a glance

• Cohort genes: 1
• ClinVar variants: 5

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive dyskeratosis congenita 4
Mondo ID	MONDO:0027353
DOID	DOID:0070021
UMLS	C3151444
MedGen	462794
GARD	0025496
Is cancer (heuristic)	no

Also known as: dyskeratosis congenita, autosomal recessive 4

Data availability: 5 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › hereditary neoplastic syndrome › dyskeratosis congenita › autosomal recessive dyskeratosis congenita 4

Related subtypes (15): 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, 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

5 retrieved; paginated sample, class counts are floors:

3 conflicting classifications of pathogenicity, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
39108	NM_198253.3(TERT):c.2110C>T (p.Pro704Ser)	TERT	Pathogenic/Likely 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
12730	NM_198253.3(TERT):c.1234C>T (p.His412Tyr)	TERT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
29900	NM_198253.3(TERT):c.2431C>T (p.Arg811Cys)	TERT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
29901	NM_198253.3(TERT):c.2701C>T (p.Arg901Trp)	TERT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 9 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

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

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
TERT	HGNC:11730	ENSG00000164362	O14746	Telomerase reverse transcriptase	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.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TERT	Other/Unknown	no		RT_dom, Telomerase_RT, Telomerase_RBD

Expression context

Cohort genes with no expression data: 0.

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
olfactory bulb	1
stromal cell of endometrium	1
type B pancreatic cell	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

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TERT	5,717

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TERT	O14746	23

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. 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
Regulation of MITF-M-dependent genes involved in DNA replication, damage repair and senescence	1	1631.4×	0.008	TERT
Extension of Telomeres	1	601.0×	0.009	TERT
Telomere Extension By Telomerase	1	456.8×	0.009	TERT
Telomere Maintenance	1	368.4×	0.009	TERT
Chromosome Maintenance	1	211.5×	0.012	TERT
MITF-M-dependent gene expression	1	181.3×	0.012	TERT
Formation of the beta-catenin:TCF transactivating complex	1	120.2×	0.012	TERT
TCF dependent signaling in response to WNT	1	117.7×	0.012	TERT
MITF-M-regulated melanocyte development	1	114.2×	0.012	TERT
Signaling by WNT	1	112.0×	0.012	TERT
Cell Cycle	1	36.0×	0.033	TERT
Developmental Biology	1	14.5×	0.075	TERT
Signal Transduction	1	10.2×	0.098	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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
RNA-templated transcription	1	16852.0×	5e-04	TERT
DNA strand elongation	1	16852.0×	5e-04	TERT
siRNA transcription	1	16852.0×	5e-04	TERT
positive regulation of transdifferentiation	1	16852.0×	5e-04	TERT
RNA-templated DNA biosynthetic process	1	8426.0×	6e-04	TERT
positive regulation of hair cycle	1	8426.0×	6e-04	TERT
positive regulation of protein localization to nucleolus	1	2808.7×	0.002	TERT
establishment of protein localization to telomere	1	2106.5×	0.002	TERT
siRNA processing	1	1872.4×	0.002	TERT
telomere maintenance via recombination	1	1532.0×	0.002	TERT
replicative senescence	1	991.3×	0.003	TERT
positive regulation of vascular associated smooth muscle cell migration	1	991.3×	0.003	TERT
DNA biosynthetic process	1	802.5×	0.003	TERT
telomere maintenance via telomerase	1	732.7×	0.003	TERT
response to cadmium ion	1	732.7×	0.003	TERT
negative regulation of cellular senescence	1	648.1×	0.003	TERT
positive regulation of stem cell proliferation	1	526.6×	0.004	TERT
negative regulation of endothelial cell apoptotic process	1	495.6×	0.004	TERT
positive regulation of D-glucose import across plasma membrane	1	455.5×	0.004	TERT
positive regulation of vascular associated smooth muscle cell proliferation	1	432.1×	0.004	TERT
negative regulation of extrinsic apoptotic signaling pathway in absence of ligand	1	411.0×	0.004	TERT
positive regulation of G1/S transition of mitotic cell cycle	1	401.2×	0.004	TERT
positive regulation of Wnt signaling pathway	1	383.0×	0.004	TERT
positive regulation of miRNA transcription	1	290.6×	0.005	TERT
telomere maintenance	1	267.5×	0.005	TERT
mitochondrion organization	1	151.8×	0.008	TERT
protein import into nucleus	1	144.0×	0.008	TERT
regulation of protein stability	1	125.8×	0.009	TERT
cellular response to hypoxia	1	121.2×	0.009	TERT
positive regulation of angiogenesis	1	115.4×	0.009	TERT

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
TERT	BERBERINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TERT	10	4

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

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: 1; 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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.