Dyskeratosis congenita, digenic

Summary

Dyskeratosis congenita, digenic (MONDO:0031057) is a disease with 2 cohort genes.

At a glance

• Cohort genes: 2
• ClinVar variants: 4

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	dyskeratosis congenita, digenic
Mondo ID	MONDO:0031057
OMIM	620040
DOID	DOID:0060984
UMLS	C5774217
MedGen	1823990
GARD	0025688
Is cancer (heuristic)	no

Also known as: DKCD · dyskeratosis congenita, digenic

Data availability: 4 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 › dyskeratosis congenita, digenic

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, autosomal recessive dyskeratosis congenita 4, 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

4 retrieved; paginated sample, class counts are floors:

3 pathogenic, 1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
1693537	NM_001071.4(TYMS):c.486_487del (p.Arg163fs)	ENOSF1	Pathogenic	criteria provided, single submitter
1693535	NM_001071.4(TYMS):c.343C>T (p.Arg115Ter)	TYMS	Pathogenic	criteria provided, single submitter
1693538	NM_001071.4(TYMS):c.534_535insTG (p.Met179Ter)	TYMS	Pathogenic	criteria provided, single submitter
1693536	NM_001071.4(TYMS):c.480A>T (p.Gln160His)	ENOSF1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TYMS	Orphanet:1775	Dyskeratosis congenita

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TYMS	HGNC:12441	ENSG00000176890	P04818	Thymidylate synthase	clinvar
ENOSF1	HGNC:30365	ENSG00000132199	Q7L5Y1	Mitochondrial enolase superfamily member 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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…
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.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Enzyme (other)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TYMS	Enzyme (other)	yes	2.1.1.45	Thymidylate_synthase, Thymidylate_synthase_AS, Thymidate_synth/dCMP_Mease_dom
ENOSF1	Other/Unknown	no		Mandelate_racemase_N, Mandelate_racemase_C, Mandel_Rmase/mucon_lact_enz_CS

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
embryo	1
trabecular bone tissue	1
ventricular zone	1
mucosa of stomach	1
right lobe of thyroid gland	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TYMS	262	ubiquitous	marker	ventricular zone, embryo, trabecular bone tissue
ENOSF1	289	ubiquitous	marker	right uterine tube, mucosa of stomach, right lobe of thyroid gland

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TYMS	4,628
ENOSF1	872

Intra-cohort edges

A	B	Sources
ENOSF1	TYMS	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TYMS	P04818	61
ENOSF1	Q7L5Y1	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 2 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
Interconversion of nucleotide di- and triphosphates	1	356.9×	0.003	TYMS
G1/S-Specific Transcription	1	356.9×	0.003	TYMS

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
dTMP biosynthetic process	1	1685.2×	0.001	TYMS
dTTP biosynthetic process	1	1685.2×	0.001	TYMS
carbohydrate catabolic process	1	1685.2×	0.001	ENOSF1
amino acid catabolic process	1	1404.3×	0.001	ENOSF1
tetrahydrofolate interconversion	1	842.6×	0.002	TYMS
DNA biosynthetic process	1	401.2×	0.003	TYMS
negative regulation of translation	1	98.0×	0.012	TYMS
methylation	1	85.1×	0.012	TYMS

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) 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
TYMS	FOLIC ACID

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TYMS	9	4
ENOSF1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FOLIC ACID	4	TYMS
RALTITREXED	4	TYMS
PEMETREXED	4	TYMS
PEMETREXED DISODIUM	4	TYMS
METHOTREXATE	4	TYMS
PHENOLPHTHALEIN	4	TYMS
NOLATREXED	3	TYMS
OSI-7904	2	TYMS
METESIND	2	TYMS

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
TYMS	376	Binding:373, ADMET:2, Functional:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TYMS	2.1.1.45	thymidylate synthase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
TYMS	376

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

9 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)
FOLIC ACID	4	TYMS
RALTITREXED	4	TYMS
PEMETREXED	4	TYMS
PEMETREXED DISODIUM	4	TYMS
METHOTREXATE	4	TYMS
PHENOLPHTHALEIN	4	TYMS
NOLATREXED	3	TYMS
OSI-7904	2	TYMS
METESIND	2	TYMS

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	TYMS
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	1	ENOSF1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ENOSF1	0	TYMS

Clinical trials & evidence

Clinical trials

Clinical trials: 0.