Revesz syndrome

Summary

Revesz syndrome (MONDO:0009990) is a disease caused by TINF2 (GenCC Definitive), with 2 cohort genes and 2 clinical trials. Top therapeutic interventions include fludarabine phosphate and doxecitine.

At a glance

• Prevalence: (Worldwide) [Orphanet-validated]
• Causal gene: TINF2 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 64
• Phenotypes (HPO): 17
• Clinical trials: 2

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		4	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

17 HPO clinical features (Orphanet curated; top 17 by frequency):

HPO ID	Term	Frequency
HP:0005528	Bone marrow hypocellularity	Very frequent (80-99%)
HP:0430048	Intracranial calcification	Very frequent (80-99%)
HP:0000252	Microcephaly	Frequent (30-79%)
HP:0000541	Retinal detachment	Frequent (30-79%)
HP:0001321	Cerebellar hypoplasia	Frequent (30-79%)
HP:0001510	Growth delay	Frequent (30-79%)
HP:0001915	Aplastic anemia	Frequent (30-79%)
HP:0002745	Oral leukoplakia	Frequent (30-79%)
HP:0007617	Fine, reticulate skin pigmentation	Frequent (30-79%)
HP:0007898	Exudative retinopathy	Frequent (30-79%)
HP:0008070	Sparse hair	Frequent (30-79%)
HP:0008404	Nail dystrophy	Frequent (30-79%)
HP:0012758	Neurodevelopmental delay	Frequent (30-79%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001251	Ataxia	Occasional (5-29%)
HP:0001531	Failure to thrive in infancy	Occasional (5-29%)
HP:0004334	Dermal atrophy	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Revesz syndrome
Mondo ID	MONDO:0009990
MeSH	C538371
OMIM	268130
Orphanet	3088
DOID	DOID:0070026
NCIT	C152064
SNOMED CT	723512008
UMLS	C1327916
MedGen	231230
GARD	0004695
Is cancer (heuristic)	no

Also known as: DKCA5 · dyskeratosis congenita with bilateral exudative retinopathy · dyskeratosis congenita, autosomal dominant 5 · exudative retinopathy with bone marrow failure · retinopathy-anemia-central nervous system anomalies syndrome · Revesz syndrome · Revesz-DeBuse syndrome

Data availability: 64 ClinVar variants · 3 GenCC gene-disease records.

Disease family

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

Related subtypes (15): dyskeratosis congenita, autosomal dominant 1, dyskeratosis congenita, autosomal recessive 1, 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

64 retrieved; paginated sample, class counts are floors:

31 uncertain significance, 12 conflicting classifications of pathogenicity, 11 benign/likely benign, 5 benign, 2 likely benign, 2 pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
31542	NM_001099274.3(TINF2):c.839del (p.Lys280fs)	TINF2	Pathogenic	no assertion criteria provided
5625	NM_001099274.3(TINF2):c.845G>A (p.Arg282His)	TINF2	Pathogenic	criteria provided, multiple submitters, no conflicts
3576544	NM_001099274.3(TINF2):c.848C>T (p.Pro283Leu)	TINF2	Likely pathogenic	criteria provided, single submitter
312957	NM_001099274.3(TINF2):c.62A>G (p.Gln21Arg)	LOC130055403	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
417880	NM_001099274.3(TINF2):c.81C>A (p.Cys27Ter)	LOC130055403	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
312958	NM_001099274.3(TINF2):c.-50A>G	LOC130055404	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
38918	NM_001099274.3(TINF2):c.841G>A (p.Glu281Lys)	TGM1	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
312948	NM_001099274.3(TINF2):c.1074T>C (p.Asp358=)	TINF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
312953	NM_001099274.3(TINF2):c.507+5C>T	TINF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
38916	NM_001099274.3(TINF2):c.734C>A (p.Ser245Tyr)	TINF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
662182	NM_001099274.3(TINF2):c.1307C>T (p.Ala436Val)	TINF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
846888	NM_001099274.3(TINF2):c.318G>C (p.Lys106Asn)	TINF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
880974	NM_001099274.3(TINF2):c.253C>G (p.His85Asp)	TINF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
882334	NM_001099274.3(TINF2):c.30A>G (p.Ala10=)	TINF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1422121	NM_001099274.3(TINF2):c.166C>G (p.Arg56Gly)	LOC130055403	Uncertain significance	criteria provided, multiple submitters, no conflicts
1467172	NM_001099274.3(TINF2):c.128C>A (p.Ala43Asp)	LOC130055403	Uncertain significance	criteria provided, multiple submitters, no conflicts
3001449	NM_001099274.3(TINF2):c.73G>A (p.Gly25Arg)	LOC130055403	Uncertain significance	criteria provided, multiple submitters, no conflicts
3576546	NM_001099274.3(TINF2):c.106G>A (p.Glu36Lys)	LOC130055403	Uncertain significance	criteria provided, multiple submitters, no conflicts
312960	NM_001099274.3(TINF2):c.-93T>C	LOC130055404	Uncertain significance	criteria provided, single submitter
312963	NM_001099274.3(TINF2):c.-223C>G	LOC130055404	Uncertain significance	criteria provided, single submitter
882601	NM_001099274.3(TINF2):c.-130A>G	LOC130055404	Uncertain significance	criteria provided, single submitter
883384	NM_001099274.3(TINF2):c.-233T>G	LOC130055404	Uncertain significance	criteria provided, single submitter
1042066	NM_001099274.3(TINF2):c.932T>C (p.Ile311Thr)	TINF2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1043543	NM_001099274.3(TINF2):c.278T>C (p.Ile93Thr)	TINF2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1385538	NM_001099274.3(TINF2):c.802G>C (p.Val268Leu)	TINF2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1395836	NM_001099274.3(TINF2):c.1061+4_1061+7del	TINF2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1445405	NM_001099274.3(TINF2):c.1076G>A (p.Cys359Tyr)	TINF2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1494138	NM_001099274.3(TINF2):c.679C>T (p.Leu227Phe)	TINF2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1516884	NM_001099274.3(TINF2):c.1285C>A (p.Leu429Ile)	TINF2	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 8 · 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
TINF2	Definitive	Autosomal dominant	Revesz syndrome	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TINF2	Orphanet:1775	Dyskeratosis congenita
TINF2	Orphanet:3088	Revesz syndrome
TINF2	Orphanet:3322	Hoyeraal-Hreidarsson syndrome
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

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
TINF2	HGNC:11824	ENSG00000092330	Q9BSI4	TERF1-interacting nuclear factor 2	gencc,clinvar
TGM1	HGNC:11777	ENSG00000092295	P22735	Protein-glutamine gamma-glutamyltransferase K	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TINF2	TERF1-interacting nuclear factor 2	Component of the shelterin complex (telosome) that is involved in the regulation of telomere length and protection.
TGM1	Protein-glutamine gamma-glutamyltransferase K	Catalyzes the cross-linking of proteins and the conjugation of polyamines to proteins.

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
Antibody/Immunoglobulin	1	14.6×	0.135
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TINF2	Other/Unknown	no		TINF2_N, TINF2
TGM1	Antibody/Immunoglobulin	yes	2.3.2.13	Transglutaminase_N, Transglutaminase-like, Transglutaminase_C

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
granulocyte	1
right adrenal gland	1
right adrenal gland cortex	1
esophagus mucosa	1
lower esophagus mucosa	1
skin of leg	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TINF2	144	ubiquitous	marker	granulocyte, right adrenal gland, right adrenal gland cortex
TGM1	135	broad	marker	lower esophagus mucosa, esophagus mucosa, skin of leg

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TGM1	1,978
TINF2	1,769

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TINF2	Q9BSI4	3
TGM1	P22735	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 17. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Telomere C-strand synthesis initiation	1	407.9×	0.013	TINF2
Processive synthesis on the C-strand of the telomere	1	380.7×	0.013	TINF2
Telomere C-strand (Lagging Strand) Synthesis	1	380.7×	0.013	TINF2
Removal of the Flap Intermediate from the C-strand	1	317.2×	0.013	TINF2
Telomere Extension By Telomerase	1	228.4×	0.013	TINF2
Polymerase switching on the C-strand of the telomere	1	211.5×	0.013	TINF2
Packaging Of Telomere Ends	1	109.8×	0.016	TINF2
Recognition and association of DNA glycosylase with site containing an affected purine	1	102.0×	0.016	TINF2
Cleavage of the damaged purine	1	102.0×	0.016	TINF2
Recognition and association of DNA glycosylase with site containing an affected pyrimidine	1	92.1×	0.016	TINF2
Cleavage of the damaged pyrimidine	1	92.1×	0.016	TINF2
Inhibition of DNA recombination at telomere	1	84.0×	0.016	TINF2
DNA Damage/Telomere Stress Induced Senescence	1	81.6×	0.016	TINF2
Meiotic synapsis	1	70.5×	0.017	TINF2
Formation of the cornified envelope	1	43.9×	0.026	TGM1
Keratinization	1	27.9×	0.038	TGM1
Developmental Biology	1	7.2×	0.134	TGM1

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
regulation of telomere maintenance via telomere lengthening	1	8426.0×	0.002	TINF2
cell envelope organization	1	2808.7×	0.002	TGM1
telomere assembly	1	2106.5×	0.002	TINF2
protein localization to chromosome, telomeric region	1	766.0×	0.004	TINF2
telomere capping	1	648.1×	0.004	TINF2
cornification	1	526.6×	0.004	TGM1
positive regulation of keratinocyte proliferation	1	495.6×	0.004	TGM1
negative regulation of telomere maintenance via telomerase	1	366.4×	0.004	TINF2
positive regulation of telomere maintenance	1	255.3×	0.006	TINF2
positive regulation of cell cycle	1	221.7×	0.006	TGM1
negative regulation of epithelial cell proliferation	1	145.3×	0.008	TINF2
keratinocyte differentiation	1	123.9×	0.008	TGM1
protein modification process	1	122.1×	0.008	TGM1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TINF2	0	0
TGM1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
TGM1	11	Binding:11

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TGM1	2.3.2.13	protein-glutamine gamma-glutamyltransferase

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

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	TGM1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	TINF2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TINF2	0	—
TGM1	11	—

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
NCT01659606	PHASE2	ACTIVE_NOT_RECRUITING	Radiation- and Alkylator-free Bone Marrow Transplantation Regimen for Patients With Dyskeratosis Congenita
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	1
DOXECITINE	2	1