Rothmund-Thomson syndrome type 1

Summary

Rothmund-Thomson syndrome type 1 (MONDO:0016368) is a disease caused by ANAPC1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ANAPC1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 17
• Phenotypes (HPO): 64

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		100	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

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

HPO ID	Term	Frequency
HP:0001029	Poikiloderma	Very frequent (80-99%)
HP:0001118	Juvenile cataract	Very frequent (80-99%)
HP:0000028	Cryptorchidism	Frequent (30-79%)
HP:0000164	Abnormality of the dentition	Frequent (30-79%)
HP:0000519	Developmental cataract	Frequent (30-79%)
HP:0000953	Hyperpigmentation of the skin	Frequent (30-79%)
HP:0001009	Telangiectasia	Frequent (30-79%)
HP:0001010	Hypopigmentation of the skin	Frequent (30-79%)
HP:0001041	Facial erythema	Frequent (30-79%)
HP:0001510	Growth delay	Frequent (30-79%)
HP:0001518	Small for gestational age	Frequent (30-79%)
HP:0002164	Nail dysplasia	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0004334	Dermal atrophy	Frequent (30-79%)
HP:0005775	Multiple skeletal anomalies	Frequent (30-79%)
HP:0008070	Sparse hair	Frequent (30-79%)
HP:0000135	Hypogonadism	Occasional (5-29%)
HP:0000282	Facial edema	Occasional (5-29%)
HP:0000670	Carious teeth	Occasional (5-29%)
HP:0000682	Abnormality of dental enamel	Occasional (5-29%)
HP:0000684	Delayed eruption of teeth	Occasional (5-29%)
HP:0000691	Microdontia	Occasional (5-29%)
HP:0000821	Hypothyroidism	Occasional (5-29%)
HP:0001249	Intellectual disability	Occasional (5-29%)
HP:0001263	Global developmental delay	Occasional (5-29%)
HP:0001875	Decreased total neutrophil count	Occasional (5-29%)
HP:0001903	Anemia	Occasional (5-29%)
HP:0002013	Vomiting	Occasional (5-29%)
HP:0002014	Diarrhea	Occasional (5-29%)
HP:0002863	Myelodysplasia	Occasional (5-29%)
HP:0007018	Attention deficit hyperactivity disorder	Occasional (5-29%)
HP:0007418	Alopecia totalis	Occasional (5-29%)
HP:0007556	Plantar hyperkeratosis	Occasional (5-29%)
HP:0008066	Abnormal blistering of the skin	Occasional (5-29%)
HP:0008069	Neoplasm of the skin	Occasional (5-29%)
HP:0008209	Premature ovarian insufficiency	Occasional (5-29%)
HP:0009804	Tooth agenesis	Occasional (5-29%)
HP:0010978	Abnormality of immune system physiology	Occasional (5-29%)
HP:0012719	Functional abnormality of the gastrointestinal tract	Occasional (5-29%)
HP:0020110	Bone fracture	Occasional (5-29%)
HP:0031367	Metaphyseal striations	Occasional (5-29%)
HP:0040288	Nasogastric tube feeding	Occasional (5-29%)
HP:0100671	Abnormal trabecular bone morphology	Occasional (5-29%)
HP:0100840	Aplasia/Hypoplasia of the eyebrow	Occasional (5-29%)
HP:0200102	Sparse or absent eyelashes	Occasional (5-29%)
HP:0000938	Osteopenia	Very rare (<1-4%)
HP:0001909	Leukemia	Very rare (<1-4%)
HP:0001915	Aplastic anemia	Very rare (<1-4%)
HP:0002669	Osteosarcoma	Very rare (<1-4%)
HP:0002671	Basal cell carcinoma	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Rothmund-Thomson syndrome type 1
Mondo ID	MONDO:0016368
OMIM	618625
Orphanet	221008
ICD-11	717855330
NCIT	C178826
UMLS	C5231433
MedGen	1684764
GARD	0017134
Is cancer (heuristic)	no

Also known as: poikiloderma of Rothmund-Thomson type 1 · Rothmund-Thomson syndrome, type 1 · RTS1

Data availability: 17 ClinVar variants · 7 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 › Rothmund-Thomson syndrome › Rothmund-Thomson syndrome type 1

Related subtypes (3): Rothmund-Thomson syndrome type 3, Rothmund-Thomson syndrome type 2, Rothmund-Thomson syndrome type 4

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

17 retrieved; paginated sample, class counts are floors:

6 benign, 3 likely pathogenic, 2 conflicting classifications of pathogenicity, 2 pathogenic, 2 benign/likely benign, 1 uncertain significance, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
692104	NM_022662.4(ANAPC1):c.2705-198C>T	ANAPC1	Pathogenic/Likely pathogenic	no assertion criteria provided
692105	NM_022662.4(ANAPC1):c.1778dup (p.Asn593fs)	ANAPC1	Pathogenic	no assertion criteria provided
692106	NM_022662.4(ANAPC1):c.4373+1G>A	ANAPC1	Pathogenic	no assertion criteria provided
694458	NM_022662.4(ANAPC1):c.[1778dup;2705-198C>T]		Likely pathogenic	no assertion criteria provided
694459	NM_022662.4(ANAPC1):c.[2705-198C>T;4373+1G>A]		Likely pathogenic	no assertion criteria provided
694496	NM_022662.4(ANAPC1):c.[2705-198C>T;4880_4881AC[1]]		Likely pathogenic	no assertion criteria provided
2439034	NM_022662.4(ANAPC1):c.1452A>T (p.Lys484Asn)	ANAPC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
790439	NM_022662.4(ANAPC1):c.3100G>A (p.Val1034Met)	ANAPC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2439035	NM_022662.4(ANAPC1):c.236G>A (p.Gly79Glu)	ANAPC1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1188976	NM_022662.4(ANAPC1):c.*2C>T	ANAPC1	Benign	criteria provided, multiple submitters, no conflicts
1192325	NM_022662.4(ANAPC1):c.1791G>A (p.Leu597=)	ANAPC1	Benign	criteria provided, multiple submitters, no conflicts
1192326	NM_022662.4(ANAPC1):c.1651-23A>G	ANAPC1	Benign	criteria provided, multiple submitters, no conflicts
1192386	NM_022662.4(ANAPC1):c.685+25A>G	ANAPC1	Benign	criteria provided, multiple submitters, no conflicts
767814	NM_022662.4(ANAPC1):c.5373C>A (p.Ile1791=)	ANAPC1	Benign	criteria provided, multiple submitters, no conflicts
769572	NM_022662.4(ANAPC1):c.4341G>A (p.Pro1447=)	ANAPC1	Benign	criteria provided, multiple submitters, no conflicts
778261	NM_022662.4(ANAPC1):c.2513C>T (p.Thr838Met)	ANAPC1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
783338	NM_022662.4(ANAPC1):c.681T>C (p.Ser227=)	ANAPC1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 1 · 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
ANAPC1	Definitive	Autosomal recessive	Rothmund-Thomson syndrome type 1	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ANAPC1	Orphanet:221008	Rothmund-Thomson syndrome type 1

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
ANAPC1	HGNC:19988	ENSG00000153107	Q9H1A4	Anaphase-promoting complex subunit 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ANAPC1	Anaphase-promoting complex subunit 1	Component of the anaphase promoting complex/cyclosome (APC/C), a cell cycle-regulated E3 ubiquitin ligase that controls progression through mitosis and the G1 phase of the cell cycle.

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)
ANAPC1	Other/Unknown	no		ARM-like, APC1, APC1_C

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
colonic epithelium	1
pancreatic ductal cell	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ANAPC1	206	ubiquitous	marker	primordial germ cell in gonad, colonic epithelium, pancreatic ductal cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ANAPC1	2,652

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ANAPC1	Q9H1A4	21

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 47. 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
Inhibition of the proteolytic activity of APC/C required for the onset of anaphase by mitotic spindle checkpoint components	1	634.4×	0.009	ANAPC1
Phosphorylation of the APC/C	1	543.8×	0.009	ANAPC1
Inactivation of APC/C via direct inhibition of the APC/C complex	1	519.1×	0.009	ANAPC1
Conversion from APC/C:Cdc20 to APC/C:Cdh1 in late anaphase	1	519.1×	0.009	ANAPC1
Aberrant regulation of mitotic exit in cancer due to RB1 defects	1	519.1×	0.009	ANAPC1
APC/C:Cdc20 mediated degradation of Cyclin B	1	456.8×	0.009	ANAPC1
APC-Cdc20 mediated degradation of Nek2A	1	423.0×	0.009	ANAPC1
APC:Cdc20 mediated degradation of cell cycle proteins prior to satisfation of the cell cycle checkpoint	1	423.0×	0.009	ANAPC1
Activation of APC/C and APC/C:Cdc20 mediated degradation of mitotic proteins	1	407.9×	0.009	ANAPC1
Aberrant regulation of mitotic cell cycle due to RB1 defects	1	407.9×	0.009	ANAPC1
Diseases of mitotic cell cycle	1	393.8×	0.009	ANAPC1
APC/C:Cdc20 mediated degradation of mitotic proteins	1	356.9×	0.009	ANAPC1
APC/C-mediated degradation of cell cycle proteins	1	335.9×	0.009	ANAPC1
Regulation of mitotic cell cycle	1	335.9×	0.009	ANAPC1
DNA Replication Pre-Initiation	1	317.2×	0.009	ANAPC1
Regulation of APC/C activators between G1/S and early anaphase	1	308.6×	0.009	ANAPC1
Switching of origins to a post-replicative state	1	300.5×	0.009	ANAPC1
Synthesis of DNA	1	300.5×	0.009	ANAPC1
Transcriptional Regulation by VENTX	1	265.6×	0.009	ANAPC1
DNA Replication	1	237.9×	0.010	ANAPC1
Autodegradation of Cdh1 by Cdh1:APC/C	1	190.3×	0.011	ANAPC1
APC/C:Cdc20 mediated degradation of Securin	1	190.3×	0.011	ANAPC1
S Phase	1	181.3×	0.011	ANAPC1
Cdc20:Phospho-APC/C mediated degradation of Cyclin A	1	173.0×	0.011	ANAPC1
APC/C:Cdh1 mediated degradation of Cdc20 and other APC/C:Cdh1 targeted proteins in late mitosis/early G1	1	170.4×	0.011	ANAPC1
CDK-mediated phosphorylation and removal of Cdc6	1	170.4×	0.011	ANAPC1
Mitotic Spindle Checkpoint	1	158.6×	0.011	ANAPC1
Assembly of the pre-replicative complex	1	139.3×	0.012	ANAPC1
Cellular Senescence	1	137.6×	0.012	ANAPC1
Senescence-Associated Secretory Phenotype (SASP)	1	99.3×	0.015	ANAPC1

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
metaphase/anaphase transition of mitotic cell cycle	1	2106.5×	0.003	ANAPC1
protein branched polyubiquitination	1	842.6×	0.003	ANAPC1
regulation of meiotic cell cycle	1	766.0×	0.003	ANAPC1
anaphase-promoting complex-dependent catabolic process	1	702.2×	0.003	ANAPC1
protein K11-linked ubiquitination	1	391.9×	0.004	ANAPC1
regulation of mitotic cell cycle	1	240.7×	0.006	ANAPC1
protein K48-linked ubiquitination	1	168.5×	0.007	ANAPC1
cell division	1	46.2×	0.022	ANAPC1

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ANAPC1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	ANAPC1

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)
ANAPC1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.