Rothmund-Thomson syndrome type 2

Summary

Rothmund-Thomson syndrome type 2 (MONDO:0016369) is a disease caused by RECQL4 (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: RECQL4 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 259
• Phenotypes (HPO): 67

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		200	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

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

HPO ID	Term	Frequency
HP:0000953	Hyperpigmentation of the skin	Very frequent (80-99%)
HP:0001010	Hypopigmentation of the skin	Very frequent (80-99%)
HP:0001029	Poikiloderma	Very frequent (80-99%)
HP:0010783	Erythema	Very frequent (80-99%)
HP:0000164	Abnormality of the dentition	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:0100840	Aplasia/Hypoplasia of the eyebrow	Frequent (30-79%)
HP:0200102	Sparse or absent eyelashes	Frequent (30-79%)
HP:0000028	Cryptorchidism	Occasional (5-29%)
HP:0000175	Cleft palate	Occasional (5-29%)
HP:0000218	High palate	Occasional (5-29%)
HP:0000282	Facial edema	Occasional (5-29%)
HP:0000417	Slender nose	Occasional (5-29%)
HP:0000519	Developmental cataract	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:0000938	Osteopenia	Occasional (5-29%)
HP:0001373	Joint dislocation	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:0002665	Lymphoma	Occasional (5-29%)
HP:0002669	Osteosarcoma	Occasional (5-29%)
HP:0002671	Basal cell carcinoma	Occasional (5-29%)
HP:0002750	Delayed skeletal maturation	Occasional (5-29%)
HP:0002756	Pathologic fracture	Occasional (5-29%)
HP:0002860	Squamous cell carcinoma	Occasional (5-29%)
HP:0002863	Myelodysplasia	Occasional (5-29%)
HP:0002970	Genu varum	Occasional (5-29%)
HP:0003065	Patellar hypoplasia	Occasional (5-29%)
HP:0003189	Long nose	Occasional (5-29%)
HP:0003995	Abnormality of the radial head	Occasional (5-29%)
HP:0004039	Abnormality of ulnar metaphysis	Occasional (5-29%)
HP:0004979	Metaphyseal sclerosis	Occasional (5-29%)
HP:0006443	Patellar aplasia	Occasional (5-29%)
HP:0006496	Aplasia/hypoplasia involving bones of the upper limbs	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%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Rothmund-Thomson syndrome type 2
Mondo ID	MONDO:0016369
OMIM	268400
Orphanet	221016
ICD-11	2111040755
NCIT	C178827
UMLS	C5203410
MedGen	1684753
GARD	0017135
Is cancer (heuristic)	no

Also known as: poikiloderma of Rothmund-Thomson type 2 · Rothmund-Thomson syndrome, type 2 · RTS2

Data availability: 259 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › disorder of orbital region › eye disorder › Rothmund-Thomson syndrome type 2

Related subtypes (119): ptosis, eye accommodation disease, corneal disorder, asthenopia, lens disorder, keratomalacia, scleral disorder, ocular siderosis, coloboma, luxation of globe, mucopolysaccharidosis type 1, lacrimal apparatus disorder, Foster-Kennedy syndrome, anterior dislocation of lens, uveal disorder, eyelid disorder, ocular hypotension, scotoma, exophthalmos, ophthalmia nodosa, eye degenerative disorder, refractive error, glaucoma, retinal disorder, eye allergy, ocular vascular disorder, optic neuritis, conjunctival disorder, ocular hypertension, Tietz syndrome, Alagille syndrome, glaucoma-sleep apnea syndrome, Marshall syndrome, microcornea-glaucoma-absent frontal sinuses syndrome, nail-patella syndrome, oculodentodigital dysplasia, piebaldism, Sturge-Weber syndrome, cerebrotendinous xanthomatosis, ocular cystinosis, alpha-mannosidosis, megalocornea-intellectual disability syndrome, mucolipidosis type IV, mucopolysaccharidosis type 6, Netherton syndrome, galactosialidosis, Niemann-Pick disease type A, ocular motor apraxia, Cogan type, Peters plus syndrome, isolated Pierre-Robin syndrome, ectodermal dysplasia-blindness syndrome, Sandhoff disease, SHORT syndrome, Sjogren-Larsson syndrome, Smith-Lemli-Opitz syndrome, Tay-Sachs disease, tyrosinemia type II, Ito hypomelanosis, X-linked cone dysfunction syndrome with myopia, red color blindness, oculocerebrorenal syndrome, Lowry-MacLean syndrome, pigment dispersion syndrome, hereditary hyperferritinemia with congenital cataracts, dyssegmental dysplasia-glaucoma syndrome, mevalonic aciduria, familial cavitary optic disk anomaly, blindness - scoliosis - arachnodactyly syndrome, fatty acyl-CoA reductase 1 deficiency, microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome, neurotrophic keratopathy, Cogan syndrome, atopic keratoconjunctivitis, rhizomelic chondrodysplasia punctata, Ehlers-Danlos syndrome, kyphoscoliotic type 1, IRVAN syndrome, microcornea-corectopia-macular hypoplasia syndrome, isolated anophthalmia-microphthalmia syndrome, Spasmus nutans, toxic maculopathy due to antimalarial drugs, syndromic recessive X-linked ichthyosis, acute zonal occult outer retinopathy, acute annular outer retinopathy, phakomatosis pigmentovascularis, lamellar ichthyosis, idiopathic linear interstitial keratitis, chondroectodermal dysplasia with night blindness, galactosemia, GM1 gangliosidosis, Gaucher disease, visual snow syndrome, extensive peripapillary myelinated nerve fibers, IgG4-related ophthalmic disorder, global developmental delay-visual anomalies-progressive cerebellar atrophy-truncal hypotonia syndrome, vernal keratoconjunctivitis, Gardner syndrome, anterior segment dysgenesis, isolated ankyloblepharon filiforme adnatum, hereditary optic neuropathy, essential strabismus, Axenfeld anomaly, eye neoplasm, isolated blepharochalasis, punctate inner choroidopathy, eye infectious disorder, vitreous body disorder, 9q33.3q34.11 microdeletion syndrome, autoimmune/inflammatory optic neuropathy, LTBP2-related ocular dysgenesis, ocular growth disorder, ocular dysgenesis caused by defects in PAX6 regulation, choroidal neovascularization, anterior segment developmental abnormality with extraocular manifestations, congenital optic disk excavation, neuroocular syndrome, isolated angioid streaks, multiple evanescent white dot syndrome, stellate multiform amelanotic choroidopathy, macular telangiectasia

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

259 retrieved; paginated sample, class counts are floors:

120 uncertain significance, 48 conflicting classifications of pathogenicity, 29 benign/likely benign, 21 benign, 16 pathogenic, 13 pathogenic/likely pathogenic, 10 likely benign, 2 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
3064077	XM_011517384.2:c.1149G>A		Pathogenic	criteria provided, single submitter
998012	NM_004260.4(RECQL4):c.[1724_1725del;691G>A]		Pathogenic	no assertion criteria provided
1070358	NM_004260.4(RECQL4):c.1162G>T (p.Glu388Ter)	RECQL4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1074968	NM_004260.4(RECQL4):c.2650del (p.Gln884fs)	RECQL4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1687357	NM_004260.4(RECQL4):c.988dup (p.Ala330fs)	RECQL4	Pathogenic	criteria provided, multiple submitters, no conflicts
1920986	NM_004260.4(RECQL4):c.2486_2501del (p.Arg829fs)	RECQL4	Pathogenic	criteria provided, multiple submitters, no conflicts
197759	NM_004260.4(RECQL4):c.1048_1049del (p.Arg350fs)	RECQL4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
239724	NM_004260.4(RECQL4):c.2412_2420del (p.Ala805_Arg807del)	RECQL4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
239754	NM_004260.4(RECQL4):c.3072_3073del (p.Val1026fs)	RECQL4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3377799	NM_004260.4(RECQL4):c.2428C>T (p.Gln810Ter)	RECQL4	Pathogenic	criteria provided, multiple submitters, no conflicts
3381973	NM_004260.4(RECQL4):c.757C>T (p.Gln253Ter)	RECQL4	Pathogenic	criteria provided, single submitter
407029	NM_004260.4(RECQL4):c.1568_1573delinsCCCCC (p.Ser523fs)	RECQL4	Pathogenic	criteria provided, multiple submitters, no conflicts
459307	NM_004260.4(RECQL4):c.1166_1167del (p.Cys389fs)	RECQL4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
547041	NM_004260.4(RECQL4):c.359_374delGACCAGCCCTGGGCCG	RECQL4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
56406	NM_004260.4(RECQL4):c.2476C>T (p.Arg826Ter)	RECQL4	Pathogenic	criteria provided, multiple submitters, no conflicts
568068	NM_004260.4(RECQL4):c.1699C>T (p.Gln567Ter)	RECQL4	Pathogenic	criteria provided, multiple submitters, no conflicts
6062	NM_004260.4(RECQL4):c.1650_1656del (p.Ala551fs)	RECQL4	Pathogenic	criteria provided, single submitter
6063	NM_004260.4(RECQL4):c.2269C>T (p.Gln757Ter)	RECQL4	Pathogenic	criteria provided, multiple submitters, no conflicts
6064	NM_004260.4(RECQL4):c.2492_2493del (p.His831fs)	RECQL4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6065	NM_004260.4(RECQL4):c.2059-1G>T	RECQL4	Pathogenic	no assertion criteria provided
6066	NM_004260.4(RECQL4):c.1573del (p.Cys525fs)	RECQL4	Pathogenic	criteria provided, multiple submitters, no conflicts
6067	NM_004260.4(RECQL4):c.1391-1G>A	RECQL4	Pathogenic	criteria provided, multiple submitters, no conflicts
6069	NM_004260.4(RECQL4):c.2059-1G>C	RECQL4	Pathogenic	criteria provided, single submitter
6073	NM_004260.4(RECQL4):c.3061C>T (p.Arg1021Trp)	RECQL4	Pathogenic	criteria provided, multiple submitters, no conflicts
6077	NM_004260.4(RECQL4):c.1704+1G>A	RECQL4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
649166	NM_004260.4(RECQL4):c.644_645del (p.Glu215fs)	RECQL4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
666165	NM_004260.4(RECQL4):c.2662C>T (p.Gln888Ter)	RECQL4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
804413	NM_004260.4(RECQL4):c.1038_1039del (p.Arg347fs)	RECQL4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
94889	NM_004260.4(RECQL4):c.2464-1G>C	RECQL4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2039945	NM_004260.4(RECQL4):c.214-2A>G	RECQL4	Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 15 · Orphanet: 4 · 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
RECQL4	Definitive	Autosomal recessive	Rothmund-Thomson syndrome	15

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RECQL4	Orphanet:1225	Baller-Gerold syndrome
RECQL4	Orphanet:221016	Rothmund-Thomson syndrome type 2
RECQL4	Orphanet:3021	RAPADILINO syndrome
ANAPC1	Orphanet:221008	Rothmund-Thomson syndrome type 1

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
RECQL4	HGNC:9949	ENSG00000160957	O94761	ATP-dependent DNA helicase Q4	gencc,clinvar
ANAPC1	HGNC:19988	ENSG00000153107	Q9H1A4	Anaphase-promoting complex subunit 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RECQL4	ATP-dependent DNA helicase Q4	An ATP-dependent DNA helicase which unwinds dsDNA with a 3’-overhang in a 3’-5’ direction.
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: 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)
RECQL4	Enzyme (other)	yes	3.6.4.12	Helicase_C-like, DNA_helicase_ATP-dep_RecQ, DEAD/DEAH_box_helicase_dom
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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
lower esophagus mucosa	1
mucosa of transverse colon	1
ventricular zone	1
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
RECQL4	212	ubiquitous	yes	lower esophagus mucosa, ventricular zone, mucosa of transverse colon
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
RECQL4	6,330
ANAPC1	2,652

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ANAPC1	Q9H1A4	21
RECQL4	O94761	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 47. 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
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 2 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	1053.2×	0.007	ANAPC1
telomeric D-loop disassembly	1	936.2×	0.007	RECQL4
protein branched polyubiquitination	1	421.3×	0.007	ANAPC1
regulation of meiotic cell cycle	1	383.0×	0.007	ANAPC1
anaphase-promoting complex-dependent catabolic process	1	351.1×	0.007	ANAPC1
protein K11-linked ubiquitination	1	195.9×	0.011	ANAPC1
telomere maintenance	1	133.8×	0.013	RECQL4
regulation of mitotic cell cycle	1	120.4×	0.013	ANAPC1
protein K48-linked ubiquitination	1	84.3×	0.015	ANAPC1
DNA replication	1	82.6×	0.015	RECQL4
double-strand break repair via homologous recombination	1	78.0×	0.015	RECQL4
DNA repair	1	31.9×	0.034	RECQL4
cell division	1	23.1×	0.043	ANAPC1

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 2 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
RECQL4	0	0
ANAPC1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
RECQL4	3.6.4.12	DNA helicase

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	RECQL4
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	ANAPC1

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)
RECQL4	0	—
ANAPC1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.