Rothmund-Thomson syndrome

Summary

Rothmund-Thomson syndrome (MONDO:0010002) is a disease caused by RECQL4 (GenCC Definitive), with 2 cohort genes and 2 clinical trials.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: RECQL4 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 52
• Phenotypes (HPO): 56
• Clinical trials: 2

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		500	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

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

HPO ID	Term	Frequency
HP:0000988	Skin rash	Very frequent (80-99%)
HP:0001029	Poikiloderma	Very frequent (80-99%)
HP:0025300	Malar rash	Very frequent (80-99%)
HP:0000164	Abnormality of the dentition	Frequent (30-79%)
HP:0000653	Sparse eyelashes	Frequent (30-79%)
HP:0000789	Infertility	Frequent (30-79%)
HP:0000924	Abnormality of the skeletal system	Frequent (30-79%)
HP:0001518	Small for gestational age	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0004349	Reduced bone mineral density	Frequent (30-79%)
HP:0007556	Plantar hyperkeratosis	Frequent (30-79%)
HP:0007588	Reticular hyperpigmentation	Frequent (30-79%)
HP:0008066	Abnormal blistering of the skin	Frequent (30-79%)
HP:0008070	Sparse hair	Frequent (30-79%)
HP:0010765	Palmar hyperkeratosis	Frequent (30-79%)
HP:0045075	Sparse eyebrow	Frequent (30-79%)
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:0000685	Hypoplasia of teeth	Occasional (5-29%)
HP:0000691	Microdontia	Occasional (5-29%)
HP:0000938	Osteopenia	Occasional (5-29%)
HP:0001010	Hypopigmentation of the skin	Occasional (5-29%)
HP:0001118	Juvenile cataract	Occasional (5-29%)
HP:0001592	Selective tooth agenesis	Occasional (5-29%)
HP:0001597	Abnormality of the nail	Occasional (5-29%)
HP:0001792	Small nail	Occasional (5-29%)
HP:0001871	Abnormality of blood and blood-forming tissues	Occasional (5-29%)
HP:0002013	Vomiting	Occasional (5-29%)
HP:0002014	Diarrhea	Occasional (5-29%)
HP:0002164	Nail dysplasia	Occasional (5-29%)
HP:0002659	Increased susceptibility to fractures	Occasional (5-29%)
HP:0003022	Hypoplasia of the ulna	Occasional (5-29%)
HP:0003993	Broad ulna	Occasional (5-29%)
HP:0006498	Aplasia/Hypoplasia of the patella	Occasional (5-29%)
HP:0006501	Aplasia/Hypoplasia of the radius	Occasional (5-29%)
HP:0008065	Aplasia/Hypoplasia of the skin	Occasional (5-29%)
HP:0008069	Neoplasm of the skin	Occasional (5-29%)
HP:0009778	Short thumb	Occasional (5-29%)
HP:0011069	Supernumerary tooth	Occasional (5-29%)
HP:0031367	Metaphyseal striations	Occasional (5-29%)
HP:0100585	Telangiectasia of the skin	Occasional (5-29%)
HP:0100671	Abnormal trabecular bone morphology	Occasional (5-29%)
HP:0001875	Decreased total neutrophil count	Very rare (<1-4%)
HP:0001903	Anemia	Very rare (<1-4%)
HP:0001909	Leukemia	Very rare (<1-4%)
HP:0001915	Aplastic anemia	Very rare (<1-4%)
HP:0002671	Basal cell carcinoma	Very rare (<1-4%)
HP:0002860	Squamous cell carcinoma	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Rothmund-Thomson syndrome
Mondo ID	MONDO:0010002
MeSH	D011038
OMIM	268400
Orphanet	2909
DOID	DOID:2732
ICD-11	652761118
NCIT	C3335
SNOMED CT	69093006
UMLS	C0032339
MedGen	10819
GARD	0004392
NORD	1678
Is cancer (heuristic)	no

Also known as: poikiloderma congenitale · poikiloderma of Rothmund-Thomson · Rothmund-Thomson syndrome · RTS

Data availability: 52 ClinVar variants · 1 GenCC gene-disease record · 13 cell lines.

Disease family

An umbrella term covering 4 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › hereditary neoplastic syndrome › Rothmund-Thomson syndrome

Related subtypes (116): mosaic variegated aneuploidy syndrome, tuberous sclerosis, hereditary breast ovarian cancer syndrome, hereditary multiple osteochondromas, nevoid basal cell carcinoma syndrome, leukemia, chronic lymphocytic, susceptibility to, 2, blue rubber bleb nevus, cherubism, Beckwith-Wiedemann syndrome, multiple self-healing squamous epithelioma, erythroleukemia, familial, susceptibility to, goiter, multinodular 1, with or without Sertoli-Leydig cell tumors, hyperparathyroidism 2 with jaw tumors, Kaposi sarcoma, susceptibility to, hereditary leiomyomatosis and renal cell cancer, susceptibility to uveal melanoma, melanoma and neural system tumor syndrome, nasopharyngeal carcinoma, susceptibility to, 2, WAGR syndrome, neuroblastoma, susceptibility to, 1, mismatch repair cancer syndrome 1, Wiskott-Aldrich syndrome, N syndrome, hereditary thrombocytopenia and hematologic cancer predisposition syndrome, prostate cancer/brain cancer susceptibility, Brooke-Spiegler syndrome, pancreatic cancer, susceptibility to, 1, Carney-Stratakis syndrome, nasopharyngeal carcinoma, susceptibility to, 1, ovarian cancer, susceptibility to, 1, colorectal cancer, susceptibility to, 1, lung cancer susceptibility 1, leukemia, chronic lymphocytic, susceptibility to, 1, Kostmann syndrome, colorectal cancer, susceptibility to, 2, colorectal cancer, susceptibility to, 3, colorectal cancer, susceptibility to, 5, colorectal cancer, susceptibility to, 6, colorectal cancer, susceptibility to, 7, leukemia, chronic lymphocytic, susceptibility to, 3, leukemia, chronic lymphocytic, susceptibility to, 4, leukemia, chronic lymphocytic, susceptibility to, 5, lung cancer susceptibility 3, colorectal cancer, susceptibility to, 8, colorectal cancer, susceptibility to, 9, colorectal cancer, susceptibility to, 10, colorectal cancer, susceptibility to, 11, lung cancer susceptibility 4, neuroblastoma, susceptibility to, 3, neuroblastoma, susceptibility to, 4, neuroblastoma, susceptibility to, 5, neuroblastoma, susceptibility to, 6, leukemia, acute lymphocytic, susceptibility to, 1, leukemia, acute lymphocytic, susceptibility to, 2, lung cancer susceptibility 5, BAP1-related tumor predisposition syndrome, familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome, Maffucci syndrome, basal cell carcinoma, susceptibility to, 7, colorectal cancer, susceptibility to, 12, leukemia, acute lymphoblastic, susceptibility to, 3, cholangiocarcinoma, susceptibility to, progeroid features-hepatocellular carcinoma predisposition syndrome, neuroblastoma, susceptibility to, 7, DDX41-related hematologic malignancy predisposition syndrome, nasopharyngeal carcinoma, susceptibility to, 3, familial isolated hyperparathyroidism, intestinal polyposis syndrome, dyskeratosis congenita, familial rhabdoid tumor, multiple endocrine neoplasia, hereditary pheochromocytoma-paraganglioma, PTEN hamartoma tumor syndrome, familial multiple fibrofolliculoma, hereditary retinoblastoma, familial atypical multiple mole melanoma syndrome, hereditary nonpolyposis colon cancer, Li-Fraumeni syndrome, Cobb syndrome, neurofibromatosis, susceptibility to familial cutaneous melanoma, pancreatic cancer, susceptibility to, 5, leukemia, acute myeloid, susceptibility to, diffuse gastric and lobular breast cancer syndrome with or without cleft lip and/or palate, glioma susceptibility, hemangioma, capillary infantile, susceptibility to, CDH1-related diffuse gastric and lobular breast cancer syndrome, NTHL1-deficiency tumor predisposition syndrome, SAMD9-related spectrum and myeloid neoplasm risk, neuroblastoma, susceptibility to, 2, BARD1-related cancer predisposition, BRCA1-related cancer predisposition, BRCA2-related cancer predisposition, ATM-related cancer predisposition, CHEK2-related cancer predisposition, PALB2-related cancer predisposition, RAD51C-related cancer predisposition, RAD51D-related cancer predisposition, Li-fraumeni-like syndrome, breast cancer, familial, susceptibility to, 1, breast cancer, familial, susceptibility to, 2, breast cancer, familial, susceptibility to, 3, colorectal cancer, susceptibility to, 4, colorectal cancer, susceptibility to, on chromosome 15, ovarian cancer, familial, susceptibility to, 1, ovarian cancer, familial, susceptibility to, 2, ovarian cancer, familial, susceptibility to, 3, inherited hematologic cancer-predisposing syndrome, mosaic neurofibromatosis/schwannomatosis, tumor predisposition syndrome 2, prostate cancer, hereditary, X-linked 3, follicular lymphoma, susceptibility to, GPR161-related medulloblastoma predisposition, SAMD9L-related spectrum and myeloid neoplasm risk, HAVCR2-related cancer predisposition, EGLN1-related erythrocytosis and pheochromocytoma/paraganglioma predisposition

Subtypes (4): Rothmund-Thomson syndrome type 3, Rothmund-Thomson syndrome type 1, 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

52 retrieved; paginated sample, class counts are floors:

23 uncertain significance, 14 conflicting classifications of pathogenicity, 8 pathogenic, 4 likely pathogenic, 2 pathogenic/likely pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1710081	NM_001080449.3(DNA2):c.588-2214A>G	DNA2	Pathogenic	criteria provided, single submitter
1710083	NM_001080449.3(DNA2):c.1711dup (p.Ile571fs)	DNA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1710084	NC_000010.11:g.68413754_68420303del	DNA2	Pathogenic	criteria provided, single submitter
1710085	NM_001080449.3(DNA2):c.2208+2456_2403-18del	DNA2	Pathogenic	criteria provided, single submitter
1710086	NM_001080449.3(DNA2):c.442-768_587+648del	DNA2	Pathogenic	criteria provided, single submitter
459388	NM_004260.4(RECQL4):c.221_222del (p.Glu74fs)	RECQL4	Pathogenic	criteria provided, single submitter
561097	NM_004260.4(RECQL4):c.1149G>A (p.Trp383Ter)	RECQL4	Pathogenic	criteria provided, multiple submitters, no conflicts
6063	NM_004260.4(RECQL4):c.2269C>T (p.Gln757Ter)	RECQL4	Pathogenic	criteria provided, multiple submitters, no conflicts
6066	NM_004260.4(RECQL4):c.1573del (p.Cys525fs)	RECQL4	Pathogenic	criteria provided, multiple submitters, no conflicts
666982	NM_004260.4(RECQL4):c.1089C>G (p.Tyr363Ter)	RECQL4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1710082	NM_001080449.3(DNA2):c.143T>C (p.Leu48Pro)	DNA2	Likely pathogenic	criteria provided, single submitter
225453	NM_004260.4(RECQL4):c.1390+1G>T	RECQL4	Likely pathogenic	criteria provided, single submitter
559921	NM_004260.4(RECQL4):c.3293_3294insGCAGGATGAGGAGCGCAGCA (p.Arg1099fs)	RECQL4	Likely pathogenic	criteria provided, single submitter
559922	NM_004260.4(RECQL4):c.2336_2357del (p.Asp779fs)	RECQL4	Likely pathogenic	criteria provided, single submitter
135133	NM_004260.4(RECQL4):c.1868G>A (p.Arg623His)	RECQL4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
135144	NM_004260.4(RECQL4):c.3172C>G (p.Arg1058Gly)	RECQL4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
135170	NM_004260.4(RECQL4):c.1151G>A (p.Arg384Gln)	RECQL4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
239694	NM_004260.4(RECQL4):c.1219G>A (p.Glu407Lys)	RECQL4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
239773	NM_004260.4(RECQL4):c.385C>T (p.Pro129Ser)	RECQL4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
259258	NM_004260.4(RECQL4):c.1568G>C (p.Ser523Thr)	RECQL4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
288908	NM_004260.4(RECQL4):c.1570C>T (p.Pro524Ser)	RECQL4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
406917	NM_004260.4(RECQL4):c.2761G>A (p.Glu921Lys)	RECQL4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
407023	NM_004260.4(RECQL4):c.3317G>A (p.Arg1106His)	RECQL4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
407037	NM_004260.4(RECQL4):c.1064G>A (p.Arg355Gln)	RECQL4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
459315	NM_004260.4(RECQL4):c.1345A>C (p.Thr449Pro)	RECQL4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
459352	NM_004260.4(RECQL4):c.1892G>A (p.Arg631His)	RECQL4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
459412	NM_004260.4(RECQL4):c.2543G>A (p.Arg848His)	RECQL4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
528975	NM_004260.4(RECQL4):c.3528G>A (p.Val1176=)	RECQL4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
406965	NM_004260.4(RECQL4):c.20T>G (p.Val7Gly)	LOC130001411	Uncertain significance	criteria provided, multiple submitters, no conflicts
212027	NM_004260.4(RECQL4):c.1649C>T (p.Ala550Val)	RECQL4	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 15 · Orphanet: 6 · 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
DNA2	Orphanet:352470	DNA2-related mitochondrial DNA deletion syndrome
DNA2	Orphanet:715635	Rothmund-Thomson syndrome type 4
DNA2	Orphanet:808	Seckel syndrome

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
DNA2	HGNC:2939	ENSG00000138346	P51530	DNA replication ATP-dependent helicase/nuclease DNA2	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.
DNA2	DNA replication ATP-dependent helicase/nuclease DNA2	Key enzyme involved in DNA replication and DNA repair in nucleus and mitochondrion.

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
DNA2	Other/Unknown	no		PDDEXK-like_dom_sf, DNA_replication_fac_Dna2_N, Dna2/JHS1_DEXXQ-box

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
Brodmann (1909) area 10	1
primordial germ cell in gonad	1
secondary oocyte	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
DNA2	192	ubiquitous	marker	secondary oocyte, primordial germ cell in gonad, Brodmann (1909) area 10

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RECQL4	6,330
DNA2	2,792

Intra-cohort edges

A	B	Sources
DNA2	RECQL4	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RECQL4	O94761	2
DNA2	P51530	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 16. 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
Removal of the Flap Intermediate	1	815.7×	0.005	DNA2
Removal of the Flap Intermediate from the C-strand	1	634.4×	0.005	DNA2
Impaired BRCA2 binding to PALB2	1	456.8×	0.005	DNA2
Defective homologous recombination repair (HRR) due to BRCA1 loss of function	1	423.0×	0.005	DNA2
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function	1	423.0×	0.005	DNA2
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function	1	423.0×	0.005	DNA2
Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)	1	393.8×	0.005	DNA2
Homologous DNA Pairing and Strand Exchange	1	380.7×	0.005	DNA2
Impaired BRCA2 binding to RAD51	1	308.6×	0.005	DNA2
Resolution of D-loop Structures through Holliday Junction Intermediates	1	300.5×	0.005	DNA2
HDR through Single Strand Annealing (SSA)	1	292.8×	0.005	DNA2
Presynaptic phase of homologous DNA pairing and strand exchange	1	271.9×	0.005	DNA2
HDR through Homologous Recombination (HRR)	1	190.3×	0.006	DNA2
G2/M DNA damage checkpoint	1	120.2×	0.009	DNA2
Regulation of TP53 Activity through Phosphorylation	1	117.7×	0.009	DNA2
Processing of DNA double-strand break ends	1	114.2×	0.009	DNA2

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
telomere maintenance	2	267.5×	2e-04	RECQL4, DNA2
DNA replication	2	165.2×	3e-04	RECQL4, DNA2
DNA replication, Okazaki fragment processing	1	8426.0×	7e-04	DNA2
mitotic telomere maintenance via semi-conservative replication	1	2808.7×	0.002	DNA2
DNA replication, removal of RNA primer	1	2106.5×	0.002	DNA2
replication fork reversal	1	1685.2×	0.002	DNA2
telomere maintenance via semi-conservative replication	1	1404.3×	0.002	DNA2
mitochondrial DNA repair	1	1203.7×	0.002	DNA2
DNA geometric change	1	1053.2×	0.002	DNA2
telomeric D-loop disassembly	1	936.2×	0.002	RECQL4
DNA double-strand break processing	1	766.0×	0.002	DNA2
mitochondrial DNA replication	1	766.0×	0.002	DNA2
t-circle formation	1	702.2×	0.002	DNA2
DNA replication checkpoint signaling	1	648.1×	0.002	DNA2
positive regulation of DNA replication	1	290.6×	0.004	DNA2
base-excision repair	1	234.1×	0.005	DNA2
double-strand break repair via homologous recombination	1	78.0×	0.014	RECQL4
DNA repair	1	31.9×	0.031	RECQL4

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
RECQL4	0	0
DNA2	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
DNA2	23	Binding:23

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	DNA2

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	—
DNA2	23	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03050268	Not specified	RECRUITING	Familial Investigations of Childhood Cancer Predisposition
NCT01304407	Not specified	COMPLETED	Calcium Absorption in Patients With Rothmund-Thomson Syndrome