Rapadilino syndrome

Summary

Rapadilino syndrome (MONDO:0009955) is a disease caused by RECQL4 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: RECQL4 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 175
• Phenotypes (HPO): 15

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		20	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

15 HPO clinical features (Orphanet curated; top 15 by frequency):

HPO ID	Term	Frequency
HP:0001511	Intrauterine growth retardation	Very frequent (80-99%)
HP:0008897	Postnatal growth retardation	Very frequent (80-99%)
HP:0000175	Cleft palate	Frequent (30-79%)
HP:0000218	High palate	Frequent (30-79%)
HP:0000417	Slender nose	Frequent (30-79%)
HP:0002014	Diarrhea	Frequent (30-79%)
HP:0006498	Aplasia/Hypoplasia of the patella	Frequent (30-79%)
HP:0006501	Aplasia/Hypoplasia of the radius	Frequent (30-79%)
HP:0009601	Aplasia/Hypoplasia of the thumb	Frequent (30-79%)
HP:0011968	Feeding difficulties	Frequent (30-79%)
HP:0040064	Abnormality of limbs	Frequent (30-79%)
HP:0004313	Decreased circulating antibody level	Occasional (5-29%)
HP:0005403	Decreased total T cell count	Occasional (5-29%)
HP:0001029	Poikiloderma	Excluded (0%)
HP:0001249	Intellectual disability	Excluded (0%)

Identifiers

Disease identifiers

Field	Value
Canonical name	rapadilino syndrome
Mondo ID	MONDO:0009955
MeSH	C535288
OMIM	266280
Orphanet	3021
DOID	DOID:0050774
ICD-11	1439614760
SNOMED CT	702413000
UMLS	C1849453
MedGen	336602
GARD	0004637
Is cancer (heuristic)	no

Also known as: absent thumbs, dislocated joints, long face with narrow palpebral fissures, long slender nose, arched palate · radial and patellar aplasia · radial and patellar hypoplasia · rapadilino syndrome

Data availability: 175 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 › autosomal genetic disease › autosomal recessive disease › rapadilino syndrome

Related subtypes (218): immunodeficiency-centromeric instability-facial anomalies syndrome, hypercalcemia, infantile, Ochoa syndrome, autosomal recessive Ehlers-Danlos syndrome, vascular type, hydrolethalus syndrome, 3-M syndrome, isolated hyperchlorhidrosis, dacryocystitis-osteopoikilosis syndrome, Hutchinson-Gilford progeria syndrome, achalasia microcephaly syndrome, acrorenal syndrome, autosomal recessive, beta-ketothiolase deficiency, autosomal recessive Alport syndrome, Alstrom syndrome, microphthalmia with limb anomalies, camptodactyly-arthropathy-coxa vara-pericarditis syndrome, Behr syndrome, bifid nose, autosomal recessive, Bloom syndrome, Bowen-Conradi syndrome, camptodactyly with fibrous tissue hyperplasia and skeletal dysplasia, heart defects-limb shortening syndrome, autosomal recessive palmoplantar keratoderma and congenital alopecia, COFS syndrome, craniometaphyseal dysplasia, autosomal recessive, Fraser syndrome, cystic fibrosis, polycystic lipomembranous osteodysplasia with sclerosing leukoencephaly, persistent hyperplastic primary vitreous, autosomal recessive, Donnai-Barrow syndrome, Schöpf-Schulz-Passarge syndrome, cleft lip/palate-ectodermal dysplasia syndrome, Ellis-van Creveld syndrome, Wolcott-Rallison syndrome, autosomal recessive faciodigitogenital syndrome, acromesomelic dysplasia 2B, brittle cornea syndrome, triple-A syndrome, autosomal recessive humeroradial synostosis, multinucleated neurons-anhydramnios-renal dysplasia-cerebellar hypoplasia-hydranencephaly syndrome, hydrocephalus, nonsyndromic, autosomal recessive 1, autosomal recessive hydrocephalus due to congenital stenosis of aqueduct of Sylvius, hypertelorism, microtia, facial clefting syndrome, hypoparathyroidism-retardation-dysmorphism syndrome, Vici syndrome, Johanson-Blizzard syndrome, autosomal recessive Kenny-Caffey syndrome, Papillon-Lefevre disease, Haim-Munk syndrome, Laurence-Moon syndrome, Donohue syndrome, lipase deficiency, combined, autosomal recessive familial Mediterranean fever, thiamine-responsive megaloblastic anemia syndrome, cartilage-hair hypoplasia, Nijmegen breakage syndrome, pseudo-TORCH syndrome, Galloway-Mowat syndrome, mulibrey nanism, myotonia congenita, autosomal recessive, Schwartz-Jampel syndrome, proteosome-associated autoinflammatory syndrome, Netherton syndrome, Niemann-Pick disease type A, oculodentodigital dysplasia, autosomal recessive, odonto-onycho-dermal dysplasia, autosomal recessive omodysplasia, osteoporosis-pseudoglioma syndrome, Shwachman-Diamond syndrome, phenylketonuria, Bjornstad syndrome, Laron syndrome, autosomal recessive polycystic kidney disease, autosomal recessive inherited pseudoxanthoma elasticum, autosomal recessive multiple pterygium syndrome, short-rib thoracic dysplasia 9 with or without polydactyly, autosomal recessive Robinow syndrome, Sjogren-Larsson syndrome, scapuloperoneal spinal muscular atrophy, autosomal recessive, spondyloepiphyseal dysplasia tarda, autosomal recessive, inherited threoninemia, Pendred syndrome, autosomal recessive spondylocostal dysostosis, Werner syndrome, ABCD syndrome, Naxos disease, autosomal recessive amelia, human HOXA1 syndromes, sickle cell disease, autosomal recessive proximal renal tubular acidosis, hyper-IgM syndrome type 2, temtamy preaxial brachydactyly syndrome, TH-deficient dopa-responsive dystonia, craniosynostosis syndrome, autosomal recessive, Niemann-Pick disease type B, skin fragility-woolly hair-palmoplantar keratoderma syndrome, CoQ-responsive OXPHOS deficiency, familial adenomatous polyposis 2, Pierson syndrome, palmoplantar keratoderma-XX sex reversal-predisposition to squamous cell carcinoma syndrome, cardiomyopathy-hypotonia-lactic acidosis syndrome, PHARC syndrome, Kahrizi syndrome, cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies, congenital prothrombin deficiency, immunodeficiency 31B, dyskeratosis congenita, autosomal recessive 2, dyskeratosis congenita, autosomal recessive 3, Nestor-Guillermo progeria syndrome, leukoencephalopathy with calcifications and cysts, mitochondrial pyruvate carrier deficiency, branched-chain keto acid dehydrogenase kinase deficiency, dyskeratosis congenita, autosomal recessive 5, hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome, alacrima, achalasia, and intellectual disability syndrome, hyperlipoproteinemia, type 1D, microcephaly and chorioretinopathy 2, congenital stationary night blindness 1G, combined oxidative phosphorylation deficiency 29, hypermanganesemia with dystonia 2, growth retardation, intellectual developmental disorder, hypotonia, and hepatopathy, gnb5-related intellectual disability-cardiac arrhythmia syndrome, autosomal recessive spastic paraplegia type 78, autosomal recessive limb-girdle muscular dystrophy, Bardet-Biedl syndrome, autosomal recessive cerebellar ataxia, neuronopathy, distal hereditary motor, autosomal recessive, UV-sensitive syndrome, Ehlers-Danlos syndrome, kyphoscoliotic type 1, Cockayne syndrome, hyperphenylalaninemia due to tetrahydrobiopterin deficiency, leukoencephalopathy-palmoplantar keratoderma syndrome, autosomal recessive hypohidrotic ectodermal dysplasia, Warburg micro syndrome, autosomal recessive primary microcephaly, autosomal recessive progressive external ophthalmoplegia, Meier-Gorlin syndrome, autosomal recessive sideroblastic anemia, autosomal recessive intermediate Charcot-Marie-Tooth disease, Perrault syndrome, autosomal recessive hypophosphatemic rickets, de Barsy syndrome, leukocyte adhesion deficiency, Senior-Loken syndrome, autosomal recessive spastic ataxia, childhood-onset autosomal recessive myopathy with external ophthalmoplegia, autosomal recessive cerebral atrophy, GM3 synthase deficiency, autosomal recessive distal renal tubular acidosis, pigmentation defects-palmoplantar keratoderma-skin carcinoma syndrome, autosomal recessive brachyolmia, Aicardi-Goutieres syndrome, homocystinuria without methylmalonic aciduria, Niemann-Pick disease type C, nephronophthisis, autosomal recessive osteopetrosis, peroxisome biogenesis disorder, congenital non-bullous ichthyosiform erythroderma, Seckel syndrome, Usher syndrome, autosomal recessive cutis laxa type 1, autosomal recessive cutis laxa type 2, hearing loss, autosomal recessive, microcephaly, growth restriction, and increased sister chromatid exchange 2, encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 1, congenital vertebral-cardiac-renal anomalies syndrome, hair defect with photosensitivity and intellectual disability syndrome, autosomal recessive severe congenital neutropenia, severe combined immunodeficiency due to CARMIL2 deficiency, extraoral halitosis due to methanethiol oxidase deficiency, neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities, mitochondrial complex 2 deficiency, nuclear type 3, mitochondrial complex 2 deficiency, nuclear type 4, mismatch repair cancer syndrome, spondyloepimetaphyseal dysplasia with joint laxity, type 3, Kilquist syndrome, Duane anomaly-myopathy-scoliosis syndrome, autosomal recessive axonal charcot-marie-tooth disease due to copper metabolism defect, immune dysregulation-inflammatory bowel disease-arthritis-recurrent infections-lymphopenia syndrome, optic atrophy-ataxia-peripheral neuropathy-global developmental delay syndrome, congenital myopathy with reduced type 2 muscle fibers, NAD(P)HX dehydratase deficiency, autosomal recessive ocular albinism, ichthyosis linearis circumflexa, eosinophil peroxidase deficiency, hyperphenylalaninemia due to DNAJC12 deficiency, autosomal recessive epidermolytic ichthyosis, Ehlers-Danlos syndrome, classic-like, 2, joint laxity, short stature, and myopia, HELIX syndrome, auditory neuropathy-optic atrophy syndrome, glycosylphosphatidylinositol biosynthesis defect 15, neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures, SCN4A-related myopathy, autosomal recessive, Uner Tan Syndrome, nephropathic cystinosis, Imerslund-Grasbeck syndrome type 1, Imerslund-Grasbeck syndrome type 2, permanent neonatal diabetes mellitus 1, growth hormone insensitivity with immune dysregulation 1, autosomal recessive, Rajab interstitial lung disease with brain calcifications 1, Roberts-SC phocomelia syndrome, neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities, RPE65-related recessive retinopathy, GUCY2D-related recessive retinopathy, autosomal recessive titinopathy, intellectual disability, autosomal recessive, ALPL-related autosomal recessive hypophosphatasia, spastic paraplegia 18b, autosomal recessive, CEP164-related ciliopathy, RP1-related recessive retinopathy, pseudohypoaldosteronism, type IB2, autosomal recessive, pseudohypoaldosteronism, type IB3, autosomal recessive, spastic paraplegia 30B, autosomal recessive, cerebral arteriopathy, autosomal recessive, with subcortical infarcts and leukoencephalopathy 1, brain small vessel disease 2B, autosomal recessive, IMPG1-related recessive retinopathy, PROM1-related recessive retinopathy

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

175 retrieved; paginated sample, class counts are floors:

62 uncertain significance, 37 benign/likely benign, 28 conflicting classifications of pathogenicity, 19 benign, 13 pathogenic/likely pathogenic, 7 likely pathogenic, 7 pathogenic, 2 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
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
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
56398	NM_004260.4(RECQL4):c.1390+2del	RECQL4	Pathogenic	criteria provided, single submitter
56399	NM_004260.4(RECQL4):c.1397C>T (p.Pro466Leu)	RECQL4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
56402	NM_004260.4(RECQL4):c.1887_1890del (p.Glu630fs)	RECQL4	Pathogenic	criteria provided, single submitter
56404	NM_004260.4(RECQL4):c.2059-1G>A	RECQL4	Pathogenic	criteria provided, single submitter
56406	NM_004260.4(RECQL4):c.2476C>T (p.Arg826Ter)	RECQL4	Pathogenic	criteria provided, multiple submitters, no conflicts
56407	NM_004260.4(RECQL4):c.3072del (p.Val1026fs)	RECQL4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
56409	NM_004260.4(RECQL4):c.3271C>T (p.Gln1091Ter)	RECQL4	Pathogenic/Likely pathogenic	no assertion criteria provided
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
6066	NM_004260.4(RECQL4):c.1573del (p.Cys525fs)	RECQL4	Pathogenic	criteria provided, multiple submitters, no conflicts
6072	NM_004260.4(RECQL4):c.806G>A (p.Trp269Ter)	RECQL4	Pathogenic	criteria provided, single submitter
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
225453	NM_004260.4(RECQL4):c.1390+1G>T	RECQL4	Likely pathogenic	criteria provided, single submitter
2581064	NM_004260.4(RECQL4):c.3561C>G (p.Tyr1187Ter)	RECQL4	Likely pathogenic	criteria provided, single submitter
4845760	NM_004260.4(RECQL4):c.3502+1G>A	RECQL4	Likely pathogenic	criteria provided, single submitter
56401	NM_004260.4(RECQL4):c.1885_1888del (p.Arg629fs)	RECQL4	Likely pathogenic	no assertion criteria provided
56408	NM_004260.4(RECQL4):c.3214A>T (p.Arg1072Ter)	RECQL4	Likely pathogenic	no assertion criteria provided
56410	NM_004260.4(RECQL4):c.3599_3600del (p.Thr1200fs)	RECQL4	Likely pathogenic	no assertion criteria provided
1009497	NM_004260.4(RECQL4):c.2554_2565dup (p.Ala852_Cys855dup)	RECQL4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
135128	NM_004260.4(RECQL4):c.1684C>T (p.Arg562Trp)	RECQL4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
135133	NM_004260.4(RECQL4):c.1868G>A (p.Arg623His)	RECQL4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 15 · Orphanet: 3 · 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	Strong	Autosomal recessive	rapadilino 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

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
RECQL4	HGNC:9949	ENSG00000160957	O94761	ATP-dependent DNA helicase Q4	gencc,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.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Enzyme (other)	1	12.0×	0.083

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

Expression context

Cohort genes with no expression data: 0.

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
lower esophagus mucosa	1
mucosa of transverse colon	1
ventricular zone	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

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RECQL4	6,330

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RECQL4	O94761	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

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
telomeric D-loop disassembly	1	1872.4×	0.003	RECQL4
telomere maintenance	1	267.5×	0.008	RECQL4
DNA replication	1	165.2×	0.008	RECQL4
double-strand break repair via homologous recombination	1	156.0×	0.008	RECQL4
DNA repair	1	63.8×	0.016	RECQL4

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

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)
RECQL4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.