RIDDLE syndrome

Summary

RIDDLE syndrome (MONDO:0012764) is a disease caused by RNF168 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: RNF168 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 33
• Phenotypes (HPO): 43

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		2	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

43 HPO clinical features (Orphanet curated; top 43 by frequency):

HPO ID	Term	Frequency
HP:0002720	Decreased circulating IgA level	Very frequent (80-99%)
HP:0002721	Immunodeficiency	Very frequent (80-99%)
HP:0004315	Decreased circulating IgG level	Very frequent (80-99%)
HP:0004322	Short stature	Very frequent (80-99%)
HP:0006254	Elevated alpha-fetoprotein	Very frequent (80-99%)
HP:0010997	Chromosomal breakage induced by ionizing radiation	Very frequent (80-99%)
HP:0001328	Specific learning disability	Frequent (30-79%)
HP:0001954	Recurrent fever	Frequent (30-79%)
HP:0001999	Abnormal facial shape	Frequent (30-79%)
HP:0002090	Pneumonia	Frequent (30-79%)
HP:0006532	Recurrent pneumonia	Frequent (30-79%)
HP:0011108	Recurrent sinusitis	Frequent (30-79%)
HP:0011109	Chronic sinusitis	Frequent (30-79%)
HP:0012387	Bronchitis	Frequent (30-79%)
HP:0000252	Microcephaly	Occasional (5-29%)
HP:0000388	Otitis media	Occasional (5-29%)
HP:0000524	Conjunctival telangiectasia	Occasional (5-29%)
HP:0000712	Emotional lability	Occasional (5-29%)
HP:0001009	Telangiectasia	Occasional (5-29%)
HP:0001251	Ataxia	Occasional (5-29%)
HP:0001263	Global developmental delay	Occasional (5-29%)
HP:0001288	Gait disturbance	Occasional (5-29%)
HP:0001369	Arthritis	Occasional (5-29%)
HP:0001824	Weight loss	Occasional (5-29%)
HP:0002014	Diarrhea	Occasional (5-29%)
HP:0002027	Abdominal pain	Occasional (5-29%)
HP:0002091	Restrictive ventilatory defect	Occasional (5-29%)
HP:0002206	Pulmonary fibrosis	Occasional (5-29%)
HP:0002312	Clumsiness	Occasional (5-29%)
HP:0002315	Headache	Occasional (5-29%)
HP:0002500	Abnormal cerebral white matter morphology	Occasional (5-29%)
HP:0002850	Decreased circulating total IgM	Occasional (5-29%)
HP:0002878	Respiratory failure	Occasional (5-29%)
HP:0004429	Recurrent viral infections	Occasional (5-29%)
HP:0006530	Abnormal pulmonary interstitial morphology	Occasional (5-29%)
HP:0007057	Poor hand-eye coordination	Occasional (5-29%)
HP:0007108	Demyelinating peripheral neuropathy	Occasional (5-29%)
HP:0008940	Generalized lymphadenopathy	Occasional (5-29%)
HP:0010677	Enuresis nocturna	Occasional (5-29%)
HP:0010783	Erythema	Occasional (5-29%)
HP:0012768	Neonatal asphyxia	Occasional (5-29%)
HP:0030746	Intraventricular hemorrhage	Occasional (5-29%)
HP:0040189	Scaling skin	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	RIDDLE syndrome
Mondo ID	MONDO:0012764
MeSH	C567453
OMIM	611943
Orphanet	420741
DOID	DOID:0090113
UMLS	C2677792
MedGen	394368
GARD	0017701
Is cancer (heuristic)	no

Also known as: radiosensitivity-immunodeficiency-dysmorphic features-learning difficulties syndrome · RIDDLE syndrome · RNF168 deficiency

Data availability: 33 ClinVar variants · 5 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 › autosomal recessive cerebellar ataxia › RIDDLE syndrome

Related subtypes (28): Charlevoix-Saguenay spastic ataxia, infantile-onset autosomal recessive nonprogressive cerebellar ataxia, autosomal recessive spinocerebellar ataxia 7, autosomal recessive ataxia, Beauce type, autosomal recessive ataxia due to ubiquinone deficiency, autosomal recessive spinocerebellar ataxia 10, ataxia with oculomotor apraxia type 3, autosomal recessive spinocerebellar ataxia 14, autosomal recessive spinocerebellar ataxia 16, Lichtenstein-Knorr syndrome, autosomal recessive spinocerebellar ataxia 20, spinocerebellar ataxia, autosomal recessive 22, spinocerebellar ataxia, autosomal recessive 24, autosomal recessive cerebellar ataxia - epilepsy - intellectual disability syndrome, autosomal recessive congenital cerebellar ataxia, autosomal recessive metabolic cerebellar ataxia, autosomal recessive degenerative and progressive cerebellar ataxia, autosomal recessive syndromic cerebellar ataxia, spinocerebellar ataxia, autosomal recessive, with axonal neuropathy, spinocerebellar ataxia, autosomal recessive 29, spinocerebellar ataxia, autosomal recessive 30, spinocerebellar ataxia, autosomal recessive 31, spinocerebellar ataxia, autosomal recessive 27, spinocerebellar ataxia, autosomal recessive 28, spinocerebellar ataxia, autosomal recessive 25, spinocerebellar ataxia, autosomal recessive 26, spinocerebellar ataxia, autosomal recessive 32, spinocerebellar ataxia, autosomal recessive 33

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

33 retrieved; paginated sample, class counts are floors:

9 uncertain significance, 8 benign, 6 likely pathogenic, 5 benign/likely benign, 4 pathogenic/likely pathogenic, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1325008	NM_152617.4(RNF168):c.659_662del (p.Arg220fs)	RNF168	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1375368	NM_152617.4(RNF168):c.412G>T (p.Glu138Ter)	RNF168	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
140755	NM_152617.4(RNF168):c.391C>T (p.Arg131Ter)	RNF168	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
487	NM_152617.4(RNF168):c.397dup (p.Ala133fs)	RNF168	Pathogenic	no assertion criteria provided
489117	NM_152617.4(RNF168):c.493C>T (p.Arg165Ter)	RNF168	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1985421	NM_152617.4(RNF168):c.559-1_560del	RNF168	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3589114	NM_152617.4(RNF168):c.1463del (p.Asn488fs)	RNF168	Likely pathogenic	criteria provided, single submitter
3589116	NM_152617.4(RNF168):c.192C>G (p.Tyr64Ter)	RNF168	Likely pathogenic	criteria provided, single submitter
3892297	NM_152617.4(RNF168):c.1427T>G (p.Leu476Ter)	RNF168	Likely pathogenic	criteria provided, single submitter
4077463	NM_152617.4(RNF168):c.511C>T (p.Gln171Ter)	RNF168	Likely pathogenic	criteria provided, single submitter
488	NM_152617.4(RNF168):c.1323_1326del (p.Gln442fs)	RNF168	Likely pathogenic	criteria provided, single submitter
1030267	NM_152617.4(RNF168):c.496A>G (p.Arg166Gly)	RNF168	Uncertain significance	criteria provided, single submitter
1389802	NM_152617.4(RNF168):c.1435A>G (p.Thr479Ala)	RNF168	Uncertain significance	criteria provided, single submitter
1418311	NM_152617.4(RNF168):c.596T>C (p.Leu199Ser)	RNF168	Uncertain significance	criteria provided, multiple submitters, no conflicts
1418915	NM_152617.4(RNF168):c.1019C>T (p.Ser340Leu)	RNF168	Uncertain significance	criteria provided, multiple submitters, no conflicts
1482561	NM_152617.4(RNF168):c.919G>A (p.Glu307Lys)	RNF168	Uncertain significance	criteria provided, multiple submitters, no conflicts
1491317	NM_152617.4(RNF168):c.470A>G (p.Glu157Gly)	RNF168	Uncertain significance	criteria provided, multiple submitters, no conflicts
1527849	NM_152617.4(RNF168):c.1591_1594dup (p.Asn532delinsSerTer)	RNF168	Uncertain significance	criteria provided, single submitter
992520	NM_152617.4(RNF168):c.237A>G (p.Ile79Met)	RNF168	Uncertain significance	criteria provided, multiple submitters, no conflicts
993672	NM_152617.4(RNF168):c.529G>A (p.Glu177Lys)	RNF168	Uncertain significance	criteria provided, multiple submitters, no conflicts
1327960	NM_152617.4(RNF168):c.559-46A>G	RNF168	Benign	criteria provided, multiple submitters, no conflicts
1327961	NM_152617.4(RNF168):c.378+26del	RNF168	Benign	criteria provided, single submitter
1617383	NM_152617.4(RNF168):c.681-19T>G	RNF168	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
218846	NM_152617.4(RNF168):c.508G>A (p.Glu170Lys)	RNF168	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
284163	NM_152617.4(RNF168):c.1237G>A (p.Glu413Lys)	RNF168	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
403381	NM_152617.4(RNF168):c.1202C>A (p.Pro401Gln)	RNF168	Benign	criteria provided, multiple submitters, no conflicts
708391	NM_152617.4(RNF168):c.864A>G (p.Gln288=)	RNF168	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
716856	NM_152617.4(RNF168):c.1481C>T (p.Pro494Leu)	RNF168	Benign	criteria provided, multiple submitters, no conflicts
726053	NM_152617.4(RNF168):c.1132T>C (p.Cys378Arg)	RNF168	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
767946	NM_152617.4(RNF168):c.1160A>G (p.Lys387Arg)	RNF168	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
RNF168	Strong	Autosomal recessive	RIDDLE syndrome	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RNF168	Orphanet:420741	RIDDLE 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
RNF168	HGNC:26661	ENSG00000163961	Q8IYW5	E3 ubiquitin-protein ligase RNF168	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RNF168	E3 ubiquitin-protein ligase RNF168	E3 ubiquitin-protein ligase required for accumulation of repair proteins to sites of DNA damage.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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
Transcription factor	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RNF168	Transcription factor	no		Znf_RING, Znf_RING/FYVE/PHD, RNF168

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
epithelial cell of pancreas	1
sperm	1
tendon of biceps brachii	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RNF168	253	ubiquitous	marker	sperm, tendon of biceps brachii, epithelial cell of pancreas

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RNF168	1,941

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RNF168	Q8IYW5	39

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 17. 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
DNA Double Strand Break Response	1	475.8×	0.012	RNF168
Homology Directed Repair	1	308.6×	0.012	RNF168
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	1	308.6×	0.012	RNF168
DNA Double-Strand Break Repair	1	248.3×	0.012	RNF168
SUMO E3 ligases SUMOylate target proteins	1	178.4×	0.012	RNF168
Nonhomologous End-Joining (NHEJ)	1	167.9×	0.012	RNF168
SUMOylation	1	163.1×	0.012	RNF168
SUMOylation of DNA damage response and repair proteins	1	146.4×	0.012	RNF168
Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks	1	146.4×	0.012	RNF168
G2/M Checkpoints	1	134.3×	0.012	RNF168
G2/M DNA damage checkpoint	1	120.2×	0.012	RNF168
Processing of DNA double-strand break ends	1	114.2×	0.012	RNF168
DNA Repair	1	98.5×	0.013	RNF168
Cell Cycle Checkpoints	1	88.5×	0.014	RNF168
Cell Cycle	1	36.0×	0.031	RNF168
Post-translational protein modification	1	19.2×	0.055	RNF168
Metabolism of proteins	1	12.4×	0.081	RNF168

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
double-strand break repair via classical nonhomologous end joining	1	1685.2×	0.004	RNF168
isotype switching	1	842.6×	0.004	RNF168
negative regulation of transcription elongation by RNA polymerase II	1	766.0×	0.004	RNF168
DNA repair-dependent chromatin remodeling	1	674.1×	0.004	RNF168
interstrand cross-link repair	1	432.1×	0.004	RNF168
double-strand break repair via nonhomologous end joining	1	421.3×	0.004	RNF168
response to ionizing radiation	1	411.0×	0.004	RNF168
epigenetic regulation of gene expression	1	383.0×	0.004	RNF168
positive regulation of DNA repair	1	358.6×	0.004	RNF168
protein K63-linked ubiquitination	1	267.5×	0.005	RNF168
double-strand break repair	1	203.0×	0.006	RNF168
ubiquitin-dependent protein catabolic process	1	74.2×	0.016	RNF168
DNA damage response	1	53.5×	0.020	RNF168
protein ubiquitination	1	41.4×	0.024	RNF168

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RNF168	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
RNF168	3	Binding:3

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	RNF168

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)
RNF168	3	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.