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MCID: RDD003
MIFTS: 45

Riddle Syndrome

Categories: Genetic diseases, Neuronal diseases, Blood diseases, Rare diseases, Immune diseases
Genes Variations Tissues Related diseases Publications Pathways Symptoms & Phenotypes
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Aliases & Classifications for Riddle Syndrome

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MalaCards integrated aliases for Riddle Syndrome:

Name: Riddle Syndrome 57 12 59 75 37 29 13 6 40 73
Radiosensitivity-Immunodeficiency-Dysmorphic Features-Learning Difficulties Syndrome 12 59
Rnf168 Deficiency 12 59
Radiosensitivity, Immunodeficiency, Dysmorphic Features, and Learning Difficulties 57
Riddles 75

Characteristics:

Orphanet epidemiological data:

59
riddle syndrome
Inheritance: Autosomal recessive; Prevalence: <1/1000000 (Worldwide); Age of onset: Adolescent,Infancy; Age of death: adult;

OMIM:

57
Inheritance:
autosomal recessive

Miscellaneous:
two unrelated patients have been reported (last curated july 2014) onset in infancy or childhood


HPO:

32
riddle syndrome:
Inheritance autosomal recessive inheritance


Classifications:

MalaCards categories:
Global: Genetic diseases Rare diseases
Anatomical: Neuronal diseases Blood diseases Immune diseases
See all MalaCards categories (disease lists)
ICD10: 33 34
Orphanet: 59  
Rare neurological diseases
Rare immunological diseases


Sources

Summaries for Riddle Syndrome

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Disease Ontology : 12 An autosomal recessive disease characterized by increased radiosensitivity, immunodeficiency, mild motor control and learning difficulties, facial dysmorphism, and short stature that has material basis in homozygous or compound heterozygous mutation in the RNF168 gene on chromosome 3q29.

MalaCards based summary : Riddle Syndrome, also known as radiosensitivity-immunodeficiency-dysmorphic features-learning difficulties syndrome, is related to canavan disease and aplastic anemia, and has symptoms including ataxia and dry skin. An important gene associated with Riddle Syndrome is RNF168 (Ring Finger Protein 168), and among its related pathways/superpathways are Metabolism of proteins and Signaling by Rho GTPases. Affiliated tissues include skin and eye, and related phenotypes are emotional lability and ataxia

UniProtKB/Swiss-Prot : 75 Riddle syndrome: Characterized by increased radiosensitivity, immunodeficiency, mild motor control and learning difficulties, facial dysmorphism, and short stature. Defects are probably due to impaired localization of TP53BP1 and BRCA1 at DNA lesions.

Wikipedia : 76 RIDDLE syndrome is a rare genetic syndrome. The name is an acronym for Radiosensitivity,... more...

Description from OMIM: 611943
Sources

Related Diseases for Riddle Syndrome

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Diseases related to Riddle Syndrome via text searches within MalaCards or GeneCards Suite gene sharing:

(show all 48)
# Related Disease Score Top Affiliating Genes
1 canavan disease 11.0
2 aplastic anemia 9.8
3 acute promyelocytic leukemia 9.8
4 pulmonary fibrosis and/or bone marrow failure, telomere-related, 2 9.8
5 leukemia 9.8
6 exhibitionism 9.8
7 tropical sprue 9.8
8 syringomyelia 9.8
9 brachydactyly, type a1 9.7
10 immune deficiency disease 9.7
11 niemann-pick disease, type c1 9.7
12 focal segmental glomerulosclerosis 1 9.7
13 malaria 9.7
14 hydrops fetalis, nonimmune, and/or atrial septal defect 9.7
15 west syndrome 9.7
16 chronic granulomatous disease 9.7
17 focal segmental glomerulosclerosis 9.7
18 niemann-pick disease 9.7
19 brachydactyly 9.7
20 anosognosia 9.7
21 hypospadias 9.7
22 hemiplegia 9.7
23 exotropia 9.7
24 gastroparesis 9.7
25 bell's palsy 9.7
26 diarrhea 9.7
27 cholestasis 9.7
28 rheumatic disease 9.7
29 intrahepatic cholestasis 9.7
30 cholecystitis 9.7
31 enthesopathy 9.7
32 essential thrombocythemia 9.7
33 acalculous cholecystitis 9.7
34 cerebritis 9.7
35 intestinal pseudo-obstruction 9.7
36 elephantiasis 9.7
37 acute disseminated encephalomyelitis 9.7
38 scarlet fever 9.7
39 myeloid leukemia 9.7
40 psoriasis 9.7
41 learning disability 9.7
42 neurofibroma 9.7
43 fetal edema 9.7
44 hydrops fetalis 9.7
45 nephrogenic systemic fibrosis 9.7
46 schindler disease 9.7
47 myoclonus 9.7
48 ataxia-telangiectasia 9.4 BRCA1 TP53BP1

Graphical network of the top 20 diseases related to Riddle Syndrome:



Diseases related to Riddle Syndrome
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Symptoms & Phenotypes for Riddle Syndrome

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Symptoms via clinical synopsis from OMIM:

57
Neurologic Central Nervous System:
ataxia
learning difficulties (in 1 patient)
impaired motor control, mild

Immunology:
immunodeficiency
variably decreased serum iga, igg, and igm

Head And Neck Head:
microcephaly (in some patients)

Head And Neck Eyes:
ocular telangiectasia

Growth Height:
short stature

Skin Nails Hair Skin:
dry skin

Laboratory Abnormalities:
increased alpha-fetoprotein
cells show increased sensitivity to ionizing radiation
defect in double-stranded dna repair

Respiratory:
progressive pulmonary failure (1 patient)
interstitial pneumonia (1 patient)
pulmonary fibrosis (1 patient)
bronchial telangiectasia (1 patient)


Clinical features from OMIM:

611943

Human phenotypes related to Riddle Syndrome:

59 32 (show all 46)
# Description HPO Frequency Orphanet Frequency HPO Source Accession
1 emotional lability 59 32 occasional (7.5%) Occasional (29-5%) HP:0000712
2 ataxia 59 32 occasional (7.5%) Occasional (29-5%) HP:0001251
3 gait disturbance 59 32 occasional (7.5%) Occasional (29-5%) HP:0001288
4 global developmental delay 59 32 occasional (7.5%) Occasional (29-5%) HP:0001263
5 arthritis 59 32 occasional (7.5%) Occasional (29-5%) HP:0001369
6 abnormal facial shape 59 32 frequent (33%) Frequent (79-30%) HP:0001999
7 microcephaly 59 32 occasional (7.5%) Occasional (29-5%) HP:0000252
8 short stature 59 32 hallmark (90%) Very frequent (99-80%) HP:0004322
9 pulmonary fibrosis 59 32 occasional (7.5%) Occasional (29-5%) HP:0002206
10 immunodeficiency 59 32 hallmark (90%) Very frequent (99-80%) HP:0002721
11 abdominal pain 59 32 occasional (7.5%) Occasional (29-5%) HP:0002027
12 scaling skin 59 32 occasional (7.5%) Occasional (29-5%) HP:0040189
13 weight loss 59 32 occasional (7.5%) Occasional (29-5%) HP:0001824
14 specific learning disability 59 32 frequent (33%) Frequent (79-30%) HP:0001328
15 conjunctival telangiectasia 59 32 occasional (7.5%) Occasional (29-5%) HP:0000524
16 respiratory failure 59 32 occasional (7.5%) Occasional (29-5%) HP:0002878
17 diarrhea 59 32 occasional (7.5%) Occasional (29-5%) HP:0002014
18 erythema 59 32 occasional (7.5%) Occasional (29-5%) HP:0010783
19 otitis media 59 32 occasional (7.5%) Occasional (29-5%) HP:0000388
20 recurrent pneumonia 59 32 frequent (33%) Frequent (79-30%) HP:0006532
21 clumsiness 59 32 occasional (7.5%) Occasional (29-5%) HP:0002312
22 headache 59 32 occasional (7.5%) Occasional (29-5%) HP:0002315
23 elevated alpha-fetoprotein 59 32 hallmark (90%) Very frequent (99-80%) HP:0006254
24 enuresis nocturna 59 32 occasional (7.5%) Occasional (29-5%) HP:0010677
25 recurrent viral infections 59 32 occasional (7.5%) Occasional (29-5%) HP:0004429
26 iga deficiency 59 32 hallmark (90%) Very frequent (99-80%) HP:0002720
27 igm deficiency 59 32 occasional (7.5%) Occasional (29-5%) HP:0002850
28 igg deficiency 59 32 hallmark (90%) Very frequent (99-80%) HP:0004315
29 interstitial pulmonary abnormality 59 32 occasional (7.5%) Occasional (29-5%) HP:0006530
30 restrictive ventilatory defect 59 32 occasional (7.5%) Occasional (29-5%) HP:0002091
31 demyelinating peripheral neuropathy 59 32 occasional (7.5%) Occasional (29-5%) HP:0007108
32 episodic fever 59 32 frequent (33%) Frequent (79-30%) HP:0001954
33 chromosomal breakage induced by ionizing radiation 59 32 hallmark (90%) Very frequent (99-80%) HP:0010997
34 chronic sinusitis 59 32 frequent (33%) Frequent (79-30%) HP:0011109
35 abnormality of the cerebral white matter 59 32 occasional (7.5%) Occasional (29-5%) HP:0002500
36 neonatal asphyxia 59 32 occasional (7.5%) Occasional (29-5%) HP:0012768
37 bronchitis 59 32 frequent (33%) Frequent (79-30%) HP:0012387
38 recurrent sinusitis 59 32 frequent (33%) Frequent (79-30%) HP:0011108
39 generalized lymphadenopathy 59 32 occasional (7.5%) Occasional (29-5%) HP:0008940
40 poor hand-eye coordination 59 32 occasional (7.5%) Occasional (29-5%) HP:0007057
41 intraventricular hemorrhage 59 32 occasional (7.5%) Occasional (29-5%) HP:0030746
42 dry skin 32 HP:0000958
43 mild global developmental delay 32 HP:0011342
44 pneumonia 59 Frequent (79-30%)
45 increased sensitivity to ionizing radiation 32 HP:0011133
46 telangiectasia 59 Occasional (29-5%)

UMLS symptoms related to Riddle Syndrome:


ataxia, dry skin

GenomeRNAi Phenotypes related to Riddle Syndrome according to GeneCards Suite gene sharing:

26 (show all 32)
# Description GenomeRNAi Source Accession Score Top Affiliating Genes
1 Increased shRNA abundance (Z-score > 2) GR00366-A-105 10.56 HIST2H2AA4 HIST2H2AA3 HIST1H2AE
2 Increased shRNA abundance (Z-score > 2) GR00366-A-11 10.56 TP53BP1
3 Increased shRNA abundance (Z-score > 2) GR00366-A-116 10.56 HIST1H2AE BRCA1
4 Increased shRNA abundance (Z-score > 2) GR00366-A-121 10.56 RNF168
5 Increased shRNA abundance (Z-score > 2) GR00366-A-135 10.56 BRCA1
6 Increased shRNA abundance (Z-score > 2) GR00366-A-137 10.56 BRCA1 TP53BP1
7 Increased shRNA abundance (Z-score > 2) GR00366-A-168 10.56 HIST2H2AA4 HIST2H2AA3 BRCA1 TP53BP1 RNF168
8 Increased shRNA abundance (Z-score > 2) GR00366-A-174 10.56 RNF168
9 Increased shRNA abundance (Z-score > 2) GR00366-A-185 10.56 BRCA1 TP53BP1
10 Increased shRNA abundance (Z-score > 2) GR00366-A-205 10.56 RNF168
11 Increased shRNA abundance (Z-score > 2) GR00366-A-43 10.56 HIST2H2AA4 HIST2H2AA3 BRCA1
12 Increased shRNA abundance (Z-score > 2) GR00366-A-46 10.56 RNF168
13 Increased shRNA abundance (Z-score > 2) GR00366-A-50 10.56 HIST1H2AE BRCA1
14 Increased shRNA abundance (Z-score > 2) GR00366-A-63 10.56 RNF168 TP53BP1
15 Increased shRNA abundance (Z-score > 2) GR00366-A-7 10.56 BRCA1
16 Increased shRNA abundance (Z-score > 2) GR00366-A-73 10.56 HIST1H2AE
17 Increased shRNA abundance (Z-score > 2) GR00366-A-76 10.56 RNF168
18 Increased shRNA abundance (Z-score > 2) GR00366-A-8 10.56 TP53BP1
19 Increased shRNA abundance (Z-score > 2) GR00366-A-82 10.56 HIST2H2AA4 HIST2H2AA3
20 Increased shRNA abundance (Z-score > 2) GR00366-A-96 10.56 TP53BP1
21 Increased shRNA abundance (Z-score > 2) GR00366-A-99 10.56 HIST2H2AA4 HIST2H2AA3 HIST1H2AE
22 Decreased shRNA abundance (Z-score < -2) GR00366-A-119 10.41 TP53BP1
23 Decreased shRNA abundance (Z-score < -2) GR00366-A-139 10.41 HIST2H2AA3 HIST2H2AA4 HIST1H2AE BRCA1
24 Decreased shRNA abundance (Z-score < -2) GR00366-A-165 10.41 HIST2H2AA4 HIST2H2AA3
25 Decreased shRNA abundance (Z-score < -2) GR00366-A-204 10.41 BRCA1
26 Decreased shRNA abundance (Z-score < -2) GR00366-A-211 10.41 BRCA1
27 Decreased shRNA abundance (Z-score < -2) GR00366-A-213 10.41 TP53BP1
28 Decreased shRNA abundance (Z-score < -2) GR00366-A-216 10.41 HIST2H2AA3 HIST2H2AA4 TP53BP1
29 Decreased shRNA abundance (Z-score < -2) GR00366-A-40 10.41 HIST2H2AA4 HIST2H2AA3 HIST1H2AE
30 Decreased shRNA abundance (Z-score < -2) GR00366-A-53 10.41 BRCA1
31 Decreased shRNA abundance (Z-score < -2) GR00366-A-71 10.41 BRCA1
32 Increased viability with MLN4924 (a NAE inhibitor) GR00250-A-3 8.8 BRCA1 RNF168 TP53BP1
Sources

Drugs & Therapeutics for Riddle Syndrome

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Search Clinical Trials , NIH Clinical Center for Riddle Syndrome

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Genetic Tests for Riddle Syndrome

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Genetic tests related to Riddle Syndrome:

# Genetic test Affiliating Genes
1 Riddle Syndrome 29 RNF168
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Anatomical Context for Riddle Syndrome

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MalaCards organs/tissues related to Riddle Syndrome:

41
Skin, Eye
Sources

Publications for Riddle Syndrome

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Articles related to Riddle Syndrome:

# Title Authors Year
1
An E2-guided E3 Screen Identifies the RNF17-UBE2U Pair as Regulator of the Radiosensitivity, Immunodeficiency, Dysmorphic Features, and Learning Difficulties (RIDDLE) Syndrome Protein RNF168. ( 27903633 )
2017
2
Genomic instability, defective spermatogenesis, immunodeficiency, and cancer in a mouse model of the RIDDLE syndrome. ( 21552324 )
2011
3
DNA double-strand break repair, immunodeficiency and the RIDDLE syndrome. ( 21426255 )
2011
4
The RIDDLE syndrome protein mediates a ubiquitin-dependent signaling cascade at sites of DNA damage. ( 19203578 )
2009
Sources

Variations for Riddle Syndrome

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ClinVar genetic disease variations for Riddle Syndrome:

6
# Gene Variation Type Significance SNP ID Assembly Location
1 RNF168 RNF168, 1-BP DUP, 397G duplication Pathogenic
2 RNF168 RNF168, 4-BP DEL, 1323ACAA deletion Pathogenic
3 RNF168 NM_152617.3(RNF168): c.391C> T (p.Arg131Ter) single nucleotide variant Likely pathogenic rs201915239 GRCh37 Chromosome 3, 196214437: 196214437
4 RNF168 NM_152617.3(RNF168): c.391C> T (p.Arg131Ter) single nucleotide variant Likely pathogenic rs201915239 GRCh38 Chromosome 3, 196487566: 196487566
Sources

Expression for Riddle Syndrome

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Search GEO for disease gene expression data for Riddle Syndrome.
Sources

Pathways for Riddle Syndrome

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Pathways related to Riddle Syndrome according to GeneCards Suite gene sharing:

(show all 17)
# Super pathways Score Top Affiliating Genes
1
Metabolism of proteins 66
Show member pathways
 13.16 BRCA1 HIST1H2AE HIST2H2AA3 HIST2H2AA4 RNF168 TP53BP1
2
Signaling by Rho GTPases 66
Show member pathways
 12.6 HIST1H2AE HIST2H2AA3 HIST2H2AA4
3
Cell Cycle, Mitotic 66
Show member pathways
 12.59 BRCA1 HIST1H2AE HIST2H2AA3 HIST2H2AA4 RNF168 TP53BP1
4
Chromatin organization 66
Show member pathways
 12.58 HIST1H2AE HIST2H2AA3 HIST2H2AA4
5
Signaling by Wnt 66
Show member pathways
 12.49 HIST1H2AE HIST2H2AA3 HIST2H2AA4
6
Deubiquitination 66
Show member pathways
 12.34 BRCA1 HIST1H2AE HIST2H2AA3 HIST2H2AA4
7
Mitotic Prophase 66
Show member pathways
 12.32 HIST1H2AE HIST2H2AA3 HIST2H2AA4
8
Cell Cycle Checkpoints 66
Show member pathways
 12.26 BRCA1 RNF168 TP53BP1
9
SUMOylation 66
Show member pathways
 12.19 BRCA1 RNF168 TP53BP1
10
Chromosome Maintenance 66
Show member pathways
 12.16 HIST1H2AE HIST2H2AA3 HIST2H2AA4
11
DNA Double Strand Break Response 66
Show member pathways
 11.97 BRCA1 RNF168 TP53BP1
12
DNA Damage/Telomere Stress Induced Senescence 66
Show member pathways
 11.93 HIST1H2AE HIST2H2AA3 HIST2H2AA4
13
Meiosis 66
Show member pathways
 11.92 BRCA1 HIST1H2AE HIST2H2AA3 HIST2H2AA4
14
Necroptosis 37
Show member pathways
 11.78 HIST1H2AE HIST2H2AA3 HIST2H2AA4
15
ATM Pathway 64
Show member pathways
 11.48 BRCA1 TP53BP1
16
ATM Signaling Network in Development and Disease 1
11.16 RNF168 TP53BP1
17
Metalloprotease DUBs 66
10.5 BRCA1 HIST1H2AE HIST2H2AA3 HIST2H2AA4
Sources

GO Terms for Riddle Syndrome

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Cellular components related to Riddle Syndrome according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 nucleus GO:0005634 9.85 BRCA1 HIST1H2AE HIST2H2AA3 HIST2H2AA4 RNF168 TP53BP1
2 nuclear chromatin GO:0000790 9.33 HIST1H2AE HIST2H2AA3 HIST2H2AA4
3 ubiquitin ligase complex GO:0000151 9.32 BRCA1 RNF168
4 site of double-strand break GO:0035861 9.26 RNF168 TP53BP1
5 nucleosome GO:0000786 9.13 HIST1H2AE HIST2H2AA3 HIST2H2AA4
6 chromosome GO:0005694 9.02 BRCA1 HIST1H2AE HIST2H2AA3 HIST2H2AA4 TP53BP1

Biological processes related to Riddle Syndrome according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 cellular response to DNA damage stimulus GO:0006974 9.61 BRCA1 RNF168 TP53BP1
2 DNA repair GO:0006281 9.5 BRCA1 RNF168 TP53BP1
3 chromatin organization GO:0006325 9.46 HIST1H2AE HIST2H2AA3 HIST2H2AA4 RNF168
4 double-strand break repair GO:0006302 9.4 BRCA1 RNF168
5 response to ionizing radiation GO:0010212 9.37 BRCA1 RNF168
6 positive regulation of DNA repair GO:0045739 9.26 BRCA1 RNF168
7 double-strand break repair via nonhomologous end joining GO:0006303 9.13 BRCA1 RNF168 TP53BP1
8 chromatin silencing GO:0006342 8.8 HIST1H2AE HIST2H2AA3 HIST2H2AA4

Molecular functions related to Riddle Syndrome according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 protein heterodimerization activity GO:0046982 9.33 HIST1H2AE HIST2H2AA3 HIST2H2AA4
2 histone binding GO:0042393 9.26 RNF168 TP53BP1
3 DNA binding GO:0003677 9.02 BRCA1 HIST1H2AE HIST2H2AA3 HIST2H2AA4 TP53BP1
4 damaged DNA binding GO:0003684 8.96 BRCA1 TP53BP1
Sources

Sources for Riddle Syndrome

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3 CDC
7 CNVD
9 Cosmic
10 dbSNP
11 DGIdb
17 ExPASy
19 FMA
28 GO
29 GTR
30 HGMD
31 HMDB
32 HPO
33 ICD10
34 ICD10 via Orphanet
35 ICD9CM
36 IUPHAR
37 KEGG
38 LifeMap
40 LOVD
42 MedGen
44 MeSH
45 MESH via Orphanet
46 MGI
49 NCI
50 NCIt
51 NDF-RT
54 NINDS
55 Novoseek
57 OMIM
58 OMIM via Orphanet
62 PubMed
64 QIAGEN
69 SNOMED-CT via HPO
70 SNOMED-CT via Orphanet
71 TGDB
72 Tocris
73 UMLS
74 UMLS via Orphanet
The MalaCards human disease database index: 1-9 A B C D E F G H I J K L M N O P Q R S T U V W X Y Z
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