WS4A
MCID: WRD020
MIFTS: 48

Waardenburg Syndrome, Type 4a (WS4A)

Categories: Ear diseases, Eye diseases, Fetal diseases, Gastrointestinal diseases, Genetic diseases, Rare diseases, Skin diseases

Aliases & Classifications for Waardenburg Syndrome, Type 4a

MalaCards integrated aliases for Waardenburg Syndrome, Type 4a:

Name: Waardenburg Syndrome, Type 4a 56 13 39 71
Waardenburg Syndrome Type 4a 12 29 6 15
Shah-Waardenburg Syndrome 56 58 73 54
Waardenburg-Shah Syndrome 56 58 73
Ws4a 56 12 73
Waardenburg Syndrome with Hirschsprung Disease Type 4a 12 73
Waardenburg Syndrome Type Iva 12 73
Ws4 56 58
Waardenburg Syndrome with Hirschsprung Disease, Type 4a 56
Hirschsprung Disease with Pigmentary Anomaly 73
Waardenburg-Hirschsprung Syndrome 58
Waardenburg Syndrome, Type Iva 56
Waardenburg Syndrome Type 4 58
Waardenburg Syndrome 4a 73

Characteristics:

Orphanet epidemiological data:

58
waardenburg-shah syndrome
Inheritance: Autosomal dominant,Autosomal recessive; Prevalence: <1/1000000 (Worldwide); Age of onset: Neonatal; Age of death: normal life expectancy;

OMIM:

56
Inheritance:
autosomal recessive
autosomal dominant

Miscellaneous:
genetic heterogeneity
variable severity, intrafamilial
incomplete penetance of some features
both homozygous and heterozygous ednrb mutations have been found


HPO:

31

Classifications:

Orphanet: 58  
Rare gastroenterological diseases
Rare otorhinolaryngological diseases
Rare skin diseases
Developmental anomalies during embryogenesis


Summaries for Waardenburg Syndrome, Type 4a

OMIM : 56 Waardenburg syndrome type 4 (WS4), also known as Waardenburg-Shah syndrome, is an auditory-pigmentary syndrome characterized by pigmentary abnormalities of the hair, skin, and eyes, congenital sensorineural hearing loss, and Hirschsprung disease (reviews by Read and Newton, 1997 and Pingault et al., 2010). WS type 4A is caused by mutation in the EDNRB gene (131244). (277580)

MalaCards based summary : Waardenburg Syndrome, Type 4a, also known as waardenburg syndrome type 4a, is related to waardenburg syndrome type 4 and waardenburg syndrome, type 2b. An important gene associated with Waardenburg Syndrome, Type 4a is EDNRB (Endothelin Receptor Type B), and among its related pathways/superpathways are Neural Crest Differentiation and Melanocyte Development and Pigmentation. Affiliated tissues include skin, eye and colon, and related phenotypes are hearing impairment and premature graying of hair

Disease Ontology : 12 A Waardenburg's syndrome characterized by pigmentary abnormalities of the hair, skin, and eyes, congenital sensorineural hearing loss, and Hirschsprung disease that has material basis in heterozygous or homozygous mutation in the EDNRB gene on chromosome 13q22.

UniProtKB/Swiss-Prot : 73 Waardenburg syndrome 4A: A disorder characterized by the association of Waardenburg features (depigmentation and deafness) with the absence of enteric ganglia in the distal part of the intestine (Hirschsprung disease).

Related Diseases for Waardenburg Syndrome, Type 4a

Diseases in the Waardenburg's Syndrome family:

Waardenburg Syndrome, Type 3 Waardenburg Syndrome, Type 1
Waardenburg Syndrome, Type 2a Waardenburg Syndrome, Type 4a
Waardenburg Syndrome, Type 2b Waardenburg Syndrome, Type 2c
Waardenburg Syndrome, Type 2d Waardenburg Syndrome, Type 2e
Waardenburg Syndrome, Type 4b Waardenburg Syndrome, Type 4c
Waardenburg Syndrome Type 4

Diseases related to Waardenburg Syndrome, Type 4a via text searches within MalaCards or GeneCards Suite gene sharing:

(show top 50) (show all 91)
# Related Disease Score Top Affiliating Genes
1 waardenburg syndrome type 4 32.3 SOX10 MITF EDNRB EDN3
2 waardenburg syndrome, type 2b 32.2 SOX10 MITF EDN3
3 peripheral demyelinating neuropathy, central dysmyelination, waardenburg syndrome, and hirschsprung disease 32.1 SOX10 POLR2F PAX3 MPZ MITF GJB1
4 waardenburg syndrome, type 4c 31.7 SOX10 POLR2F PAX3 MITF EDNRB EDN3
5 waardenburg syndrome, type 2c 31.6 SOX10 PAX3 MITF EDNRB EDN3
6 waardenburg syndrome, type 2d 31.2 SOX10 SNAI2 PAX3 MITF EDNRB
7 intestinal obstruction 30.8 RET EDNRB EDN3
8 waardenburg's syndrome 30.5 SOX10 SNAI2 RET POLR2F PAX3 MITF
9 sensorineural hearing loss 30.2 SOX10 RET PAX3 MITF
10 megacolon 30.1 SOX10 RET PAX3 MITF EDNRB EDN3
11 waardenburg syndrome, type 4b 29.7 UPF1 SOX10 SNAI2 PAX3 PABPC1 MITF
12 hirschsprung disease 1 29.4 SOX10 SNAI2 RET POLR2F PAX3 MITF
13 waardenburg syndrome, type 1 29.3 SOX10 SNAI2 PAX3 MITF EDNRB EDN3
14 waardenburg syndrome, type 2e 28.7 SOX10 SNAI2 POLR2F PAX3 MITF EDNRB
15 branchiootic syndrome 1 10.6
16 catatrichy 10.5
17 aganglionosis, total intestinal 10.5 EDNRB-AS1 EDNRB
18 hirschsprung disease 2 10.5 EDNRB-AS1 EDNRB
19 ataxia, combined cerebellar and peripheral, with hearing loss and diabetes mellitus 10.4
20 constipation 10.4
21 abcd syndrome 10.4 EDNRB-AS1 EDNRB
22 gallbladder melanoma 10.4 SOX10 MITF
23 malignant choroid melanoma 10.4 SOX10 MITF
24 malignant spindle cell melanoma 10.4 SOX10 MITF
25 ocular albinism with congenital sensorineural deafness 10.3 PAX3 MITF
26 pulmonary hypertension, primary, 4 10.3
27 cochlear disease 10.3 SOX10 EDNRB EDN3
28 down syndrome 10.3
29 dandy-walker syndrome 10.3
30 alkuraya-kucinskas syndrome 10.3
31 distal arthrogryposis 10.3
32 cholelithiasis 10.3
33 leukodystrophy 10.3
34 short bowel syndrome 10.3
35 microphthalmia 10.3
36 hydrocephalus 10.3
37 acute chest syndrome 10.3
38 dermatitis 10.3
39 irritant dermatitis 10.3
40 hemoglobinopathy 10.3
41 food allergy 10.3
42 mutism 10.3
43 demyelinating polyneuropathy 10.3
44 peripheral nervous system disease 10.3
45 neuropathy 10.3
46 sickle cell disease 10.3
47 hypotonia 10.3
48 avascular necrosis 10.3
49 congenital amyoplasia 10.3
50 goldberg-shprintzen syndrome 10.2 RET EDNRB EDN3

Graphical network of the top 20 diseases related to Waardenburg Syndrome, Type 4a:



Diseases related to Waardenburg Syndrome, Type 4a

Symptoms & Phenotypes for Waardenburg Syndrome, Type 4a

Human phenotypes related to Waardenburg Syndrome, Type 4a:

58 31 (show all 34)
# Description HPO Frequency Orphanet Frequency HPO Source Accession
1 hearing impairment 58 31 hallmark (90%) Very frequent (99-80%) HP:0000365
2 premature graying of hair 58 31 hallmark (90%) Very frequent (99-80%) HP:0002216
3 aganglionic megacolon 58 31 hallmark (90%) Very frequent (99-80%) HP:0002251
4 abnormality of vision 58 31 hallmark (90%) Very frequent (99-80%) HP:0000504
5 constipation 58 31 hallmark (90%) Very frequent (99-80%) HP:0002019
6 intestinal obstruction 58 31 hallmark (90%) Very frequent (99-80%) HP:0005214
7 white forelock 58 31 hallmark (90%) Very frequent (99-80%) HP:0002211
8 white eyebrow 58 31 hallmark (90%) Very frequent (99-80%) HP:0002226
9 white eyelashes 58 31 hallmark (90%) Very frequent (99-80%) HP:0002227
10 abnormal macular morphology 58 31 hallmark (90%) Very frequent (99-80%) HP:0001103
11 wide nasal bridge 58 31 frequent (33%) Frequent (79-30%) HP:0000431
12 abdominal pain 58 31 frequent (33%) Frequent (79-30%) HP:0002027
13 prominent nasal bridge 58 31 frequent (33%) Frequent (79-30%) HP:0000426
14 underdeveloped nasal alae 58 31 frequent (33%) Frequent (79-30%) HP:0000430
15 synophrys 58 31 frequent (33%) Frequent (79-30%) HP:0000664
16 olfactory lobe agenesis 58 31 frequent (33%) Frequent (79-30%) HP:0001341
17 abnormality of retinal pigmentation 58 31 occasional (7.5%) Occasional (29-5%) HP:0007703
18 telecanthus 58 31 occasional (7.5%) Occasional (29-5%) HP:0000506
19 global developmental delay 31 HP:0001263
20 muscular hypotonia 31 HP:0001252
21 sensorineural hearing impairment 31 HP:0000407
22 ataxia 31 HP:0001251
23 nystagmus 31 HP:0000639
24 hypopigmented skin patches 31 HP:0001053
25 blue irides 31 HP:0000635
26 hypopigmentation of hair 58 Very frequent (99-80%)
27 abnormality of the eye 58 Very frequent (99-80%)
28 heterochromia iridis 31 HP:0001100
29 abnormality of the eyebrow 58 Very frequent (99-80%)
30 abnormality of the nose 58 Frequent (79-30%)
31 leukodystrophy 31 HP:0002415
32 polyneuropathy 31 HP:0001271
33 abnormal intestine morphology 58 Very frequent (99-80%)
34 spastic paraparesis 31 HP:0002313

Symptoms via clinical synopsis from OMIM:

56
Skin Nails Hair Skin:
hypopigmented skin patches

Skin Nails Hair Hair:
white forelock
white eyelashes
white eyebrows
premature graying

Abdomen Gastrointestinal:
hirschsprung disease
decreased myenteric and submucosal ganglia in the bowel

Head And Neck Eyes:
heterochromia iridis
bright blue irides
bicolored irides

Head And Neck Ears:
deafness, sensorineural

Clinical features from OMIM:

277580

MGI Mouse Phenotypes related to Waardenburg Syndrome, Type 4a:

45
# Description MGI Source Accession Score Top Affiliating Genes
1 behavior/neurological MP:0005386 10.14 APPL1 EDN3 EDNRB GJB1 MITF MPZ
2 hematopoietic system MP:0005397 10.02 APPL1 EDNRB GJB1 MITF MPZ PAX3
3 embryo MP:0005380 9.97 EDN3 EDNRB MITF PAX3 RET SNAI2
4 immune system MP:0005387 9.96 APPL1 EDNRB GJB1 MITF MPZ PAX3
5 integument MP:0010771 9.76 EDN3 EDNRB MITF MPZ PAX3 SH3KBP1
6 nervous system MP:0003631 9.65 EDN3 EDNRB GJB1 MITF MPZ PAX3
7 pigmentation MP:0001186 9.1 EDN3 EDNRB MITF PAX3 SNAI2 SOX10

Drugs & Therapeutics for Waardenburg Syndrome, Type 4a

Search Clinical Trials , NIH Clinical Center for Waardenburg Syndrome, Type 4a

Genetic Tests for Waardenburg Syndrome, Type 4a

Genetic tests related to Waardenburg Syndrome, Type 4a:

# Genetic test Affiliating Genes
1 Waardenburg Syndrome Type 4a 29 EDNRB

Anatomical Context for Waardenburg Syndrome, Type 4a

MalaCards organs/tissues related to Waardenburg Syndrome, Type 4a:

40
Skin, Eye, Colon

Publications for Waardenburg Syndrome, Type 4a

Articles related to Waardenburg Syndrome, Type 4a:

(show top 50) (show all 58)
# Title Authors PMID Year
1
Mutation of the endothelin-3 gene in the Waardenburg-Hirschsprung disease (Shah-Waardenburg syndrome). 54 56 6
8630502 1996
2
Novel nonsense mutation of the endothelin-B receptor gene in a family with Waardenburg-Hirschsprung disease. 6 56
10528251 1999
3
Mutation of the endothelin-receptor B gene in Waardenburg-Hirschsprung disease. 56 6
8634719 1995
4
A missense mutation of the endothelin-B receptor gene in multigenic Hirschsprung's disease. 56 6
8001158 1994
5
Clinical variability of Waardenburg-Shah syndrome in patients with proximal 13q deletion syndrome including the endothelin-B receptor locus. 54 56
19764031 2009
6
A de novo missense mutation in the gene encoding the SOX10 transcription factor in a Spanish sporadic case of Waardenburg syndrome type IV. 6 54
18348274 2008
7
Deletions at the SOX10 gene locus cause Waardenburg syndrome types 2 and 4. 6 54
17999358 2007
8
ABCD syndrome is caused by a homozygous mutation in the EDNRB gene. 54 56
11891690 2002
9
A heterozygous endothelin 3 mutation in Waardenburg-Hirschsprung disease: is there a dosage effect of EDN3/EDNRB gene mutations on neurocristopathy phenotypes? 6 54
11303518 2001
10
SOX10 mutations in patients with Waardenburg-Hirschsprung disease. 6 54
9462749 1998
11
Waardenburg syndrome. 54 56
9279758 1997
12
A homozygous mutation in the endothelin-3 gene associated with a combined Waardenburg type 2 and Hirschsprung phenotype (Shah-Waardenburg syndrome). 54 6
8630503 1996
13
Hearing loss in Waardenburg syndrome: a systematic review. 56
26100139 2016
14
Perturbation of the consensus activation site of endothelin-3 leads to Waardenburg syndrome type IV. 6
20583152 2010
15
Genetic and phenotypic heterogeneity in two novel cases of Waardenburg syndrome type IV. 6
19764030 2009
16
A mouse model of Waardenburg syndrome type 4 with a new spontaneous mutation of the endothelin-B receptor gene. 56
11773966 2002
17
The Sox10(Dom) mouse: modeling the genetic variation of Waardenburg-Shah (WS4) syndrome. 6
10077527 1999
18
Chromosome 13q deletion with Waardenburg syndrome: further evidence for a gene involved in neural crest function on 13q. 56
7562965 1995
19
Interaction of endothelin-3 with endothelin-B receptor is essential for development of epidermal melanocytes and enteric neurons. 56
8001160 1994
20
Preliminary definition of a "critical region" of chromosome 13 in q32: report of 14 cases with 13q deletions and review of the literature. 56
8418661 1993
21
Waardenburg syndrome and Hirschsprung disease: evidence for pleiotropic effects of a single dominant gene. 56
2301458 1990
22
Genetic heterogeneity in Waardenburg's syndrome. 56
2738907 1989
23
Piebaldism-Waardenburg syndrome: histopathologic evidence for a neural crest syndrome. 56
3228147 1988
24
Waardenburg syndrome, Hirschsprung megacolon, and Marcus Gunn ptosis. 56
3631139 1987
25
Association of megacolon with a new dominant spotting gene (Dom) in the mouse. 56
6512238 1984
26
Waardenburg's syndrome associated with total aganglionosis. 56
6651333 1983
27
Waardenburg and Hirschsprung syndromes. 56
6842346 1983
28
Bilateral bicolored irides with Hirschsprung's disease. A neural crest syndrome. 56
6849656 1983
29
White forelock, pigmentary disorder of irides, and long segment Hirschsprung disease: possible variant of Waardenburg syndrome. 56
7264803 1981
30
Anal atresia and the Klein-Waardenburg syndrome. 56
7241550 1981
31
The association of Waardenburg syndrome and Hirschsprung megacolon. 56
484594 1979
32
Letter: Hirschsprung's disease and congenital deafness. 56
1121019 1975
33
Congenital deafness and Hirschsprung's disease. 56
4687269 1973
34
Association of megacolon with two recessive spotting genes in the mouse. 56
5917257 1966
35
A de novo deletion mutation in SOX10 in a Chinese family with Waardenburg syndrome type 4. 61
28128317 2017
36
Genetic interaction between Sox10 and Zfhx1b during enteric nervous system development. 54
20206619 2010
37
Involvement of SOX10 in the pathogenesis of Hirschsprung disease: report of a truncating mutation in an isolated patient. 54
20130826 2010
38
A zebrafish model for Waardenburg syndrome type IV reveals diverse roles for Sox10 in the otic vesicle. 54
19132125 2009
39
A mouse model of Waardenburg syndrome type IV resulting from an ENU-induced mutation in endothelin 3. 54
17516928 2007
40
Interactions between Sox10, Edn3 and Ednrb during enteric nervous system and melanocyte development. 54
16650841 2006
41
Sumoylation of the SOX10 transcription factor regulates its transcriptional activity. 54
16494873 2006
42
Deletion of long-range sequences at Sox10 compromises developmental expression in a mouse model of Waardenburg-Shah (WS4) syndrome. 54
16330480 2006
43
Shah-Waardenburg syndrome and PCWH associated with SOX10 mutations: a case report and review of the literature. 54
16504559 2006
44
Novel mutation of Endothelin-B receptor gene in Waardenburg-Hirschsprung disease. 54
16237557 2005
45
Genome-wide linkage identifies novel modifier loci of aganglionosis in the Sox10Dom model of Hirschsprung disease. 54
15843399 2005
46
Congenital hypomyelinating neuropathy, central dysmyelination, and Waardenburg-Hirschsprung disease: phenotypes linked by SOX10 mutation. 54
12447940 2002
47
Human Connexin 32, a gap junction protein altered in the X-linked form of Charcot-Marie-Tooth disease, is directly regulated by the transcription factor SOX10. 54
11734543 2001
48
Relationship between the type of RET/GDNF/NTN or SOX10 gene mutations and long-term results after surgery for total colonic aganglionosis with small bowel involvement. 54
11685702 2001
49
SOX10 is abnormally expressed in aganglionic bowel of Hirschsprung's disease infants. 54
11454798 2001
50
Hirschsprung disease in an infant with a contiguous gene syndrome of chromosome 13. 54
11484199 2001

Variations for Waardenburg Syndrome, Type 4a

ClinVar genetic disease variations for Waardenburg Syndrome, Type 4a:

6 (show all 15) ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎
# Gene Name Type Significance ClinVarId dbSNP ID GRCh37 Pos GRCh38 Pos
1 SOX10 NM_006941.3(SOX10):c.429-1G>ASNV Pathogenic 590850 rs1569169328 22:38374143-38374143 22:37978136-37978136
2 SOX10 NM_006941.4(SOX10):c.1315_1329del (p.Ile439_Ser443del)deletion Pathogenic 620636 rs1569167515 22:38369574-38369588 22:37973567-37973581
3 EDNRB NM_001122659.3(EDNRB):c.828G>T (p.Trp276Cys)SNV Pathogenic 16633 rs104894387 13:78475316-78475316 13:77901181-77901181
4 EDNRB NM_001122659.3(EDNRB):c.548C>G (p.Ala183Gly)SNV Pathogenic 16634 rs104894388 13:78477678-78477678 13:77903543-77903543
5 EDNRB NM_001122659.3(EDNRB):c.521del (p.Cys174fs)deletion Pathogenic 547293 rs1458799604 13:78477705-78477705 13:77903570-77903570
6 EDNRB NM_001122659.3(EDNRB):c.757C>T (p.Arg253Ter)SNV Pathogenic 16639 rs104894390 13:78477335-78477335 13:77903200-77903200
7 EDNRB NM_001122659.3(EDNRB):c.601C>T (p.Arg201Ter)SNV Pathogenic 16640 rs104894391 13:78477491-78477491 13:77903356-77903356
8 EDNRB NM_001122659.3(EDNRB):c.57C>A (p.Cys19Ter)SNV Pathogenic/Likely pathogenic 545012 rs768126403 13:78492652-78492652 13:77918517-77918517
9 EDNRB NM_001122659.3(EDNRB):c.550T>C (p.Ser184Pro)SNV Likely pathogenic 547294 rs1555290659 13:78477676-78477676 13:77903541-77903541
10 EDNRB NM_001122659.3(EDNRB):c.914G>A (p.Ser305Asn)SNV Conflicting interpretations of pathogenicity 16638 rs5352 13:78475230-78475230 13:77901095-77901095
11 EDNRB NM_001122659.3(EDNRB):c.-26G>ASNV Conflicting interpretations of pathogenicity 225346 rs2070591 13:78492734-78492734 13:77918599-77918599
12 EDNRB NM_001122659.3(EDNRB):c.791C>T (p.Ala264Val)SNV Uncertain significance 547950 rs1212186974 13:78477301-78477301 13:77903166-77903166
13 EDNRB NM_001122659.3(EDNRB):c.403G>A (p.Gly135Ser)SNV Uncertain significance 545011 rs760677132 13:78492306-78492306 13:77918171-77918171
14 EDNRB NM_001122659.3(EDNRB):c.973G>A (p.Val325Ile)SNV Uncertain significance 547295 rs201437745 13:78474768-78474768 13:77900633-77900633
15 EDNRB NM_001122659.3(EDNRB):c.778G>T (p.Val260Phe)SNV Likely benign 585146 rs77132068 13:78477314-78477314 13:77903179-77903179

UniProtKB/Swiss-Prot genetic disease variations for Waardenburg Syndrome, Type 4a:

73
# Symbol AA change Variation ID SNP ID
1 EDNRB p.Ala183Gly VAR_003470 rs104894388
2 EDNRB p.Phe292Leu VAR_015294

Expression for Waardenburg Syndrome, Type 4a

Search GEO for disease gene expression data for Waardenburg Syndrome, Type 4a.

Pathways for Waardenburg Syndrome, Type 4a

Pathways related to Waardenburg Syndrome, Type 4a according to GeneCards Suite gene sharing:

# Super pathways Score Top Affiliating Genes
1 11.11 SOX10 SNAI2 PAX3 MPZ MITF GJB1
2 10.74 SOX10 PAX3 MITF

GO Terms for Waardenburg Syndrome, Type 4a

Biological processes related to Waardenburg Syndrome, Type 4a according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 negative regulation of apoptotic process GO:0043066 9.8 SOX10 SNAI2 MPZ MITF EDNRB
2 pigmentation GO:0043473 9.5 SNAI2 MITF EDNRB
3 peripheral nervous system development GO:0007422 9.48 SOX10 EDNRB
4 response to pain GO:0048265 9.46 RET EDNRB
5 vasoconstriction GO:0042310 9.43 EDNRB EDN3
6 vein smooth muscle contraction GO:0014826 9.37 EDNRB EDN3
7 enteric nervous system development GO:0048484 9.33 SOX10 RET EDNRB
8 posterior midgut development GO:0007497 9.26 RET EDNRB
9 neural crest cell migration GO:0001755 9.26 SOX10 RET EDNRB EDN3
10 melanocyte differentiation GO:0030318 8.92 SOX10 MITF EDNRB EDN3

Sources for Waardenburg Syndrome, Type 4a

3 CDC
7 CNVD
9 Cosmic
10 dbSNP
11 DGIdb
17 EFO
18 ExPASy
19 FMA
28 GO
29 GTR
30 HMDB
31 HPO
32 ICD10
33 ICD10 via Orphanet
34 ICD9CM
35 IUPHAR
36 KEGG
37 LifeMap
39 LOVD
41 MedGen
43 MeSH
44 MESH via Orphanet
45 MGI
48 NCI
49 NCIt
50 NDF-RT
53 NINDS
54 Novoseek
56 OMIM
57 OMIM via Orphanet
61 PubMed
63 QIAGEN
68 SNOMED-CT via HPO
69 TGDB
70 Tocris
71 UMLS
72 UMLS via Orphanet
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