WS4B
MCID: WRD019
MIFTS: 46

Waardenburg Syndrome, Type 4b (WS4B)

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

Aliases & Classifications for Waardenburg Syndrome, Type 4b

MalaCards integrated aliases for Waardenburg Syndrome, Type 4b:

Name: Waardenburg Syndrome, Type 4b 57 13 39 70
Waardenburg Syndrome Type 4b 12 29 6 15
Ws4b 57 12 72
Waardenburg Syndrome with Hirschsprung Disease Type 4b 12 72
Waardenburg Syndrome Type Ivb 12 72
Waardenburg Syndrome, Type 4b, with Hirschsprung Disease 57
Hirschsprung Disease with Pigmentary Anomaly 72
Waardenburg Syndrome, Type Ivb 57
Waardenburg Syndrome, Type 4a 70
Waardenburg-Shah Syndrome 72
Shah-Waardenburg Syndrome 72
Waardenburg Syndrome 4b 72

Characteristics:

OMIM®:

57 (Updated 20-May-2021)
Inheritance:
autosomal recessive
autosomal dominant

Miscellaneous:
genetic heterogeneity
variable severity, intrafamilial
incomplete penetrance of some features
both homozygous and heterozygous edn3 mutations have been found


HPO:

31

Classifications:



External Ids:

Disease Ontology 12 DOID:0110954
OMIM® 57 613265
OMIM Phenotypic Series 57 PS193500
MeSH 44 D014849
MedGen 41 C2750457
UMLS 70 C1848519 C2750457

Summaries for Waardenburg Syndrome, Type 4b

OMIM® : 57 Waardenburg syndrome type 4 is an auditory-pigmentary syndrome characterized by pigmentary abnormalities of the eye, deafness, and Hirschsprung disease (review by Read and Newton, 1997). WS type 4B is caused by mutation in the EDN3 gene (131242). WS type 4 is genetically heterogeneous (see WS4A; 277580). For a description of other clinical variants of Waardenburg syndrome, see WS1 (193500), WS2 (193510), and WS3 (148820). (613265) (Updated 20-May-2021)

MalaCards based summary : Waardenburg Syndrome, Type 4b, also known as waardenburg syndrome type 4b, is related to peripheral demyelinating neuropathy, central dysmyelination, waardenburg syndrome, and hirschsprung disease and waardenburg syndrome type 4. An important gene associated with Waardenburg Syndrome, Type 4b is EDN3 (Endothelin 3), and among its related pathways/superpathways are Aldosterone synthesis and secretion and Development Angiotensin activation of ERK. Affiliated tissues include eye, skin and kidney, and related phenotypes are sensorineural hearing impairment and blue irides

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 homozygous and heterozygous mutation in the EDN3 gene on chromosome 20q13.

UniProtKB/Swiss-Prot : 72 Waardenburg syndrome 4B: 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 4b

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 4b via text searches within MalaCards or GeneCards Suite gene sharing:

(show top 50) (show all 106)
# Related Disease Score Top Affiliating Genes
1 peripheral demyelinating neuropathy, central dysmyelination, waardenburg syndrome, and hirschsprung disease 32.6 SOX10 PAX3 MITF EDNRB EDN3
2 waardenburg syndrome type 4 32.5 SOX10 MITF EDNRB EDN3
3 waardenburg syndrome, type 4c 31.9 SOX10 PAX3 MITF EDNRB EDN3
4 waardenburg syndrome, type 4a 31.2 UPF1 TYR SOX10 SNAI2 PAX3 PABPC1
5 intestinal obstruction 30.3 KIT EDNRB EDN3
6 megacolon 30.2 SOX10 PAX3 EDNRB EDN3 ECE1
7 waardenburg's syndrome 30.0 TYR TFEB SOX10 SNAI2 PMEL PAX3
8 hirschsprung disease 1 29.5 SOX10 SNAI2 PAX3 MITF KIT EDNRB
9 microphthalmia 29.0 TYR TFEB SOX10 PMEL PAX3 MITF
10 waardenburg syndrome, type 2e 28.5 TYR TFEB SOX10 SNAI2 PMEL PAX3
11 branchiootic syndrome 1 10.4
12 catatrichy 10.3
13 ataxia, combined cerebellar and peripheral, with hearing loss and diabetes mellitus 10.3
14 sensorineural hearing loss 10.3
15 malignant choroid melanoma 10.3 SOX10 MITF
16 melanoma, cutaneous malignant 8 10.3 TYR MITF
17 epithelioid cell melanoma 10.3 TYR MITF
18 melanoacanthoma 10.3 TYR PMEL
19 halo nevi 10.3 TYR PMEL
20 constipation 10.3
21 diffuse meningeal melanocytosis 10.2 TYR PMEL
22 ochronosis 10.2 TYR MITF
23 waardenburg syndrome, type 2b 10.2 SOX10 MITF EDN3
24 ocular albinism with congenital sensorineural deafness 10.2 TYR PAX3 MITF
25 albinism, ocular, with late-onset sensorineural deafness 10.2 TYR PAX3 MITF
26 gallbladder melanoma 10.2 SOX10 PMEL MITF
27 orbit rhabdomyosarcoma 10.2 TYR PAX3
28 cutaneous ganglioneuroma 10.1 MITF KIT
29 crest syndrome 10.1 SOX10 EDNRB
30 plexiform schwannoma 10.1 SOX10 KIT
31 autoimmune disease of skin and connective tissue 10.1 TYR PMEL MITF
32 actinic keratosis 10.1 TYR SOX10 MITF
33 childhood kidney cell carcinoma 10.1 TFEB MITF
34 waardenburg syndrome, type 2c 10.1 SOX10 MITF EDNRB EDN3
35 down syndrome 10.1
36 distal arthrogryposis 10.1
37 cholelithiasis 10.1
38 leukodystrophy 10.1
39 short bowel syndrome 10.1
40 hydrocephalus 10.1
41 acute chest syndrome 10.1
42 dermatitis 10.1
43 irritant dermatitis 10.1
44 hemoglobinopathy 10.1
45 food allergy 10.1
46 mutism 10.1
47 demyelinating polyneuropathy 10.1
48 peripheral nervous system disease 10.1
49 neuropathy 10.1
50 sickle cell disease 10.1

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



Diseases related to Waardenburg Syndrome, Type 4b

Symptoms & Phenotypes for Waardenburg Syndrome, Type 4b

Human phenotypes related to Waardenburg Syndrome, Type 4b:

31 (show all 9)
# Description HPO Frequency HPO Source Accession
1 sensorineural hearing impairment 31 HP:0000407
2 blue irides 31 HP:0000635
3 premature graying of hair 31 HP:0002216
4 aganglionic megacolon 31 HP:0002251
5 heterochromia iridis 31 HP:0001100
6 hypopigmented skin patches 31 HP:0001053
7 white forelock 31 HP:0002211
8 white eyebrow 31 HP:0002226
9 white eyelashes 31 HP:0002227

Symptoms via clinical synopsis from OMIM®:

57 (Updated 20-May-2021)
Skin Nails Hair Skin:
hypopigmented skin patches

Head And Neck Ears:
deafness, sensorineural

Head And Neck Eyes:
bright blue irides
hypopigmented irides

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

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

Clinical features from OMIM®:

613265 (Updated 20-May-2021)

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

46 (show all 23)
# Description MGI Source Accession Score Top Affiliating Genes
1 embryo MP:0005380 10.42 DACT1 ECE1 EDN3 EDNRA EDNRB KIT
2 behavior/neurological MP:0005386 10.39 DMD EDN3 EDNRA EDNRB KIT MITF
3 growth/size/body region MP:0005378 10.37 DACT1 DMD ECE1 EDNRA EDNRB KIT
4 cardiovascular system MP:0005385 10.35 DACT1 DMD ECE1 EDNRA EDNRB KIT
5 mortality/aging MP:0010768 10.33 DACT1 DMD ECE1 EDN3 EDNRA EDNRB
6 digestive/alimentary MP:0005381 10.32 DACT1 DMD ECE1 EDN3 EDNRA EDNRB
7 endocrine/exocrine gland MP:0005379 10.31 DMD ECE1 EDNRA EDNRB KIT KITLG
8 integument MP:0010771 10.31 ECE1 EDN3 EDNRA EDNRB KIT KITLG
9 cellular MP:0005384 10.3 DMD EDNRA EDNRB KIT KITLG MITF
10 homeostasis/metabolism MP:0005376 10.3 DMD ECE1 EDNRA EDNRB KIT KITLG
11 hearing/vestibular/ear MP:0005377 10.25 DMD ECE1 EDNRA EDNRB KIT KITLG
12 craniofacial MP:0005382 10.24 ECE1 EDNRA EDNRB KIT KITLG MITF
13 hematopoietic system MP:0005397 10.24 DMD ECE1 EDNRA EDNRB KIT KITLG
14 nervous system MP:0003631 10.22 DACT1 DMD ECE1 EDN3 EDNRA EDNRB
15 immune system MP:0005387 10.21 DMD ECE1 EDNRA EDNRB KIT KITLG
16 limbs/digits/tail MP:0005371 10.13 DACT1 DMD EDNRB KIT KITLG MITF
17 pigmentation MP:0001186 10.03 ECE1 EDN3 EDNRB KIT KITLG MITF
18 no phenotypic analysis MP:0003012 9.97 DACT1 DMD KIT MITF PAX3 PMEL
19 normal MP:0002873 9.97 DMD ECE1 EDNRA KIT MITF PAX3
20 neoplasm MP:0002006 9.91 EDNRB KIT KITLG PAX3 SOX10 TYR
21 renal/urinary system MP:0005367 9.76 DACT1 DMD EDNRA EDNRB KIT MITF
22 skeleton MP:0005390 9.73 DACT1 DMD ECE1 EDNRA EDNRB KIT
23 vision/eye MP:0005391 9.4 DMD ECE1 EDNRA EDNRB KIT KITLG

Drugs & Therapeutics for Waardenburg Syndrome, Type 4b

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

Genetic Tests for Waardenburg Syndrome, Type 4b

Genetic tests related to Waardenburg Syndrome, Type 4b:

# Genetic test Affiliating Genes
1 Waardenburg Syndrome Type 4b 29 EDN3

Anatomical Context for Waardenburg Syndrome, Type 4b

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

40
Eye, Skin, Kidney, Lung, Ovary, Tonsil

Publications for Waardenburg Syndrome, Type 4b

Articles related to Waardenburg Syndrome, Type 4b:

# Title Authors PMID Year
1
Perturbation of the consensus activation site of endothelin-3 leads to Waardenburg syndrome type IV. 6 57
20583152 2010
2
Genetic and phenotypic heterogeneity in two novel cases of Waardenburg syndrome type IV. 6 57
19764030 2009
3
A heterozygous endothelin 3 mutation in Waardenburg-Hirschsprung disease: is there a dosage effect of EDN3/EDNRB gene mutations on neurocristopathy phenotypes? 6 57
11303518 2001
4
A homozygous mutation in the endothelin-3 gene associated with a combined Waardenburg type 2 and Hirschsprung phenotype (Shah-Waardenburg syndrome). 57 6
8630503 1996
5
Mutation of the endothelin-3 gene in the Waardenburg-Hirschsprung disease (Shah-Waardenburg syndrome). 57 6
8630502 1996
6
Hearing loss in Waardenburg syndrome: a systematic review. 57
26100139 2016
7
Waardenburg syndrome. 57
9279758 1997
8
Interaction of endothelin-3 with endothelin-B receptor is essential for development of epidermal melanocytes and enteric neurons. 57
8001160 1994
9
Genetic analysis of an Indian family with members affected with Waardenburg syndrome and Duchenne muscular dystrophy. 61
22876130 2012

Variations for Waardenburg Syndrome, Type 4b

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

6
# Gene Name Type Significance ClinVarId dbSNP ID Position
1 EDN3 NM_207034.3(EDN3):c.262_263delinsT (p.Ala88fs) Indel Pathogenic 16643 rs1568823517 GRCh37: 20:57876674-57876675
GRCh38: 20:59301619-59301620
2 EDN3 NM_207034.3(EDN3):c.476G>T (p.Cys159Phe) SNV Pathogenic 16644 rs74315384 GRCh37: 20:57896182-57896182
GRCh38: 20:59321127-59321127
3 EDN3 NM_207034.3(EDN3):c.507C>A (p.Cys169Ter) SNV Pathogenic 16649 rs74315385 GRCh37: 20:57896213-57896213
GRCh38: 20:59321158-59321158
4 EDN3 NM_207034.3(EDN3):c.335A>G (p.His112Arg) SNV Pathogenic 16650 rs267606778 GRCh37: 20:57876747-57876747
GRCh38: 20:59301692-59301692
5 EDN3 NM_207034.3(EDN3):c.277C>G (p.Arg93Gly) SNV Pathogenic 16651 rs267606779 GRCh37: 20:57876689-57876689
GRCh38: 20:59301634-59301634
6 EDN3 NM_207034.3(EDN3):c.293C>A (p.Thr98Lys) SNV Pathogenic 339123 rs745795470 GRCh37: 20:57876705-57876705
GRCh38: 20:59301650-59301650
7 EDN3 NM_207034.3(EDN3):c.334C>A (p.His112Asn) SNV Likely pathogenic 547292 rs977075341 GRCh37: 20:57876746-57876746
GRCh38: 20:59301691-59301691
8 EDN3 NM_207034.3(EDN3):c.332G>T (p.Cys111Phe) SNV Likely pathogenic 545507 rs773779627 GRCh37: 20:57876744-57876744
GRCh38: 20:59301689-59301689
9 EDN3 NM_207034.3(EDN3):c.565dup (p.Thr189fs) Duplication Likely benign 227351 rs11570344 GRCh37: 20:57897443-57897444
GRCh38: 20:59322388-59322389
10 EDN3 NM_207034.3(EDN3):c.670G>A (p.Ala224Thr) SNV Likely benign 16647 rs11570351 GRCh37: 20:57899467-57899467
GRCh38: 20:59324412-59324412

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

72
# Symbol AA change Variation ID SNP ID
1 EDN3 p.Cys159Phe VAR_002353 rs74315384
2 EDN3 p.Tyr127Cys VAR_015238 rs752400458

Expression for Waardenburg Syndrome, Type 4b

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

Pathways for Waardenburg Syndrome, Type 4b

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

# Super pathways Score Top Affiliating Genes
1
Show member pathways
12.57 TYR MITF KITLG KIT EDNRB
2
Show member pathways
12.52 KITLG KIT EDNRB EDN3
3 12.49 MITF KITLG KIT EDNRB EDNRA
4
Show member pathways
11.76 SNAI2 MITF KITLG KIT
5 11.27 SOX10 SNAI2 PAX3 MITF
6 11.22 EDNRB EDNRA EDN3
7 10.86 EDNRB EDNRA ECE1
8 10.64 KITLG KIT
9 10.63 SOX10 PAX3 MITF KITLG KIT

GO Terms for Waardenburg Syndrome, Type 4b

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

(show all 18)
# Name GO ID Score Top Affiliating Genes
1 multicellular organism development GO:0007275 10.02 SNAI2 PAX3 MITF KIT EDN3 DACT1
2 positive regulation of cell proliferation GO:0008284 9.89 KITLG KIT EDNRB EDN3 DMD
3 regulation of gene expression GO:0010468 9.87 TFEB MITF EDN3 DMD
4 positive regulation of MAP kinase activity GO:0043406 9.63 KITLG KIT EDN3
5 regulation of vasoconstriction GO:0019229 9.58 EDN3 ECE1
6 embryonic hemopoiesis GO:0035162 9.56 KITLG KIT
7 melanin biosynthetic process GO:0042438 9.54 TYR PMEL
8 developmental pigmentation GO:0048066 9.52 KIT EDNRB
9 artery smooth muscle contraction GO:0014824 9.51 EDNRA EDN3
10 vasoconstriction GO:0042310 9.5 EDNRB EDNRA EDN3
11 endothelin receptor signaling pathway GO:0086100 9.48 EDNRB EDNRA
12 neural crest cell migration GO:0001755 9.46 SOX10 KITLG EDNRB EDN3
13 ectopic germ cell programmed cell death GO:0035234 9.43 KITLG KIT
14 enteric nervous system development GO:0048484 9.43 SOX10 EDNRB EDNRA
15 regulation of systemic arterial blood pressure by endothelin GO:0003100 9.4 EDN3 ECE1
16 vein smooth muscle contraction GO:0014826 9.37 EDNRB EDN3
17 pigmentation GO:0043473 9.35 TYR SNAI2 MITF KIT EDNRB
18 melanocyte differentiation GO:0030318 9.02 SOX10 MITF KIT EDNRB EDN3

Molecular functions related to Waardenburg Syndrome, Type 4b according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 endothelin receptor activity GO:0004962 8.62 EDNRB EDNRA

Sources for Waardenburg Syndrome, Type 4b

3 CDC
7 CNVD
9 Cosmic
10 dbSNP
11 DGIdb
17 EFO
18 ExPASy
19 FMA
20 GARD
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
44 MeSH
45 MESH via Orphanet
46 MGI
49 NCI
50 NCIt
51 NDF-RT
53 NINDS
54 Novoseek
56 OMIM via Orphanet
57 OMIM® (Updated 20-May-2021)
61 PubMed
63 QIAGEN
68 SNOMED-CT via HPO
69 Tocris
70 UMLS
71 UMLS via Orphanet
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