WS4B
MCID: WRD019
MIFTS: 47

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 56 13 39 71
Waardenburg Syndrome Type 4b 12 29 6 15
Ws4b 56 12 73
Waardenburg Syndrome with Hirschsprung Disease Type 4b 12 73
Waardenburg Syndrome Type Ivb 12 73
Waardenburg Syndrome, Type 4b, with Hirschsprung Disease 56
Hirschsprung Disease with Pigmentary Anomaly 73
Waardenburg Syndrome, Type Ivb 56
Waardenburg Syndrome, Type 4a 71
Waardenburg-Shah Syndrome 73
Shah-Waardenburg Syndrome 73
Waardenburg Syndrome 4b 73

Characteristics:

OMIM:

56
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 56 613265
OMIM Phenotypic Series 56 PS193500
MeSH 43 D014849
MedGen 41 C2750457
UMLS 71 C1848519 C2750457

Summaries for Waardenburg Syndrome, Type 4b

OMIM : 56 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)

MalaCards based summary : Waardenburg Syndrome, Type 4b, also known as waardenburg syndrome type 4b, is related to waardenburg syndrome type 4 and peripheral demyelinating neuropathy, central dysmyelination, waardenburg syndrome, and hirschsprung disease. 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 heart, and related phenotypes are sensorineural hearing impairment and hypopigmented skin patches

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 : 73 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 110)
# Related Disease Score Top Affiliating Genes
1 waardenburg syndrome type 4 33.7 SOX10 MITF EDNRB EDN3
2 peripheral demyelinating neuropathy, central dysmyelination, waardenburg syndrome, and hirschsprung disease 33.4 SOX10 PAX3 MITF EDNRB EDN3
3 waardenburg syndrome, type 4a 33.3 SOX10 PMEL PAX3 MITF EDNRB EDN3
4 waardenburg syndrome, type 4c 32.8 SOX10 PAX3 MITF EDNRB EDN3
5 waardenburg's syndrome 31.0 TYR SOX10 SNAI2 PAX3 MITF KITLG
6 intestinal obstruction 30.4 KIT EDNRB EDN3
7 megacolon 29.7 SOX10 PAX3 KIT EDNRB EDN3 ECE1
8 hirschsprung disease 1 29.2 SOX10 SNAI2 PAX3 MITF KIT EDNRB
9 microphthalmia 28.8 TYR TFEB SOX10 PMEL PAX3 MITF
10 waardenburg syndrome, type 2e 28.5 TYR SOX10 SNAI2 PMEL PAX3 MITF
11 branchiootic syndrome 1 10.6
12 catatrichy 10.5
13 sensorineural hearing loss 10.5
14 malignant choroid melanoma 10.4 SOX10 MITF
15 ataxia, combined cerebellar and peripheral, with hearing loss and diabetes mellitus 10.4
16 constipation 10.4
17 epithelioid cell melanoma 10.3 TYR MITF
18 halo nevi 10.3 TYR PMEL
19 waardenburg syndrome, type 2b 10.3 SOX10 MITF EDN3
20 ochronosis 10.3 TYR MITF
21 down syndrome 10.3
22 dandy-walker syndrome 10.3
23 alkuraya-kucinskas syndrome 10.3
24 distal arthrogryposis 10.3
25 cholelithiasis 10.3
26 leukodystrophy 10.3
27 short bowel syndrome 10.3
28 hydrocephalus 10.3
29 acute chest syndrome 10.3
30 dermatitis 10.3
31 irritant dermatitis 10.3
32 hemoglobinopathy 10.3
33 food allergy 10.3
34 mutism 10.3
35 demyelinating polyneuropathy 10.3
36 peripheral nervous system disease 10.3
37 neuropathy 10.3
38 sickle cell disease 10.3
39 hypotonia 10.3
40 avascular necrosis 10.3
41 congenital amyoplasia 10.3
42 intestinal pseudo-obstruction 10.3 SOX10 EDNRB EDN3
43 gallbladder melanoma 10.2 SOX10 PMEL MITF
44 glioblastoma classical subtype 10.2 SNAI2 APPL1
45 childhood kidney cell carcinoma 10.2 TFEB MITF
46 ocular albinism with congenital sensorineural deafness 10.2 TYR PAX3 MITF
47 actinic keratosis 10.2 TYR SOX10 MITF
48 mixed cell uveal melanoma 10.2 TYR PMEL
49 plexiform schwannoma 10.2 SOX10 KIT
50 prostate embryonal rhabdomyosarcoma 10.1 PAX3 KIT

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 hypopigmented skin patches 31 HP:0001053
3 heterochromia iridis 31 HP:0001100
4 premature graying of hair 31 HP:0002216
5 aganglionic megacolon 31 HP:0002251
6 blue irides 31 HP:0000635
7 white forelock 31 HP:0002211
8 white eyebrow 31 HP:0002226
9 white eyelashes 31 HP:0002227

Symptoms via clinical synopsis from OMIM:

56
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

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

45 (show all 24)
# Description MGI Source Accession Score Top Affiliating Genes
1 behavior/neurological MP:0005386 10.43 APPL1 DMD EDN3 EDNRA EDNRB KIT
2 growth/size/body region MP:0005378 10.41 APPL1 DACT1 DMD ECE1 EDNRA EDNRB
3 embryo MP:0005380 10.4 DACT1 ECE1 EDN3 EDNRA EDNRB KIT
4 cardiovascular system MP:0005385 10.35 APPL1 DACT1 DMD ECE1 EDNRA EDNRB
5 homeostasis/metabolism MP:0005376 10.35 APPL1 DMD ECE1 EDNRA EDNRB KIT
6 mortality/aging MP:0010768 10.35 APPL1 DACT1 DMD ECE1 EDN3 EDNRA
7 digestive/alimentary MP:0005381 10.33 DACT1 DMD ECE1 EDN3 EDNRA EDNRB
8 endocrine/exocrine gland MP:0005379 10.32 DMD ECE1 EDNRA EDNRB KIT KITLG
9 integument MP:0010771 10.32 ECE1 EDN3 EDNRA EDNRB KIT KITLG
10 cellular MP:0005384 10.3 APPL1 DMD EDNRA EDNRB KIT KITLG
11 hematopoietic system MP:0005397 10.29 APPL1 DMD ECE1 EDNRA EDNRB KIT
12 immune system MP:0005387 10.26 APPL1 DMD ECE1 EDNRA EDNRB KIT
13 craniofacial MP:0005382 10.25 ECE1 EDNRA EDNRB KIT KITLG MITF
14 nervous system MP:0003631 10.22 DACT1 DMD ECE1 EDN3 EDNRA EDNRB
15 hearing/vestibular/ear MP:0005377 10.21 DMD ECE1 EDNRA EDNRB KIT KITLG
16 limbs/digits/tail MP:0005371 10.15 DACT1 DMD EDNRB KIT KITLG MITF
17 pigmentation MP:0001186 10.03 ECE1 EDN3 EDNRB KIT KITLG MITF
18 no phenotypic analysis MP:0003012 10.02 APPL1 DACT1 DMD KIT MITF PAX3
19 muscle MP:0005369 10 APPL1 DMD ECE1 EDNRA EDNRB KIT
20 normal MP:0002873 9.97 DMD ECE1 EDNRA KIT MITF PAX3
21 neoplasm MP:0002006 9.91 EDNRB KIT KITLG PAX3 SOX10 TYR
22 renal/urinary system MP:0005367 9.76 DACT1 DMD EDNRA EDNRB KIT MITF
23 skeleton MP:0005390 9.73 DACT1 DMD ECE1 EDNRA EDNRB KIT
24 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, Heart, Kidney, Ovary, Prostate, 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. 56 6
20583152 2010
2
Genetic and phenotypic heterogeneity in two novel cases of Waardenburg syndrome type IV. 56 6
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? 56 6
11303518 2001
4
A homozygous mutation in the endothelin-3 gene associated with a combined Waardenburg type 2 and Hirschsprung phenotype (Shah-Waardenburg syndrome). 56 6
8630503 1996
5
Mutation of the endothelin-3 gene in the Waardenburg-Hirschsprung disease (Shah-Waardenburg syndrome). 56 6
8630502 1996
6
Hearing loss in Waardenburg syndrome: a systematic review. 56
26100139 2016
7
Waardenburg syndrome. 56
9279758 1997
8
Interaction of endothelin-3 with endothelin-B receptor is essential for development of epidermal melanocytes and enteric neurons. 56
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 GRCh37 Pos GRCh38 Pos
1 EDN3 NM_207034.3(EDN3):c.507C>A (p.Cys169Ter)SNV Pathogenic 16649 rs74315385 20:57896213-57896213 20:59321158-59321158
2 EDN3 NM_207034.3(EDN3):c.335A>G (p.His112Arg)SNV Pathogenic 16650 rs267606778 20:57876747-57876747 20:59301692-59301692
3 EDN3 NM_207034.3(EDN3):c.277C>G (p.Arg93Gly)SNV Pathogenic 16651 rs267606779 20:57876689-57876689 20:59301634-59301634
4 EDN3 NM_207034.3(EDN3):c.262_263delinsT (p.Ala88fs)indel Pathogenic 16643 rs1568823517 20:57876674-57876675 20:59301619-59301620
5 EDN3 NM_207034.3(EDN3):c.476G>T (p.Cys159Phe)SNV Pathogenic 16644 rs74315384 20:57896182-57896182 20:59321127-59321127
6 EDN3 NM_207034.3(EDN3):c.332G>T (p.Cys111Phe)SNV Likely pathogenic 545507 rs773779627 20:57876744-57876744 20:59301689-59301689
7 EDN3 NM_207034.3(EDN3):c.334C>A (p.His112Asn)SNV Likely pathogenic 547292 rs977075341 20:57876746-57876746 20:59301691-59301691
8 EDN3 NM_207034.3(EDN3):c.293C>A (p.Thr98Lys)SNV Conflicting interpretations of pathogenicity 339123 rs745795470 20:57876705-57876705 20:59301650-59301650
9 EDN3 NM_207034.3(EDN3):c.670G>A (p.Ala224Thr)SNV Likely benign 16647 rs11570351 20:57899467-57899467 20:59324412-59324412
10 EDN3 NM_207034.3(EDN3):c.565dup (p.Thr189fs)duplication Benign/Likely benign 227351 rs11570344 20:57897443-57897444 20:59322388-59322389

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

73
# 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 12.36 MITF KITLG KIT EDNRB EDNRA APPL1
4
Show member pathways
11.83 SNAI2 MITF KITLG KIT
5 11.27 EDNRB EDNRA EDN3
6 11.27 SOX10 SNAI2 PAX3 MITF
7 10.96 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 19)
# Name GO ID Score Top Affiliating Genes
1 negative regulation of apoptotic process GO:0043066 9.92 SOX10 SNAI2 MITF KITLG EDNRB
2 positive regulation of cell proliferation GO:0008284 9.91 KITLG KIT EDNRB EDN3 DMD
3 regulation of gene expression GO:0010468 9.8 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 neural crest cell development GO:0014032 9.58 SNAI2 EDNRA
7 embryonic hemopoiesis GO:0035162 9.57 KITLG KIT
8 melanin biosynthetic process GO:0042438 9.56 TYR PMEL
9 developmental pigmentation GO:0048066 9.55 KIT EDNRB
10 artery smooth muscle contraction GO:0014824 9.54 EDNRA EDN3
11 vasoconstriction GO:0042310 9.5 EDNRB EDNRA EDN3
12 ectopic germ cell programmed cell death GO:0035234 9.48 KITLG KIT
13 neural crest cell migration GO:0001755 9.46 SOX10 KITLG EDNRB EDN3
14 regulation of systemic arterial blood pressure by endothelin GO:0003100 9.43 EDN3 ECE1
15 enteric nervous system development GO:0048484 9.43 SOX10 EDNRB EDNRA
16 vein smooth muscle contraction GO:0014826 9.4 EDNRB EDN3
17 endothelin receptor signaling pathway GO:0086100 9.37 EDNRB EDNRA
18 pigmentation GO:0043473 9.35 TYR SNAI2 MITF KIT EDNRB
19 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
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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