SHFM4
MCID: SPL034
MIFTS: 38

Split-Hand/foot Malformation 4 (SHFM4)

Categories: Bone diseases, Ear diseases, Fetal diseases, Genetic diseases, Mental diseases, Neuronal diseases, Rare diseases

Aliases & Classifications for Split-Hand/foot Malformation 4

MalaCards integrated aliases for Split-Hand/foot Malformation 4:

Name: Split-Hand/foot Malformation 4 57 72 29 13 6 70
Shfm4 57 12 72 54
Split Hand-Foot Malformation 4 12 15
Split-Hand/foot Malformation, Type 4 39

Characteristics:

OMIM®:

57 (Updated 05-Apr-2021)
Inheritance:
autosomal dominant

Miscellaneous:
variable phenotype
reduced penetrance has been reported


HPO:

31
split-hand/foot malformation 4:
Inheritance autosomal dominant inheritance


Classifications:



External Ids:

Disease Ontology 12 DOID:0090023
OMIM® 57 605289
OMIM Phenotypic Series 57 PS183600
ICD9CM 34 755.58
SNOMED-CT 67 81208006
ICD10 32 Q71.6
MedGen 41 C1854442
UMLS 70 C0265554 C1854442

Summaries for Split-Hand/foot Malformation 4

OMIM® : 57 Split-hand/split-foot malformation is a limb malformation involving the central rays of the autopod and presenting with syndactyly, median clefts of the hands and feet, and aplasia and/or hypoplasia of the phalanges, metacarpals, and metatarsals. Some patients with SHFM4 have been found to have mental retardation, ectodermal findings, and orofacial clefting (Elliott and Evans, 2006). For additional phenotypic information and a discussion of genetic heterogeneity in this disorder, see SHFM1 (183600). (605289) (Updated 05-Apr-2021)

MalaCards based summary : Split-Hand/foot Malformation 4, also known as shfm4, is related to split-hand/foot malformation 1 and split hand-foot malformation. An important gene associated with Split-Hand/foot Malformation 4 is TP63 (Tumor Protein P63), and among its related pathways/superpathways is MECP2 and Associated Rett Syndrome. Affiliated tissues include eye and heart, and related phenotypes are split hand and triphalangeal thumb

Disease Ontology : 12 A split-hand/foot malformation that has material basis in heterozygous mutation in the TP63 on chromosome 3q28.

UniProtKB/Swiss-Prot : 72 Split-hand/foot malformation 4: A limb malformation involving the central rays of the autopod and presenting with syndactyly, median clefts of the hands and feet, and aplasia and/or hypoplasia of the phalanges, metacarpals, and metatarsals. Some patients have been found to have mental retardation, ectodermal and craniofacial findings, and orofacial clefting.

Related Diseases for Split-Hand/foot Malformation 4

Diseases in the Split Hand-Foot Malformation family:

Split-Hand/foot Malformation 1 Split-Hand/foot Malformation 6
Split-Hand/foot Malformation 3 Split-Hand/foot Malformation 2
Split-Hand/foot Malformation 4 Split-Hand/foot Malformation 5

Diseases related to Split-Hand/foot Malformation 4 via text searches within MalaCards or GeneCards Suite gene sharing:

(show all 24)
# Related Disease Score Top Affiliating Genes
1 split-hand/foot malformation 1 29.9 TP63 SEM1 DLX5
2 split hand-foot malformation 29.7 WNT10B TP63 SEM1 FBXW4 DPCD DLX6
3 isolated split hand-split foot malformation 28.6 WNT10B TP63 SEM1 EPS15L1 DLX6 DLX5
4 split hand split foot malformation autosomal recessive 10.9
5 split hand/foot malformation x-linked 10.9
6 agnathia-otocephaly complex 10.0 DLX6 DLX5
7 paranoid personality disorder 10.0 SEM1 DYNC1I1
8 orofacial cleft 10.0 TP63 DLX6 DLX5
9 orofacial cleft 8 9.9 TP63 DLX6 DLX5
10 rapp-hodgkin syndrome 9.9 TP63 DLX6 DLX5
11 ectodermal dysplasia 9.9
12 tp63-related disorders 9.9
13 lacrimoauriculodentodigital syndrome 9.9 FBXW4 BHLHA9
14 tooth agenesis 9.8 WNT10B TP63 DLX5
15 orofacial cleft 4 9.8 WNT10B TP63 SEM1 DLX6
16 cleft palate, isolated 9.7 TP63 DLX6 DLX5
17 brachydactyly, type a2 9.6 LBX1 FBXW4 DPCD
18 split-hand/foot malformation 5 9.4 TP63 SEM1 FBXW4 DLX6 DLX5 BHLHA9
19 ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3 9.2 WNT10B TP63 DYNC1I1 DLX6 DLX5 BHLHA9
20 split-hand/foot malformation 2 9.2 WNT10B TP63 SEM1 FBXW4 DLX6 DLX5
21 chromosome 2q35 duplication syndrome 9.1 WNT10B TP63 SEM1 FBXW4 DLX6 DLX5
22 split-hand/foot malformation 3 9.0 SEM1 LBX1 FBXW4 DPCD DLX6 DLX5
23 split-hand/foot malformation 1 with sensorineural hearing loss, autosomal recessive 8.9 WNT10B TP63 SEM1 FBXW4 DYNC1I1 DLX6
24 split-hand/foot malformation 6 8.1 WNT10B TP63 SEM1 LBX1 FBXW4 EPS15L1

Graphical network of the top 20 diseases related to Split-Hand/foot Malformation 4:



Diseases related to Split-Hand/foot Malformation 4

Symptoms & Phenotypes for Split-Hand/foot Malformation 4

Human phenotypes related to Split-Hand/foot Malformation 4:

31 (show all 9)
# Description HPO Frequency HPO Source Accession
1 split hand 31 HP:0001171
2 triphalangeal thumb 31 HP:0001199
3 ectrodactyly 31 HP:0100257
4 aplasia/hypoplasia involving the metacarpal bones 31 HP:0005914
5 split foot 31 HP:0001839
6 aplasia/hypoplasia of the phalanges of the hand 31 HP:0009767
7 aplasia/hypoplasia of the phalanges of the toes 31 HP:0010173
8 syndactyly 31 HP:0001159
9 aplasia/hypoplasia of metatarsal bones 31 HP:0001964

Symptoms via clinical synopsis from OMIM®:

57 (Updated 05-Apr-2021)
Skeletal Hands:
triphalangeal thumb
syndactyly
monodactyly
split hand, unilateral or bilateral
'lobster-claw anomaly
more
Skeletal Feet:
syndactyly
'lobster-claw anomaly
webbing
split foot, unilateral or bilateral
missing metatarsals

Clinical features from OMIM®:

605289 (Updated 05-Apr-2021)

MGI Mouse Phenotypes related to Split-Hand/foot Malformation 4:

46
# Description MGI Source Accession Score Top Affiliating Genes
1 embryo MP:0005380 9.63 DLX5 DLX6 EPS15L1 FBXW4 LBX1 TP63
2 limbs/digits/tail MP:0005371 9.5 BHLHA9 DLX5 DLX6 EPS15L1 FBXW4 LBX1
3 respiratory system MP:0005388 9.02 DLX5 DLX6 DPCD EPS15L1 TP63

Drugs & Therapeutics for Split-Hand/foot Malformation 4

Search Clinical Trials , NIH Clinical Center for Split-Hand/foot Malformation 4

Genetic Tests for Split-Hand/foot Malformation 4

Genetic tests related to Split-Hand/foot Malformation 4:

# Genetic test Affiliating Genes
1 Split-Hand/foot Malformation 4 29 TP63

Anatomical Context for Split-Hand/foot Malformation 4

MalaCards organs/tissues related to Split-Hand/foot Malformation 4:

40
Eye, Heart

Publications for Split-Hand/foot Malformation 4

Articles related to Split-Hand/foot Malformation 4:

(show all 25)
# Title Authors PMID Year
1
Split-hand/split-foot malformation is caused by mutations in the p63 gene on 3q27. 6 57
10839977 2000
2
Anomalous inheritance in a kindred with split hand, split foot malformation. 57 6
3366140 1988
3
Genotype-phenotype correlations in mapped split hand foot malformation (SHFM) patients. 57 54 61
16688749 2006
4
Duplications of BHLHA9 are associated with ectrodactyly and tibia hemimelia inherited in non-Mendelian fashion. 57
22147889 2012
5
Discrepancies in upper and lower limb patterning in split hand foot malformation. 57
16207208 2005
6
Isolated ectrodactyly caused by a heterozygous missense mutation in the transactivation domain of TP63. 6
15736220 2005
7
Homozygous WNT10b mutation and complex inheritance in Split-Hand/Foot Malformation. 54 61
18515319 2008
8
p63-associated disorders. 54 61
17224651 2007
9
Delineation of the ADULT syndrome phenotype due to arginine 298 mutations of the p63 gene. 54 61
16724007 2006
10
Split-hand/split-foot malformation 3 (SHFM3) at 10q24, development of rapid diagnostic methods and gene expression from the region. 54 61
16691619 2006
11
A novel mutation (c.1010G>T; p.R337L) in TP63 as a cause of split-hand/foot malformation with hypodontia. 61
31420900 2019
12
Duplication of 10q24 locus: broadening the clinical and radiological spectrum. 61
30622331 2019
13
Genetic analysis of a congenital split‑hand/split‑foot malformation 4 pedigree. 61
29620206 2018
14
Variable expressivity of a familial 1.9 Mb microdeletion in 3q28 leading to haploinsufficiency of TP63: Refinement of the critical region for a new microdeletion phenotype. 61
26117585 2015
15
Split-hand/foot malformation - molecular cause and implications in genetic counseling. 61
24163146 2014
16
A novel homozygous missense mutation in WNT10B in familial split-hand/foot malformation. 61
21554266 2012
17
Analysis of large phenotypic variability of EEC and SHFM4 syndromes caused by K193E mutation of the TP63 gene. 61
22574117 2012
18
Somatic/gonadal mosaicism in a syndromic form of ectrodactyly, including eye abnormalities, documented through array-based comparative genomic hybridization. 61
21485001 2011
19
TP63-Related Disorders 61
20556892 2010
20
The association of split hand foot malformation (SHFM) and congenital heart defects. 61
18383509 2008
21
Abnormal urethra formation in mouse models of split-hand/split-foot malformation type 1 and type 4. 61
17878916 2008
22
Frequency of genomic rearrangements involving the SHFM3 locus at chromosome 10q24 in syndromic and non-syndromic split-hand/foot malformation. 61
16761290 2006
23
[A DNA duplication at chromosome 10q24.3 is associated with split-hand split-foot malformation in a Chinese family]. 61
16681918 2006
24
Molecular genetic characterization of a Korean split hand/split foot malformation (SHFM). 61
15232212 2004
25
Association of ectrodactyly and distal phocomelia. 61
12416640 2002

Variations for Split-Hand/foot Malformation 4

ClinVar genetic disease variations for Split-Hand/foot Malformation 4:

6
# Gene Name Type Significance ClinVarId dbSNP ID Position
1 TP63 NM_003722.5(TP63):c.697A>G (p.Lys233Glu) SNV Pathogenic 6531 rs121908838 GRCh37: 3:189582138-189582138
GRCh38: 3:189864349-189864349
2 TP63 NM_003722.5(TP63):c.955C>T (p.Arg319Cys) SNV Pathogenic 6532 rs121908839 GRCh37: 3:189585694-189585694
GRCh38: 3:189867905-189867905
3 TP63 NM_003722.5(TP63):c.289C>T (p.Arg97Cys) SNV Pathogenic 6549 rs121908848 GRCh37: 3:189456528-189456528
GRCh38: 3:189738739-189738739
4 TP63 NM_003722.5(TP63):c.1825G>A (p.Glu609Lys) SNV Uncertain significance 69817 rs142762485 GRCh37: 3:189612073-189612073
GRCh38: 3:189894284-189894284

UniProtKB/Swiss-Prot genetic disease variations for Split-Hand/foot Malformation 4:

72
# Symbol AA change Variation ID SNP ID
1 TP63 p.Lys233Glu VAR_020869 rs121908838
2 TP63 p.Lys232Glu VAR_032737 rs156027424
3 TP63 p.Arg319His VAR_032743 rs886039442

Expression for Split-Hand/foot Malformation 4

Search GEO for disease gene expression data for Split-Hand/foot Malformation 4.

Pathways for Split-Hand/foot Malformation 4

Pathways related to Split-Hand/foot Malformation 4 according to GeneCards Suite gene sharing:

# Super pathways Score Top Affiliating Genes
1 10.42 DLX6 DLX5

GO Terms for Split-Hand/foot Malformation 4

Cellular components related to Split-Hand/foot Malformation 4 according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 chromatin GO:0000785 9.02 TP63 LBX1 DLX6 DLX5 BHLHA9

Biological processes related to Split-Hand/foot Malformation 4 according to GeneCards Suite gene sharing:

(show all 14)
# Name GO ID Score Top Affiliating Genes
1 regulation of transcription by RNA polymerase II GO:0006357 9.85 WNT10B TP63 LBX1 DLX6 DLX5 BHLHA9
2 multicellular organism development GO:0007275 9.7 WNT10B TP63 LBX1 FBXW4 DLX6 DLX5
3 positive regulation of canonical Wnt signaling pathway GO:0090263 9.63 WNT10B SEM1 DLX5
4 skeletal system development GO:0001501 9.61 TP63 DLX6 DLX5
5 positive regulation of osteoblast differentiation GO:0045669 9.54 WNT10B TP63
6 roof of mouth development GO:0060021 9.52 DLX6 DLX5
7 positive regulation of epithelial cell proliferation GO:0050679 9.51 DLX6 DLX5
8 inner ear morphogenesis GO:0042472 9.49 DLX6 DLX5
9 developmental process GO:0032502 9.48 TP63 BHLHA9
10 epithelial cell differentiation GO:0030855 9.43 TP63 DLX6 DLX5
11 head development GO:0060322 9.4 DLX6 DLX5
12 embryo development GO:0009790 9.32 DLX6 DLX5
13 anatomical structure formation involved in morphogenesis GO:0048646 9.13 TP63 DLX6 DLX5
14 embryonic limb morphogenesis GO:0030326 8.92 TP63 FBXW4 DLX6 DLX5

Molecular functions related to Split-Hand/foot Malformation 4 according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 DNA-binding transcription factor activity, RNA polymerase II-specific GO:0000981 9.02 TP63 LBX1 DLX6 DLX5 BHLHA9

Sources for Split-Hand/foot Malformation 4

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 05-Apr-2021)
61 PubMed
63 QIAGEN
68 SNOMED-CT via HPO
69 Tocris
70 UMLS
71 UMLS via Orphanet
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