Introduction: Split hand and foot malformation (SHFM) or ectrodactyly is a rare limb deformity characterized by median cleft of the hand and foot with impaired or missing central rays. It can occur as an isolated anomaly or in association with abnormalities of other body parts. Methods: After delineating the clinical features of two families (A–B), with non-syndromic SHFM, exome and Sanger sequencing were employed to search for the disease-causing variants. Results: Analysis of exome and Sanger sequencing data revealed two causative variants in the WNT10B gene in affected members of the two families. This included a novel missense change [c.338G>C; p.(Gly113Ala)] in family A and a previously reported frameshift variant [c.884-896delTCCAGCCCCGTCT; p.(Phe295Cysfs*87)] in family B. Conclusion: Our findings add a novel variant in WNT10B gene as the underlying cause of SHFM. The finding adds to the growing body of knowledge about the genetic basis of developmental disorders and provides valuable insights into the molecular mechanisms that regulate limb development.

1.
Armour
CM
,
Bulman
DE
,
Jarinova
O
,
Rogers
RC
,
Clarkson
KB
,
DuPont
BR
et al
.
17p13.3 microduplications are associated with split-hand/foot malformation and long-bone deficiency (SHFLD)
.
Eur J Hum Genet
.
2011
;
19
(
11
):
1144
51
.
2.
Aziz
A
,
Irfanullah
,
Khan
S
,
Zimri
FK
,
Muhammad
N
,
Rashid
S
et al
.
Novel homozygous mutations in the WNT10B gene underlying autosomal recessive split hand/foot malformation in three consanguineous families
.
Gene
.
2014
;
534
(
2
):
265
71
.
3.
Babbs
C
,
Heller
R
,
Everman
DB
,
Crocker
M
,
Twigg
SR
,
Schwartz
CE
et al
.
A new locus for split hand/foot malformation with long bone deficiency (SHFLD) at 2q14.2 identified from a chromosome translocation
.
Hum Genet
.
2007
;
122
(
2
):
191
9
.
4.
Barrow
JR
,
Thomas
KR
,
Boussadia-Zahui
O
,
Moore
R
,
Kemler
R
,
Capecchi
MR
et al
.
Ectodermal Wnt3/beta-catenin signaling is required for the establishment and maintenance of the apical ectodermal ridge
.
Genes Dev
.
2003
;
17
(
3
):
394
409
.
5.
Bilal
M
,
Hayat
A
,
Umair
M
,
Ullah
A
,
Khawaja
S
,
Malik
E
et al
.
Sequence variants in theWNT10B and TP63 Genes underlying isolated split-hand/split-foot malformation
.
Genet Test Mol Biomarkers
.
2020
;
24
(
9
):
600
7
.
6.
Blattner
A
,
Huber
AR
,
Rothlisberger
B
.
Homozygous nonsense mutation in WNT10B and sporadic split-hand/foot malformation (SHFM) with autosomal recessive inheritance
.
Am J Med Genet A
.
2010
;152A(8):2053–6.
7.
Brunelle
P
,
Jourdain
AS
,
Escande
F
,
Martinovic
J
,
Dupont
J
,
Busa
T
et al
.
WNT10B variants in split hand/foot malformation: Report of three novel families and review of the literature
.
Am J Med Genet A
.
2019
;179(7):1351–6.
8.
Cadigan
KM
,
Nusse
R
.
Wnt signaling: a common theme in animal development
.
Genes Dev
.
1997
;
11
(
24
):
3286
305
.
9.
Cawthorn
WP
,
Bree
AJ
,
Yao
Y
,
Du
B
,
Hemati
N
,
Martinez-Santibañez
G
et al
.
Wnt6, Wnt10a and Wnt10b inhibit adipogenesis and stimulate osteoblastogenesis through a β-catenin-dependent mechanism
.
Bone
.
2012
;
50
(
2
):
477
89
.
10.
Christodoulides
C
,
Scarda
A
,
Granzotto
M
,
Milan
G
,
Dalla Nora
E
,
Keogh
J
et al
.
WNT10B mutations in human obesity
.
Diabetologia
.
2006
;
49
(
4
):
678
84
.
11.
Falb
RJ
,
Müller
AJ
,
Klein
W
,
Grimmel
M
,
Grasshoff
U
,
Spranger
S
et al
.
Bi-allelic loss-of-function variants in KIF21A cause severe fetal akinesia with arthrogryposis multiplex
.
J Med Genet
.
2023
;
60
(
1
):
48
56
.
12.
Geetha-Loganathan
P
,
Nimmagadda
S
,
Scaal
M
.
Wnt signaling in limb organogenesis
.
Organogenesis
.
2008
;
4
(
2
):
109
15
.
13.
Holder-Espinasse
M
,
Jamsheer
A
,
Escande
F
,
Andrieux
J
,
Petit
F
,
Sowinska-Seidler
A
et al
.
Duplication of 10q24 locus: broadening the clinical and radiological spectrum
.
Eur J Hum Genet
.
2019
;
27
(
4
):
525
34
.
14.
Kantaputra
PN
,
Kapoor
S
,
Verma
P
,
Intachai
W
,
Ketudat Cairns
JR
.
Split hand-foot malformation and a novel WNT10B mutation
.
Eur J Med Genet
.
2018
;
61
(
7
):
372
5
.
15.
Khan
S
,
Basit
S
,
Zimri
FK
,
Ali
N
,
Ali
G
,
Ansar
M
et al
.
A novel homozygous missense mutation in WNT10B in familial split-hand/foot malformation
.
Clin Genet
.
2012
;
82
(
1
):
48
55
.
16.
Malik
S
,
Percin
FE
,
Bornholdt
D
,
Albrecht
B
,
Percesepe
A
,
Koch
MC
et al
.
Mutations affecting the BHLHA9 DNA-binding domain cause MSSD, mesoaxial synostotic syndactyly with phalangeal reduction, Malik-Percin type
.
Am J Hum Genet
.
2014
;
95
(
6
):
649
59
.
17.
Meng
L
,
Pammi
M
,
Saronwala
A
,
Magoulas
P
,
Ghazi
AR
,
Vetrini
F
et al
.
Use of Exome Sequencing for Infants in Intensive Care Units: Ascertainment of Severe Single-Gene Disorders and Effect on Medical Management
.
JAMA Pediatr
.
2017
;171(12):e173438.
18.
Monies
D
,
Abouelhoda
M
,
AlSayed
M
,
Alhassnan
Z
,
Alotaibi
M
,
Kayyali
H
et al
.
The landscape of genetic diseases in Saudi Arabia based on the first 1000 diagnostic panels and exomes
.
Hum Genet
.
2017
;136(8):921–9.
19.
Paththinige
CS
,
Sirisena
ND
,
Escande
F
,
Manouvrier
S
,
Petit
F
,
Dissanayake
VHW
.
Split hand/foot malformation with long bone deficiency associated with BHLHA9 gene duplication: a case report and review of literature
.
BMC Med Genet
.
2019
;
20
(
1
):
108
.
20.
Peifer
M
,
Polakis
P
.
Wnt signaling in oncogenesis and embryogenesis--a look outside the nucleus
.
Science
.
2000
;
287
(
5458
):
1606
9
.
21.
Ugur
SA
,
Tolun
A
.
Homozygous WNT10b mutation and complex inheritance in Split-Hand/Foot Malformation
.
Hum Mol Genet
.
2008
;
17
(
17
):
2644
53
.
22.
Ullah
A
,
Ali
RH
,
Majeed
AI
,
Liaqat
K
,
Shah
PW
,
Khan
B
et al
.
A novel insertion and deletion mutation in the BHLHA9 underlies polydactyly and mesoaxial synostotic syndactyly with phalangeal reduction
.
Eur J Med Genet
.
2019
;
62
(
4
):
278
81
.
23.
Ullah
A
,
Ullah
MF
,
Khalid
ZM
,
Ahmad
W
.
Novel heterozygous frameshift mutation in distal-less homeobox 5 underlies isolated split hand/foot malformation type 1
.
Pediatr Int
.
2016
;
58
(
12
):
1348
50
.
24.
Ullah
A
,
Gul
A
,
Umair
M
,
Irfanullah
Ahmad F
,
Aziz
A
et al
.
Homozygous sequence variants in the WNT10B gene underlie split hand/foot malformation
.
Genet Mol Biol
.
2018
;
41
(
1
):
1
8
.
25.
Ullah
A
,
Hammid
A
,
Umair
M
,
Ahmad
W
.
A novel heterozygous intragenic sequence variant in DLX6 probably underlies first case of autosomal dominant split-hand/foot malformation type 1
.
Mol Syndromol
.
2017
;
8
(
2
):
79
84
.
26.
Umair
M
,
Alhaddad
B
,
Rafique
A
,
Jan
A
,
Haack
TB
,
Graf
E
et al
.
Exome sequencing reveals a novel homozygous splice site variant in the WNT1 gene underlying osteogenesis imperfecta type 3
.
Pediatr Res
.
2017
;
82
(
5
):
753
8
.
27.
Umair
M
,
Ahamd
F
,
Bilal
M
,
Asiri
A
,
Younus
M
,
Khan
A
.
A comprehensive review of genetic skeletal disorders reported from Pakistan: a brief commentary
.
Metagene
.
2019
;
20
:
100559
.
28.
Umair
M
,
Hayat
A
.
Nonsyndromic split-hand/foot malformation: recent classification
.
Mol Syndromol
.
2020
;
10
(
5
):
243
54
.
29.
Umair
M
,
Ullah
A
,
Abbas
S
,
Ahmad
F
,
Basit
S
,
Ahmad
W
.
First direct evidence of involvement of a homozygous loss-of-function variant in the EPS15L1 gene underlying split-hand/split-foot malformation
.
Clin Genet
.
2018
;
93
(
3
):
699
702
.
30.
Umair
M
.
Rare genetic disorders: beyond whole-exome sequencing
.
J Gene Med
.
2023
;
28
:
e3503
.
31.
Yamaguchi
TP
,
Takada
S
,
Yoshikawa
Y
,
Wu
N
,
McMahon
AP
.
T (Brachyury) is a direct target of Wnt3a during paraxial mesoderm specification
.
Genes Dev
.
1999
;
13
(
24
):
3185
90
.
32.
Zhou
H
,
Mak
W
,
Zheng
Y
,
Dunstan
CR
,
Seibel
MJ
.
Osteoblasts directly control lineage commitment of mesenchymal progenitor cells through Wnt signaling
.
J Biol Chem
.
2008
;
283
(
4
):
1936
45
.
You do not currently have access to this content.