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The genetic landscape and clinical implications
of vertebral anomalies in VACTERL association
Yixin Chen,
1
Zhenlei Liu,
1
Jia Chen,
1
Yuzhi Zuo,
1
Sen Liu,
1,2
Weisheng Chen,
1
Gang Liu,
1
Guixing Qiu,
1,2
Philip F Giampietro,
3
Nan Wu,
1,2
Zhihong Wu
2,4
1
Department of Orthopedic
Surgery, Peking Union Medical
College Hospital, Peking Union
Medical College and Chinese
Academy of Medical Sciences,
Beijing, China
2
Beijing Key Laboratory for
Genetic Research of Skeletal
Deformity, Beijing, China
3
Department of Pediatrics,
University of Wisconsin School
of Medicine and Public Health,
Madison, Wisconsin, USA
4
Department of Central
Laboratory, Peking Union
Medical College Hospital,
Peking Union Medical College
and Chinese Academy of
Medical Sciences, Beijing,
China
Correspondence to
Dr Nan Wu, Department of
Orthopedic Surgery, Peking
Union Medical College
Hospital, Peking Union Medical
College and Chinese Academy
of Medical Sciences, No.1
Shuaifuyuan, Beijing 100730,
China; Beijing Key Laboratory
for Genetic Research of
Skeletal Deformity, China;
dr.wunan@pumch.cn
Dr Zhihong Wu, Department of
Central Laboratory, Peking
Union Medical College
Hospital, Peking Union College
and Chinese Academic of
Medical Sciences, No 1
Shuaifuyuan, Beijing 100730,
China; Beijing Key Laboratory
for Genetic Reserach of
Skeletal Deformity, China;
wuzh3000@126.com
Received 30 November 2015
Revised 3 March 2016
Accepted 17 March 2016
To cite: Chen Y, Liu Z,
Chen J, et al.J Med Genet
Published Online First:
[please include Day Month
Year] doi:10.1136/
jmedgenet-2015-103554
ABSTRACT
VACTERL association is a condition comprising
multisystem congenital malformations, causing severe
physical disability in affected individuals. It is typically
defined by the concurrence of at least three of the
following component features: vertebral anomalies (V),
anal atresia (A), cardiac malformations (C), tracheo-
oesophageal fistula (TE), renal dysplasia (R) and limb
abnormalities (L). Vertebral anomaly is one of the most
important and common defects that has been reported
in approximately 60–95% of all VACTERL patients.
Recent breakthroughs have suggested that genetic
factors play an important role in VACTERL association,
especially in those with vertebral phenotypes. In this
review, we summarised the genetic studies of the
VACTERL association, especially focusing on the genetic
aetiology of patients with vertebral anomalies.
Furthermore, genetic reports of other syndromes with
vertebral phenotypes overlapping with VACTERL
association are also included. We aim to provide a
further understanding of the genetic aetiology and a
better evidence for genetic diagnosis of the association
and vertebral anomalies.
OVERVIEW OF VACTERL ASSOCIATION
VACTERL association is a condition with multisys-
tem congenital malformations: Vertebral anomalies
(V), anal atresia (A), cardiac malformation (C),
tracheo-oesophageal fistula (TE) with or without
oesophageal atresia, renal dysplasia (R) and limb
abnormalities (L).
12
It was first named as VATER
(without ‘C’and ‘L’) association in 1973.
3
The
prevalence of VACTERL/VATER association is
between 1/7000 and 1/40 000.
45
As there is no available objective laboratory test
for its diagnosis, VACTERL association is diagnosed
totally based on the clinical manifestations men-
tioned above. Most clinicians and researchers
require the presence of at least three component fea-
tures for diagnosis. Besides, due to its heterogeneous
phenotype and the abundance of overlapping
defects of other syndromes, VACTERL association is
typically considered a diagnosis of exclusion
5–8
with
no clear evidence for an alternative or overlapping
diagnosis such as Coloboma, Heart anomaly, Atresia
of choanae, Retardation of mental and somatic
development, Genital hypoplasia, Ear abnormalities
(CHARGE) syndrome, DiGeorge syndrome and
Pallister–Hall syndrome.The presence of other fea-
tures not typically seen in VACTERL association
may suggest other disorders. Thus, a physical exam-
ination and family history are essential to rule out
potentially overlapping diagnoses. It is worth men-
tioning that 5–10% patients with Fanconi anaemia
(FA) have birth defects meeting the diagnosis of
VACTERL association with hydrocephalus
(VACTERL-H).
910
It is suggested that FA with
VACTERL-H should be treated separately from the
VACTERL association because of the core character-
istics of FA such as haematological anomalies and
skin pigmentary changes, the different frequencies
of VACTERL-associated phenotypes and the prog-
nosis and therapeutic intervention.
10 11
Although the clinical criteria for VACTERL asso-
ciation appear to be straightforward, the overlap-
ping in either clinical manifestation or genetic
finding is challenging for clinicians and geneticists.
The CHD7 gene mutation, which is proved to be
associated with CHARGE syndrome, may also be
found in patients diagnosed with VACTERL associ-
ation, even CHARGE syndrome is clinically
excluded.
12
Besides, most of the conditions listed
are monogenic disorders. Careful genetic evaluation
may help ruling out these conditions. In this review,
we listed the related monogenic diseases that share
two more overlapping manifestations and their
genetic findings (table 1). We propose that(1) these
syndromes as well as these candidate genes should
be considered in diagnostic and genetic studies in
VACTERL association; and (2) VACTERL syndrome
remains a diagnosis of exclusion following a
thoughtful clinical evaluation and consideration of
genetic testing for overlapping syndromes.
Prior studies have estimated that 90% of the
patients diagnosed with VACTERL association had
three or fewer phenotypes (referred to as
VACTERL-like association) and <1% of patients
had all six anomalies.
4
Although the frequency of
the six clinical features (CFs) varies, vertebral
anomalies is the most common observation in many
cohorts of VACTERL association, which have been
reported in approximately 60–95% of affected indi-
viduals.
730–33
Additionally, vertebral anomalies are
the most prevalent findings in the first-degree rela-
tives of the probands in some cohorts,
34 35
thus
highlighting the importance of vertebral anomalies
as a major diagnostic feature for VACTERL associ-
ation. In this review, we will summarise the genetic
studies of the VACTERL association with an
emphasis on vertebral anomalies.
Vertebral anomalies
Vertebral anomalies in VACTERL association can
be classified as (1) failure of formation, such as
hemivertebrae, butterfly or wedge-shaped verte-
brae; (2) failure of segmentation such as
vertebral bars, fused vertebrae and block vertebrae;
and (3) a combination of these two features, result-
ing in a mixed deformity.
36 37
Rib anomalies such
Chen Y, et al.J Med Genet 2016;0:1–7. doi:10.1136/jmedgenet-2015-103554 1
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as rib fusion and increased or decreased number of ribs are
commonly accompanied with vertebral anomalies. In some
studies, rib anomalies may occur without vertebral anomal-
ies.
7303839
Although patients with anorectal malformations
may be have dysplastic sacral vertebrae, it is not clear whether
these should be regarded as a vertebral anomalies component
for diagnosis of VACTERL syndrome.
2
Clinical signs of scoli-
osis or kyphosis may be the first sign of vertebral anomalies
when VACTERL association is suspected.
40
Radiology is needed
for discerning vertebral and rib anomalies.
As an example, we present a 2-year-old Chinese boy with
VACTERL association. He was born with oesophageal atresia
that was surgically corrected 4 days later. He had an uneventful
infancy until his mother found him with a hump at lower waist
a year later. Spinal X-ray and CT scan found a left hemivertebra
between L3 and L4, and a right hemivertebra between L5 and
S1 (figure 1), which caused evident lumbar scoliosis. He also
had an extra thoracic vertebra and an extra pair of ribs without
clinical symptoms. Abdominal ultrasound examination revealed
horseshoe kidney without impairment of his renal function. He
underwent resection of both hemivertebrae with internal fix-
ation and recovered well postoperatively.
GENETIC STUDIES ON VACTERL ASSOCIATION
The aetiology of VACTERL association is not well understood
(figure 2). As its phenotypes are too heterogeneous to be
defined as a syndrome, and there is no major gene for this con-
dition, thus it is still referred to as an ‘association’. The familial
clustering phenomenon suggests a genetic role in its
causality.
34 41 42
X-linked VACTERL association by ZIC3 mutation
So far, the ZIC3 gene has been demonstrated to cause X-linked
VACTERL association. Different types of ZIC3 mutations,
including point mutations, deletions and polyalanine expansion,
have been reported to be responsible for both VACTERL or
VACTERL-like association.
43–45
Cardiac defects are most com-
monly found as ZIC3 has important function in cardiac devel-
opment and mutations in ZIC3 also cause X-linked heterotaxy
(MIM#306955);
43 46 47
anal atresia is present in most patients
with ZIC3 mutations; vertebral anomalies are not commonly
observed and demonstrated phenotypic variability.
45
In animal
models, Zic3 knockout mice mimic the human heterotaxy and
cardiac phenotype with occasional vertebral/rib anomalies.
Zic3expression was present at all stages of embryonic
Table 1 Monogenic diseases overlapping with VACTERL association
Syndrome OMIM Locus Gene Vertebral anomalies
Overlap
malformations
Characteristic features beyond
VACTERL association Reference
Fanconi anaemia
with VACTERL-H
227650;
300514
16q24; Xp22 FANCA;
FANCB,etc.*
Same phenotype with
VACTERL but lower
frequency
V, A, C TE, R, L Haematological anomalies;
pigmentary changes;
hydrocephalus
Holden et al
13
Alagille syndrome 118450 20p12;
1p12-p11
JAG1;
NOTCH2
Mostly butterfly vertebra,
occasionally
hemivertebrae, fusion of
vertebrae
V, C, R Jaundice with conjugated
hyperbilirubinemia; dysmorphic
facies; posterior embryotoxon and
retinal pigmentary changes
Turnpenny and
Ellard
14
Basal cell nevus
syndrome
109400 9q22; 1p32;
10q24-q25
PTCH1;
PTCH2;SUFU
Multiple fusion of
vertebral bodies and ribs
V, L Odontogenic keratocysts of the
jaw; palmar or plantar pits;
bilamellar calcification of the falx
cerebri; basal cell tumours
Oostra and Maas;
15
Pino et al
16
Baller–Gerold
syndromes
218600 8q24 RECQL4 Rib fusion and flat
vertebrae
V, A, C, R, L Craniosynostosis; microcephaly Murthy et al
17
DiGeorge syndrome
(22q11.2 deletion
syndrome)
188400 22q11 TBX1 Hemivertebrae V, C, R, L Thymic abnormality;conotruncal
cardiac anomaly; facial
dysmorphism; hypocalcaemia
Tsirikos et al;
18
Maggadottir and
Sullivan
19
Feingold syndrome 164280 2p23-24 N-MYC Absence of the fifth
sacral vertebra and
fusion of C5–C7in a case
V, C, TE, R, L Microcephaly;
brachymesophalangy
Celli et al
20
McKusick–Kaufman
syndrome
236700 20p12 MKKS Vertebral anomalies in
one case
V, C, L Hydrometrocolpos; gastrointestinal
malformations
Knowles et al
21
CHARGE syndrome 214800 8q12 CHD7 Idiopathic scoliosis
without vertebral
anomalies
C, TE, R Coloboma; choanal atresia/
stenosis;hypoplasia/aplasia of
semicircular, etc.
Hsu et al;
22
Verloes
23
Pallister–Hall
syndrome
146510 7p14.1 GLI3 NA A, C, R, L Hypothalamic hamartoma; bifid
epiglottis; craniofacial
abnormalities
Demurger et al
24
Townes–Brocks
syndrome
107480 16q21.1 SALL1 NA A, C, R, L Dysplastic ears with hearing
impairment; intellectual disability
Sudo et al
25
Holt–Oram syndrome 142900 12q24 TBX5 NA C, L NA Goldfarb and
Wall2014
26
Hemifacial
microsomia (OAVS)
164210 14q32 NA Hemivertebrae, fusion of
vertebrae
V, C Craniofacial anomalies; central
nervous system defects: visual and
hearing impairment
Beleza-Meireles
et al
27
TAR syndrome 274000 1q21 RBM8ANA NA C, R, L Thrombocytopenia Tassanoet al
28
*Numbers of genes been implicated in the pathogenesis associated with Fanconi anaemia.
29
A, anal atresia; C, cardiac malformations; CHARGE, Coloboma, Heart anomaly, Atresia of choanae, Retardation of mental and somatic development, Genital hypoplasia, Ear
abnormalities; L, limb abnormalities; NA, not available; OAVS, oculo-auriculo-vertebral spectrum; R, renal anomalies; TAR, thrombocytopenia-absent radius; TE, tracheo-oesophageal
fistula; V, vertebral anomalies; VACTERL, vertebral anomalies (V), anal atresia (A), cardiac malformations (C), tracheo-oesophageal fistula (TE), renal dysplasia (R) and limb abnormalities
(L); VACTERL-H, VACTERL association with hydrocephalus.
2 Chen Y, et al.J Med Genet 2016;0:1–7. doi:10.1136/jmedgenet-2015-103554
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development within the anterior pre-somitic mesoderm but not
in the developing anal region. Thus, anal atresia was not
reported in Zic3-deficient mice,
45
which differs from humans
where anal atresia is also prevalent with ZIC3 mutations.
Sonic hedgehog pathway in VACTERL association
SHH gene has been implicated as the key inductive signal in pat-
terning of the ventral neural tube, the anterior–posterior limb
axis and the ventral somites.
48
Studies on animal models indi-
cate that sonic hedgehog (Shh) pathway is important for
VACTERL association. Kim et al
49 50
identified the first animal
model that recapitulated the human VACTERL syndrome by
knocking out genes (Shh and Gli) in Shh pathway. With differ-
ent genes of the Shh signalling pathway affected, the mutant
mice display various combinations, ranges and severity of the
VACTERL phenotypes, implying a dosage-dependent effect.
Furthermore, a VACTERL-like phenotype was reported in
murine with a novel hypomorphic mutation in the Intraflagellar
Transport Protein 172 (Ift172) gene.
51
The Ift172gene encodes
a component of the intraflagellar transport, which appears to
play an active role in Shh signalling, and Ift proteins are
required for both Gli activator and Gli repressor function.
52 53
To the best of our knowledge, SHH or GLI3 mutations have
not been identified in VACTERL patients.
54
In humans, SHH
mutation may cause more severe VACTERL phenotypes.
Nowaczyk et al
55
reported a patient with holoprosencephaly 3
and SHH haploinsufficiency who suffered from sacral anomalies
(cleft S1, hemivertebra at S2 and absence of the rest of the
sacrum and coccyx), genitourinary abnormality, multiple seg-
ments of bowel atresia and limb anomalies. Although this
patient has a distinctive diagnosis, the phenotypic features
overlap with VACTERL association. There is a possibility that
SHH mutation causes these overlapping phenotypes.
Figure 1 Radiology of a 2-year-old
boy diagnosed with VACTERL
association. Preoperative spinal X-ray
(A) and CT scan (B) revealed a left
hemivertebra between L3 and L4, and
a right hemivertebra between L5 and
S1 that was fused with S1 vertebra
(white arrows). R, right side of the
body; VACTERL, vertebral anomalies
(V), anal atresia (A), cardiac
malformations (C),
tracheo-oesophageal fistula (TE),
renal dysplasia (R) and limb
abnormalities (L).
Figure 2 General view of genetic findings and vertebral
manifestations in VACTERL association. Mitochondrial, mitochondrial
dysfunction; SNVs, single-nucleotide variants; VACTERL, vertebral
anomalies (V), anal atresia (A), cardiac malformations (C), tracheo-
oesophageal fistula (TE), renal dysplasia (R) and limb abnormalities (L).
Chen Y, et al.J Med Genet 2016;0:1–7. doi:10.1136/jmedgenet-2015-103554 3
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Some genes that play roles in Shh pathway have been
reported to be associated with VACTERL association. A hetero-
zygous de novo 21bp deletion (c.163_183del) in the exon 1 of
the HOXD13 gene,
56
a downstream target of SHH,
57
was iden-
tified in a 17-year-old girl, who was diagnosed with VACTERL
association without vertebral anomalies. Another patient with
rib anomalies diagnosed with VACTERL association was found
with a 451 kb deletion at chromosome 3q28, which contains a
single LPP gene.
39
This gene encodes LIM domain containing
preferred translocation partner in lipoma that has been shown
to bind PEA3, an ETS domain transcription factor that has a
role in regulating the SHH pathway.
58
Moreover, CNV (micro-
deletions) as well as point mutation in FOXF1 gene have been
identified in patients with VACTERL phenotypes.
45 59
In animal
models, Foxf1 has been found to be downregulated in Shh−/−
mice
60 61
and the Foxf1heterozygotes have been shown to
display tracheo-oesophageal atresia and fistulas.
62 63
Although
HOXD13,LPP and FOXF1 mutation were sporadic findings in
individuals,
64 65
these studies argue in favour of that SHH
pathway dysfunction is associated with VACTERL association.
Candidate gene mutations and CNVs
Several candidate gene mutations and CNVs have been reported
to be related to VACTERL association (summarised in table 2).
So far, these candidate gene mutations and CNVs listed are
found mostly in sporadic cases, which need further large sample
verification or functional experiments to confirm their
pathogenicity.
Although the genetic aetiology of VACTERL association has
been far from established, previous studies did reveal some genetic
mutations that can account for one or a few of the six CFs (table
2). For example, DLL3 gene, which encodes a ligand for the
Notch signalling pathway that coordinates somitogenesis,
66
has
been found to cause block vertebrae in a Caucasian male
VACTERL patient.
67
Saisawat et al
68
identified recessive mutations
in the TNF receptor-associated protein 1 (TRAP1)geneinthree
families with VACTERL association. They also proved that Trap1
gene is highly expressed in the renal epithelia of 13.5-day-old
mouse embryos and its mutations contribute to renal dysplasia.
Intriguingly, mutations of the same gene may cause variable
expressivity among VACTERL patients, even within the same
Table 2 Candidate genes and CNVs in VACTERL association
Chromosome
region Gene Mutation Function Inheritance Manifestations
Vertebral
anomalies Overlap syndrome Reference
16p13.3 TRAP1 p.I253V and
p.L525F*
Missense Homozygous/
compound
heterozygous
V, A, C, TE, R Hemivertebrae
with rib anomalies
–Saisawat et al
68
9q21.13 PCSK5 p.C1624fs Frameshift
mutation
Heterozygous
(inherited-fat)
V, C, R, L Hemivertebrae –Nakamura et al
71
16q24.1-q24.2 FOXF1 p.G220C Missense/
deletion
De novo V, A, C, TE Butterfly vertebrae ACD/MPV Stankiewicz et al;
59
Hilger et al
45
1q41 –– Duplication De novo V, A, C, TE, R Butterfly vertebrae Hilger et al
73
8q24.3 –– Duplication De novo V, A, C TE, R Butterfly vertebrae –Hilger et al
73
13q31.2-qter –– Deletion De novo V, A, R, L Butterfly vertebrae –Dworschak et al
69
17p13.3 –– Deletion NA V, A, C, L Butterfly vertebrae Miller–Dieker syndrome Ueda et al
74
19q13.2 DLL3 p.G269A Missense Heterozygous
(inherited-mat)
V, C, R, L Block vertebrae Spondylocostal
dysostosis type I
Giampietro et al
67
13q33.2-qter –– Deletion De novo V, A Block vertebrae –Dworschak et al
69
22q11.2 –– Duplication De novo V, A, R Fusion vertebrae
(L4–L5)
22q11.2 duplication
syndrome; DiGeorge
syndrome
Schramm et al
75
Y–– Deletion in Yq
and duplication
in Yp
NA V, A, R, L Block and
hemivertebrae in
lumbar
–Bhagat
76
18q10-q11.2 –– Duplication De novo V, A, R, L Dysplastic lumbar
and sacral
vertebrae, NO
detail
–Felix et al;
77
van
der Veken et al
78
10q23.31 PTEN p.H61D Missense De novo V, C, TE, L Rib anomalies
(13 pairs of ribs)
Cowden syndrome Reardon et al
38
3q28 LPP –Deletion De novo V, C, TE, R Rib anomalies –Arrington et al;
39
Hernandez-Garcia
et al
65
5q11.2 –– Deletion De novo V, A, C No detail –de Jonget al
79
19p13.3 –– Deletion De novo/
inherited-mat
V, A, C, TE, R, L No detail –Peddibhotla et al
72
2q31.1 HOXD13 –Deletion De novo A, C, L Not reported Brachydactyly-syndactyly
syndrome
Garcia-Barcelo
et al
56
10q24.32 FGF8 p.G29_R34dup;
p.P26L
In-frame
duplication;
missense
Heterozygous A, C, TE, R, L Not reported Kallmann syndrome Zeidler et al
80
*Four cases of TRAP1 mutations have been reported and the only case with vertebral anomalies is listed.
A, anal atresia; ACD/MPV, alveolar capillary dysplasia with misalignment of pulmonary veins; C, cardiac malformations; L, limb abnormalities; NA, not available; R, renal anomalies; TE,
tracheo-oesophageal fistula; V, vertebral anomalies; VACTERL, vertebral anomalies (V), anal atresia (A), cardiac malformations (C), tracheo-oesophageal fistula (TE), renal dysplasia (R)
and limb abnormalities (L).
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family. Dworschak et al
69
identified chromosome 13q deletions
in two patients with VACTERL phenotypes. The girl was born
with perineal fistula, renal hypoplasia, bilateral triphalangeal
thumbs and oligodactyly, butterfly vertebrae and cerebral anom-
alies, and died at 10 months of age. The second patient, a male
child, suffered from perineal fistula, block vertebrae at C2–C3
and C4–C5–C6 and bilateral hearing loss. Pcsk5 gene has been
identified as a candidate gene of VACTERL association in mice.
70
Nakamura et al
71
reported a Japanese VACTERL boy with eighth
thoracic hemivertebra having a frameshift mutation of PCSK5,
while his healthy father also shared the same mutation.
Peddibhotla et al
72
reported eight patients with chromosome
19p13.3 microdeletions and six of them fulfilled the diagnostic
criteria for VACTERL association. Among the six VACTERL
patients, one patient has vertebral anomalies while her two chil-
dren, although with VACTERL association, are free from verte-
bral anomalies. These phenomena imply other modification
factors desperate for further investigation in this condition.
Chromosomal aberrations
Chromosomal aberrations also contribute to VACTERL associa-
tions. Several case reports have been published that describe
chromosomal anomalies in VACTERL patients as Felix et al
77
and Brosenset al
81
reviewed previously. However, chromosomal
aberrations are not included here as they also contribute to the
occurrence of congenital malformations beyond what is typically
observed in VACTERL association.
Mitochondrial dysfunction
Damian et al
82
first reported an A to G transversion in the mito-
chondrial NP3243 mutation in cystic kidney of a VACTERL child.
Spinal radiograph showed multiple cervical and thoracic vertebral
wedging, fusion and fission. She also had limb abnormalities,
cardiac malformations and renal anomalies. This child belonged to
a family in which other members had mitochondrial encephalo-
myopathy, lactic acidosis, and stroke-like episodes syndrome and
chronic progressive external ophthalmoplegia, which suggests
mitochondrial dysfunction may contribute to VACTERL syn-
drome.
83
Stone et al
84
studied a cohort of 62 patients with
VACTERL association and none of the affected children had meas-
urable levels of the NP 3243 mutation. A few authors have previ-
ously reported an association of VACTERL association in patients
with mitochondrial disorders known as complex IV respiratory
chain deficiency.
85–87
Overall, four of the five individuals pre-
sented with vertebral anomalies; three showed oesophageal
involvement; two had anal atresia and two patients presented with
additional minor dysmorphic features. Different combinations of
other multiple congenital malformations have also been reported
in a series of children with respiratory chain deficiency, leading to
the hypothesis that in these patients congenital anomalies might
result from an abnormal development during embryogenesis
through either a lack of ATP or an alteration of apoptosis con-
trolled by the mitochondrial machinery. However, it is also pos-
sible that mitochondrial dysfunction and congenital
malformations in the patient described here are both secondary to
an as yet unidentified process.
88
In conclusion, whether mutation
of mitochondrial dysfunction causes VACTERL association is still
controversial. Some clinical signs and symptoms that may be not
common in patients with VACTERL association, including pro-
gressive muscle weakness, characteristic patterns of cardiac, neuro-
logical and exocrine dysfunction,
89
may suggest a potential
existence of mitochondrial dysfunction.
In summary, the aetiology of VACTERL association appears to
be heterogeneous, suggesting that it may be a complex condition.
Besides the gene mutations and CNVs mentioned above, some
other factors such as intronic mutations or epigenetic factors
may also play important roles in this condition. Environmental
factors including maternal diabetes
90
and exposure to statins,
91
which may associated with congenital anomalies, may play a
significant role in the pathogenesis of VACTERL syndrome.
CONCLUSION
VACTERL association is a rare and complex condition with highly
heterogeneous aetiology and manifestations. At the present time,
there appears to be evidence for genetic factors contributing to
VACTERL syndrome including single-gene mutations, CNVs and
structure variants to mitochondrial dysfunction. Future studies are
needed to identify epigenetics and environmental causes for
VACTERL syndrome. Targeted genetic testing can contribute to
eliminating overlapping diagnoses from further consideration in
an affected individual. Notably, a given variant may explain a par-
ticular CF of VACTERL association, so it may be worth trying to
investigate this sophisticated association by focusing on one of the
six component features. ‘Vertebral anomalies’is one of the core
component features of VACTERL association, including formation
and segmentation vertebral. Wu et al
92
recently described a com-
pound heterozygous model in which a null allele mutation in com-
bination with a common haplotype of TBX6 causes congenital
scoliosis, suggesting that genetic factors play an important role in
vertebral anomalies. Additionally, we suggest that the genetic
mutations may contribute to vertebral anomalies in a certain syn-
drome. Alternatively, VACTERL association may be caused by a
‘two-hit’model in which two genes or one gene in combination
with an epigenetic factor may elicit all associated features.
93
In the
future, combination of new genomic technologies such as whole-
exome sequencing, whole-genome sequencing, comparative
genomic hybridisation array and whole-genome bisulfite sequen-
cing may well reveal a surprising number of additional contribut-
ing loci, delineating the entire spectrum of the VACTERL
association in humans.
Acknowledgements The authors thank Dr Pengfei Liu from the Department of
Molecular and Human Genetics, Baylor College of Medicine, and Dr Xiaoyue Wang
from the State Key Laboratory of Medical Molecular Biology, Chinese Academy of
Medical Sciences, for their comments on the manuscript. They also express gratitude
to the patient described in this article for his willingness to take part in this study.
Contributors YC, ZL and JC contributed equally to this article. YC, NW and ZW
conceived and designed the review. YC interpreted data and contributed to the
manuscript preparation. ZL and JC drafted the main manuscript. NW,ZW, YZ,GQ and
PFG critically revised the manuscript and made comments on the structure, details
and grammar for the article. SL, WC and GL contributed to data acquisition. All
authors approved the final manuscript.
Funding The research was supported by National Natural Sciences Foundation of
China (81501852, 81472046, 81271942, 81130034, 81472045), Distinguished
Young Scholars of Peking Union Medical College Hospital (JQ201506), Beijing nova
program (2016) and The Central Level Public Interest Program for Science Research
Institue (No 13, 2015).
Competing interests None declared.
Ethics approval Ethics Committee of Peking Union Medical College Hospital.
Provenance and peer review Commissioned; externally peer reviewed.
Open Access This is an Open Access article distributed in accordance with the
Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which
permits others to distribute, remix, adapt, build upon this work non-commercially,
and license their derivative works on different terms, provided the original work is
properly cited and the use is non-commercial. See: http://creativecommons.org/
licenses/by-nc/4.0/
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VACTERL association
implications of vertebral anomalies in
The genetic landscape and clinical
Gang Liu, Guixing Qiu, Philip F Giampietro, Nan Wu and Zhihong Wu
Yixin Chen, Zhenlei Liu, Jia Chen, Yuzhi Zuo, Sen Liu, Weisheng Chen,
published online April 15, 2016J Med Genet
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