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Disorders of leftЦright asymmetry Heterotaxy and situs inversus.

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American Journal of Medical Genetics Part C (Seminars in Medical Genetics) 151C:307 – 317 (2009)
Disorders of Left–Right Asymmetry:
Heterotaxy and Situs Inversus
Cilia function is critical to the development of proper organ laterality. Primary ciliary dyskinesia (PCD) causes
randomization of situs. Heterotaxy, or situs ambiguus, is an abnormal arrangement of the thoracic and abdominal
organs that results in congenital anomalies. Animal models and developmental biological approaches have
defined pathways required during embryogenesis for proper left–right pattern formation. New candidates for
genetic causes of human laterality disorders have emerged from recent studies on the assembly, transport, and
signaling functions of cilia at the node as well as identification of cilia within the developing heart. There is
evidence that deleterious genetic variants within one or more developmental pathways may disrupt signaling in a
synergistic or combinatorial fashion to cause congenital anomalies. The molecular pathways underlying PCD and
heterotaxy are being discovered at a rapid pace, and there is increasing recognition of the overlap between these
two categories of laterality disorders and their relationship to isolated cardiovascular malformations. This review
focuses on the clinical manifestations, molecular mechanisms, and human genetics of these disorders of
laterality. ß 2009 Wiley-Liss, Inc.
KEY WORDS: cilia; heterotaxy; left–right asymmetry; situs inversus; primary ciliary dyskinesia
How to cite this article: Sutherland MJ, Ware SM. 2009. Disorders of left–right asymmetry:
Heterotaxy and situs inversus. Am J Med Genet Part C Semin Med Genet 151C:307–317.
Heterotaxy and situs inversus are disorders of laterality in which the internal
organs do not have their typical pattern
of asymmetry. In situs inversus, the
internal organ arrangement is mirror
image of normal anatomy, termed situs
solitus. Baillie first described situs inversus in 1793. One hundred forty years
later, Kartagener [1933], a pulmonoloStephanie M. Ware, M.D., Ph.D. is an
Assistant Professor in the Divisions of
Molecular Cardiovascular Biology, Human
Genetics, and Cardiology at Cincinnati Children’s Hospital Medical Center. Her laboratory
investigates the genetic basis of cardiac
disease in children. She is board certified in
Pediatrics and Clinical Genetics.
Mardi J. Sutherland is a graduate student
in the Molecular and Developmental Biology
graduate program at Cincinnati Children’s
Hospital Medical Center and the University
of Cincinnati College of Medicine.
*Correspondence to: Stephanie M. Ware,
M.D., Ph.D., Cincinnati Children’s Hospital
Medical Center, 240 Albert Sabin Way, MLC
7020, Cincinnati, OH 45229.
DOI 10.1002/ajmg.c.30228
Published online 27 October 2009 in Wiley
ß 2009 Wiley-Liss, Inc.
gist, reported four patients with the triad
of sinusitis, bronchiectasis, and situs
inversus. In the 1970s, the relationship
between situs inversus and ciliary
abnormalities was established when
Afzelius reported cilia immotility in
infertile males, half of whom had
Kartagener’s triad [Afzelius, 1976]. His
In the 1970s, the relationship
between situs inversus and
ciliary abnormalities was
established when Afzelius
reported cilia immotility in
infertile males, half of
whom had Kartagener’s triad.
His speculation that cilia
played a role in determining
laterality would require
several more decades
to prove.
speculation that cilia played a role
in determining laterality would require
several more decades to prove.
Primary ciliary dyskinesia (PCD),
previously known as immotile cilia
syndrome, is one of the most widely
recognized ciliopathies. Kartagener
syndrome (OMIM #244400), in which
situs is randomized, is a subset of PCD
and accounts for approximately 20%
of these cases. PCD has an estimated
prevalence of 1:15,000.
Heterotaxy, or situs ambiguus, is an
abnormal arrangement of the thoracic
and/or abdominal viscera. It is characterized by multiple congenital malformations, with the major morbidity
and mortality resulting from complex
cardiovascular malformations. A variety
of descriptive (e.g., asplenia or
polysplenia syndrome, left or right
isomerism) or eponymous (e.g., Ivemark
syndrome) designations arose in an
attempt to precisely classify constellations of clinical and phenotypic features
of patients with laterality disorders.
In reality, both clinical observation
and molecular investigation indicate
that exceptions are the rule, and the
designations encompass an overlapping
spectrum. It is therefore more precise
and clinically useful to use the term
heterotaxy or situs ambiguus followed
by the exact anatomic description.
The International Nomenclature Committee for Pediatric and Congenital
Heart Disease recently published cardiac
evaluation and nomenclature recommendations for heterotaxy, and details
of the cardiac and extra-cardiac anomalies have been reviewed in detail
previously [Zhu et al., 2006; Jacobs
et al., 2007; Ware and Belmont, 2008].
Heterotaxy accounts for approximately 3% of all congenital heart defects.
‘‘Classic’’ heterotaxy, in which typical
cardiac defects are seen in conjunction
with visceral situs anomalies, has an
The International
Nomenclature Committee for
Pediatric and Congenital Heart
Disease recently published
cardiac evaluation and
nomenclature recommendations
for heterotaxy.
estimated prevalence of 1:10,000 [Lin
et al., 2000]. Because of the wide
phenotypic spectrum identified in laterality disorders, it is likely that this underestimates the true prevalence. It is now
clear, for example, that gene mutations
that cause classic forms of heterotaxy
can also result in isolated cardiovascular
malformations without evidence of visceral anomalies [Megarbane et al., 2000;
Goldmuntz et al., 2002; Ware et al., 2004].
Similarly, patients with PCD can have
cardiovascular malformations with or
without dextrocardia. A recent study by
Kennedy et al. [2007] demonstrates that
6.3% of patients with PCD have heterotaxy. These data illustrate the spectrum
of disease caused by abnormal left–
right development during embryogenesis.
Patients with PCD frequently have
neonatal respiratory distress, but the
diagnosis of a ciliopathy may not
be made until months or years later.
Classically, patients with PCD have
significant problems with mucociliary
clearance, leading to sinusitis, persistent
otitis media, or bronchiectasis (Table I).
Situs inversus or heterotaxy may occur.
Infertility is reported in greater than 50%
of PCD males due to decreased or absent
sperm motility. Cystic fibrosis shares
many overlapping features and needs to
be ruled out. The standard for diagnosis
is transmission electron microscopy for
analysis of ciliary ultrastructure. Common findings include abnormalities of
the outer or inner dynein arms (most
frequent), radial spokes, central microtubules, or absence of cilia. Although
abnormal electron microscopy confirms
the diagnosis of PCD, normal electron
microscopy does not rule out the
diagnosis. Additional methods are being
developed to better analyze cilia structure and function, including analysis of
ciliary motility on high-speed videomicroscopy, analysis of mucociliary
clearance, demonstration of decreased
nasal nitric oxide levels, or immunohistochemical analysis of the outer dynein
arms [Zariwala et al., 2007]. Strict
clinical diagnostic criteria have not yet
been developed for PCD [Leigh et al.,
2009]. As more data regarding the
overlap of clinical features between
heterotaxy and PCD emerge, diagnostic
recommendations can be formalized
(Table I).
Heterotaxy is most frequently diagnosed in the newborn period due
TABLE I. Clinical Features and Diagnosis of PCD and Heterotaxy
Clinical features
Variable age of presentation
Neonatal respiratory distress
Situs inversus or heterotaxy
Chronic sinusits, otitis media, or bronchiectasis
Persistent cough, nasal congestion, or respiratory infection
Male infertility/impaired sperm motility
Diagnostic evaluation
Ultrastructural analysis (TEM) of cilia
Consider chromosomes and chromosome microarray analysis
Gene mutation analysis (DNAH5, DNAI1)
Imaging studies as necessary
TEM, transmission electron microscopy.
Presentation in infancy in classic form
Congenital heart disease, dextrocardia, or mesocardia
Malrotation, microgastria, abdominal situs anomalies
Biliary atresia
Vertebral or rib anomalies
Asplenia or polysplenia
Imaging studies to define anatomy (echocardiogram/cardiac MRI;
head ultrasound or brain MRI; upper gastrointestinal series;
abdominal ultrasound; chest X-ray and spine films; consideration
of hepatobiliary scintigraphy)
Chromosomes and chromosome microarray analysis
Consider gene mutation analysis (ZIC3)
to cyanotic congenital heart disease.
These patients require an extensive
diagnostic evaluation and multiple
imaging studies in order to define their
anatomy (Table I). While it may not be
practical to perform all of the diagnostic
evaluations in a critically ill infant, the
spectrum of potential anomalies needs to
be recognized, particularly in the case of
sudden decompensation. All patients
should have chromosomes and chromosome microarray analysis due to associations with chromosome abnormalities,
as described in more detail below.
Strong consideration should be given
to ZIC3 mutation testing particularly
in males. The prevalence of PCD in
patients with heterotaxy remains to
be determined. Nevertheless, consideration should be given to evaluation for
PCD since respiratory and pulmonary
management could be optimized in
an attempt to improve the higher
than expected surgical morbidity and
mortality in this patient group. The
development of improved methods for
PCD diagnosis, as described above, is
important to better define the patient
subsets and direct management and
(LPM), (5) signaling from the LPM to
organ primordia. Heterotaxy may result
from defects in any of these five steps.
Isolated dextrocardia or congenital heart
defects related to abnormal laterality can
also result from abnormalities at various
stages of left–right patterning. In contrast, situs inversus caused by PCD
usually results from defects in signaling
at the node involving cilia structure and
Signaling Upstream of the Node
The early stage of left–right patterning
occurs before cilia are established at the
node, a transient embryonic organizer.
This involves processes including planar
cell polarity in which asymmetric
gradients are established within a cell,
across a sheet of cells and ultimately
throughout the embryo [Aw and Levin,
2009]. The signaling pathways and
molecular mechanisms underlying these
events during left–right patterning are
not yet well defined, and these early
steps of asymmetry may vary by model
organism. There is some evidence
that asymmetry is first established as
intracellular gradients [Palmer, 2004;
Vandenberg, 2009]. No pathogenic
mutations have been described at this
early stage of axis formation in humans
with laterality defects.
The left–right axis is established early
in development subsequent to the
development of anterior–posterior and
dorsal–ventral axes. A basic understanding of the embryonic tissues and molecular events necessary for left–right axis
formation is beneficial for initiating a
diagnostic work-up, understanding the
genetic basis of disease, and assessing
recurrence risk.
Recent work with model organisms
has offered a detailed view of the steps
taken to establish asymmetry in the
vertebrate. Figure 1 illustrates five steps
for left–right patterning: (1) signaling
upstream of the node, (2) signaling at the
node involving cilia structure and function, (3) leftward flow breaking bilateral
symmetry at the node, (4) transfer of
asymmetric gene expression from the
node to the lateral plate mesoderm
Figure 1. Overview of left–right asymmetry in the mouse embryo. Before the
establishment of the node or cilia, there is evidence for early intracellular asymmetry
involving mechanisms such as planar cell polarity (PCP). PCP also plays a later role in the
proper orientation of cilia at the node. In the second stage, the node and functioning
motile and sensory cilia form. Although the genetic control of node morphogenesis is
largely unknown, Notch signaling is necessary for both proper node structure as well as
later asymmetric nodal expression. Foxj1 is a master regulator of ciliogenesis, and
intraflagellar transport is required for cilia assembly. Centrally located monocilia are
motile and peripheral monocilia lack left–right dynein and are immotile. In stage 3, the
movement of cilia at the node creates a leftward flow of morphogens. FGF signaling
triggers the release of Shh and retinoic acid. An increase in cytoplasmic calcium occurs.
Nodal expression is initially bilateral, but becomes asymmetrically expressed on the left,
providing molecular evidence of left–right asymmetry. In stage 4, Nodal signal is
propagated from the node to the LPM where asymmetric gene expression is
established. The Nodal signal transduction pathway occurs when the TGF-b ligand
Nodal is cleaved to its active form. It requires EGF-CFC co-receptors to bind to Type I/II
activin receptors. Lefty proteins interfere with binding of the mature ligand. After
binding, phosphorylated Smad complexes translocate to the nucleus where they bind
DNA with co-factors such as FoxHI. Through this pathway, Nodal can activate Lefty1,
Lefty2, Pitx2 and its own expression in the LPM. In stage 5, asymmetric signaling is
propagated from the LPM to organ primordia in order for proper morphogenesis to
occur. IFT, intraflagellar transport; LPM, lateral plate mesoderm; PCP, planar cell
Signaling at the Node Involving
Cilia Structure and Function
Although the existence of an organizing
left-right coordinator has been documented in all vertebrate species studied
to date, its structure varies. In mouse, this
structure is known as the ventral node; in
chick, Henson’s node; in zebrafish,
kupffer’s vesicle (KV); in Xenopus, the
gastrocoel roof plate (GRP); and in
rabbit, the posterior notochordal
plate (PNC) [Essner et al., 2002; Okada
et al., 2005; Lee and Anderson, 2008].
Although the existence of
an organizing left-right
coordinator has been
documented in all vertebrate
species studied to date, its
structure varies. In mouse, this
structure is known as the ventral
node; in chick, Henson’s node;
in zebrafish, kupffer’s vesicle
(KV); in Xenopus, the
gastrocoel roof plate (GRP);
and in rabbit, the posterior
notochordal plate (PNC).
Additionally, the coordinating structure
has recently been examined in pig. The
organizer is required for proper axis
formation prior to organogenesis. In
mouse, the node is present between
7.5 and 8.5 days post coitum, which is
equivalent to Carnegie stages 7–10 in
The node structure in pig and chick
begins with bilateral symmetry, but later
in development exhibits leftward displacement and asymmetric gene expression. These structural and molecular
changes result from cell migration to
the left of the node [Gros et al., 2009]. In
mouse, rabbit, and zebrafish, the organizing structures contain monociliated
cells with motile cilia which generate a
‘‘nodal flow.’’ Experimental evidence in
mouse and zebrafish has linked the
Notch pathway with both node formation and downstream activation of
asymmetric Nodal gene expression at
the node [Krebs et al., 2003; Przemeck
et al., 2003; Takeuchi et al., 2007].
Leftward fluid flow at the node results
from the clockwise rotational motion of
the cilia creating a unidirectional flow. In
many vertebrate species examined,
including rabbit, fish, and mouse, cilia
are detected as being tilted toward the
posterior axis [Nonaka et al., 2002;
Okada et al., 2005]. This posterior tilt
is predicted as a necessary component of
the leftward unidirectional flow at the
node, which is essential for proper left–
right asymmetry [Nonaka et al., 1998;
Okada et al., 1999].
There are two populations of cilia
located at the mouse node [McGrath
et al., 2003]. These consist of the
There are two populations of
cilia located at the mouse node.
These consist of the central
motile cilia and the peripheral
sensory cilia.
central motile cilia and the peripheral
sensory cilia. Typical motile cilia contain
nine microtubule doublets surrounding
two central microtubules and are
referred to as 9 þ 2 motile cilia. Motile
cilia of the node lack the two central
microtubules and are referred to as 9 þ 0
motile cilia. Sensory cilia (9 þ 0) also
lack the central microtubules but, in
addition, lack dynein arms and are
immotile. Proteins necessary for ciliary
movement are specific to motile cilia,
and include dynein proteins which make
up the inner and outer dynein arms
along the microtubules [Ibanez-Tallon
et al., 2003; McGrath et al., 2003; Inglis
et al., 2006; Satir and Christensen,
2007]. Motile cilia of the node also
contain the left–right dynein protein
(Dnahc11 gene, homologous to human
DNAH11), which is required for their
functional motility [Supp et al., 1997,
1999; Okada et al., 1999; McGrath et al.,
Motile cilia of the node
also contain the left–right
dynein protein (Dnahc11
gene, homologous to
human DNAH11), which
is required for their
functional motility.
Recent data have provided insight
into the genetic program required for
motile ciliogenesis. Foxj1, a forkhead
transcription factor, is expressed in tissues
with motile cilia. Foxj1 is required for
induction of gene expression necessary
for motile ciliogenesis [Stubbs et al.,
2008; Yu et al., 2008] in multiple species
including zebrafish, mice, and Xenopus
[Chen et al., 1998; Brody et al., 2000;
Zhang et al., 2004; Stubbs et al., 2008; Yu
et al., 2008]. Thus, Foxj1 is acting as an
upstream regulator of cilia formation and
function at the organizer [Whitsett and
Tichelaar, 1999; Zhang et al., 2004;
Stubbs et al., 2008].
Intraflagellar transport (IFT) is
important for cilia formation, structural
function and motility, and signaling
function. It is the mechanism responsible
for delivering proteins necessary for
ciliary formation and function from the
cytoplasm of the cell to the cilia. This
process involves anterograde transport,
toward the tip of the ciliary structure,
Intraflagellar transport (IFT) is
important for cilia formation,
structural function and
motility, and signaling
function. It is the
mechanism responsible for
delivering proteins necessary
for ciliary formation and
function from the cytoplasm of
the cell to the cilia.
performed by plus-end directed motor
protein complexes involving kinesins,
and retrograde transport, directed
toward the base of the cilium, carried
out by minus-end directed motor
protein complexes involving dyneins
[Rosenbaum and Witman, 2002]. Studies of loss of function in mouse models
demonstrate the necessity of these proteins for left–right patterning [Supp
et al., 1997; Nonaka et al., 1998;
Marszalek et al., 1999; Takeda et al.,
1999; Rana et al., 2004]. Recent IFT
studies in mouse have also uncovered the
critical role for cilia in signal transduction in a number of developmental
pathways including Sonic hedgehog and
Wnt pathways [Huangfu et al., 2003;
Huangfu and Anderson, 2005, 2006; Liu
et al., 2005; Davis et al., 2006; Singla and
Reiter, 2006; Corbit et al., 2008; Jopling
and Izpisua Belmonte, 2009]. Studies in
zebrafish and Xenopus have also linked
FGF signaling with the intraflagellar
pathway and thus, ciliogenesis [Hong
and Dawid, 2009; Neugebauer et al.,
2009]. New intracellular roles for
molecular motor proteins apart from
their role in ciliogenesis are also being
examined in left–right asymmetry
[Armakolas and Klar, 2007; Levin and
Palmer, 2007].
Leftward Flow Breaks Bilateral
Symmetry at the Node
In mouse, Nodal, a ligand of the TGF-b
signaling pathway, is first expressed symmetrically in crown cells surrounding the
node, followed by asymmetrical leftsided expression. The development of
asymmetric gene expression at the node is
the first molecular evidence of asymmetry and is critical for subsequent left-sided
gene expression in the LPM.
Two theories exist involving the
mechanism by which information is
transferred by the leftward flow of cilia.
The first involves secretion of morphogenetic proteins at the node into the
extracellular fluid. FGF signaling triggers the release of particles carrying
morphogens Sonic hedgehog and retinoic acid, which are forced to the left of
the node inducing a cascade of gene
expression [Okada et al., 2005; Hirokawa et al., 2006]. There is also evidence
that the leftward flow of extracellular
fluid causes bending of the peripheral
immotile cilia surrounding the node
[McGrath et al., 2003]. An asymmetric
calcium flux is subsequently induced and
may trigger left-sided signaling. Both of
these pathways seem likely to play a role,
but the precise mechanism by which
asymmetric Nodal expression is induced
at the node is not known.
Transfer of Asymmetric Gene
Expression From the Node to
the LPM
The role of the Nodal signal transduction pathway in vertebrate left–right
asymmetry is a common pathway in all
vertebrates studied thus far and has been
extensively described [Palmer, 2004;
Raya and Belmonte, 2004; Levin,
2005; Levin and Palmer, 2007]. The
majority of known human heterotaxy
mutations have been discovered in
this pathway using a candidate gene
approach. However, mutations within
this pathway cause heterotaxy in
a minority of cases, indicating that novel
genetic etiologies remain to be determined (Table II).
After left-sided expression of Nodal
is established at the mouse node, the
signal is propagated to the left LPM
where Nodal, in the presence of an
EGF-CFC co-factor, signals through
Type I and Type II receptors. Nodal
can activate two antagonists, Lefty-1,
expressed in the midline, and Lefty-2,
expressed in the LPM (homologous to
human LEFTYA and LEFTYB, respectively). The activation of these Nodal
antagonists limits Nodal expression and
inhibits the transfer of left-sided gene
expression across the midline of the
embryo. The role of the midline in the
establishment of left–right asymmetry
was recently reviewed [Lee and Anderson, 2008]. Pitx2, a homeobox transcription factor, is also activated by
Nodal and is asymmetrically expressed
in the LPM as well as various organs.
This molecular asymmetry is conserved
across vertebrates.
Signaling From the LPM to
Organ Primordial
The asymmetric expression of Pitx2 is
initiated by Nodal signaling but persists
after the disappearance of these signals in
the LPM [Shiratori et al., 2001]. Pitx2 is
involved in organogenesis in the heart,
gut, and lung and demonstrates asymmetric expression in developing organ
primordia. Recent work examining the
looping of the linear gut tube [Davis et al.,
2008; Kurpios et al., 2008], found that
Pitx2 and Isl2 act upstream of asymmetric
cellular morphology and regulate expression of adhesion molecules. Information
about cardiac specific targets during
looping morphogenesis is currently lacking and needs further investigation.
Interestingly, recent work has identified
cilia within the developing heart [Van der
Heiden et al., 2006; Slough et al., 2008]
and suggested a potential role in cardiac
development distinct from their role
in left–right asymmetry. In addition,
Interestingly, recent work has
identified cilia within the
developing heart and
suggested a potential role in
cardiac development distinct
from their role in
left–right asymmetry.
there is evidence that cilia are acting as
sensors for endothelial shear stress produced by the flow of fluid through vessels
[Iomini et al., 2004]. Preliminary work
suggests involvement of cilia in nitric
oxide production and endothelial cell
dysfunction [Van der Heiden et al., 2008;
AbouAlaiwi et al., 2009]. Further investigation into these additional roles for cilia
in the cardiovascular system may lead to a
better understanding of the pathogenesis
of heterotaxy and PCD.
New Approaches and Advantages
Using Model Organisms
Recently, new approaches in the study
of left–right asymmetry using model
TABLE II. Gene Mutations Identified in Human Laterality Disorders
Mutation prevalence
1% in sporadic; >75% in familial X-linked
Mohapatra et al. [2009], Roessler et al. [2008]
Ware et al. [2004]
Bamford et al. [2000], Roessler et al. [2008], Selamet Tierney
et al. [2007]
Robinson et al. [2003]
Roessler et al. [2008]
Peeters et al. [2003, 2006]
Kosaki et al. [1999a]
Karkera et al. [2007], Roessler et al. [2008]
Kosaki et al. [1999b]
Watanabe et al. [2002]
Heterotaxy þ PCD
organisms have emerged. Given that the
core components of the Nodal signaling
pathway are conserved across species, it is
useful to exploit the advantages that each
model organism provides to study the
establishment of left–right asymmetry.
For example, a recent zebrafish mutagenesis study [Zhang et al., 2009] using
forward genetic screening followed by
massively parallel sequencing identified
a gene, Megf8, involved in the propagation of the Nodal signal from the node to
the LPM. This is a relatively fast and cost
efficient method to identify new pathways and genes implicated in left–right
development. Additionally, Xenopus
offers the advantage of combinatorial
knockdown of genes using morpholinos
as well as right- and left-side specific
knockdown of genes. These processes
can be observed and directly manipulated with dorsal explants in which
unidirectional flow can be established.
The advantages of this system have
recently been reviewed [Levin and
Palmer, 2007; Blum et al., 2009]. While
differences in left–right patterning
Failly et al. [2009], Hornef et al. [2006], Olbrich et al. [2002]
Failly et al. [2008], Zariwala et al. [2001], Zariwala et al. [2006]
Guichard et al. [2001], Pennarun et al. [1999]
Loges et al. [2008]
Bartoloni et al. [2002], Schwabe et al. [2008]
Duriez et al. [2007]
Moore et al. [2006]
Omran et al. [2008]
Kennedy et al. [2007]
exist between model organisms, there
are also core conserved mechanisms
involved in the establishment of asymmetry, and exploiting the strengths of a
variety of model organisms will
undoubtedly uncover new pathways as
well as new roles for previously discovered genes.
In the majority of cases, situs inversus
associated with PCD is an autosomal
recessive condition. The differential
would include other ciliopathies in
which situs inversus can be found,
including Bardet–Biedl syndrome.
Heterotaxy most often occurs as a
sporadic condition. Complex inheritance or autosomal dominant inheritance with reduced penetrance and
variable expressivity are presumed
genetic mechanisms. Familial clustering
of heterotaxy has been documented,
with pedigrees suggestive of autosomal
recessive and autosomal dominant
inheritance [Vitale et al., 2001; Belmont
et al., 2004; Zhu et al., 2006; Wessels
et al., 2008]. X-linked inheritance is well
documented in heterotaxy and is caused
by mutations in ZIC3. A large number of
genetic syndromes and chromosome
abnormalities have been associated
with heterotaxy, including aneuploidies,
complex chromosomal rearrangements,
and microdeletions [Bisgrove et al.,
2003; Ware and Belmont, 2008; Song
et al., 2009]. For example, patients with
trisomy 13 or trisomy 18 have been
reported. A number of submicroscopic
chromosomal deletions, including
22q11.2 (DiGeorge/VCFS syndrome),
have been identified in patients with
heterotaxy. Bisgrove et al. [2003] review
unbalanced translocations, terminal
deletions, inversions, and more complex
chromosomal rearrangements associated
with heterotaxy. Analysis of genes
located within submicroscopic chromosomal imbalances in patients with abnormal left–right asymmetry should be a
useful tool in uncovering novel genes
and pathways in laterality defects.
X-Linked Inheritance
An X-linked form of PCD has been
described in association with retinitis
pigmentosa, resulting from mutations in
RPGR (OMIM #300455). The visual
abnormalities are associated with hearing loss, sinusitis, and chronic recurrent
respiratory tract infections, and abnormalities of the ciliary axoneme have been
identified by electron microscopy [Zito
et al., 2003; Moore et al., 2006]. The Xlinked form of heterotaxy, HTX-1
(OMIM #306955) is caused by mutations in a zinc finger transcription factor,
ZIC3 [Ferrero et al., 1997; Gebbia et al.,
1997]. Approximately 1% of sporadic
heterotaxy cases (male and female)
are caused by mutations in ZIC3, and
affected females have been described
with point mutations or with chromosomal translocations [Megarbane et al.,
2000; Ware et al., 2004; Fritz et al., 2005;
Tzschach et al., 2006; Chhin et al.,
2007]. In X-linked pedigrees, ZIC3
mutations are commonly identified
(Table II). Clinical testing is available.
The mutations cause loss of function
and, in some cases, result in abnormal
subcellular localization and trafficking
[Bedard et al., 2007]. Loss of function of
ZIC3 has been correlated with a range
of phenotypes ranging from classic
heterotaxy to isolated cardiovascular
malformations typical of abnormal heart
looping, such as double outlet right
ventricle, L-transposition of the great
arteries, and ventricular inversion.
There is evidence in model organisms
that ZIC3 acts upstream of Nodal
signaling at the node, but its precise
developmental function is not yet
known [Purandare et al., 2002; Ware
et al., 2006].
Autosomal Dominant Inheritance
Heterotaxy patients without mutations
in ZIC3 have been screened for mutations in genes involved in the conserved
Nodal signal transduction pathway.
Given the importance of the Nodal
pathway in establishing left–right asymmetry, it is not surprising that mutations
in components of this pathway, including NODAL itself, have been identified
in human heterotaxy (Table II) [Kosaki
et al., 1999a,b; Bamford et al., 2000;
Goldmuntz et al., 2002; Selamet Tierney et al., 2007; Roessler et al., 2008;
Mohapatra et al., 2009].
Mutations have been identified in
genes encoding the ligand (NODAL),
ligand co-receptor (CFC-1), receptor
(ACVRIIB), transcriptional co-activator
(FOXH1), and midline inhibitor
(LEFTYA) within the Nodal signal
transduction pathway (Table II).
Recently, NODAL variants were investigated in 269 patients with heterotaxy
or isolated cardiovascular mutations
thought to be associated with irregular
looping of the heart. Missense mutations
were observed in 14 of the unrelated
patients [Mohapatra et al., 2009]. Functional analysis of the mutant proteins
showed a decrease in Nodal signaling.
Similarly, functional analysis of mutations in Cryptic, a gene encoding an
epidermal growth factor family protein,
CFC1, which functions as a NODAL
co-receptor, revealed abnormal cellular
localization of the mutant protein
[Bamford et al., 2000]. In addition,
mutations in CFC1 have been identified
in patients with transposition of the
great arteries but without extra-cardiac
anomalies [Goldmuntz et al., 2002].
ACVRIIB mutations were identified in
3 of 126 patients with left–right anomalies and mutations in LEFTYA were
discovered in 2 patients [Kosaki et al.,
1999a,b]. In the latter case, each
patient inherited the mutant allele
from an unaffected carrier parent, indicating incomplete penetrance. Candidate gene analysis has also focused
on GDF1, a gene expressed in the
node encoding a TGF-b ligand. In
375 patients, 8 potential disease-causing
mutations were discovered [Karkera
et al., 2007].
With over 100 candidate genes
identified through mouse models of
left–right patterning defects, it is likely
that significant genetic heterogeneity
will be found in human heterotaxy. To
date, the majority of genes identified
have either not yet been tested in larger
heterotaxy populations (e.g., NKX2.5,
CRELD1), or have been found to have
mutations at low frequency [Watanabe
et al., 2002; Robinson et al., 2003]. For
example, positional cloning of a region
involved in a reciprocal translocation in
one patient identified SESN1, a gene
involved in left–right patterning. Functional analysis of this protein revealed
that it plays a role in activating Nodal
signaling. However, the prevalence of
disease causing mutations in this gene is
less than 1% based on an initial screen of a
heterotaxy cohort [Peeters et al., 2003,
Efforts are ongoing to identify novel
genes that cause or contribute to the
heterotaxy phenotype. Mapping studies
in two different families with autosomal
dominant inheritance with reduced
penetrance [Vitale et al., 2001; Wessels
et al., 2008] have identified a locus on
chromosome 6p encompassing approximately 12 Mb and a small number of
strong candidate genes. Interestingly, two
of the candidates are dynein heavy chain
genes, while another is a kinesin gene.
Autosomal Recessive Inheritance
PCD disorders are characterized by
abnormalities of ciliary structure and
function and are most commonly autosomal recessive. Mutations in DNAH5
are the most commonly identified cause
In addition, it has recently
been shown that patients with
PCD have a higher risk for
congenital heart disease,
similar to patients with
heterotaxy, or situs
of PCD [Olbrich et al., 2002], with
mutations in DNAI1 [Pennarun et al.,
1999] and DNAH11 [Pan et al., 1998;
Bartoloni et al., 2002] also contributing.
All are outer dynein arm components
which are essential for ciliary function at
the node. Mutations in these genes result
in randomized situs, leading to situs
inversus in approximately 50% of
patients [Noone et al., 2004]. In addition, it has recently been shown that
patients with PCD have a higher risk for
congenital heart disease, similar to
patients with heterotaxy, or situs ambiguus [Kennedy et al., 2007].
Complex Inheritance
Approximately 10% of patients with
heterotaxy have a family history of a
close relative with a congenital heart
defect. To date, the majority of mutations identified have been shown to have
reduced penetrance and variable expressivity, indicating multifactorial causation.
X-linked heterotaxy, caused by
mutations in ZIC3, is the best understood genetic cause of heterotaxy. Interestingly, mutations in this gene can cause
classic heterotaxy or isolated congenital
heart defects. In one family, three of nine
female carriers exhibited situs inversus
[Gebbia et al., 1997; Ware et al., 2004].
In vitro analyses of these ZIC3 mutations
indicate similar levels of functional
abnormalities, suggesting that the range
of phenotypes results from genetic
modifiers, environmental modifiers,
epigenetic effects, or developmental
stochasticity. There are reports to support each of these mechanisms. For
example, in a small number of cases,
mutations in two or more genes within
the Nodal signal transduction pathway,
or in NODAL and ZIC3 in a female
patient, have been identified. In addition, a common NODAL polymorphism that reduces gene activity has
been identified. These findings support
the hypothesis that common or rare
deleterious genetic variants within
developmental pathways may disrupt
signaling in a synergistic or combinatorial fashion to cause congenital anomalies [Gebbia et al., 1997; Roessler et al.,
2008]. Environmental modifiers such as
maternal diabetes, maternal cocaine use,
and monozygotic twinning have all been
associated with heterotaxy spectrum
defects [Kuehl and Loffredo, 2002].
Stochastic levels of Nodal expression
have been reported in inbred mouse
lines deficient for Gdf3, a TGF-b ligand
that acts in a Nodal-related pathway
[Chen et al., 2006]. Taken together,
these mechanisms likely account for the
significant degree of the variability
within the heterotaxy/congenital heart
disease/PCD population.
The molecular players involved in PCD
and heterotaxy are being discovered at a
rapid pace and there is increasing
recognition of the overlap between these
two categories of laterality disorders.
Over 100 genes have been identified as
important in left–right asymmetry in
animal models. Combined with recent
The molecular players involved
in PCD and heterotaxy are
being discovered at a rapid pace
and there is increasing
recognition of the overlap
between these two categories of
laterality disorders. Over
100 genes have been identified
as important in left–right
asymmetry in animal models.
studies on the ciliome, the number of
candidates for laterality disorders is quite
large [Inglis et al., 2006]. This heterogeneity, combined with a prediction of
reduced penetrance and variable expressivity, makes clinical molecular diagnostics challenging. Further clinical
insight into the relationship between
situs inversus, situs ambiguus, and
isolated cardiovascular malformations
within the heterotaxy spectrum will be
important for clinical management and
diagnosis. An improved comprehension
of the developmental basis of disease and
the interactions of pathways involved in
the establishment of proper left–right
asymmetry is needed for a fully integrated understanding of phenotypic
expression. Recent improvements in
sequencing cost and throughput will
improve the ability to interrogate
gene gene interactions by facilitating
pathway approaches to screening. Future
studies will focus on the challenges
inherent in the interpretation and functional analysis of the sequence variation
identified from genomic data in order to
identify combinations of deleterious
variants. The long-term challenge is
to translate a functional understanding
of developmental pathway interactions
into a prediction of phenotypic effects
and provision of reliable risk estimates
for families.
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asymmetric, leftцright, disorder, heterotaxia, situ, inversus
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