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Congenital diaphragmatic hernia (CDH) etiology as revealed by pathway genetics.

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American Journal of Medical Genetics Part C (Seminars in Medical Genetics) 145C:217 – 226 (2007)
A R T I C L E
Congenital Diaphragmatic Hernia (CDH) Etiology
as Revealed by Pathway Genetics
SIBEL KANTARCI AND PATRICIA K. DONAHOE*
Congenital diaphragmatic hernia (CDH) is a common birth defect with high mortality and morbidity. Two
hundred seventy CDH patients were ascertained, carefully phenotyped, and classified as isolated (diaphragm
defects alone) or complex (with additional anomalies) cases. We established different strategies to reveal CDHcritical chromosome loci and genes in humans. Candidate genes for sequencing analyses were selected from CDH
animal models, genetic intervals of recurrent chromosomal aberration in humans, such as 15q26.1–q26.2 or
1q41–q42.12, as well as genes in the retinoic acid and related pathways and those known to be involved in
embryonic lung development. For instance, FOG2, GATA4, and COUP-TFII are all needed for both normal
diaphragm and lung development and are likely all in the same genetic and molecular pathway. Linkage analysis
was applied first in a large inbred family and then in four multiplex families with Donnai–Barrow syndrome (DBS)
associated with CDH. 10K SNP chip and microsatellite markers revealed a DBS locus on chromosome 2q23.3–
q31.1. We applied array-based comparative genomic hybridization (aCGH) techniques to over 30, mostly
complex, CDH patients and found a de novo microdeletion in a patient with Fryns syndrome related to CDH.
Fluorescence in situ hybridization (FISH) and multiplex ligation-dependent probe amplification (MLPA) techniques
allowed us to further define the deletion interval. Our aim is to identify genetic intervals and, in those, to prioritize
genes that might reveal molecular pathways, mutations in any step of which, might contribute to the same
phenotype. More important, the elucidation of pathways may ultimately provide clues to treatment strategies.
ß 2007 Wiley-Liss, Inc.
KEY WORDS: congenital diaphragmatic hernia (CDH); genetic pathways; Fryns syndrome; Donnai–Barrow syndrome; homozygosity
mapping
How to cite this article: Kantarci S, Donahoe PK. 2007. Congenital diaphragmatic hernia (CDH) etiology
as revealed by pathway genetics. Am J Med Genet Part C Semin Med Genet 145C:217–226
INTRODUCTION
The discovery of gene mutations as a
cause of congenital anomalies or birth
defects has been difficult, but recently
progress has been made in uncovering
causal or contributing mutations. His-
torically, congenital anomalies were
thought to be the result of accidents in
utero, because experimental fetal injury
models were found to produce defects at
birth that resemble birth defects in
humans. Some examples include in
utero occlusions of the vascular supply
Sibel Kantarci, Ph.D. is a Research Fellow at the Peadiatric Surgical Research Laboratories at
Massachusetts General Hospital and American Board of Medical Genetics (ABMG)-approved
Clinical Cytogenetics Fellow at Harvard Medical School. Dr. Kantarci has completed her ABMGapproved Clinical Molecular Genetic Training Program at Harvard Medical School. Dr. Kantarci’s
research in congenital diaphragmatic hernia (CDH) in humans focuses on identifying
chromosomal regions and/or genes responsible from CDH by applying molecular and
cytogenetics techniques.
Patricia K. Donahoe, M.D. is the Director of the Pediatric Surgical Research Laboratories at the
Massachusetts General Hospital and the Martial K. Bartlett Professor of Surgery at the Harvard
Medical School. She is the Principle Investigator on an NICHD funded grant to study the genetics
of Congenital Diaphragmatic Hernia. Her other appointments are as an Associate Member of the
Broad Institute of MIT and Harvard and on the faculty of the Harvard Stem Cell Institute. Her work
on Congenital Diaphragmatic Hernia focuses on discovery of gene mutations responsible for the
defect with the aim of discovering pathway defects which could lead to therapeutic strategies.
*Correspondence to: Patricia K. Donahoe, M.D., Pediatric Surgical Research Laboratories,
Massachusetts General Hospital, CPZN North, 6.206, Boston, MA 02114.
E-mail: pdonahoe@partners.org
DOI 10.1002/ajmg.c.30132
ß 2007 Wiley-Liss, Inc.
of the bowel producing jejunal or ileal
atresia [Louw and Barnard, 1955], or
directed laser injury in chick embryos
resulting in cloacal/bladder exstrophy at
birth [Thomalla et al., 1985].
Clinical geneticists have for some
time suspected that gene defects are
responsible for nonsyndromic birth
defects and have recently proven this to
be the case with such disorders as
Hirschsprung disease [Gabriel et al.,
2002], cardiomyopathies [Ahmad et al.,
2005], brain malformations [Ferland
et al., 2004], and craniofacial anomalies
[Jugessur and Murray, 2005]. The use of
families for genetic linkage has not
proven to be feasible for the study a large
number of birth defects since many of
them are either lethal or result in a
phenotype that is disadvantageous for
reproduction. Thus, it is necessary to
utilize different strategies to detect
candidate genes for these disorders since
218
AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS): DOI 10.1002/ajmg.c
large multiple affected families are unavailable for traditional linkage studies.
Such is the case for congenital diaphragmatic hernia (CDH), a common human
birth defect characterized by diaphragm
defect, arrested lung development with
pulmonary hypoplasia, and pulmonary
hypertension which continues to be
associated with a high mortality and
morbidity. The fact that genetically
altered knockout mice produced by
homologous recombination or from
ENU screens manifest phenotypes with
CDH supports a genetic cause of the
disorder, as does its appearance in small
multiplex CDH families, and the fact
that different chromosomal abnormalities are associated with CDH in 10% of
cases (see article by Pober in this issue for
further discussion). The low recurrence
rate or precurrence in siblings uncovered
in several studies [David and Illingworth,
1976; Czeizel and Kovacs, 1990], and
recently in a 30-year active malformation surveillance program of 203 cases of
CDH from a single urban academic
institution [Pober et al., 2005] suggests
that the mutations in these defects are
likely to be de novo in countries or
regions where consanguinity is low.
It has been reported that vitamin A
deficiency in pregnant rodents, as well as
exposure to nitrofen, which suppresses a
key enzyme in the vitamin A pathway,
cause CDH [Andersen, 1941, 1949;
Suen et al., 1994], while reintroduction
of vitamin A rescues the phenotype
[Wilson et al., 1953; Thebaud et al.,
1999]. This scenario predicts that rescue
downstream of a genetic pathway, once
elucidated, may be of therapeutic value.
It has been reported that
vitamin A deficiency in
pregnant rodents, as well as
exposure to nitrofen, which
suppresses a key enzyme in the
vitamin A pathway, cause
CDH, while reintroduction
of vitamin A rescues the
phenotype. This scenario
predicts that rescue downstream
of a genetic pathway, once
elucidated, may be of
therapeutic value.
Such observations also indicate that
common pathways may exist that
explains why disruption of genes in
seemingly disparate chromosomal hot
spot regions can produce similar phenotypes. These heterogeneous loci,
thus, may be related by affecting different
steps in related pathways or networks.
To study CDH patients genetically,
we established an infrastructure to enroll
CDH patients both at the MassGeneral
Hospital for Children and Children’s
Hospital in Boston. Parent support
groups and the international community
of pediatric genetics voluntarily engaged
in an effort to detect multiple affected
families worldwide. This program is
funded by the National Institutes of
Health under the auspices of a Birth
Defects initiative sponsored by the
Institute of Child Health and Development (NICHD). This effort entitled
‘‘Gene Mutation and Rescue in Human
Congenital Diaphragmatic Hernia: (HD
055150) required the input of many
surgeons, geneticists, and nurse and
study coordinators at both institutions,
and the extraordinary involvement of all
families, particularly those with multiple
affected sibs. We have recruited over 270
CDH patients as well as parents and
healthy siblings from both institutions,
with additional patients recruited
through CHERUBS (The Association
of Congenital Diaphragmatic Hernia
Research, Advocacy, and Support) or
from genetic and surgical colleagues
around the world. The Institutional
Review Boards at MassGeneral Hospital
for Children and Children’s Hospital,
Boston provided annual review and
approval of consents and study protocols.
Phenotypic classification of the
CDH patients was performed based on
information obtained from a parental
questionnaire, medical record review,
family pedigree, and physical examination. This information was entered into
ARTICLE
an Oracle based, IRB approved, HIPPA
compliant database. DNA samples were
obtained from various sources including
blood, skin, amniotic fluid, formalinfixed pathological material, or frozen
tissue. About half of CDH patients have
only diaphragm malformations and are
classified as isolated cases. The remaining
patients have additional anomalies either
as part of non-syndromic associations,
chromosome abnormalities, or recognized syndromes, and are referred to as
complex cases. EB virus transformed
lymphoblast or primary fibroblast cell
lines were established for each patient
and, when necessary, for both parents
and siblings. Literature and database
searches were done, and 30 years of data
analyzed from an active malformation
single institution surveillance monitoring program conducted at the Brigham
and Women’s Hospital, Boston. Recurrent chromosomal anomalies associated
with CDH were catalogued from this
database and from the literature, and
analyzed to determine if molecular
pathways would emerge indicating that
CDH might have multiple molecular
defects contributing to this same phenotype and explaining why the defects
might vary in severity.
STRATEGIES TO IDENTIFY
GENETIC ABNORMALITIES
RELATED TO CDH
CDH is a phenotypically and genetically
heterogeneous disorder. To identify
chromosome loci and genes responsible
from CDH requires different strategies.
We used a number of different techniques to analyze patients with CDH: (A)
Sequencing of multiple CDH candidate
genes revealed from animal models,
developmental studies, and regions of
recurrent chromosomal aberrations
associated with CDH. (B) If multiplex
consanguineous families were available,
genome wide SNP array analysis was
used to determine shared homozygosity
by descent in affecteds. For instance, this
method was applied to a consanguineous
kindred with multiple affected patients
with Donnai–Barrow Syndrome (DBS)
[OMIM#222448] associated with CDH.
Subsequently, microsatellite markers in
this and additional multiplex DBS
ARTICLE
AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS): DOI 10.1002/ajmg.c
families narrowed the DBS critical locus.
(C) We simultaneously performed arraybased comparative genomic hybridization (aCGH) to detect microdeletions or
microduplications on DNA isolated
from fresh lymphocytes or from archival
pathology specimens, concentrating on
syndromic, complex CDH. Intervals
were narrowed using fluorescence in
situ hybridization (FISH) and multiplex
ligation-dependent probe amplification
(MLPA) techniques. The occurance of
copy number variations was compared
to regions of microdeletions or microduplications. Our hypothesis was that
the study of syndromic CDH or CDH
associated with cytogenetic deletions
detected by routine chromosomal analysis, or microdeletions detected by
aCGH analysis, would provide clues
about the etiology of nonsyndromic or
isolated CDH. Using these techniques,
we recently identified a possible critical
locus, chromosome 1q41–q42.12, for
Fryns syndrome [OMIM#229850] associated with CDH [Kantarci et al., 2006]
and narrowed a previously detected
locus of interest of 15q26.1–q26.2
Our hypothesis was that the
study of syndromic CDH
or CDH associated with
cytogenetic deletions detected by
routine chromosomal analysis,
or microdeletions detected by
aCGH analysis, would provide
clues about the etiology of
nonsyndromic or isolated
CDH. Using these techniques,
we recently identified a possible
critical locus, chromosome
1q41–q42.12, for Fryns
syndrome [OMIM#229850]
associated with CDH and
narrowed a previously detected
locus of interest of
15q26.1–q26.2.
[Klaassens et al., 2005a,b; Scott et al.,
2007; Kantarci et al., in preparation].
These three approaches have
yielded different loci associated with
syndromic CDH. It is possible that the
analysis of genes in these regions may, in
turn, point us toward potential genetic
pathways or networks for CDH. Identification of genes is a goal, as genetic
pathways will yield therapeutic strategies
that can be employed for CDH either in
utero or after birth when lung development still continues in the human.
Selection and Sequence Analysis
of Candidate Genes
Candidate genes (see Table I) were
selected for mutational analysis in
CDH patients, both isolated and complex, based on the following criteria:
(a) Mutation of the gene in mice either
by homologous recombination or in
an ENU screen produced a phenotype of CDH, as observed with Slit3
[Liu et al., 2003; Yuan et al., 2003],
Robo1 (the Slit receptor) [Xian et al.,
2001], CouptfII [You et al., 2005],
Wt1 [Kreidberg et al., 1993; Moore
et al., 1998], and Fog2 [Ackerman
et al., 2005]. The first causative gene
in a human, FOG2, was found to be
due to a de novo mutation in a
patient with lung hypoplasia and a
diaphragm defect in the eventration
spectrum [Ackerman et al., 2005]
(futher discussed in the articles by
Ackerman and by Pober in this
issue).
(b) Genes whose expression patterns
were changed at the time of branching morphogenesis during embryonic lung development, as was
reported for Sonic hedgehog protein (SHH) [Bellusci et al., 1997;
Litingtung et al., 1998; Pepicelli
et al., 1998], its downstream transcription factors, GLI2 and GLI3
[Grindley et al., 1997], and Forkhead-related transcription factor 1
(Foxf1) [Kim et al., 2005].
(c) Genes found in chromosomal
regions known to be associated with
the human CDH phenotype. For
example, aCGH was used to compare two patients with deletions in
219
15q26 with severe growth retardation, cardiac defects, and musculoskeletal defects, but without CDH, to
seven 15q26 deletion patients with
similar severe anomalies, but with
CDH [Klaassens et al., 2005a].
Those with CDH had deletions
limited to a region which contains
at least five known genes that were
chosen for subsequent sequence
analysis, namely SIAT8B, CHD2,
RGMA, MCTP2, and COUP-TFII
(NR2F2).
(d) Insulin-like growth factor I receptor
(IGFR1), which is adjacent to the
15q26.2 CDH critical region
[Klaassens et al., 2005b; Scott et al.,
2007] was also sequenced since
growth retardation is prominent in
syndromic forms of CDH. Moreover, during a Drosophila tracheal
development screen a candidate
gene, thrombospondin, was discovered [L. Perkins, personal communication]. Thrombospondin is a
coactivator with insulin and insulin
like growth factor in the integrin
pathway.
(e) Genes in the retinoic acid (RA)
pathway were selected because of
their functional importance in lung
[Kumar et al., 2005] and diaphragm
development [Kluth et al., 1996;
Greer et al., 2000; Gallot et al., 2005]
and/or their location in the 15q26
locus, and included RALDH3,
CRABP1, RLBP1, COUP-TFII,
and RALDH2.
(f) Other migration molecules sequenced (aside from RGMA and
SIAT8B) included SLIT2 and
SLIT3, a mutation of which caused
CDH in knockout mice [Liu et al.,
2003; Yuan et al., 2003], and the
SLIT receptors ROBO1 and
ROBO2, mutations of which also
cause lung hypoplasia [Anselmo
et al., 2003].
(g) Potential FOG2 pathway genes
including the transcription factors
GATA4 [Ackerman et al., 2006; Jay
et al., 2007], GATA5, and GATA6
and COUP-TFII [Ackerman et al.,
2005] which is also part of the
retinoic acid pathway [Kimura
et al., 2002].
GLI2
GLI3
Wingless family secreted
WNT5A
Receptor for SLIT
Receptor for SLIT
Chromodomain helicase II
ROBO1
ROBO2
CHD2
ROH—RA
ROH—RA
Cellular binding protein for RA
Retinaldehyde binding protein
RA/TH receptor
Complexes transcription factors GATA4,
GATA5, GATA6, and COUP-TFII
RALDH2
RALDH3
CRABP1
RLBP1
COUP-TFII
FOG2
Retanoic acid pathway
Secreted neural guidance molecule
SLIT3
Gene name
Secreted neural guidance molecule
SLIT2
Migration molecules
Sonic hedgehog, secreted
SHH
Gene name
Insulin growth factor receptor
IGF1R
Growth factors/receptors
Target of SHH
Target of SHH
GATA5
GATA6
COUP-TFII
FOXF1
Gene name
Zinc finger transcription factor
Zinc finger transcription factor
Orphan nuclear receptor
Hfh8 forkhead homolog target of SHH
GATA4
Transcription factors
Complexes transcription factors GATA4,
GATA5, GATA6, and COUP-TFII
Zinc finger transcription factor
FOG2
Gene name
Function
Modulation of retinoic acid response,
retinoic metabolism
An acceptor of 11-cis-retinol in the
isomerization reaction of the visual
cycle
Retinoic acid signaling
Co-repression GATA and
COUP-TFII, binds RXR
Enzyme converts ROH to RA
Enzyme converts ROH to RA
Helicase
Controls midline crossing
Controls midline crossing
Alters cell migration
Function
Early branching stimulates mesenchyme, FGF10
Alveolarization, branching
General homeostatsis and growth
Function
Transcription factor
Branching morphogenesis
Transcription factor
Haploinsufficiency ! poor
alveolarization and vascular
branching
Early branching
Early branching
Transcription factor
Transcription cofactor
Function
Early lethal, cardiac, vascular, diaphragm defects
Eventration and lung hypoplasia, cardiac defects
Rhodopsin regeneration, 11-cis-retinal production,
and dark adaptation after illumination are delayed
Dispensable
Embryonic lethal (abnormal expression in
CDH nitrofen)
Neonatal lethal, choanal atresia
Abnormal expression
CDH7-CHARGE syndrome
Abnormal CNS formation
Pulmonary hypoplasia, abnormal CNS
formation
Increased bronchial wall thickening and
abnormal alveolar formation
Central tendon CDH
Abnormal expression
Over expression lung hypoplasia phenotype
Abnormal lung development
Abnormal expression
Abnormal lung
Abnormal Lung
No lung or diaphragm defect
Early embryonic lethal, branching defects
Cardiac, vascular, stomach, and diaphragm
Thickened mesenchyme
Cardiac defects, eventration of the diaphragm
Eventration and lung hypoplasia, cardiac defects
Abnormal expression
15q26.2
8q23.1
15q26
15q24
15q26.3
15q21.3
Gene locus
15q26.2
3p12.3
3p12
5q35-34
4p15.2
Gene locus
3p21-p24
7q36
15q26.3
Gene locus
2q14
7p13
20q13.33
18q11.1-q11.2
15q26.2
16q24
8p23.1
8q23.1
Gene locus
AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS): DOI 10.1002/ajmg.c
Lungs, mesenchyme, heart
Mesenchyme, lung, heart, diaphragm
Main bronchi and developing lamina
propria of the small intestine
Neural Crest (cytoplasmic, nuclear, and
mitochondrial)
Retina
Pleuroperitoneal folds
Expression
Lung mesenchyme and probably
epithelium
Lung mesenchyme and probably
epithelium
Lung mesenchyme and on the basal
epithelium surface. Also found in
central diaphragm
Lung mesenchyme and on the basal
epithelium surface. Also found in
central diaphragm
Nuclear
Expression
Distal branching tips
Insulin like growth factor in ligated
trachea
Branching tips epithelium
Expression
Lung mesenchyme
Lung mesenchyme
Liver, lung mesenchyme, diaphragm
(septum transversum)
Lung mesenchyme and diaphragm
Lung epithelium and diaphragm
Lung mesenchyme
Lung epithelium and mesenchyme, later
mesenchyme
Lung mesenchyme and diaphragm
Expression
TABLE I. Candidate Genes for Congenital Diaphragmatic Hernia
220
ARTICLE
ARTICLE
AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS): DOI 10.1002/ajmg.c
Since the genetics of CDH is
complex, and it is probable that CDH
may be caused by de novo mutations in
pathway genes, identification and resequencing of these candidate genes will
hopefully help us better understand the
pathogenesis of CDH.
Evaluation of sequence changes. Nonsynonymous SNPs (nsSNP) are analyzed
by PolyPhen [http://genetics.bwh.
harvard.edu/pph/] and SIFT [http://
blocks.fhcrc.org/sift/SIFT.html] programs to predict the effect of amino acid
changes on physical 3D structure and
protein function. SNP allele and genotype frequencies in CDH patients are
then compared to an ethically matched
control group recruited as part of the
study. As the work progresses, with a
growing sample size of both CDH
patients and controls, we are focusing
on nsSNPs not found in either the public
databases or in our own control population. Genes are prioritized for further
study based on recurring SNPs particularly those in coding regions and in
highly conserved promoter or enhancer
domains. SNPs are analyzed for variants
associated with the CDH phenotype,
loss of heterozygosity, or association
studies to uncover haplotypes indicating
common variants contributing to or
creating susceptibility loci. Loss of
heterozygous regions identified by SNPs
across a gene has been evaluated with
MLPA to determine whether it reflects
the loss of one copy of that gene.
Families With Donnai–Barrow
Syndrome and
Homozygosity Mapping
The search to discover gene defects
responsible for CDH and agenesis of
the corpus callosum joined the efforts of
two research teams in the study of the
rare autosomal recessive multiple anomaly condition known as Donnai–Barrow syndrome (DBS). Patients with this
autosomal recessive disorder may have
CDH, and characteristically also have
agenesis of the corpus callosum, craniofacial anomalies, hypertelorism, high
myopia, sensorineural hearing loss, and
developmental delay. Case reports of
The search to discover gene
defects responsible for CDH
and agenesis of the corpus
callosum joined the efforts of
two research teams in the study
of the rare autosomal recessive
multiple anomaly condition
known as Donnai–Barrow
syndrome (DBS). Patients
with this autosomal recessive
disorder may have CDH, and
characteristically also have
agenesis of the corpus callosum,
craniofacial anomalies,
hypertelorism, high myopia,
sensorineural hearing loss, and
developmental delay.
multiple affected siblings born to healthy
parents or of affected children born to
consanguineous parents suggested that
DBS followed an autosomal recessive
pattern of inheritance. We recruited a
large inbred family including five
patients with clinical features of DBS
from the United Arab Emirates. The
parents were healthy. The proband with
characteristic craniofacial features of
DBS died of complications secondary
to CDH. Among the four surviving
patients, each with normal chromosomal complements, one had left-sided
diaphragmatic eventration and pulmonary hypoplasia. aCGH performed on
two of the survivors did not reveal copy
number aberrations. We also recruited
four additional families previously
reported with characteristic features of
DBS including CDH, absence of corpus
callosum, exomphalos, hypertelorism,
myopia, and sensorineural deafness
[Donnai and Barrow, 1993; Chassaing
et al., 2003], and recently, an unreported
multiplex consanguineous family from
221
Qatar. Additionally, we ascertained a
previously reported family with clinically overlapping features of DBS and
Facio Oculo Acoustico Renal (FOAR)
[OMIM 227920] syndrome including
CDH, hypertelorism, a large anterior
fontanelle, high myopia, sensorineural
hearing loss, macrocephaly, proteinuria,
mental retardation, and developmental
delay [Devriendt et al., 1998].
A genome wide screen using the
Affymetrix 10K SNP array, performed
on the four affected members of the large
inbred UAE family for homozygosity
mapping,
identified
homozygous
regions with identical genotypes in all
patients. The largest region of identity
by descent was 17 cM (21Mb) on
chromosome 2q23.3–q31.1. Subsequently, microsatellite marker analyses
on the multiplex DBS families narrowed
the DBS critical region to 18 Mb and
generated a maximum single point LOD
score of 3.26. Sequencing analysis of 51
candidate genes mapped to the DBS
critical region is in progress.
Molecular Cytogenetics and
Molecular Analyses of
Microdeletions in CDH Hot Spots
About 10% of CDH patients have a
chromosome abnormality detectable
by standard cytogenetic techniques.
Advanced molecular cytogenetic analyses, such as aCGH have revealed
various small chromosomal abnormalities in CDH patients, such as 15q26.2–
q26.3 microdeletions, in addition to
those apparent in standard chromosomal
analyses (see article by Pober in this issue
for further discussion). It is anticipated
that novel molecular analyses of CDHcritical chromosomal regions may ultimately define smaller regions and identify genes responsible for CDH. For
instance, aCGH was a crucial technique
in identifying the genetic basis of
the CHARGE syndrome (CHARGE
association-coloboma, heart anomaly,
choanal atresia, retardation, genital, and
ear anomalies) in a 2.3-Mb de novo
overlapping microdeletion on chromosome 8q12. Subsequently, sequence
analysis of genes mapped to this critical
region revealed mutations in CHD7 in
222
AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS): DOI 10.1002/ajmg.c
other patients with CHARGE syndrome who did not have microdeletions
[Vissers et al., 2004]. Deletions previously reported in unrelated CDH
patients
include
15q261–q26.2
[Schlembach et al., 2001; Lurie, 2003;
Biggio et al., 2004; Hengstschlager et al.,
2004; Tumer et al., 2004; Slavotinek
et al., 2005, 2006; Klaassens et al., 2005a;
Scott et al., 2007], and 1q41–q42
[Youssoufian et al., 1988; Rogers et al.,
1995; Lurie, 2003; Kantarci et al., 2006;
Slavotinek et al., 2006]; these regions
were subjected to further analyses.
Chromosome 15q26.1–q26.2 deletion.
Several reports suggest that a gene
critical for normal diaphragm development is likely located on chromosome
15q26.1–q26.2, based on the occurrence of CDH in patients with cytogenetically visible aberrations in this region.
Recent studies using aCGH and FISH in
nine patients (seven out of nine with
CDH) with 15q26.1–q26.2 aberrations
identified an 5Mb commonly deleted
interval in the CDH cases [Klaassens
Several reports suggest that a
gene critical for normal
diaphragm development is
likely located on chromosome
15q26.1–q26.2, based on the
occurrence of CDH in patients
with cytogenetically visible
aberrations in this region.
Recent studies using aCGH
and FISH in nine patients
(seven out of nine with CDH)
with 15q26.1–q26.2
aberrations identified an
5Mb commonly deleted
interval in the CDH cases.
et al., 2005a]. The 15q26.2 critical
region for CDH referred to as Diaphragmatic Hernia 1 (DIH1) [OMIM
#142340] contains five known genes:
ST8
alpha-N-acetyl-neuraminide
(SIAT8B), chromodomain helicase
DNA binding protein 2 (CHD2), repulsive guidance molecule domain family
member A (RGMA), multiple C2domains, transmembrane 2 (MCTP2),
and chicken ovalbumin upstream promoter transcription factor 2 (COUPTFII; NR2F2). Subsequent analyses by
these investigators, of only those patients
with CDH, narrowed the region to
4 Mb, thereby eliminating SIAT8B
from the critical region [Klaassens et al.,
2005b]. Further narrowing to isolate the
single critical gene associated with CDH
was not possible [Castiglia et al., 2005].
A recent study showed that additional
genes mapped to 15q26.1–q26.2 CDH
critical region, ARRDC4, IGF1R,
DMN, TTC23, HSP90B2P, and
LRRC28 [Scott et al., 2007], are worthy
of study.
COUP-TFII, a member of the
steroid/thyroid hormone nuclear receptor family, is a likely candidate gene in
diaphragm development, due to its
location within DIH1 as well as the fact
that Couptf2 conditional null mice have
diaphragmatic defects [You et al., 2005].
Of 15 cases reported to have
COUP-TFII deletion, 11 have CDH
[Tumer et al., 2004; Klaassens et al.,
2005a; Slavotinek et al., 2006], while
four do not [Tonnies et al., 2001;
Castiglia et al., 2005; Glass et al.,
2006]. Thus, in cases studied to date,
deletion of COUP-TFII is strongly
associated with CDH [Scott et al.,
2007, Kantarci et al., in preparation].
Chromosome 1q41–q42.12 deletion.
1q41–1q42 aberrations were reported
in five CDH patients with additional
birth defects [Youssoufian et al., 1988;
Smith et al., 1994; Rogers et al., 1995;
Slavotinek et al., 2006], one of whom
was clinically diagnosed with Fryns
syndrome [Kantarci et al., 2006], a
multiple malformation disorder of
unknown etiology characterized by
congenital abnormality of the diaphragm, coarse facial features, distal
digital hypoplasia of the nails and/or
terminal phalanges, pulmonary hypoplasia, genitourinary anomalies, cardio-
ARTICLE
vascular malformations, and orofacial
clefting.
We analyzed 29 CDH patients with
normal karyotypes using the Spectral
GenomeChipTM V1.2 arrays. (Spectral
Genomics, Inc., Houston, TX), which
contains 2,632 bacterial artificial chromosome (BAC) clones with 1 Mb
resolution. Eleven cases were clinically
classified as having isolated CDH, while
18 were classified as having complex
CDH. The BAC clones previously
reported in an analysis of large scale copy
number variations (CNVs) [Iafrate
et al., 2004] [http://projects.tcag.ca/
variation/], as well as single BAC clones,
were excluded from further analysis.
The patients with isolated CDH did
not have additional copy number aberrations over those previously reported.
However, aCGH and FISH analyses
revealed a de novo deletion of three
consecutive BAC clones over an interval
of 5–7 Mb on chromosome 1q41–
q42.12 in a new patient clinically
diagnosed with Fryns syndrome who
died at 1 hr of age. The postmortem
examination of the patient showed a
large left diaphragm hernia, mild right
diaphragmatic eventration, and bilateral
pulmonary hypoplasia along with other
characteristics features of Fryns syndrome [Kantarci et al., 2006]. Routine
chromosomal analysis was normal, but
the microdeletion was confirmed independently in a CLIA-certified laboratory (Signature Genomics, Spokane,
WA) using the SignatureChipTM array
and FISH. Moreover, the deletion
interval was further delineated by the
MLPA technique [Kantarci et al., in
preparation]. Although Fryns syndrome
is considered to be an autosomal recessive disorder, based on case reports of
parental consanguinity and of sibling
recurrences, it could also be caused
by (1) de novo autosomal dominant
mutations as were found for the disorders Campomelic Dysplasia [OMIM
#114290] and Osteogenesis Imperfecta
type II [OMIM #166210], historically
thought to be autososomal recessive
disorders but now known to be autosomal dominant; (2) gonadal mosaicism
in one of the parents; (3) deletion of a
causal gene on chromosome1q41–
ARTICLE
AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS): DOI 10.1002/ajmg.c
q42.12 on one allele, combined with a
point mutation in the causal gene on the
other allele to produce a heterogeneous
compound heterozygote; (4) the appearance of phenotypically similar characteristics resulting from mutations at
different genetic loci (locus heterogeneity) each resulting in haploinsufficiency
which when combined could lead to
increased phenotypic severity.
Two reported CDH cases with
1q41–q42.12 deletions [Kantarci et al.,
2006; Slavotinek et al. 2006] defined a
putative CDH-critical region (6.5
Mb) containing 29 known genes. Analysis of which might provide a number of
worthy CDH candidate genes.
Two reported CDH cases
with 1q41–q42.12 deletions
defined a putative CDHcritical region (6.5 Mb)
containing 29 known genes.
Analysis of which might
provide a number of worthy
CDH candidate genes.
Thus, CDH associated chromosomal hot spots (see Fig. 1) such as
15q26.1–q26.2, 1q41–q42.12, and
others including: 8q23 (FOG2);
8p23.1 (GATA4); 2q23.3–q31.1 (Donnai–Barrow families); and 4p16.3
(Wolf–Hirschhorn syndrome) may contain genes which when deleted or
disrupted lead to CDH. Furthermore,
these hot spots may not be random, but
rather reveal genes belonging to com-
223
mon pathways, which can contribute by
addictive haploinsufficiency to the
appearance or severity of the phenotype.
Such findings may provide insight into
both mechanism and potential treatment
targets for CDH. Genes in these regions
are being studied for such possibilities.
We hypothesized that the phenotypic severity differences between and
within the isolated and complex subtypes could be explained by defects in
different genes in a molecular pathway,
coexpression of risk factors related to
sensitized backgrounds, and haploinsufficiency as a cause of variable penetrance.
FUTURE DIRECTIONS
In future, high resolution genome wide
association studies with copy number
variations could be performed on all
Figure 1. The CDH candidate genes and loci located on ‘‘CDH-critical’’ chromosome regions. Arrows indicate CDH chromosomal
hot spot regions.
224
AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS): DOI 10.1002/ajmg.c
patients with CDH and eventually,
should this approach prove to be successful for CDH, it can be recommended for
all patients with major congenital
anomalies. Customized chips with dense
SNP markers across loci and genes
discovered in hot spots should be
designed for CDH and other complex
disorders. This will allow comparison of
dense markers from, for example, the
HapMap [http://www.hapmap.org/]
populations may uncover common
SNP signatures associated with and
potentially contributing to phenotypic
variations, severity, and associated
anomalies in CDH. Genes in regions of
interest will be analyzed for their
potential contributions to a molecular
pathway. Understanding such pathways
will permit one to conceive downstream
replacement therapies, with the ultimate
aim of ameliorating or even preventing
the severe CDH phenotypes. If variations of the same phenotype can be
caused by multiple mutations in a
molecular pathway, then the importance
of a single SNP change could be missed
in the larger population unless one is
aware of probable heterogeneous contributions to the same phenotype, based
on the principle that most mutations will
be autosomal recessive. For the disease to
be manifest, loss of the same gene
on both alleles, or, more likely, an
accumulated contribution from both
parents of different allelic changes in
the same or different genes in the same
molecular pathway will be required.
However, less common can be a single
defect which causes a dominant negative
effect.
As discussed above, an Oracle webbased database was developed to support
the data collected on patients with CDH
and their families. Although this database was devised to support our ongoing
CDH study, importantly, it can serve as a
platform that is transportable to studies
of other congenital anomalies and to
monitor the progress of studies of
congenital anomalies already in progress.
Since the molecular genetic study of
CDH and other birth defects requires
multi-institutional collaboration, this
type of database is a crucial element of
such studies.
SUMMARY
Thus, the molecular and genetic etiologies of a congenital anomaly such as
CDH, in the absence of large families for
traditional linkage analysis, may be
studied for genetic abnormalities by a
combination of techniques including
candidate gene sequencing, novel high
resolution molecular cytogenetics, and
loss of homozygosity mapping. Such
strategies can reveal multiple chromosomal hot spots associated with changes
which can produce the same phenotype
(see Fig. 1). The challenge will be to
‘‘connect the dots’’ between each chromosomal region to determine if common molecular pathways will emerge
from the analysis. This recently proved
to be the case in cleft lip and palate
[Lidral and Murray, 2004], Kallmann
syndrome 2 [OMIM# 147950],
and interstitial pulmonary fibrosis
[OMIM#178500]. The later disorder,
for example, can occur because of
abnormalities in surfactant protein C
(SPC), SPB, or the ABCA3 transporter
[Bullard et al., 2006]. Murray and
colleagues defined that IRF6 mutations
cause van der Woude syndrome [OMIM
#119300] [Kondo et al., 2002], while
over-transmission of a common IRF6
variant increases the risk for isolated
non-syndromic cleft lip and palate
[Zucchero et al., 2004]. FOG2,
GATA4, and COUP-TFII are all needed
for both normal diaphragm and lung
development and are likely all in the
same pathway in in vivo development
[Ackerman et al., 2005; You et al., 2005;
Jay et al., 2007]. The importance of the
retinoic acid signaling pathway in lung
[Kumar et al., 2005] and diaphragm
development [Kluth et al., 1996; Greer
et al., 2000; Gallot et al., 2005] was
highlighted by a recent report showing
that mutations in STRA6, a member of
‘‘stimulated by retinoic acid’’ gene
family caused the CDH phenotype in
patients with distinct feature of
anophthalmia and varying features of
congenital heart defect, lung hypoplasia,
alveolar capillary dysplasia, and mental
retardation [Pasutto et al., 2007].
Accordingly, it is possible that mutations
in gene(s) located in the DBS locus
ARTICLE
(chromosome 2q23.3–q31.1) or other
loci found either by homozygosity
mapping or aCGH might cause complex
syndromic forms of CDH, while single
nucleotide polymorphisms (SNPs) and/
or variants in the same gene(s) might lead
us to an understanding of the molecular
bases of isolated non-syndromic forms
of CDH.
The ultimate aim of this paradigm is
to uncover genetic pathways which can
be perturbed to provide a therapeutic
intervention and to reveal the window of
opportunity in which that therapeutic
can be employed to alleviate the phenotype or even prevent the disorder from
occurring. To pursue these technology
driven approaches requires a large investment of resources, genetic and
surgical talent, but most importantly,
dedicated families and patients. We
believe, however, that such strategies
will be successful, and will bring both
understanding and more effective, less
invasive treatments to patients with
CDH. Birth defects such as CDH
occupy one third of U.S. hospital beds
and place a high economic burden on
the health care system. Identifying the
etiology of even a single birth defect,
such as CDH, will have a major impact
on its own, but can also provide a
paradigm for how to approach other
congenital anomalies.
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