234
Xenopus
Congenital Malformations of the Heart, in 1947. Her observations of naturally occurring CHD in animals led to an effort to
study cardiac development in other species to better understand
human CHD pathology (Gelb 2015). All these early CHD scientists recognized the potential role of inheritance and linkage
between CHD, arrested development, and non-cardiac developmental disorders, including neurodevelopmental disorders
(NDDs). Dr. Taussig and cardiologist John Maurice Hardman
Campbell also observed that neither the pattern of genetic
inheritance of CHD nor environmental causes of CHD could
be simply explained, leaving them to suggest that genetic complexity could be at play (Gelb 2015; Taussig 1947).
While some doctors and scientists worked to understand
the underlying causes of CHD for future diagnosis and
therapies, others were working on clinical strategies to ease
more immediate patient suffering.
16.1.2. SURGICAL INTERVENTIONS AND
CLINICAL THERAPIES IN CHD
Dr. Daniel Hale Williams performed the f rst open-heart
surgery in 1893 to repair a stab wound (Fenderson and
Miller 1971). However, extracardiac corrective surgeries for
CHD did not successfully take place until 1938 (Gross and
Hubbard 1939), with further improvements by Dr. Taussig
and her contemporaries in 1945 (Crafoord and Nylin 1945;
Blalock and Taussig 1945). In order to correct the wider
spectrum of CHD structural defects, surgeons needed
access to the inside of the heart. To do so, they needed to
stop the heart from beating, stop blood fow to the heart, and
fnally restart the heart to recover the patient. Eventually,
surgeons developed methods for cardiopulmonary bypass
using a pump and an external oxygenator, enabling them
to stop the heart and, with cooling, also slow the patient’s
metabolic requirements (Castaneda et al. 1984). With these
advancements, surgeons were able to do open-heart surgery
on patients for corrective rather than palliative procedures
for internal cardiac defects.
Further combination of palliative and corrective procedures drastically reduced hospital mortality rates due to CHD
between the late 1950s and late 1990s (Castañeda 2005). Not
only was this better for patient survival, but the now-singleweek-long hospitalization reduced psychological, logistical,
and fnancial impacts on patients and their families.
16.1.3. DIFFICULTIES IN DIAGNOSING AND STUDYING CHD
Although doctors achieved great innovations in surgical
interventions, there is still much to improve. One vexing
problem is the variability in outcomes for a given anatomical diagnosis. Patients with CHD are cohorted based on
cardiac anatomy. Based on surgical and peri-operative care,
most patients with the same anatomy have similar clinical
outcomes. However, some patients do more poorly than
expected based on their anatomical diagnosis alone. We propose that these outliers may relate through genotype rather
than phenotype.
As sequencing technology has advanced, researchers identify more candidate genes and unique alleles.
Remarkably, many of these candidate genes have no known
role in cardiac development, no role in embryonic development, or no identifed role in biology. A greater number of
unique alleles also complicates genotype/phenotype correlations and reduces genetic cohort sizes. This is due to
the complexity of cardiac development, in which multiple
genes are critical. Genetic studies of CHD patient cohorts
have identifed high rates of locus heterogeneity, or mutation
contributions from multiple genetic loci (Fakhro et al. 2011;
Zaidi et al. 2013; Homsy et al. 2015; Jin et al. 2017). This, in
combination with the low rate of second alleles, makes it diffcult to demonstrate disease causality (Fakhro et al. 2011),
creating a problem for identifying gene function. Therefore,
there is a pressing need to discover gene function.
The cohort size necessary to establish disease causality
on a purely genetic basis is often too large to be practical
and delays discoveries. We propose that the optimal solution
is to initiate studies of candidate genes in high-throughput
model systems. Importantly, a better understanding of the
molecular mechanisms of CHD candidate genes will allow
doctors and researchers to exploit genotype to inform care,
prognosis, and risk of recurrence.
16.2. PAST MOLECULAR AND GENETIC
STUDIES CONTRIBUTING TO
UNDERSTANDING CHD/HTX
The prevalence and impact of congenital heart disease on
infant health makes it important to understand in more
depth. As of 2006, about 8 million, or ~ 6%, of total worldwide births were affected by a genetically or partly genetically derived serious birth defect (Christianson, Howson,
and Modell 2006). CHD is the most common birth defect,
impacting about 20/10,000 live births in the United States
(Mai et al. 2019). The CHD spectrum can range from severe
cardiac structural defects at birth to minor abnormalities
not identif ed until adulthood (Marino et al. 2012; Mussatto
et al. 2014). Surgical correction of severe congenital cardiac
anomalies is necessary to improve patient survival in about
25% of CHD cases identifed at birth (Virani et al. 2020).
However, the patients that survive to adulthood may experience additional health impacts seemingly unrelated to their
CHD or surgery, such as infertility, pulmonary disease, neurodevelopmental disorders, and other non-cardiac congenital defects (Homsy et al. 2015; Mussatto et al. 2014; Marino
et al. 2012).
HTX is a class of related birth defects that affects proper
establishment of LR asymmetry of the internal organs.
HTX affects 1/10,000 live births (Lin et al. 2014) and 3%
of CHD patients, (Sutherland and Ware 2009) often leading
to more severe forms of CHD. As the asymmetric orientation and formations of the vessels and chambers of the heart
are important for its normal function, about 90% of HTX
patients also have CHD (Lin et al. 2014). This relation highlights the importance of understanding CHD in the context
Xenopus
Congenital Malformations of the Heart, in 1947. Her observations of naturally occurring CHD in animals led to an effort to
study cardiac development in other species to better understand
human CHD pathology (Gelb 2015). All these early CHD scientists recognized the potential role of inheritance and linkage
between CHD, arrested development, and non-cardiac developmental disorders, including neurodevelopmental disorders
(NDDs). Dr. Taussig and cardiologist John Maurice Hardman
Campbell also observed that neither the pattern of genetic
inheritance of CHD nor environmental causes of CHD could
be simply explained, leaving them to suggest that genetic complexity could be at play (Gelb 2015; Taussig 1947).
While some doctors and scientists worked to understand
the underlying causes of CHD for future diagnosis and
therapies, others were working on clinical strategies to ease
more immediate patient suffering.
16.1.2. SURGICAL INTERVENTIONS AND
CLINICAL THERAPIES IN CHD
Dr. Daniel Hale Williams performed the f rst open-heart
surgery in 1893 to repair a stab wound (Fenderson and
Miller 1971). However, extracardiac corrective surgeries for
CHD did not successfully take place until 1938 (Gross and
Hubbard 1939), with further improvements by Dr. Taussig
and her contemporaries in 1945 (Crafoord and Nylin 1945;
Blalock and Taussig 1945). In order to correct the wider
spectrum of CHD structural defects, surgeons needed
access to the inside of the heart. To do so, they needed to
stop the heart from beating, stop blood fow to the heart, and
fnally restart the heart to recover the patient. Eventually,
surgeons developed methods for cardiopulmonary bypass
using a pump and an external oxygenator, enabling them
to stop the heart and, with cooling, also slow the patient’s
metabolic requirements (Castaneda et al. 1984). With these
advancements, surgeons were able to do open-heart surgery
on patients for corrective rather than palliative procedures
for internal cardiac defects.
Further combination of palliative and corrective procedures drastically reduced hospital mortality rates due to CHD
between the late 1950s and late 1990s (Castañeda 2005). Not
only was this better for patient survival, but the now-singleweek-long hospitalization reduced psychological, logistical,
and fnancial impacts on patients and their families.
16.1.3. DIFFICULTIES IN DIAGNOSING AND STUDYING CHD
Although doctors achieved great innovations in surgical
interventions, there is still much to improve. One vexing
problem is the variability in outcomes for a given anatomical diagnosis. Patients with CHD are cohorted based on
cardiac anatomy. Based on surgical and peri-operative care,
most patients with the same anatomy have similar clinical
outcomes. However, some patients do more poorly than
expected based on their anatomical diagnosis alone. We propose that these outliers may relate through genotype rather
than phenotype.
As sequencing technology has advanced, researchers identify more candidate genes and unique alleles.
Remarkably, many of these candidate genes have no known
role in cardiac development, no role in embryonic development, or no identifed role in biology. A greater number of
unique alleles also complicates genotype/phenotype correlations and reduces genetic cohort sizes. This is due to
the complexity of cardiac development, in which multiple
genes are critical. Genetic studies of CHD patient cohorts
have identifed high rates of locus heterogeneity, or mutation
contributions from multiple genetic loci (Fakhro et al. 2011;
Zaidi et al. 2013; Homsy et al. 2015; Jin et al. 2017). This, in
combination with the low rate of second alleles, makes it diffcult to demonstrate disease causality (Fakhro et al. 2011),
creating a problem for identifying gene function. Therefore,
there is a pressing need to discover gene function.
The cohort size necessary to establish disease causality
on a purely genetic basis is often too large to be practical
and delays discoveries. We propose that the optimal solution
is to initiate studies of candidate genes in high-throughput
model systems. Importantly, a better understanding of the
molecular mechanisms of CHD candidate genes will allow
doctors and researchers to exploit genotype to inform care,
prognosis, and risk of recurrence.
16.2. PAST MOLECULAR AND GENETIC
STUDIES CONTRIBUTING TO
UNDERSTANDING CHD/HTX
The prevalence and impact of congenital heart disease on
infant health makes it important to understand in more
depth. As of 2006, about 8 million, or ~ 6%, of total worldwide births were affected by a genetically or partly genetically derived serious birth defect (Christianson, Howson,
and Modell 2006). CHD is the most common birth defect,
impacting about 20/10,000 live births in the United States
(Mai et al. 2019). The CHD spectrum can range from severe
cardiac structural defects at birth to minor abnormalities
not identif ed until adulthood (Marino et al. 2012; Mussatto
et al. 2014). Surgical correction of severe congenital cardiac
anomalies is necessary to improve patient survival in about
25% of CHD cases identifed at birth (Virani et al. 2020).
However, the patients that survive to adulthood may experience additional health impacts seemingly unrelated to their
CHD or surgery, such as infertility, pulmonary disease, neurodevelopmental disorders, and other non-cardiac congenital defects (Homsy et al. 2015; Mussatto et al. 2014; Marino
et al. 2012).
HTX is a class of related birth defects that affects proper
establishment of LR asymmetry of the internal organs.
HTX affects 1/10,000 live births (Lin et al. 2014) and 3%
of CHD patients, (Sutherland and Ware 2009) often leading
to more severe forms of CHD. As the asymmetric orientation and formations of the vessels and chambers of the heart
are important for its normal function, about 90% of HTX
patients also have CHD (Lin et al. 2014). This relation highlights the importance of understanding CHD in the context