Discovering the Function of
16 Congenital Heart Disease Genes
Delfina Pearledith González and Mustafa K. Khokha
CONTENTS
16.1. Historical and Medical Background of CHD........................................................................................................... 233
16.1.1. The Roots of CHD .................................................................................................................................... 233
16.1.2. Surgical Interventions and Clinical Therapies in CHD............................................................................. 234
16.1.3. Diff culties in Diagnosing and Studying CHD ......................................................................................... 234
16.2. Past Molecular and Genetic Studies Contributing to Understanding CHD/HTX .................................................... 234
16.2.1. Previous Studies of Vertebrate Cardiogenesis in Xenopus........................................................................ 235
16.2.2. Identifying Additional Candidate CHD Genes ......................................................................................... 235
16.3. Approaches to Studying CHD/HTX in Xenopus ..................................................................................................... 236
16.3.1. Morphological and Developmental Benefts of Studying CHD/HTX
in Xenopus ................................................................................................................................................. 236
16.3.2. Using CRISPR/Cas9 Genome Editing as a Screening Tool in Xenopus................................................... 236
16.3.3. Left-Right Patterning: A Beautiful Pathway to Guide CHD/HTX
Disease Mechanism Analysis .................................................................................................................... 236
16.4. Patient-Derived CHD Disease Mechanisms Uncovered in Xenopus ....................................................................... 237
16.4.1. Connecting Known Pathways in a New Context: Glycosylation in NOTCH
Signaling and Cilia Cell Fate Determination ............................................................................................ 237
16.4.2. Uncovering Novel Roles for Well-Studied Genes: Nucleoporins in Cilia
and Centrosomal Biology ......................................................................................................................... 237
16.4.3. Exploring Old Mysteries in Developmental Cell Signaling ..................................................................... 238
16.4.4. Shared Molecular Pathways for Multiple Diseases: Neurodevelopmental
Disorders, Craniofacial Abnormalities, and CHD .................................................................................... 239
16.5. Where to Go from Here? The Future of Studying CHD in Xenopus ....................................................................... 240
References............................................................................................................................................................................ 240
Congenital heart disease (CHD) is a class of developmental
anomalies affecting the structure and function of the heart.
CHD includes (1) septal defects (holes between chambers of
the heart), (2) hypoplasia or hypertrophy (reduction or overgrowth of cardiac tissues), (3) abnormal connection of the
major vessels, (4) misorientation of the heart along the leftright axis, or (5) any combination of 1–4. Heterotaxy (HTX),
a misorientation of internal organs across the left-right (LR)
axis, particularly affects the heart, and many HTX patients
suffer from a particularly severe form of CHD. It is critical
to understand the pathogenic mechanisms that contribute
to both CHD and HTX to improve patient care. Advances
in sequencing technologies has expedited identif cation of
CHD/HTX candidate genes, but we lack functional studies.
Developmental and molecular studies of these candidate
genes in Xenopus have uncovered surprising connections
between cell and developmental pathways that contribute to
the LR pathways that underlie CHD and HTX. These and
future studies pave the way for improvements in developmental biology and CHD/HTX patient care.
16.1. HISTORICAL AND MEDICAL
BACKGROUND OF CHD
CHD and other congenital birth defects have been documented for centuries (Afzelius 1977; Gelb 2015). Modern
medicine brought on a new age of surgical therapies.
Advances have improved patient diagnosis, survival, and
outcomes. Deeper understanding of the mechanisms leading to CHD can mitigate diffculties diagnosing the diseases
on a purely phenotypic or genetic basis.
16.1.1. THE ROOTS OF CHD
Scientists and physicians have documented CHD cases as early
as the times of Leonardo DaVinci (Castañeda 2005). It wasn’t
until the mid-1800s and early 1900s that physician Thomas
Bevill Peacock and pathologist Maude E. Abbot categorically
organized a wide range of CHD case reports into distinct
categories (Peacock 1858; Abbot 1915). Pediatric cardiologist
Helen Brooke Taussig published the f rst CHD textbook,
DOI: 10.1201/9781003050230-19
233
16 Congenital Heart Disease Genes
Delfina Pearledith González and Mustafa K. Khokha
CONTENTS
16.1. Historical and Medical Background of CHD........................................................................................................... 233
16.1.1. The Roots of CHD .................................................................................................................................... 233
16.1.2. Surgical Interventions and Clinical Therapies in CHD............................................................................. 234
16.1.3. Diff culties in Diagnosing and Studying CHD ......................................................................................... 234
16.2. Past Molecular and Genetic Studies Contributing to Understanding CHD/HTX .................................................... 234
16.2.1. Previous Studies of Vertebrate Cardiogenesis in Xenopus........................................................................ 235
16.2.2. Identifying Additional Candidate CHD Genes ......................................................................................... 235
16.3. Approaches to Studying CHD/HTX in Xenopus ..................................................................................................... 236
16.3.1. Morphological and Developmental Benefts of Studying CHD/HTX
in Xenopus ................................................................................................................................................. 236
16.3.2. Using CRISPR/Cas9 Genome Editing as a Screening Tool in Xenopus................................................... 236
16.3.3. Left-Right Patterning: A Beautiful Pathway to Guide CHD/HTX
Disease Mechanism Analysis .................................................................................................................... 236
16.4. Patient-Derived CHD Disease Mechanisms Uncovered in Xenopus ....................................................................... 237
16.4.1. Connecting Known Pathways in a New Context: Glycosylation in NOTCH
Signaling and Cilia Cell Fate Determination ............................................................................................ 237
16.4.2. Uncovering Novel Roles for Well-Studied Genes: Nucleoporins in Cilia
and Centrosomal Biology ......................................................................................................................... 237
16.4.3. Exploring Old Mysteries in Developmental Cell Signaling ..................................................................... 238
16.4.4. Shared Molecular Pathways for Multiple Diseases: Neurodevelopmental
Disorders, Craniofacial Abnormalities, and CHD .................................................................................... 239
16.5. Where to Go from Here? The Future of Studying CHD in Xenopus ....................................................................... 240
References............................................................................................................................................................................ 240
Congenital heart disease (CHD) is a class of developmental
anomalies affecting the structure and function of the heart.
CHD includes (1) septal defects (holes between chambers of
the heart), (2) hypoplasia or hypertrophy (reduction or overgrowth of cardiac tissues), (3) abnormal connection of the
major vessels, (4) misorientation of the heart along the leftright axis, or (5) any combination of 1–4. Heterotaxy (HTX),
a misorientation of internal organs across the left-right (LR)
axis, particularly affects the heart, and many HTX patients
suffer from a particularly severe form of CHD. It is critical
to understand the pathogenic mechanisms that contribute
to both CHD and HTX to improve patient care. Advances
in sequencing technologies has expedited identif cation of
CHD/HTX candidate genes, but we lack functional studies.
Developmental and molecular studies of these candidate
genes in Xenopus have uncovered surprising connections
between cell and developmental pathways that contribute to
the LR pathways that underlie CHD and HTX. These and
future studies pave the way for improvements in developmental biology and CHD/HTX patient care.
16.1. HISTORICAL AND MEDICAL
BACKGROUND OF CHD
CHD and other congenital birth defects have been documented for centuries (Afzelius 1977; Gelb 2015). Modern
medicine brought on a new age of surgical therapies.
Advances have improved patient diagnosis, survival, and
outcomes. Deeper understanding of the mechanisms leading to CHD can mitigate diffculties diagnosing the diseases
on a purely phenotypic or genetic basis.
16.1.1. THE ROOTS OF CHD
Scientists and physicians have documented CHD cases as early
as the times of Leonardo DaVinci (Castañeda 2005). It wasn’t
until the mid-1800s and early 1900s that physician Thomas
Bevill Peacock and pathologist Maude E. Abbot categorically
organized a wide range of CHD case reports into distinct
categories (Peacock 1858; Abbot 1915). Pediatric cardiologist
Helen Brooke Taussig published the f rst CHD textbook,
DOI: 10.1201/9781003050230-19
233