Scientifically, my main contributions have been in the discovery of new genes for human diseases and characterization of the mutation spectrum and molecular mechanism of disease, clinical characterization of the disorders associated with these gene mutations, and integration of these discoveries into clinical practice through the development and implementation of clinical genetic testing in medical care. The number of diseases I have studied and continue to study is much larger than most other geneticists and span rare disorders causing neurodevelopmental disorders (including autism and spinal muscular atrophy) and congenital anomalies (congenital heart disease, congenital diaphragmatic hernia and esophageal atresia/tracheoesophageal fistulas), cardiopulmonary conditions (pulmonary hypertension, cardiomyopathies, arrhythmias), cancers (breast and pancreatic cancer), rare inborn errors of metabolism, and complex diseases (obesity and diabetes). In all, I have identified over 60 new genes for human diseases.
Table of Contents
Autism and Neurodevelopmental Disorders
Congenital Anomalies
We study the genetic basis of birth defects including congenital diaphragmatic hernia (CDH), congenital heart disease and esophageal atresia/tracheoesophageal fistulas. In the case of CDH, we have an international network of 15 clinical sites in our DHREAMS study for which we perform all the genomic characterization and centrally coordinate the clinical database and data analysis. We have collected over 1500 CDH cases to date and in the majority of cases have collected diaphragm, skin, and blood to allow for future development of cell lines, iPSC, and to address the question of mosaicism as a cause of birth defects. We have identified pathogenic, de novo copy number variants in 8% of our participants. We have used exome/genome sequencing to identify mutations in rare causes of CDH. We have also demonstrated an increased burden of de novo variants in our CDH series, with almost 50% of our complex CDH cases associated with de novo variants we believe are likely pathogenic. We are part of the NHLBI Pediatric Cardiac Genomic Consortium in which we have recruited 10,000 probands with congenital heart disease and determined that there is an increased burden of de novo CNVs and sequence variants in severe forms of congenital heart disease when there is no family history of CHD. Furthermore, such de novo variants are significantly more frequent in non-isolated CHD cases associated with neurodevelopmental disorders and/or other congenital anomalies/medical problems. Through this large series of 1300 proband-parent exome sequencing analyses, we have identified over 30 novel candidate genes for CHD. These studies have been published in Nature and Science. We have recently received grants from NIH to perform genome sequencing in CHD, CDH, and esophageal atresia trios.
Autism and neurodevelopmental disorders
In addition to the gene discoveries listed above for specific diseases of major focus in my laboratory, we have identified numerous novel genes for neurodevelopmental disabilities and autism and characterized the associated neurocognitive and clinical phenotypes. The genes we have identified and characterized include KAT6A, PPP2R5D, PRUNE, EMC1, AHDC1, POGZ, PURA, ARID2, DDX3X, SETD2, and SPATA5.
CTNNB1 gene
CSNK2A1 gene
DHPS gene
GPT2 Deficiency
HNRNPH2 gene
KIF1A gene
PPP2R5D gene
PHIP gene | Chung-Jansen Syndrome
MAPK8IP3 gene
Simons Searchlight
SLC1A4 gene
SPARK
TKT Deficiency
Prospective Genetic Risk Evaluation and Assessment (PROGRESS)
We identify and study a diverse, population-based cohort of infants with monogenic risk for autism to evaluate the impact of early life identification of genomic risk variants on parent experience, neurodevelopmental trajectories, and prediction of autism diagnosis. The PROGRESS Center harnesses transdisciplinary expertise in genomics, developmental neuroscience, autism assessment and diagnosis, psychosocial assessment, and data science to address gaps in autism research. The research aims to understand the implications of genetic information early in life and integrate genomic data with behavioral trajectories in infancy to more accurately predict autism, and tailor the types and timing of therapies during infancy when brain development is most plastic.
Genomic Uniformed-Screening Against Rare Diseases In All Newborns (GUARDIAN)
We study how genomic sequencing can be used to effectively expand the conditions screened on newborn screening (NBS) and aim to diagnose babies who have certain conditions to provide treatment early in life. NBS improves equity and allows all babies to have the same chance at the healthiest life. Mothers who deliver at one of the participating hospitals are invited to have their newborn screened over 450 genetic conditions that have disease characteristics similar to the conditions on the recommended uniform screening panel (RUSP) guidelines but are not yet included on the RUSP due to diagnostic requirements for DNA sequencing methods. The conditions have effective/FDA approved treatments available, are not recognized on physical examination, and early pre-symptomatic diagnosis is associated with improved clinical outcomes.
Natural History Study to Advance the Science, Care, and Exploration of Neurodevelopmental Disorders (ASCEND)
We collect data consisting of clinical and molecular genetic data and biological specimens from participants with rare genetic conditions associated with neurodevelopmental delay to enable us to better understand and advance the science, care, and exploration of these conditions. We have identified more than 40 new gene-disease associations associated with neurological features using exome/genome sequencing. We have defined these conditions in a small number of patients with the condition and seek to better understand the natural history of these conditions and collect biospecimens to foster research in these conditions. We also assess parent reported efficacy of various interventions to gather data systematically to develop guidance about clinical care and treatment.
KIF1A Outcome Measures, Assessments, Longitudinal, And Endpoints(KOALA)
We collect clinical and molecular genetic data and biological specimens from participants with KIF1A to better understand and advance the science, care, and exploration of this condition and test bespoke treatments to improve outcomes.
Inborn errors of metabolism
We have studied several rare inborn errors of metabolism and identified novel mutations and disease associations for Wolfram syndrome, Wolman disease, Leigh syndrome due to Ashkenazi Jewish founder mutations in NDUFS4 and C20ORF7, and the novel associations of MELAS and glycogen storage disease type III with pulmonary hypertension. We have also identified a rare cause of juvenile idiopathic arthritis using homozygosity mapping to detect a deficiency of Hyaluronoglucosaminidase 1. We have identified a founder mutation in the zinc transporter SLC39A4 in Sierra Leone causing acrodermatitis enteropathic due to zinc deficiency. We demonstrated complete cure of this condition with zinc replacement, and am now initiating a simple screening program for this easily treated nutritional/genetic condition. We have identified several novel genes for inborn errors of metabolism including a transaldolase deficiency causing hepatocellular carcinoma, a transketolase deficiency causing intellectual disabilities, short stature, and congenital heart disease, a neutral amino acid transport deficiency due to mutations in SLC1A4 causing intellectual disabilities, and a deficiency of Glutamic Pyruvate Transaminase 2 causing intellectual disability.
Cardiac disease
Pulmonary arterial hypertension
We participate in programs studying other monogenic cardiac conditions. We have worked extensively on pulmonary hypertension and have fostered successful international collaborations regarding hereditary pulmonary hypertension. We have identified several novel genes for pulmonary hypertension using exome sequencing. We lead the ClinGen working group on pulmonary hypertension and are part of PVDomics.
We have focused recently on pulmonary hypertension in children, and we are working on identifying novel genes causing CHD and pulmonary hypertension.
Inherited arrhythmias
We work on inherited arrhythmias. We have genetically characterized over 500 patients with inherited arrhythmias including long QT syndrome, Brugada syndrome, short QT syndrome, catecholaminergic polymorphic ventricular tachycardia, atrial fibrillation and arrhythmogenic right ventricular cardiomyopathy. We have studied the gating properties of many of these mutant channels in vitro, and Rocky Kass is now studying iPS cells from many of our patients and testing novel compounds for efficacy in normalizing the channel properties.
Cardiomyopathies
We work on inherited cardiomyopathies and have genetically characterized over 500 patients with cardiomyopathies. Our work has led to several manuscripts describing the effects of specific mutations, identifying novel metabolic causes of cardiomyopathy, demonstrating significant variability among family members, and demonstrating the yield of genetic testing for cardiomyopathies. We have also identified genetic modifiers of disease progression in children with hypertrophic cardiomyopathy. We are using exome sequencing to identify novel genes for infantile cardiomyopathy, the most lethal of all forms of cardiomyopathy, and other familial cardiomyopathies without identifiable mutations in known genes. We are also studying the impact of the return of genetic information to patients and families with cardiomyopathies and have a portion of the study focused on the impact on returning genetic information to children. We work with the Pediatric Cardiomyopathy Registry and Children’s Cardiomyopathy Foundation.
Spinal Muscular Atrophy
We have collaborated with Darryl De Vivo, and other members of the Pediatric Neuromuscular Clinical Research Network (PNCR) on understanding the natural history and developing new therapies for Spinal Muscular Atrophy (SMA). With the PNCR we have performed important natural history studies to understand the disease’s progression and long periods of stability after an initial period of decline, and these data will serve as the comparators for clinical trials. Early phase 1 clinical trials with oligonucleotide treatment to alter splicing of SMN2 are in progress and demonstrate the safety of this strategy. Anticipating that maximally effective therapy will require early diagnosis before the period of initial decline, we are conducting a pilot study of newborn screening for SMA in collaboration with the New York State Department of Health. If the pilot study and the clinical trials prove feasible and effective, this could lead to a new paradigm for early diagnosis and intervention for the second most common hereditary cause of death in infants.
Cancer
Breast cancer
We work on inherited cancers, with the NY site of the Breast Cancer Family Registry. We have studied the prevalence and spectrum of BRCA1/BRCA2 mutations, penetrance and spectrum of cancers, and genotype/phenotype correlations within our cohort. We are conducting studies to identify novel breast cancer susceptibility genes within Ashkenazi Jewish and Hispanic families without identified mutations, and we are pursuing several genes identified with exome sequencing. We are also heavily involved in the translational work in which we are trying to better understand the impact of genetics on patient decision making, health behaviors, and health outcomes. We are developing methods to integrate primary care based online risk stratification modules and educational materials to facilitate appropriate genetic testing for hereditary breast cancer and to increase genomic screening of high risk women in underserved communities. We were funded by NCI to conduct a study called “Lessons in Epidemiology and Genetics of Adult Cancer from Youth” (LEGACY) to study the female children of breast cancer registry participants to discover epidemiologic and epigenetic pathways of childhood exposures in relation to pubertal development, age at menarche, breast tissue characteristics, selected biomarkers, genomic DNA methylation on future breast cancer risk and the psychosocial impact of increased breast cancer susceptibility related to the family history of breast cancer. We are also recently funded by NCI to conduct longitudinal follow up studies of our breast cancer cohort to study the correlation of genetics, treatment, and health behaviors with outcomes. We also received NCI funding to conduct a multicenter study (RESPECT) to return genetic research results and determine the impact on research participants and their families.
Implementation of clinical testing for common cancers
In clinical genetic testing for hereditary cancers, we have recently moved from testing two-three genes to using panels of 10-50 genes to evaluate patients with cancer or with a family history of cancer. We have reported on a large case series of 10,000 patients tested with clinical cancer panels and report on the yield of testing by cancer type and demonstrate the clinical utility of cancer panels over more focused testing.
Rare cancer syndromes
We identified a germline mutation in SH2B3 as a rare genetic cause of pediatric acute lymphoblastic leukemia and autoimmune hepatitis using homozygosity mapping and whole exome sequencing. We have also identified a recurrent PDGFRB mutation as the cause of the rare cancer infantile myofibromatosis.
Obesity and diabetes
I initially began my research focus on the inherited basis for the common metabolic conditions of obesity and type 2 diabetes. My research initially heavily utilized rodent genetic models of obesity and diabetes to identify genes for further study in humans. Much of my early work in this area focused on genetic analysis of Leptin, Leptin receptor, Melanocortin 4 Receptor, Carboxypeptidase E and Proopiomelanocortin. I mapped genes for modifiers of monogenic forms of obesity in rats and mice predisposing to type 2 diabetes. I also cloned a rodent gene, mahoganoid (an E3 ligase), that protects against obesity and characterized the cellular mechanism by which it regulates body weight.
Common genetic variants increasing susceptibility to obesity
We studied the mechanisms by which common variants increase the risk of obesity utilizing large epidemiological studies including the New York Health Project (NYHP) and Clinical Antipsychotic Trials of Intervention Effectiveness Research Program (CATIE) in which patients with psychosis were treated with antipsychotics resulting in significant weight gain in a significant proportion.
Rare genetic variants increasing susceptibility to obesity
Over the past 20 years we have collected and characterized over 3000 research participants with obesity, many with severe and/or early onset obesity. We are now studying those participants with extreme, early onset obesity utilizing exome sequencing of families.
We have studied 400 participants in detail who have a 16p11.2 deletions or duplications which is associated with obesity and the mirror phenotype of difficulty gaining weight, respectively. I am the principal investigator of a national multicenter study, Simons VIP/Simons Searchlight to perform detailed neuropsychological testing, surveys of ingestive behaviors and satiety, assessments of longitudinal growth, brain imaging, and functional brain imaging to determine the penetrance and neurological basis for autism and obesity in this genetically well defined cohort. Our preliminary data demonstrate an important developmental evolution of hyperphagia in 16p11.2 deletion carriers with 50% of participants obese with a BMI Z score of > 2 by 8 years of age although many of the children start out as having difficulty gaining weight. Deletion carriers have a full scale IQ of ~30 point below their unaffected familial controls. Duplication carriers on average have a decrease in full scale IQ of ~20 points below their unaffected familial controls, but some duplication carriers have a normal IQ. Approximately 25% of both deletion and duplication carriers have autism. Deletion carriers have larger brain volumes across regions of the brain, and reciprocally duplication carriers have smaller brain volumes.
We are studying a rare genetic condition due to mutations in PHIP called Chung-Jansen syndrome. This condition is associated with behavioral and learning differences and also with weight gain, especially during adolescence. Some individuals have been in a clinical trial using setmelanotide to help with weight loss. These studies of Chung-Jansen syndrome are ongoing and interested individuals can email ASCENDstudy@childrens.harvard.edu to join.
In addition to studies of obesity, we have characterized over 400 patients for monogenic forms of diabetes using exome sequencing. We have identified over 100 patients with mutations in established monogenic forms of diabetes and expanded the spectrum of mutations in these genes. We have also identified several novel candidate genes for diabetes that we are now replicating. We are involved in the NIH funded RADIANT study to characterize rare genetic forms of diabetes.
Ethical Legal and Social Implications of Genomics
We have been involved in understanding how genetic information impacts patients and providers including their medical and reproductive decisions as well as the psychosocial impact of this information on patients and their families. I have studied these effects extensively with Drs. Robert Klitzman and Paul Appelbaum in diverse conditions. We have also studied patients’ reproductive decisions and factors influencing use of preimplantation genetic diagnosis. We work with Ruth Ottman on the impact of returning genetic results to research participants in an epilepsy study and Alzheimer’s results studying the impact of those results on research participants and their families. We work with Ron Wapner to establish the Goals and Practices for Next Generation Prenatal Testing and the Prenatal ClinGen working group, an important emerging area of genomic medicine.
Genomic Medicine Integration
We have been leaders in the use of exome and genome sequencing as a discovery tool and for clinical care. We were early leaders in the clinical usefulness of exome sequencing in clinical care and examining the clinical yield of testing in a case series of over 3000 cases. We have also demonstrated the clinical utility of WES in the diagnosis of sudden infant death syndrome and in stillbirth.
We are part of the Columbia Electronic Medical Records and Genomics (eMERGE) investigators funded by the NIH to study the integration of genomic medicine in the electronic medical record (EMR).
Electronic Medical Records and Genomics (eMERGE)
We utilize polygenic risk scores, monogenic genetic screening tests, family history assessment and advanced electronic phenotyping, clinical risk information to provide a Genomic Informed Risk Assessment (GIRA). We are working to identify people at high risk for 10 specific diseases and recommend individualized approaches to prevention and care within a diverse and underserved population. Our goal is to determine if providing a GIRA will impact clinical actions taken by providers and patients to manage disease risk and the propensity of participants to develop a disease reported in the GIRA.
Precision Medicine
Precision Medicine is, ultimately, the right treatment for the right patient at the right time and is a metaphor for the future of medicine. Precision Medicine offers an opportunity to increase the effectiveness of health care at reduced cost with improved outcomes, decreased adverse effects, and with greater patient satisfaction. There are unprecedented opportunities for Precision Medicine enabled by recent scientific advances in genomics, biomarkers, information technology, and increasing patient engagement, making it possible to realize opportunities that previously were only theoretical. Although advances in genomics are critical to the full realization of the potential for Precision Medicine, other information technologies are also powerful drivers. These rapidly evolving technologies will enable increased and improved data collection and analysis to improve knowledge and will revolutionize medicine – and the research enterprise on which its progress is founded – in ways that are only vaguely perceptible at present. Precision medicine will be used to maintain health. It will use information from the individual patient in real time to stratify disease risk and response to interventions iteratively over time and to identify alternative methods of managing health threats to ultimately find the most effective and acceptable options for the individual to maintain health and quality of life. Dynamic longitudinal assessments of health, physiologic parameters, and changes in biomarkers of disease at regular intervals, together with iterative reassessment of genomic information as understanding of genomic data improves, will further transform and inform our ability to understand disease progression and disease risk over the life course. In addition to maintaining health, precision medicine will be used to tailor treatments for disease. When diagnosed, diseases will be stratified along molecular dimensions to provide more accurate prognostic information and to target therapies with greater effectiveness and probability of success, decrease the frequency of adverse reactions/toxicity, increase cost effectiveness, and improve patient satisfaction. Precision medicine will empower the patient to become intimately engaged in his/her own medical care using advanced methods of electronic patient communication through a personal medical portal that incorporates real time collection of patient data (e.g. FitBit data on physical activity, biosensors collecting continuous biometric data, geodata to assess environmental exposures, and apps to collect rich patient reported data on frequency and severity of symptoms) that will provide detailed quantitative information and real time feedback to the patient to motivate and positively reinforce healthy behaviors and to improve medical compliance. Using transdisciplinary teams of educators, experts in patient engagement and community outreach, genomicists, data scientists, biomedical informaticians, systems biologists, health economists, a wide range of clinicians, legal scholars, and ethicists, we are developing a comprehensive program in Precision Medicine at Columbia for an extremely large and ethnically/economically/educationally diverse population that is not available in other locations around the country.
Covid Recovery Corps
Our mission in this study was to understand how people recover from COVID-19 and the impacts of the disease on health, both today and in the future. By collecting recovery experience, we unlocked some of the mysteries behind this disease and aimed to provide important new information all affected by the virus.
This study is currently closed. With any questions, please call 212-305-5508 or email ak3578@cumc.columbia.edu .
Chung Lab at Boston Children's Hospital 