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 birth defects (congenital heart disease and congenital diaphragmatic hernia), 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 25 new genes for human diseases.
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 positionally cloned one of these diabetes modifiers in mice, Lisch-like (now Ildr2) that appears to have its main effect on beta cell longevity. 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
I 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 I have collected and characterized over 2500 research participants with obesity, many with severe and/or early onset obesity. I am now studying those probands with extreme, early onset obesity utilizing whole exome sequencing of proband parent trios and families.
I have studied 200 subjects 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, 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 now studying 39 single genes associated with autism through an online battery of behavioral instruments and gathering medical history data.
Rare genetic variants increasing susceptibility to monogenic diabetes
In addition to studies of obesity, I have characterized over 250 patients for monogenic forms of diabetes using whole 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.
Inborn errors of metabolism
In addition to the common diseases of obesity and diabetes, I have also 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. I have identified a founder mutation in the zinc transporter SLC39A4 in Sierra Leone causing acrodermatitis enteropathic due to zinc deficiency. I demonstrated complete cure of this condition with zinc replacement, and am now initiating a simple screening program for this easily treated nutritional/genetic condition in Sierra Leone. I 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.
We study the genetic basis of birth defects including congenital diaphragmatic hernia (CDH) and congenital heart disease. 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 750 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 whole exome sequencing to identify mutations in GATA4, GATA6, and MYH10, 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 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 birth defects/medical problems. Through this large series of 1300 proband-parent whole 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 whole genome sequencing in 300 CHD and 200 CDH trios.
Pulmonary arterial hypertension
I participate in programs studying other monogenic cardiac conditions. I have worked extensively on pulmonary hypertension and maintain the North American Hereditary Pulmonary Hypertension Registry and have fostered successful international collaborations regarding hereditary pulmonary hypertension. We have identified four novel genes for pulmonary hypertension using whole exome sequencing. Calveolin 1 which is a major protein forming the lipid rafts in the pulmonary artery endothelial cells, and we believe leads to aberrant TGFB signal transduction when mutated. We have identified both de novo and inherited mutations in CAV1 associated with pulmonary hypertension. We have identified a second novel gene, a potassium channel, KCNK3, with multiple missense mutations identified in both hereditary and idiopathic forms of pulmonary hypertension. We are currently working on the mechanism by this channelopathy leads to excessive pulmonary vasoconstriction. Both of these genes constitute novel mechanisms for pulmonary hypertension and could provide important insights into disease pathogenesis and ultimately therapy. We have identified autosomal recessively inherited mutations in EIF2AK4 in pulmonary capillary hemangiomatosis. We have also demonstrated that mutations in TBX4 are a common cause of pulmonary hypertension in children.
We are currently working on identifying novel genes causing CHD and pulmonary hypertension in children.
We work on inherited arrhythmias in collaboration with electrophysiologist Rocky Kass. We have genetically characterized over 200 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. We work closely with Dr. Arthur Moss, the PI of the US Long QT Registry, and am a co-investigator on an NIH Program Project to genetically characterize the Long QT Registry participants, study the function of the channelopathy using iPS cells, test novel drugs for efficacy using the iPS cells, and then testing the effects of novel drugs in vivo in LQT patients.
We work on inherited cardiomyopathies and have genetically characterized over 400 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 dilated cardiomyopathies. We have also identified genetic modifiers of disease progression in children with hypertrophic cardiomyopathy. We are using whole 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.
Spinal Muscular Atrophy
We have collaborated with Darryl De Vivo, Chris Henderson, and other members of the Motor Neuron Center on understanding the natural history and developing new therapies for Spinal Muscular Atrophy (SMA). My lab is the Molecular Genetics Core of the Pediatric Neuromuscular Clinical Research (PNCR) Network for SMA and have identified Plastin 3 as one of several biomarkers for clinical severity of 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.
We work on inherited cancers, and I am a co-investigator for 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. I am now conducting studies to identify novel breast cancer susceptibility genes within Ashkenazi Jewish and Hispanic families without identified BRCA1/2 mutations, and we are pursuing several genes identified with whole exome sequencing. I am also heavily involved in the translational working group of the registry 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 are 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 were 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.
Within the Columbia pancreas cancer genetic program we have found that 27% of the patients in our high risk program who had genetic testing had identifiable genetic causes of pancreas cancer. We have characterized all the surgical pancreatic cancer cases at Columbia for the Jewish founder BRCA1/2 mutations and found that 22.4% carried mutations, suggesting that BRCA1/2 mutations are a much more frequent cause of pancreatic cancer in this population than previously appreciated. This has extremely important treatment implications as we develop new therapies including PARP inhibitors specifically for patients with BRCA1/2 related cancers. We are molecularly characterizing the BRCA1/2 positive pancreatic tumors and have demonstrated that loss of heterozygosity of BRCA1/2 is necessary for tumor progression and is followed by p53 mutations.
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
I 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. I have also identified a recurrent PDGFRB mutation as the cause of the rare cancer infantile myofibromatosis.
Autism and neurodevelopmental disorders
In addition to the gene discoveries I have listed above for specific diseases of major focus in my laboratory, I 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.
Ethical Legal and Social Implications of Genomics
I 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 diseases including Huntington Disease, hereditary breast cancer, and alpha 1 antitrypsin deficiency. We have also studied patients’ reproductive decisions and factors influencing use of preimplantation genetic diagnosis. I am a member of the steering committee for the NIH-funded Columbia Center for Excellence in ELSI Research (CEER) on Psychiatric, Neurologic, and Behavioral Genetics. I was the PI of an R01 grant entitled “Impact of return of genetic test results to research participants in the genomic era” which focused particularly on the effect of returning results of uncertain clinical significance or unintended findings in research studies. I am also co-investigator of a NIH grant with Ruth Ottman on the impact of returning genetic results to research participants in an epilepsy study and studying the impact of those results on research participants and their families. We recently received an NIH grant to establish the Goals and Practices for Next Generation Prenatal Testing, an important emerging area of genomic medicine.
Genomic Medicine Integration
I have been a leader in the use of whole exome and whole genome sequencing as a discovery tool and for clinical care. We have had influential two publications in Genetics in Medicine on the clinical usefulness of WES in clinical care and examining the clinical yield of testing in a case series of over 3000 cases. We are currently in the process of evaluating the clinical utility of WES when we are able to provide results within 7 days. We have also demonstrated the clinical utility of WES in the diagnosis of sudden infant death syndrome and in stillbirth and have identified mutations in CLCNKB and PTPN11 using exome sequencing.
I am a member 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). I am responsible for all the clinical studies in which results will be returned to patients and for studying the impact of this information on patients and providers.
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. I play the critical leadership role in the Irving Institute in organizing and supporting these activities across Columbia, developing systems, policies, and governance to provide an efficient research infrastructure to accomplish the goals of Precision Medicine and to catalyze the careers for young investigators by providing the necessary training and ability to access data biospecimens and analytic techniques to launch research careers and programs.