Dr. Muenke's research program seeks to improve our knowledge about birth defects and normal and abnormal early embryogenesis with special emphasis on the central nervous system, cardiovascular system, and reproductive system. Major areas of focus involve holoprosencephaly (HPE), attention deficit hyperactivity disorder (ADHD), craniosynostosis, congenital heart disease (CHD), and sex chromosome anomalies.
Holoprosencephaly (HPE), the most common defect of the developing forebrain, occurs in one in 250 embryos and is characterized by the failure of the embryonic brain to divide properly into left and right hemispheres during early development. It frequently results in fetal loss; consequently, the live birth rate is low - approximately one in 10,000. Most children born with this disorder show various degrees of developmental and intellectual disabilities. Dr. Muenke's laboratory has discovered over a dozen genes associated with HPE and, in doing so, illuminated a number of key molecular pathways involved in human early embryonic development. The first human HPE-related gene his group identified was Sonic Hedgehog (SHH), a gene initially found in fruit flies and named for the prickly appearance it gives them. Dr. Muenke and other investigators have since identified a number of additional genes in the Sonic Hedgehog and Nodal signaling pathways that are implicated in HPE. However, these genes together only account for 20 percent of documented HPE cases. Thus, the Muenke lab is continuing the hunt for additional genes and other causes contributing to HPE. More recently the lab has been searching for additional genes and gene regulatory elements by using genomic approaches such as whole exome sequencing and targeted capture panels that study the coding and non-coding regions of hundreds of developmental genes expressed during early embryogenesis. This approach will contribute to understanding those HPE cases with unknown etiologies and shed light on the causes of developmental and intellectual disabilities in general.
Attention Deficit Disorder
Another major research area for Dr. Muenke's group involves understanding the genetic basis of attention deficit/hyperactivity disorder. ADHD is the most common behavioral disorder in children; it affects at least 5 to 8 percent of school-age children worldwide. The hallmark symptoms of ADHD are inattention, hyperactivity and impulsivity, which frequently persist into adulthood. Although ADHD is a distinct disorder, it is frequently accompanied by other conditions such as oppositional defiant disorder (ODD), conduct disorder (CD), substance use disorder (SUD), depression and anxiety. The causes of ADHD have remained a mystery, although in the past environmental factors have long been considered the most likely culprits. Over the past decades, studies of twins, adopted children, and families with a high prevalence of this disorder have shown that genetic factors are strongly implicated in the pathogenesis of ADHD.
Building on research initiated by investigators in Colombia studying large multigenerational families with a high incidence of ADHD, the Muenke laboratory has identified several candidate genomic regions for ADHD and one specific gene on chromosome 4q13.2, latrophilin 3 (LPHN3). Additional genetic and functional studies are now in progress to further evaluate this gene. Interactions of the LPHN3 haplotype with a region in chromosome 11q22 double the risk of developing ADHD. Interestingly, variants in 11q22 contained in NCAM1,TTC12, ANKK1, and DRD2 genes have been previously reported as implicated in alcohol and nicotine abuse in Caucasians, which are two comorbidities strongly associated with ADHD.
These studies will help to better understand the biology of ADHD and associated conditions, with the ultimate goal of translating these findings into better diagnostic and therapeutic modalities for affected individuals.
Craniosynostosis is a common craniofacial abnormality caused by premature fusion of one or several sutures of the skull. The prevalence of craniosynostosis is approximately 1 in 2,100 to 3,000 births. The most common craniosynostosis syndrome, Muenke syndrome (OMIM # 602849) is a specific form of craniosynostosis caused by a single nucleotide transversion in fibroblast growth factor receptor 3 (FGFR3), c.749C>G, resulting in p.Pro250Arg. Individuals carrying the defining mutation variably manifest coronal suture craniosynostosis, developmental delay, hearing impairment, and carpal and tarsal bone fusion. The Muenke group in collaboration with colleagues at the University of Würzburg, Germany, is currently using validated tools to better characterize the behavioral phenotype of Muenke syndrome. This improved phenotype characterization will assist the Muenke group in its search for modifying factors of this clinically highly variable disorder and allow for earlier diagnosis and interventions for patients and families affected with this disorder.
Congenital Heart Disease
Dr. Muenke's group has been studying the genetics of congenital heart disease (CHD) and discovered how variants in NODAL, FOXH1, GDF1, and CFC1 and their respective pathways contribute to normal and abnormal cardiac development. Recently, the Muenke group has initiated a large international study of CHD in under-represented populations including sites in Uganda, Nigeria, and Thailand. Existing data suggests that CHD occur in Sub-Saharan Africa at frequencies similar to the rest of the world. In this application, the Muenke lab is utilizing the unique advantages of studies in Sub-Saharan Africa - a combination of the most genetically diverse populations in the world and of diminished environmental background effects (i.e. low prevalence of smoking, alcohol abuse, obesity in comparison to western countries) - to better understand the genetic basis for congenital heart disease. Approaches include next generation genomic techniques with more traditional gene discovery methods to investigate CHD in Africa and Asia.
In collaboration with Dr. Carolyn Bondy, NICHD, Dr. Muenke and colleagues are seeking answers to common phenotypes found in Turner syndrome (TS) with special emphasis on cardiac anomalies and autoimmune disease. Bicuspid aortic valve is found frequently (34 percent) in patients with Turner syndrome and Hashimoto's thyroiditis occurs in 40 percent in TS. Using next generation sequencing technology, the Muenke group is exploring the genetic bases of these and other findings. The goal is to translate the cardiac and autoimmune genetic and molecular findings into preventive or therapeutic measures.
Non-Alcoholic Fatty Liver Disease
Non-Alcoholic Fatty Liver Disease (NAFLD) includes a spectrum of conditions from benign hepatic steatosis to liver failure. Approximately 30 percent of adults and 10 percent of children in the U.S. are affected with NAFLD, with an even higher prevalence when obesity, diabetes and hypercholesterolemia are present, associating NAFLD with the global obesity epidemic. However, NAFLD also affects non-obese individuals and the distribution of NAFLD is not homogenous among different races, which supports the hypothesis of an underlying genetic component.
Despite its high prevalence, the pathophysiology of NAFLD remains poorly understood and multiple attempts have been made to identify the underlying genetic mechanisms. The Muenke Lab is using a mouse model of fatty liver disease and targeted capture panels for human genome sequencing to identify potential genes predisposing to NAFLD.
Ovarian Health- Sufficiency/Insufficiency, the Study of Reproduction in Sisters (OH-SISTERS)
Primary Ovarian Insufficiency (POI), also called Premature Ovarian Insufficiency, or early menopause, is a poorly understood cause of infertility affecting 1 percent of women under the age of 40. The cause of POI is unknown 90 percent of the time. The Muenke group, in collaboration with Dr. James Segars, NICHD, is currently conducting research on the genetic causes of POI within families using next generation sequencing technology.
Phenotypic Consequences of Y Chromosome Variants
Patients with deletion/duplication of Y-linked genes are frequently identified by the presence of infertility. However, this group of patients has not been fully studied to determine a non-reproductive phenotype. In close collaboration with Dr. David Page at the Whitehead Institute in Boston, MA, we are systematically phenotyping a population of patients with previously identified Y-chromosome variants in order to study in vivo, specific Y-chromosome gene functions, and possibly gain a more complete understanding of the genetic basis of the Turner Syndrome phenotype.