Our research group investigates the genetic and genomic causes of rare disorders. The main focus of the lab has been on identifying the etiology of congenital heart disease through a variety of large data methods, and assessing the genetic variation for pathogenicity in functional assays.
CHD is the commonest group of birth defects in children, occurring in 6-8/1000 live births. Despite advances in medical management and surgical palliation, CHD is a leading cause of infant death and causes substantial morbidity and financial burdens for families.
Genetics of Left Side Cardiac Defects
The McBride lab has been interested in malformations of the left side of the heart. Over the last 10 years, we have accumulated a large cohort of over 1000 individuals with CHD, collected as isolated cases with parents or as a family with multiple affected individuals.
Early investigations on the epidemiology suggested a strong genetic component, but with a very complex genetic architecture (McBride 2004, PMID: 15690347; Ellesoe 2018, PMID: 29106500). Traditional linkage studies found several loci over large regions (McBride 2009, PMID: 19142209) , and subsequent studies have identified single gene defects in NOTCH1, with several variants affecting epithelial to mesenchymal transition (Riley 2011, PMID: 20951801).
We have more recently applied genomic approaches in a multi-PI project with Dr. Peter White and Vidu Garg. A genome-wide association study using SNP genotyping identified a genome wide significant association on chromosome 22 near MYH7B (Hanchard 2016, PMID: 26965164). Copy number variant analysis also added to the growing list of deletions and duplications associated with CHDs (Hanchard et al 2017, PMID: 28653806).
Currently, we have been using next generation sequencing approaches (whole exome, whole genome, and 10X) in our cohort, with a focus on our multiplex families. We have identified several novel disease causing genes and have confirmed previously identified candidates (LaHaye 2016 PMID: 27418595). Over 30 families and 300 trios are under analysis through this pipeline.
Rare Diseases Project
Nationwide Children’s Hospital is a unique resource for investigating rare diseases and congenital malformations. In collaboration with the Steve and Cindy Rasmussen Institute for Genomic Medicine, we have assisted in the identification of new disease genes or expansion of the phenotype of known disease genes for inborn errors of metabolism, lethal skeletal dysplasias, movement disorders, osteopenia, cardiomyopathy and others (Koboldt 2018, PMID: 29305346).
Cell Line Core
This shared resource is housed within the McBride lab. Services include establishing cell lines and DNA banking of human subject samples. We create EBV derived lymphoblastoid cell lines from blood samples, and fibroblast lines (both primary and hTERT immortalized) from skin biopsies. We also serve as the Muscular Dystrophy Cell Line Core under a Center for Research Translation (CORT) project directed by Dr. Kevin Flanigan.
Cardiovascular Genetics Research Group
We belong to an interdisciplinary group at NCH that unites basic scientists and clinicians (including residents and fellows) to study a variety of conditions important in pediatric cardiology. Projects include genetic testing application (microarrays in CHD, genetic test interpretation in arrhythmias and cardiomyopathies), genetic counseling (numeracy and genetic knowledge among patients), and others.
Clinical Genetic Translational Research
Dr. McBride also has a clinical and translational research portfolio that focuses on inborn errors of metabolism. Current projects include natural history studies of mucopolysaccharidosis (MPS) type II (Hunter syndrome), MPS III (Sanfilippo syndrome - Truxal 2016, PMID: 27590925) and phenylketonuria (PKU). More exciting are ongoing clinical trials in gene therapy with phase I gene transfer for MPS IIIA and IIIB (Flanigan PI) and anticipated phase I trial in MPS II (McBride PI) in late 2018.