We are committed to raising awareness for rare conditions and to driving research toward new mechanisms for treatment options. Using the knowledge from the human genome, we develop techniques to understand variation, and predict the most important variants in disease predisposition.
Functional Analysis of Variants from High Throughput Sequencing
Gene function can be influenced by variation and regulation. We probe the underlying elements that determine gene function by studying coding and non-coding regions of the genome. These studies leverage molecular biology coupled to genomics to test the effects of variation. With cell-based assays and model systems, we have identified mechanisms underlying heart disease.
Methods to Analyze Medical Genomic Data for Undiagnosed Diseases
Testing by exome sequencing for undiagnosed diseases has tremendous yield and potential. Dr. Shieh co-directs the UCSF Personalized Genomics Clinic. With thousands of variants emerging from human genomes, we determine key variants that are critical for disease. Using exome data from the population, we have develop bioinformatic means to prioritize variation. The lab’s recent studies on genes on the X-chromosome emphasize the importance of sex-chromosomal variation and sex-biased selection in diseases affecting males and females. We develop algorithms to analyze variants from exomes and identify new genes in disease.
Nationwide Health Big Data Studies
We apply analytics and statistical methods to understand disease patterns. Our recent studies have determined trends in cyanotic congenital heart conditions in the United States. By studying the epidemiology of common birth defects, we make unique associations impacting clinical genetics and clinical care. One example is 22q11.2 deletion found in velocardiofacial/DiGeorge syndrome. Though this is a common condition, many individuals remain undiagnosed. Big data studies can assist in these efforts.
Birth Defects — Congenital Heart Conditions and Brain Developmental Differences
1% of children are born with congenital heart disease. While there is a clear genetic link to congenital heart disease, it is still necessary to identify the genes and pathways in cardiac development relevant for care. The lab uses genome-wide methods to identify novel genes and variants in congenital heart disease patients. Our work aims to translate knowledge into improved screening, testing, and prevention to better understand what causes birth defects and to improve treatment for kids and adults.
To study the impact of gene variants on heart development and congenital heart disease, our lab modules gene expression and uses functional testing of cell behavior. Members of the extracellular matrix are critical to proper heart development. Data at the organismal level is performed in developing zebrafish embryos, which provide an efficient model for early cardiac development. By testing new genes and variants at the molecular, cellular, and organismal level, we can develop a comprehensive understanding of potential impact on human disease.
Deletions and Duplications in the Genome
It was previously thought that each person had two copies of every gene, however the human genome harbors deletions and duplications that give some people fewer or greater copies of certain genes. This structural variation in the genome alters gene dosage and can interrupt or even fuse genes. Our lab leverages deletions and duplications to assess gene function. These variants can underlie often unrecognized phenotypes.