Research Directions
With the advent of cheap and widespread genome sequencing, we are discovering more mutations than ever. Genetic testing in the clinic is becoming commonplace, and genomic screening for actionable Mendelian diseases is increasingly being deployed. A major challenge, however, is that a majority of variants are Variants of Uncertain Significance, blunting the clinical impact of genetic testing. Our lab uses large biobank datasets to identify candidate disease-associated variants, and high-throughput in vitro studies to test the function of these variants. We focus on arrhythmia disorders, transmembrane proteins, and ion channels. Our goal is to reclassify variants from Variants of Uncertain Significance to Pathogenic or Benign, to better predict and ultimately prevent disease.
Biobank genetic studies
We use large biobank datasets with participant genotypes and disease phenotypes to identify new variants linked to disease. These biobanks include Vanderbilt’s pioneering BioVU biobank, the eMERGE Network, the UK Biobank, and All of Us (>1M total participants). We use innovative phenotyping methods to discover associations between variants in transmembrane proteins and disease. These variants are then studied in vitro (see below).
Example paper: Arrhythmia variant associations and reclassifications in the eMERGE-III sequencing study
Automated patch clamping
Ion channels pass ions through the cell membrane in a regulated fashion and are important for many biological processes and diseases. We use automated patch clamping to characterize ion channel mutations in high-throughput. The SyncroPatch patch clamp instrument allows us to study 384 wells in a 30 minute experiment. To date we have studied >250 variants with this approach. One main focus is cardiac ion channels linked to Mendelian arrhythmia syndromes. A major future direction will be to mutations in a broad set of other “channelopathy” genes—ion channel genes where mutations lead to Mendelian syndromes.
Example paper: High-throughput reclassification of SCN5A variants
Deep Mutational Scans
Deep mutational scans are comprehensive screens of nearly every mutation in a gene, using high-throughput sequencing of mutant libraries coupled to in vitro assays. They can create a prospective list of all variants that disrupt function in important disease genes. We are deploying scans of cardiac ion channel genes linked to arrhythmia syndromes. We are also expanding to other transmembrane proteins, using a general cell surface trafficking assay.
Example paper: Deep mutational scan of an SCN5A voltage sensor