Jennifer Lai Yee, MD, MPH, PhD

2024 Norman Siegel Research Scholar Grant

Institution: University of Michigan

Project Title: Precision Medicine in Kidney Disease: Functionally Classify Variants of Nephrotic Syndrome Genes Using a Multiplex Approach

How would you sum up your overall research focus in one sentence? 

My research focuses on using molecular, informatics and precision medicine approaches to investigate genetic variant-function relationships in glomerular diseases.

Provide a brief overview of the research you will conduct with help from the grant. 

My research uses the molecular techniques of multiplex assays of variant effect (MAVEs) to interpret clinical variants experimentally on a large scale simultaneously in a pooled fashion. We use the gene WT1 as the first step to develop a variant-to-effect map, which can serve as a freely available 'lookup table' of functional evidence to support the clinical interpretation of newly encountered variants in nephrotic syndrome. We also aim to use the same approach to prospectively identify splice disruptive variants in a longitudinal observational cohort with nephrotic syndrome (NEPTUNE). This enables us to leverage the extensive patient data, including whole-genome sequencing (WGS), transcriptomics, and longitudinal clinical outcomes, to investigate splice disruptive variants, their effects on splicing events, and how these events contribute to disease pathogenesis.

What impact do you hope your research will have on patients? 

An outcome of more confident clinical variant interpretation in WT1 can spare unnecessary immunosuppressive therapy, avoiding the associated side effects in patients with potential pathogenic variants. We anticipate that this approach can improve the accuracy and actionability of genetic diagnosis for nephrotic syndrome and remove one barrier to future genotype-guided therapies and treatments. 

What are your career goals at the end of the grant period? Five years out? Ten years out? 

At the end of the grant period, I anticipate developing expertise in large-scale functional studies called multiplexed assays of variant effect (MAVEs) and being able to use these approaches as a blueprint for other kidney disease genes. My long-term career goal is to be a physician-scientist focused on realizing precision medicine approaches for nephrotic syndrome and other glomerular diseases.

What has surprised you most about your career? 

I am amazed by the advancements in molecular techniques for genome engineering, which have been truly remarkable. There are numerous ways to read, write, and edit the genome, even on a large scale. This empowers researchers to perform precise and efficient modifications to the genome and opens new possibilities for understanding biology and treating genetic diseases. 

What advice would you give to others to encourage them to apply for this grant funding? 

Believe in the importance and potential impact of your own research and maintain resilience in the face of challenges such as grant rejections.

Something you may not know about me is… 

I can drive a manual car and a pontoon boat.

In my free time, I like to… 

I enjoy outdoor activities, such as mountain biking, swimming in the summertime, and snowboarding in the winter.