The Lek lab was established on January 2018 at Yale School of Medicine and is focused on understanding the genetic mechanism of rare diseases that may lead to rational approaches for therapies.
In recent years, large genomic data sets such as gnomAD have been made publicly available and are a powerful resource for methods development. Our goal is to use these resources to build computational methods to improve our interpretation and prioritization of variants with an initial focus on mitochondrial DNA.
Novel disease gene discovery
Our group is involved in the analysis of exomes generated from the Pediatric Cardiac Genomics Consortium (PCGC), which is one of the largest congenital heart disease cohort. We are also contributing to the genomic analysis of Recurrent Pregnancy Loss (RPL). Both aim to identify novel genes underlying CHD and RPL. Lastly, through the support of CZI, we aim to advance rare disease genetics in American Asian communities through collaboration with the Asian Health Coalition
Interpretation of variants of uncertain significance
A large challenge of rare disease diagnosis is the interpretation or correcting misinterpretations of rare missense variants in well established disease genes. Computational and analytical approaches take several lines of evidence in to consideration such as allele frequency and conservation but rarely physiologically relevant functional assays. Using model cell lines, we have built scalable cost-effective high-throughput assays that can distinguish pathogenic from benign variants in muscle disease genes.
Genetic mechanisms in Muscle Diseases
We have developed cell models to further explore the genetic mechanism of various neuromuscular diseases including Facioscapulohumeral Muscular Dystrophy (FSHD), GNE Myopathy, Dysferlinopathy (LGMD2B/LGMDR2) and Duchenne and Becker muscular dystrophy. These models allow us to explore novel therapeutic approaches and also repurposing existing FDA approved drugs. Lastly, we aim to use these cell models for innovative applications such as live cell imaging and MERFISH.
Developing Tools and Resources for Genetics Community
Building upon our experiences with working on the ExAC and gnomAD projects and extensive software development and cloud infrastructure expertise, we have built the following open source website:
- SFARI Genomics Browser
- Metabolism And Genomics in Cystic Kidney (MAGICK) data portal
- PCGC Genomics Browser
- Seqr instance for Boston Childrens Hospital (internal network)
- Napari plugin for visualization of the 4D nucleome consortium data
Pediatric Cell Atlas of Skeletal Muscle
Yale is the co-ordinating site for the CZI funded Pediatric Cell Atlas of Skeletal Muscle, which is multiple institute collaboration involving 10 other principal investigators. Skeletal muscle is the largest organ system with a high global burden for disease at all life stages. While muscle retains the capacity for continued growth and regeneration, even in adulthood, an atlas of adult or of pediatric skeletal muscle has not been generated. We propose to generate a comprehensive single-cell Pediatric Cell Atlas (PCA) of healthy skeletal muscle, representing a diverse set of donor tissues across ages, gender and ethnicities, benchmarking normal development of this tissue.
Development of Genetic therapies for Muscle Diseases
One of the reasons why the Lek lab was established was “we didn’t want to just deliver bad news faster” through improving diagnosis and wanted to be involved in the full patient journey, which involves translating genetic discoveries into therapies. Through collaborations with Cure Rare Disease, Neuromuscular Disease Foundation and other patient foundations we have active projects developing therapies for Duchenne Muscular Dystrophy (DMD) using innovative approaches, which includes using CRISPR activation of non-muscle isoforms, Cas9 nickase and exploring novel Cas proteins (Metagenomi collaboration). In addition, we have projects exploring gene replace approaches in GNE Myopathy and Limb Girdle Muscular Dystrophy (LGMD2I/LGMDR3).