Five Questions with Neuromuscular Disease Researcher James Lupski

James Lupski, Cullen Professor of Molecular and Human Genetics and professor of pediatrics at Baylor College of Medicine in Houston, was awarded an MDA research grant totaling $300,000 over three years to facilitate new gene discovery and new biological insights into the pathobiology of neuromuscular disease.

Please describe your current research.

Determining genetic diagnoses in neuromuscular diseases (NMDs) is particularly difficult due to the large number of disease-causing genes and significant overlap in clinical symptoms between patients.

My team aims to advance molecular diagnostics for NMD patients who remain undiagnosed after clinical diagnostic whole exome sequencing (WES) and enhance discovery of novel disease genes.

First, we will comprehensively re-analyze clinical exome data in a research setting to confirm that a diagnosis has not been missed. Next, we will perform exome sequencing for the patient’s parents and/or other family members. This will help us find spontaneous, or de novo, mutations and novel genes associated with NMDs. For cases that remain unsolved, we will then implement RNA sequencing from affected tissue, if available. The advantage of RNA sequencing from muscle tissue is that it can provide direct evidence of the functional impact of a mutation. We also propose whole genome sequencing (WGS) for cases where tissue is not available, as with decreasing sequencing costs, it is important to test whether WGS should replace WES in the clinic.

Obtaining a molecular diagnosis is key for patients and families with NMDs as it affects disease management, prognosis, family planning decisions and participation in disease-specific registries and clinical trials.

Is this your first MDA grant?

I have received MDA grants previously, which have significantly impacted my research. My first competitive grant was from the MDA, and this allowed me to obtain preliminary data and garner an NINDS/NIH R01 grant. These initial studies led to the discovery of the CMT1A duplication (the underlying genetic cause of type 1A Charcot-Marie-Tooth disease).

What inspired you to study neuromuscular diseases?

I have a neuromuscular disease — Charcot-Marie-Tooth disease type 4B.

What is your focus in neuromuscular disease research, and why is it important?

My main focus is to improve molecular diagnostics and shorten the diagnostic odyssey for patients with rare diseases.

Obtaining a molecular diagnosis is extremely important for patients and families with NMDs as it provides recurrence risk information, relevant management of disease, can sometimes provide prognostic information, and can facilitate entry into disease-specific clinical trials.

What is the expected outcome of this research?

The expected outcome of this research is to discover novel genetic causes of neuromuscular diseases in undiagnosed patients. This will help us learn about novel genes associated with disease as well as better understand known disease genes and the genetic architecture of NMDs.

Does your work have any potential implications for other disease fields?

Yes, our research will have potential implications for understanding the genetic mechanisms underlying all inherited diseases.

To learn more about MDA’s latest neuromuscular disease research, visit

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