Each year, the Muscular Dystrophy Association (MDA) awards grants to the world’s best scientists to help accelerate treatments and cures for families living with neuromuscular diseases. Among the grant recipients this year are two HudsonAlpha Institute for Biotechnology faculty investigators. Greg Cooper, PhD, and co-PI Jane Grimwood, PhD, were recently awarded roughly $290,000 over three years from MDA for their project titled, “Long-read sequencing to diagnose neuromuscular disorders.”
Cooper and his lab are not strangers to using genome sequencing to diagnose rare diseases. Over the past decade, Cooper’s lab, along with many collaborating labs, sequenced the genomes of more than 1,790 children with rare diseases. Most of the children were showing signs of neurodevelopmental disorders, with features such as intellectual disability, developmental delay, and seizures. However, about 18 percent of the sequenced cohort also exhibit features of neuromuscular disorders like muscle weakness, contractures, ataxia, and dysphagia.
“Both exome and genome sequencing are powerful diagnostic tools for many diseases,” Cooper said. “Across all our patient cohorts, we found pathogenic or likely pathogenic variants in about 27 percent of patients, with about 17 percent of variants leading to a precise neuromuscular diagnosis. However, genome sequencing fails to identify genetic contributors to most neuromuscular disorders, despite severe, early onset phenotypes likely caused by genetic factors.”
Cooper and his lab believe that many neuromuscular disorders result from genetic variation that cannot be detected using the standard method of short-read sequencing. During short-read sequencing, long pieces of DNA are cut into shorter pieces that are sequenced and then pieced back together. Complicated DNA repeats, duplications, and expansions are often missed with this type of sequencing.
However, HudsonAlpha’s Genome Sequencing Center, of which Grimwood is the co-director, is an expert in another type of sequencing that could overcome the limitations of short-read sequencing: long-read sequencing. Long-read sequencing reads segments of DNA that are thousands of times longer than those produced using short-read sequencing. In an initial pilot study, the team used long-read sequencing on six patients whose genomes were previously sequenced with short-read technology. For two of the six patients, the team identified pathogenic/likely pathogenic variants missed by the short-read sequencing.
The goal of the recently funded grant is to refine the use of long-read sequencing to help diagnose neuromuscular disorders more frequently and effectively. The researchers will select patients with features of neuromuscular disorders from the pool of unsolved cases previously sequenced using short-read sequencing. The hope is that long-read sequencing will afford them a diagnosis. Researchers will also streamline the sequencing and diagnosis process for routine research and clinical use.
“Despite identifying hundreds of genes implicated in neuromuscular disease, there are still many people who lack a diagnosis,” said Sharon Hesterlee, Ph.D., MDA’s Chief Research Officer. “The work that Dr. Cooper and Dr. Grimwood have undertaken should help shed light on new causes of neuromuscular disease and represent the first step in developing meaningful treatments for these diseases.”