TAMPA (GenomeWeb) – While mutations to a single gene are believed to cause some of the best-characterized forms of muscular dystrophy, the growing availability of panel sequencing and whole-exome sequencing data is revealing muscular dystrophy cases that appear to involve mutations affecting more than one suspicious gene, attendees heard here today at the American College of Medical Genetics and Genomics annual meeting.
In a session on neurogenetic disorders and whole exome sequencing, Emory University Genetics Lab Executive Director Madhuri Hegde discussed her team's efforts to assess cases of progressive muscle degeneration and weakness disease that may be multigenic or involve synergistic effects between multiple contributing genes.
"Usually considered monogenic traits, neuromuscular disorders may involve two or more mutant genes in a heterozygous state contributing to the disease phenotype, a concept called synergistic heterozygosity," Hegde and her co-authors wrote in the ACMG abstract for the study.
Hegde noted that dozens of genes have been implicated in muscular dystrophy to date, with many of these apparent disease culprits coding for proteins that interact with one another near the sarcolemma membrane of muscle cells.
But because an accurate molecular diagnosis is a prerequisite for inclusion in appropriate clinical trials or treatment groups, she explained, investigators are keen to characterize the complete range of mutations that may lead to muscular dystrophy.
With that in mind, Hegde and her colleagues set out to identify causal gene mutations in 200 children with limb-girdle muscular dystrophy (LGMD), a form of muscular dystrophy that primarily present as muscle weakness but may also involve other features such as intellectual disability.
Using the medical exome sequencing approach that Hegde's lab developed alongside researchers at Harvard University's Laboratory of Molecular Medicine and the Children's Hospital of Philadelphia, the team identified recurrent mutations in three main genes: GNE, DYSF, and CAPN3. A handful of other genes contained variants that appeared to be pathogenic.
But not every case could be clearly traced to a single gene. Rather, when the researchers considered the medical exome sequence data alongside available samples from LGMD patients who had undergone gene panel testing, they found that roughly one-quarter of the individuals had apparently pathogenic variants in more than one gene.
Indeed, Hegde presented finding for three such patients or families, including a 33-year-old man whose sequence revealed loss of function changes affecting both copies of the DYSF gene and mutations expected to knock out one copy of the MYH2 gene.
That finding, together with results from other patients with multiple pathogenic mutations, prompted the team to suspect that individuals with certain mutation combinations might be more prone to LGMD with rapid progression and/or more severe symptoms.
The researchers have started to analyze a network of interacting gene products that have been linked to LGMD in the past, with the goal of distinguishing between authentic cases involving changes to multiple genes and those with one disease-related gene and another containing incidental, unrelated mutations.
To that end, Hegde emphasized the need for follow-up studies on the functions and interactions of genes and proteins suspected of contributing to LGMD, along with research into genotype and phenotype correlations in LGMD and other types of muscular dystrophy.