Whole exome sequencing may help successfully diagnose patients with limb-girdle muscular dystrophy (LGMD) when other analyses fail, according to study results published in JAMA Neurology.

Roula Ghaoui, FRACP, of the Children’s Hospital at Westmead in Sydney, Australia, and colleagues performed whole exome sequencing on 60 families with LBMG. Patients had previously been extensively investigated in protein studies and candidate gene sequencing but remained undiagnosed.

Using whole exome sequencing, the researchers identified likely pathogenic mutations in known myopathy genes for 27 of 60 families. Twelve families had mutations in known LGMD-related genes, while 15 families had variants in disease-related genes not usually associated with LGMD. Phenotypic overlap was commonly caused by mutations in congenital muscular dystrophy-related genes, as seen in four families, and collagen myopathy-related genes, as seen in four families. Less common myopathies included two families with metabolic myopathy, congenital myasthenic syndrome (DOK7), congenital myopathy (ACTA1), tubular aggregate myopathy (STIM1), myofibrillar myopathy (FLNC), and mutation of CHD7, which is usually associated with CHARGE syndrome.

By including family members, the diagnostic efficacy of whole exome sequencing increased, with a 60% rate for trios (affected proband and both parents) compared to 40% for single probands. Overall, a diagnostic success rate of 45% was achieved with whole exome sequencing in difficult to diagnose patients with LGMD. The findings also highlighted the clinical overlap between LGMD and other myopathies.


  1. Ghaoui R et al. JAMA Neurol. 2015; doi:10.1001/jamaneurol.2015.2274.