Individuals with the same genetic disorder often show remarkable differences in 
clinical severity, a finding generally attributed to the genetic background. We 
identified two patients with genetically proven Emery-Dreifuss muscular 
dystrophy (EDMD) who followed an unusual course and had uncommon 
clinicopathological findings. We hypothesized digenic inheritance and looked for 
additional molecular explanations. Mutations in additional separate genes were 
identified in both patients. The first patient was a member of a family with 
molecularly proven X-linked EDMD. However, the clinical features were unusually 
severe for this condition in the propositus: he presented at 2.5 years with 
severe proximal weakness and markedly elevated serum creatine kinase. Muscle 
weakness rapidly progressed, leading to loss of independent ambulation by the 
age of 12. In addition, the patient developed cardiac conduction system disease 
requiring pacing at the age of 11 and severe dilated cardiomyopathy in the early 
teens. Despite pacing, he had several syncopal episodes attributed to 
ventricular dysrhythmias. As these resemble the cardiac features of patients 
with the autosomal dominant variant of EDMD, we examined the lamin A/C gene, 
identifying a de-novo mutation in the propositus. The second patient had a 
cardioskeletal myopathy, similar to his mother who had died more than 20 years 
previously. Because of the dominant family history, a laminopathy was suspected 
and a mutation in exon 11 of the LMNA gene was identified. This mutation, 
however, was not present in his mother, but instead, surprisingly, was 
identified in his virtually asymptomatic father. Unusual accumulations of desmin 
found in the cardiac muscle of the propositus prompted us to examine the desmin 
gene in this patient, and in so doing, we identified a desmin mutation, in 
addition to the LMNA mutation in the propositus. These cases suggest that 
separate mutations in related proteins that are believed to interact, or that 
represent different parts of a presumed functional pathway, may synergistically 
contribute to disease severity in autosomal dominant EDMD. Furthermore, digenic 
inheritance may well contribute to the clinical severity of many other 
neuromuscular disorders.