Abstract
Advances in genetic sequencing have allowed a specific gene-based diagnosis in many patients with a suspected genetic myopathy. However, a significant minority of patients remain in whom the specific diagnosis remains elusive. In addition to the classic forms of Mendelian inheritance including autosomal recessive, autosomal dominant and X-linked, another mechanism of genetic transmission is digenic inheritance. This occurs when there is an interaction of two genes resulting in a given phenotype. In this study, we report three patients with myopathy hypothesized to follow a digenic pattern of inheritance. All of the patients had progressive weakness due to a myopathic disorder and underwent genetic analysis of a panel of genes established to cause inherited myopathies. Variants were observed in multiple genes in this panel. The data was further analyzed by review of published reports of the variants, public databases to determine the frequency and subjected to protein modeling to assess their possible pathogenic significance. One patient had variants in the CAPN3 (c.1553A>G; pGln518Arg) and SYNE2 (c.7664C>T; p.Thr2555Met) genes that our analysis indicates are the likely cause of her myopathy. Following a similar protocol, a second patient carries genes with two variants that are in cis in the TTN gene (c.85582G>A; p.Val28528Ile and c.103292C>T; p.Thr34431Met). There is another variant in the SYNE2 gene (c.18632C>T;p.Thr6211Met) and the combination of both likely result in her myopathy. In the last patient, a previously described mutation in the COL6A2 gene, c.1970-3 C>A in intron 25 was identified. This can result in limb girdle muscular dystrophy phenotype observed in this patient. In addition, a new variant was detected in the SGCG gene, c.643 G>T, p.Ala215Ser and its role as a modifier of disease phenotype is discussed. Our study suggests that digenic inheritance should be considered in patients with suspected undiagnosed myopathies in whom next generation sequencing fails to establish a diagnosis.