Limb Girdle Muscular Dystrophy due to Digenic Inheritance of < b > < i > DES < /i > < /b > and < b > < i > CAPN3 < /i > < /b > Mutations

We report the clinical and genetic analysis of a 63-year-old man with progressive weakness developing over more than 20 years. Prior to his initial visit, he underwent multiple neurological and rheumatological evaluations and was treated for possible inflammatory myopathy. He did not respond to any treatment that was prescribed and was referred to our center for another opinion. He underwent a neurological evaluation, electromyography, magnetic resonance imaging of his legs, and a muscle biopsy. All testing indicated a chronic myopathy without inflammatory features suggesting a genetic myopathy. Whole-exome sequencing testing more than 50 genes known to cause myopathy revealed variants in theCOL6A3 (rs144651558),RYR1 (rs143445685),CAPN3 (rs138172448), and DES (rs144901249) genes. We hypothesized that the inheritance pattern could follow a digenic pattern of inheritance. Screening for these polymorphisms in an unaffected sister revealed the presence of all these same variants except for that in theCAPN3 gene. All variants were studied to determine their frequency and if they had been previously reported as mutations. They were also subjected to protein modeling programs, including SIFT, PolyPhen, and MutationTaster. This analysis indicated that theCAPN3 variant c.1663G#x3e;A (rs138172448), which results in a p.Val555Ile change, and theDES gene variant c.656C#x3e;T (rs144901249), which results in a p.Thr219Ile change, are both predicted to be damaging. These 2 variants were fur...
Source: Case Reports in Neurology - Category: Neurology Source Type: research