Six novel mutations in the myophosphorylase gene in patients with McArdle disease and a family with pseudo-dominant inheritance pattern.

McArdle disease is an autosomal recessive glycogenosis due to deficiency of the enzyme myophosphorylase. It results from homozygous or compound heterozygous mutations in the gene for this enzyme, PYGM. We report six novel mutations in the PYGM gene based upon sequencing data including three missense mutations (p.D51G, p.P398L, and p.N648Y), one nonsense mutation (p.Y75X), one frame-shift mutation (p.Y114SfsX181), and one amino acid deletion (p.Y53del) in six patients with McArdle disease. We also report on a Caucasian family that appeared to transmit McArdle disease in an autosomal dominant manner. In order to evaluate the potential pathogenicity of the sequence variants, we performed in silico analysis using PolyPhen-2 and SIFT BLink, along with species conservation analysis using UCSC Genome Browser. The above mutations were all predicted to be disease associated with high probability and with at least the same level of certainty as several confirmed mutations. The current data add to the list of pathogenic mutations in the PYGM gene associated with McArdle disease.