ClinVar Genomic variation as it relates to human health

In affected members of 2 distantly related Dutch families segregating autosomal dominant myofibrillar myopathy-1 (MFM1; 601419) with a highly heterogeneous clinical picture, varying from isolated dilated cardiomyopathy to more generalized skeletal myopathy and mild respiratory problems, Bergman et al. (2007) identified heterozygosity for a c.38C-T transition in exon 1 of the DES gene, resulting in a ser13-to-phe (S13F) substitution within a highly conserved nonapeptide motif in the 'head' domain. The authors noted that the serine at position 13 serves as a phosphorylation site for protein kinase C (176960) and is required for appropriate dimer-dimer formation. The mutation was not found in unaffected family members or in 216 ethnically matched controls. Haplotype analysis confirmed the distant relationship between the 2 families, who resided in nearby villages. In a 39-year-old Chinese man who presented with complete heart block and mild proximal and distal limb weakness, Pica et al. (2008) identified heterozygosity for the S13F mutation in the DES gene. His mother and 2 sibs, who were also heterozygous for the mutation, had somewhat milder limb weakness. His affected brother also reported 2 episodes of unexplained syncope, whereas his affected sister reported episodes of palpitations. The mutation was not found in his unaffected father or in 100 unrelated controls. Transfection studies in BHK21 and MCF7 cells demonstrated a fine filamentous desmin network with both mutant and wildtype DES; however, there were significantly more large accumulations of desmin material with the S13F mutant compared to wildtype. Van Tintelen et al. (2009) restudied the Dutch kindred with MFM1 reported by Bergman et al. (2007) and expanded it to include 3 distantly related families. The authors described 2 more affected Dutch families whose ancestors could be traced to the same small, poorly populated region in which the common ancestral couple of the large Dutch kindred had lived. All 27 affected individuals were heterozygous for the S13F mutation, which was not found in 300 ethnically matched chromosomes. Based on haplotype analysis, the mutation was estimated to be between 220 and 495 years old. All affected family members demonstrated a fully penetrant yet variable, predominantly cardiologic phenotype, characterized by conduction disease at an early age and right ventricular involvement, including right bundle branch block (RBBB) and/or right ventricular tachycardias and ARVC phenocopies. Immunofluorescence of patient cardiomyocytes showed abnormal intercalated discs with a convoluted and elongated shape in a strong zigzag pattern, compared to the straight, robust lines of high intensity seen in control myocardia. These highly irregular and twisted intercalated discs were also observed on electron microscopy; however, Z discs appeared to be aligned. (less)