C.P.6 Study of a novel autosomal recessive minicore disease

Abstract

Minicore disease is a congenital myopathy of early onset, defined pathologically by the presence of multiple areas of reduced mitochondrial oxidative activity in muscle biopsies. There are currently three types of minicore disease defined; minicore myopathy with external ophthalmoplegia, caused by mutations in the RYR1 gene; minicore disease, severe classic form, caused by mutations in the SEPN1 gene and minicore myopathy, antenatal onset with arthrogryposis, with no associated disease gene. A family with three affected sibs was studied. The parents are unaffected and not known to be related, and the phenotype is consistent. The affected sibs presented at birth with extreme generalised hypotonia. There was marked delay in motor milestones, with walking only achieved after 2years of age. Neck, trunk and facial weakness was moderate, and there was moderate reduction in respiratory muscle strength. The heart was unaffected and intelligence preserved. Muscle biopsy of the quadriceps showed minicores on oxidative stains. This phenotype was not consistent with the described phenotypes of minicore disease, suggesting that this is a novel minicore disease phenotype. We combined linkage analysis with exome capture and next generation sequencing to attempt to identify the causative mutation in this family. SNP linkage analysis under a recessive model eliminated all known congenital myopathy, minicore disease and muscular dystrophy genes except for TTN, POMT1, SGCA, DMN2, and COL6A1. Subsequently, whole exome sequencing data eliminated all genes in the list except for TTN, in which two heterozygous variants were identified. Further investigation of these variants in the family found that both variants were inherited from the unaffected father, suggesting that these variants are not the cause of the disease in this family. Thus, it is suspected that a novel disease gene is the cause of this family’s disease.