C.P.14 A four-generation Japanese family with autosomal dominant nemaline myopathy associated with dilated cardiomyopathy

Abstract Nemaline myopathy (NEM) is the most common nondystrophic congenital mopathy. NEM is a clinically and genetically heterogeneous myopathy characterized by the presence of nemaline bodies in skeletal muscle. Cardiac muscle involvement has been shown to be rare. Seven causative genes of NEM have been identified: ACTA1 , TPM3 , TPM2 , NEB , TNNT1 , KBTBD13 and CFL2 . To study clinical characteristics and molecular genetics of a Japanese family of an autosomal dominant NEM associated with dilated cardiomyopathy (DCM). This four-generation Japanese family showed progressive proximal muscular atrophy and DCM with dominant inheritance. The type 1 predominance and nemaline rods were shown in skeletal muscles of the proband and his father. Genomic DNA was extracted from five individuals (two affected, two non-affected and one married-in). Genotyping was carried out using Affymetrix SNP Array 6.0 and parametric linkage analysis was performed using SNP HiTLink (BMC Bioinformatics 2009;10:121). Candidate genes were analyzed by the Sanger method. Results: The linkagae analysis revealed the total size of candidate region was approximately 800 Mb. By nucleotide sequence analysis, mutations were not identified in all exons of the genes for autosomal dominant NEM: ACTA1 , TPM3 and TPM2 . Parametric linkage analysis excluded the loci of the remaining all known NEM genes: NEB , TNNT1 , KBTBD13 and CFL2 . The causative genes for dominant DCM ( LMNA , LDB3 , TNNT2 , TTN , DES , EYA4 , CSRP3 , TCAP , ABCC9 , PLN , ACTC1 , MYH7 , TMPO , PSEN1 , TPM1 , ACTN2 , NEXN , RBM20 , MYH6 , TNNI3 and BAG3 ) were also excluded by the results of nucleotide sequence analysis or linkage analysis respectively. The molecular genetics study using linkage and sequencing analyses revealed the present family with dominant NEM not linked to the known seven causative genes for hereditary NEM. The present study suggested a novel causative gene for NEM with DCM.