We hypothesized that any causative familial mutation would be novel or rare because the proband had previously undergone negative commercial screening (CardioChip, Laboratory for Molecular Medicine, Partners HealthCare Center for Personalized Genetic Medicine, Cambridge, MA) for clinically significant variants in the coding regions and splice sites of 19 DCM genes, including ABCC9, ACTC, ACTN2, CSRP3, CTF1, DES, EMD, LDB3, LMNA, MYBPC3, MYH7, PLN, SGCD, TAZ, TCAP, TNNI3, TNNT2, TPM1, and VCL. We describe how analyzing exome sequence data from distantly related individuals in the kindred, in conjunction with internally generated reference exome sequences, allowed identification of a causative variant in RBM20. 8 – 10 In this study, WES was performed in a large, multiplex family with familial DCM of unknown cause. 7 Advances in next-generation sequencing have made whole exome sequencing (WES) a viable, powerful approach to study Mendelian disorders. The coding portion of the genome, or exome, is 1% to 3% of the genome but contains a majority of the alleles underlying known monogenic disorders, and therefore represents a highly enriched target for identifying disease-causing genes. Commercial testing that surveys coding regions and splice sites of the most common known DCM genes will not detect variants in genes that are novel or rarely implicated, and the sensitivity of commercial testing for identification of a causal variant is ≈35%. 4, 5 However, the genetic basis of most cases of familial DCM is currently unknown. There is considerable genetic heterogeneity, and implicated genes encode proteins subserving a range of functions, such as sarcomeric or cytoskeletal integrity, ion transport, and nuclear membrane or mitochondrial function. 2, 3 More than 30 genes have been linked to familial DCM, and the disorder most often has autosomal dominant inheritance.
1 Approximately 25% to 50% of DCM cases initially diagnosed as idiopathic are familial, suggesting a genetic pathogenesis. In the absence of an identifiable cause, dilated cardiomyopathy (DCM) is labeled idiopathic. Bioinformatic prioritization with Variant Annotation Analysis and Search Tool supported this result.ĭilated cardiomyopathy is a common disorder characterized by left ventricular enlargement and reduced systolic function. Exome capture and sequencing were performed in 3 remotely related, affected subjects predicted to share A) in RBM20, segregated with disease status and was absent in unaffected internal reference exomes. Customer Service and Ordering InformationĪ large family with autosomal dominant, familial dilated cardiomyopathy was identified.Stroke: Vascular and Interventional Neurology.
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