Exome Analysis of Two Limb-Girdle Muscular Dystrophy Families: Mutations Identified and Challenges Encountered
McDonald K.K. Stajich J. Blach C. Ashley-Koch A.E.
McDonald K.K.
Stajich J.
Blach C.
Ashley-Koch A.E.
An error occurred retrieving the object's statistics
Citations
Altmetric:
Alternative Title
Abstract
The molecular diagnosis of muscle disorders is challenging: genetic heterogeneity (>100 causal genes for skeletal and cardiac muscle disease) precludes exhaustive clinical testing, prioritizing sequencing of specific genes is difficult due to the similarity of clinical presentation, and the number of variants returned through exome sequencing can make the identification of the disease-causing variant difficult. We have filtered variants found through exome sequencing by prioritizing variants in genes known to be involved in muscle disease while examining the quality and depth of coverage of those genes. We ascertained two families with autosomal dominant limb-girdle muscular dystrophy of unknown etiology. To identify the causal mutations in these families, we performed exome sequencing on five affected individuals using the Agilent SureSelect Human All Exon 50 Mb kit and the Illumina HiSeq 2000 (2×100 bp). We identified causative mutations in desmin (IVS3+3A>G) and filamin C (p.W2710X), and augmented the phenotype data for individuals with muscular dystrophy due to these mutations. We also discuss challenges encountered due to depth of coverage variability at specific sites and the annotation of a functionally proven splice site variant as an intronic variant. © 2012 McDonald et al.
Keywords
creatine kinase, desmin, adolescent, article, autosomal dominant inheritance, child, clinical article, desmin gene, exome, exome sequencing, filamin C gene, gene, gene mutation, genetic variability, genotype phenotype correlation, human, intron, limb girdle muscular dystrophy, muscle weakness, mutational analysis, nonhuman, pedigree analysis, school child, sequence analysis, Adolescent, Adult, Child, Contractile Proteins, Desmin, Exome, Exons, Female, Genotype, Humans, Male, Microfilament Proteins, Middle Aged, Muscular Dystrophies, Limb-Girdle, Mutation, Pedigree, Phenotype, Sequence Analysis, DNA
Source Title
PLoS ONE
Publisher
Series/Report No.
Collections
Rights
Attribution 4.0 International
Date
2012
DOI
10.1371/journal.pone.0048864
Type
Article