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Whole exome sequencing identifies a causal RBM20 mutation in a large pedigree with familial dilated cardiomyopathy.

Wells QS, Becker JR, Su YR, Mosley JD, Weeke P, D'Aoust L, Ausborn NL, Ramirez AH, Pfotenhauer JP, Naftilan AJ, Markham L, Exil V, Roden DM, Hong CC
Circ Cardiovasc Genet. 2013 6 (4): 317-26

PMID: 23861363 · PMCID: PMC3895490 · DOI:10.1161/CIRCGENETICS.113.000011

BACKGROUND - Whole exome sequencing is a powerful technique for Mendelian disease gene discovery. However, variant prioritization remains a challenge. We applied whole exome sequencing to identify the causal variant in a large family with familial dilated cardiomyopathy of unknown pathogenesis.

METHODS AND RESULTS - A large family with autosomal dominant, familial dilated cardiomyopathy was identified. Exome capture and sequencing were performed in 3 remotely related, affected subjects predicted to share <0.1% of their genomes by descent. Shared variants were filtered for rarity, evolutionary conservation, and predicted functional significance, and remaining variants were filtered against 71 locally generated exomes. Variants were also prioritized using the Variant Annotation Analysis and Search Tool. Final candidates were validated by Sanger sequencing and tested for segregation. There were 664 shared heterozygous nonsense, missense, or splice site variants, of which 26 were rare (minor allele frequency ≤0.001 or not reported) in 2 public databases. Filtering against internal exomes reduced the number of candidates to 2, and of these, a single variant (c.1907 G>A) in RBM20, segregated with disease status and was absent in unaffected internal reference exomes. Bioinformatic prioritization with Variant Annotation Analysis and Search Tool supported this result.

CONCLUSIONS - Whole exome sequencing of remotely related dilated cardiomyopathy subjects from a large, multiplex family, followed by systematic filtering, identified a causal RBM20 mutation without the need for linkage analysis.

MeSH Terms (23)

Adolescent Adult Alleles Cardiomyopathy, Dilated Child Child, Preschool Cohort Studies Computational Biology Databases, Genetic Exome Female Gene Frequency Genetic Linkage Genotype Heterozygote Humans Male Middle Aged Mutation, Missense Pedigree RNA-Binding Proteins Sequence Analysis, DNA Young Adult

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