Whole-genome DNA/RNA sequencing identifies truncating mutations in RBCK1 in a novel Mendelian disease with neuromuscular and cardiac involvement
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Date
2013
Authors
Otieno, F. G.
Wang, Kai
Kim, Cecilia
Bradfield, Jonathan
Guo, Yunfei
Toskala, Elina
Hou, Cuiping
Thomas, Kelly
Cardinale, Christopher
Lyon, Gholson J
Journal Title
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Volume Title
Publisher
BioMed Central
Abstract
Background: Whole-exome sequencing has identified the causes of several Mendelian diseases by analyzing multiple
unrelated cases, but it is more challenging to resolve the cause of extremely rare and suspected Mendelian diseases
from individual families. We identified a family quartet with two children, both affected with a previously unreported
disease, characterized by progressive muscular weakness and cardiomyopathy, with normal intelligence. During the
course of the study, we identified one additional unrelated patient with a comparable phenotype.
Methods: We performed whole-genome sequencing (Complete Genomics platform), whole-exome sequencing
(Agilent SureSelect exon capture and Illumina Genome Analyzer II platform), SNP genotyping (Illumina
HumanHap550 SNP array) and Sanger sequencing on blood samples, as well as RNA-Seq (Illumina HiSeq platform)
on transformed lymphoblastoid cell lines.
Results: From whole-genome sequence data, we identified RBCK1, a gene encoding an E3 ubiquitin-protein ligase,
as the most likely candidate gene, with two protein-truncating mutations in probands in the first family. However,
exome data failed to nominate RBCK1 as a candidate gene, due to poor regional coverage. Sanger sequencing
identified a private homozygous splice variant in RBCK1 in the proband in the second family, yet SNP genotyping
revealed a 1.2Mb copy-neutral region of homozygosity covering RBCK1. RNA-Seq confirmed aberrant splicing of
RBCK1 transcripts, resulting in truncated protein products.
Conclusions: While the exact mechanism by which these mutations cause disease is unknown, our study
represents an example of how the combined use of whole-genome DNA and RNA sequencing can identify a
disease-predisposing gene for a novel and extremely rare Mendelian diseas
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Citation
Wang et al. Genome Medicine 2013, 5:67