Whole-genome DNA/RNA sequencing identifies truncating mutations in RBCK1 in a novel Mendelian disease with neuromuscular and cardiac involvement

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dc.contributor.authorOtieno, F. G.
dc.contributor.authorWang, Kai
dc.contributor.authorKim, Cecilia
dc.contributor.authorBradfield, Jonathan
dc.contributor.authorGuo, Yunfei
dc.contributor.authorToskala, Elina
dc.contributor.authorHou, Cuiping
dc.contributor.authorThomas, Kelly
dc.contributor.authorCardinale, Christopher
dc.contributor.authorLyon, Gholson J
dc.contributor.authorGolhar, Ryan
dc.contributor.authorHakonarson, Hakon
dc.date.accessioned2014-11-18T09:58:44Z
dc.date.available2014-11-18T09:58:44Z
dc.date.issued2013
dc.description.abstractBackground: 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 diseasen_US
dc.identifier.citationWang et al. Genome Medicine 2013, 5:67en_US
dc.identifier.other1756-994X
dc.identifier.urihttp://www.biomedcentral.com/content/pdf/gm471.pdf
dc.identifier.urihttp://ir-library.ku.ac.ke/handle/123456789/11695
dc.language.isoenen_US
dc.publisherBioMed Centralen_US
dc.titleWhole-genome DNA/RNA sequencing identifies truncating mutations in RBCK1 in a novel Mendelian disease with neuromuscular and cardiac involvementen_US
dc.typeArticleen_US
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