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  • whole-genome dna/rna sequencing identifies truncating mutations in rbck1 in a novel mendelian disease with neuromuscular and cardiac involvement

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    • تاریخ ارائه: 1392/07/24
    • تاریخ انتشار در تی پی بین: 1392/07/24
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    background: whole-exome sequencing has identified the causes of several mendelian diseases by analyzing multipleunrelated cases, but it is more challenging to resolve the cause of extremely rare and suspected mendelian diseasesfrom individual families. we identified a family quartet with two children, both affected with a previously unreporteddisease, characterized by progressive muscular weakness and cardiomyopathy, with normal intelligence. during thecourse 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 (illuminahumanhap550 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 sequencingidentified a private homozygous splice variant in rbck1 in the proband in the second family, yet snp genotypingrevealed a 1.2mb copy-neutral region of homozygosity covering rbck1. rna-seq confirmed aberrant splicing ofrbck1 transcripts, resulting in truncated protein products. conclusions: while the exact mechanism by which these mutations cause disease is unknown, our studyrepresents an example of how the combined use of whole-genome dna and rna sequencing can identify adisease-predisposing gene for a novel and extremely rare mendelian disease.

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