A family quartet was found 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, one additional unrelated patient was found with a comparable phenotype. From whole-genome sequence data, RBCK1, a gene encoding an E3 ubiquitin-protein ligase, was identified as the most likely candidate gene, with two protein-truncating mutations in
probands in the first family.
Sanger sequencing identified a private homozygous
splice variant in RBCK1 in the proband in the second family, yet
single-nucleotide polymorphism (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. Ten other individuals with mutations in RBCK1 and overlapping phenotypes have been identified. == References ==