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Clinical Exome Reanalyses Reveals Recessive Disease Cases With Second Heterozygous Variants

For a paper appearing in the European Journal of Human Genetics, investigators at Boston Children's Hospital, Harvard Medical School, the Broad Institute, and Duke University outline two autosomal recessive (AR) disease cases in which distinct heterozygous variants on the maternal and paternal versions of a gene were only found after clinical exome sequence reanalysis. From a set of 102 still-to-be-diagnosed AR cases profiled by clinical exome sequencing for a prior pilot study, the team used an in-house variant calling pipeline to reanalyze variants, unearthing heterozygous second variants in 18-month-old and nine-year-old patients with highlighted RYR1- or BBS1-related conditions, respectively. In both cases the initial analysis flagged suspicious variants on maternal alleles, but paternal allele alterations were only found with reanalysis. "Similar cases have been reported in only a tiny fraction of reanalysis diagnoses, suggesting that this aspect of reanalysis needs further evaluation," write, noting that the study "highlights the utility of [clinical exome sequence] reanalysis in undiagnosed AR cases when only a single variant in a disease-associated gene has been identified."