Whole Genome Sequencing and Analysis for Rare Pediatric Conditions

Daniel Koboldt (September 17, 2018)

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Children with rare inherited conditions are increasingly referred for clinical exome sequencing, which yields a positive finding in only ~25-35% of them. For the remaining as-yet-undiagnosed cases, research sequencing of the proband and available family members has the potential to uncover new genetic etiologies of disease. Our institute has enrolled more than 40 families suffering rare inherited conditions into a research genomics protocol. Using predominantly whole genome sequencing (WGS) of multiple family members, we have identified likely causal variants in 30% of cases and strong candidate variants in another 20%. Here, I describe the workflow of our rare disease genomics research program, including recruitment and case selection, sequencing/analysis strategies, candidate validation, and reporting of results. I will also highlight some solved cases whose underlying etiology or phenotypic association challenges the current knowledge of genotype-phenotype relationships.