Human Mutation

Funding information National Institute of General Medical Sciences, Grant/Award Numbers: R01GM104436, R01GM120364; National Human Genome Research Institute, Grant/ Award Numbers: R13HG006650, U41HG007346 Abstract Precise identification of causative variants from whole‐genome sequencing data, including both coding and noncoding variants, is challenging. The Critical Assessment of Genome Interpretation 5 SickKids clinical genome challenge provided an opportunity to assess our ability to extract such information. Participants in the challenge were required to match each of the 24 whole‐genome sequences to the correct phenotypic profile and to identify the disease class of each genome. These are all rare disease cases that have resisted genetic diagnosis in a state‐of‐the‐art pipeline. The patients have a range of eye, neurological, and connective‐tissue disorders. We used a gene‐centric approach to address this problem, assigning each gene a multiphenotype‐matching score. Mutations in the top‐scoring genes for each phenotype profile were ranked on a 6‐point scale of pathogenicity probability, resulting in an approximately equal number of top‐ranked coding and noncoding candidate variants overall. We were able to assign the correct disease class for 12 cases and the correct genome to a clinical profile for five cases. The challenge assessor found genes in three of these five cases as likely appropriate. In the postsubmission phase, after careful screening of the genes in the correct genome, we identified additional potential diagnostic variants, a high proportion of which are noncoding.

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