Project Details

Early Career

Status: Funded - Open

Genome Sequencing for Pediatric Rare Disease Diagnosis

Monica Wojcik, MD


BACKGROUND: Rare disorders, many of which have an underlying genetic basis, affect up to 10% of all children and disproportionately contribute to childhood hospitalization costs, morbidity, and mortality in the United States. Although massively parallel (“next generation”) sequencing methodologies have enabled the diagnosis of many people with genetic disorders, a substantial proportion remains undiagnosed even after techniques such as exome sequencing, which involves examining the protein-coding region of the genome. As exome sequencing is used more frequently, the question of what to do for “exome negative” patients has become more pressing, as identifying a diagnosis has multiple benefits.

GAP: Genome sequencing, which has the potential to uncover disease-causing variants not identified by other techniques, seems like the logical next step after prior testing (particularly exome sequencing) is negative, though its optimal use has not been well-defined.

HYPOTHESIS: For those with phenotypes consistent with a particular genetic syndrome and non-diagnostic prior testing, genome sequencing will identify a diagnosis in at least 40%. Individuals with presentations that are highly specific for a particular genetic syndrome are more likely to be diagnosed than those with nonspecific presentations and analysis for structural and non-coding variants will be particularly high yield in this population.

METHODS: This is a clinical research study using genome sequencing to evaluate a selected cohort of pediatric patients with presentations highly specific for a monogenic disorder who remain genetically-undiagnosed (the disease-causing variant has not been found).

RESULTS: Pending.

IMPACT: In addition to directly informing clinical care by enabling the development of a practice guideline to direct the use of genome sequencing for pediatric patients, the results of this study will inform future clinical studies to determine the yield and cost-effectiveness of genome sequencing compared to exome sequencing.

Website Link: