Project Details

Reanalyzing genomic sequencing in pediatric rare disease through the lens of digenic inheritance

Sarah Stenton, MBChB, PhD

Summary

BACKGROUND: Rare genetic diseases collectively affect over 250 million people worldwide, 50% of whom are children, and pose a significant cost burden to health care systems given high morbidity and mortality. The delivery of optimal medical care by individualized treatment depends on a genetic diagnosis, however, over 60% of patients with a high suspicion of genetic disease remain undiagnosed. GAP: Current clinical practice guidelines for variant interpretation follow a monogenic disease model, focusing on identifying disease causative variants in a single gene with the phenotypic potential to cause disease. The contribution of digenic inheritance to undiagnosed pediatric rare disease is currently under explored. HYPOTHESIS: In a subset of undiagnosed children, the co-occurrence of rare damaging variants in a gene pair results in digenic disease. This gene pair will be depleted for the co-occurrence of rare damaging variants in healthy individuals. METHODS: The study utilized trio-exome and genome sequencing data from >2,000 undiagnosed families sequenced by the Broad Institute Center for Mendelian Genomics and the Rare Genome Project. Data were systematically reanalyzed to identify candidate digenic diagnoses, driven by familial segregation data, individual-level data from healthy relatives, allele frequency data from individuals without severe early-onset disease in the population database gnomAD, as well as functional annotation. RESULTS: Approximately 500 rare high-impact variant pairs, inherited in digenic heterozygosity, were detected in gene pairs with ≥1 line of evidence supporting a functional interaction, however, clinical review found no clear relevance to phenotype for the respective probands. IMPACT: Identifying candidate digenic diagnoses in undiagnosed children has the potential to enable genetic counseling (e.g., by accurate recurrence risk calculation), illuminate targeted treatment options, and may inform future development of clinical practice guidelines for digenic variant interpretation in genomic sequencing analysis. However, detection of digenic diagnoses remains a challenge and often requires the collection of large case series, as demonstrated by the recent report of digenic early-onset skeletal muscle myopathy and digenic Leigh syndrome (see co-authored publications).

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