Narrowing the Diagnostic Gap: Genomes, Episignatures, Long-Read Sequencing and Health Economic Analyses in an Exome-Negative Intellectual Disability Cohort

Genet Med. 2024 Jan 19:101076. doi: 10.1016/j.gim.2024.101076. Online ahead of print.


Purpose: Genome sequencing (GS)-specific diagnostic rates in prospective tightly ascertained exome sequencing (ES)-negative intellectual disability (ID) cohorts have not been reported extensively.

Methods: ES, GS, epigenetic signatures, and long-read sequencing diagnoses were assessed in 74 trios with at least moderate ID.

Results: The ES diagnostic yield was 42/74 (57%). GS diagnoses were made in 9/32 (28%) ES-unresolved families. Repeated ES with a contemporary pipeline on the GS-diagnosed families identified 8/9 SNVs/CNVs undetected in older ES, confirming a GS-unique diagnostic rate of 1/32 (3%). Episignatures contributed diagnostic information in 9% with GS-corroboration in 1/32 (3%) and diagnostic clues in 2/32 (6%). A genetic aetiology for ID was detected in 51/74 (69%) families. 12 candidate disease genes were identified. Contemporary ES followed by GS cost US$4,976 (95% CI: $3,704; $6,969) per diagnosis and first-line GS at a cost of $7,062 (95% CI: $6,210; $8,475) per diagnosis.

Conclusion: Performing GS only in ID trios would be cost equivalent to ES if GS were available at $2,435, about a 60% reduction from current prices. This study demonstrates that first-line GS achieves higher diagnostic rate than contemporary ES but at a higher cost.

Keywords: episignature; exome-negative; genome sequencing; health economics; intellectual disability; long read sequencing.