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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.