Narrowing the diagnostic gap: Genomes, episignatures, long-read sequencing, and health economic analyses in an exome-negative intellectual disability cohort

Genet Med. 2024 May;26(5):101076. doi: 10.1016/j.gim.2024.101076. Epub 2024 Jan 19.


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 of 74 (57%). GS diagnoses were made in 9 of 32 (28%) ES-unresolved families. Repeated ES with a contemporary pipeline on the GS-diagnosed families identified 8 of 9 single-nucleotide variations/copy-number variations undetected in older ES, confirming a GS-unique diagnostic rate of 1 in 32 (3%). Episignatures contributed diagnostic information in 9% with GS corroboration in 1 of 32 (3%) and diagnostic clues in 2 of 32 (6%). A genetic etiology for ID was detected in 51 of 74 (69%) families. Twelve candidate disease genes were identified. Contemporary ES followed by GS cost US$4976 (95% CI: $3704; $6969) per diagnosis and first-line GS at a cost of $7062 (95% CI: $6210; $8475) per diagnosis.

Conclusion: Performing GS only in ID trios would be cost equivalent to ES if GS were available at $2435, 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Child
  • Child, Preschool
  • Cohort Studies
  • DNA Copy Number Variations / genetics
  • Exome Sequencing* / economics
  • Exome* / genetics
  • Female
  • Genetic Testing / economics
  • Genetic Testing / methods
  • Genome, Human / genetics
  • Humans
  • Intellectual Disability* / diagnosis
  • Intellectual Disability* / genetics
  • Male
  • Polymorphism, Single Nucleotide / genetics
  • Whole Genome Sequencing / economics