“Narrowing the Diagnostic Gap: Genomes, Episignatures, Long-Read Sequencing, and Health Economic Analyses in an Exome-Negative Intellectual Disability Cohort”, Kerith-Rae Dias, Rupendra Shrestha, Deborah Schofield, Carey-Anne Evans, Emily O’Heir, Ying Zhu, Futao Zhang, Krystle Standen, Ben Weisburd, Sarah L. Stenton, Alba Sanchis-Juan, Harrison Brand, Michael E. Talkowski, Alan Ma, Sondy Ghedia, Meredith Wilson, Sarah A. Sandaradura, Janine Smith, Benjamin Kamien, Anne Turner, Madhura Bakshi, Lesley C. Adès, David Mowat, Matthew Regan, George McGillivray, Ravi Savarirayan, Susan M. White, Tiong Yang Tan, Zornitza Stark, Natasha J. Brown, Luis A. Pérez-Jurado, Emma Krzesinski, Matthew F. Hunter, Lauren Akesson, Andrew Paul Fennell, Alison Yeung, Tiffany Boughtwood, Lisa J. Ewans, Jennifer Kerkhof, Christopher Lucas, Louise Carey, Hugh French, Melissa Rapadas, Igor Stevanovski, Ira W. Deveson, Corrina Cliffe, George Elakis, Edwin P. Kirk, Tracy Dudding-Byth, Janice Fletcher, Rebecca Walsh, Mark A. Corbett, Thessa Kroes, Jozef Gecz, Cliff Meldrum, Simon Cliffe, Meg Wall, Sebastian Lunke, Kathryn North, David J. Amor, Michael Field, Bekim Sadikovic, Michael F. Buckley, Anne O’Donnell-Luria, Tony Roscioli2024-01-19 (rare mutations, genome sequencing, IQ)⁠:

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

Method: 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 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 1⁄32 (3%) and diagnostic clues in 2⁄32 (6%). A genetic etiology 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]