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. Ades; David Mowat; Matthew Regan; George McGillivray; Ravi Savarirayan; Susan M. White; Tiong Yang Tan; Zornitza Stark; Natasha J. Brown; Luis A. Pérez-Jurado; Emma I. 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 Roscioli

doi:10.1016/j.gim.2024.101076

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 TurnerMadhura Bakshi, Lesley C. Ades, David Mowat, Matthew Regan, George McGillivray, Ravi Savarirayan, Susan M. White, Tiong Yang Tan, Zornitza Stark, Natasha J. Brown, Luis A. Pérez-Jurado, Emma I. 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 Roscioli

Macquarie Business School

Research output: Contribution to journal › Article › peer-review

4 Citations (Scopus)

Abstract

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.

Original language	English
Article number	101076
Pages (from-to)	1-13
Number of pages	13
Journal	Genetics in Medicine
Volume	26
Issue number	5
DOIs	https://doi.org/10.1016/j.gim.2024.101076
Publication status	Published - May 2024

Keywords

episignature
exome negative
genome sequencing
health economics
intellectual disability

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10.1016/j.gim.2024.101076

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Dias, K.-R., Shrestha, R., Schofield, D., Evans, C. A., O’Heir, E., Zhu, Y., Zhang, F., Standen, K., Weisburd, B., Stenton, S. L., Sanchis-Juan, A., Brand, H., Talkowski, M. E., Ma, A., Ghedia, S., Wilson, M., Sandaradura, S. A., Smith, J., Kamien, B., ... Roscioli, T. (2024). Narrowing the diagnostic gap: Genomes, episignatures, long-read sequencing and health economic analyses in an exome-negative intellectual disability cohort. Genetics in Medicine, 26(5), 1-13. Article 101076. https://doi.org/10.1016/j.gim.2024.101076

@article{43d1c914a8314be1a2dcd719777c9506,

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

abstract = "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",

author = "Kerith-Rae Dias and Rupendra Shrestha and Deborah Schofield and Evans, {Carey Anne} and Emily O{\textquoteright}Heir and Ying Zhu and Futao Zhang and Krystle Standen and Ben Weisburd and Stenton, {Sarah L.} and Alba Sanchis-Juan and Harrison Brand and Talkowski, {Michael E.} and Alan Ma and Sondy Ghedia and Meredith Wilson and Sandaradura, {Sarah A.} and Janine Smith and Benjamin Kamien and Anne Turner and Madhura Bakshi and Ades, {Lesley C.} and David Mowat and Matthew Regan and George McGillivray and Ravi Savarirayan and White, {Susan M.} and Tan, {Tiong Yang} and Zornitza Stark and Brown, {Natasha J.} and P{\'e}rez-Jurado, {Luis A.} and Krzesinski, {Emma I.} and Hunter, {Matthew F.} and Lauren Akesson and Fennell, {Andrew Paul} and Alison Yeung and Tiffany Boughtwood and Ewans, {Lisa J.} and Jennifer Kerkhof and Christopher Lucas and Louise Carey and Hugh French and Melissa Rapadas and Igor Stevanovski and Deveson, {Ira W.} and Corrina Cliffe and George Elakis and Kirk, {Edwin P} and Tracy Dudding-Byth and Janice Fletcher and Rebecca Walsh and Corbett, {Mark A.} and Thessa Kroes and Jozef Gecz and Cliff Meldrum and Simon Cliffe and Meg Wall and Sebastian Lunke and Kathryn North and Amor, {David J.} and Michael Field and Bekim Sadikovic and Buckley, {Michael F.} and Anne O{\textquoteright}Donnell-Luria and Tony Roscioli",

year = "2024",

month = may,

doi = "10.1016/j.gim.2024.101076",

language = "English",

volume = "26",

pages = "1--13",

journal = "Genetics in Medicine",

issn = "1098-3600",

publisher = "Elsevier",

number = "5",

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Dias, K-R, Shrestha, R, Schofield, D, Evans, CA, O’Heir, E, Zhu, Y, Zhang, F, Standen, K, Weisburd, B, Stenton, SL, Sanchis-Juan, A, Brand, H, Talkowski, ME, Ma, A, Ghedia, S, Wilson, M, Sandaradura, SA, Smith, J, Kamien, B, Turner, A, Bakshi, M, Ades, LC, Mowat, D, Regan, M, McGillivray, G, Savarirayan, R, White, SM, Tan, TY, Stark, Z, Brown, NJ, Pérez-Jurado, LA, Krzesinski, EI, Hunter, MF, Akesson, L, Fennell, AP, Yeung, A, Boughtwood, T, Ewans, LJ, Kerkhof, J, Lucas, C, Carey, L, French, H, Rapadas, M, Stevanovski, I, Deveson, IW, Cliffe, C, Elakis, G, Kirk, EP, Dudding-Byth, T, Fletcher, J, Walsh, R, Corbett, MA, Kroes, T, Gecz, J, Meldrum, C, Cliffe, S, Wall, M, Lunke, S, North, K, Amor, DJ, Field, M, Sadikovic, B, Buckley, MF, O’Donnell-Luria, A & Roscioli, T 2024, 'Narrowing the diagnostic gap: Genomes, episignatures, long-read sequencing and health economic analyses in an exome-negative intellectual disability cohort', Genetics in Medicine, vol. 26, no. 5, 101076, pp. 1-13. https://doi.org/10.1016/j.gim.2024.101076

TY - JOUR

T1 - Narrowing the diagnostic gap

T2 - Genomes, episignatures, long-read sequencing and health economic analyses in an exome-negative intellectual disability cohort

AU - Dias, Kerith-Rae

AU - Shrestha, Rupendra

AU - Schofield, Deborah

AU - Evans, Carey Anne

AU - O’Heir, Emily

AU - Zhu, Ying

AU - Zhang, Futao

AU - Standen, Krystle

AU - Weisburd, Ben

AU - Stenton, Sarah L.

AU - Sanchis-Juan, Alba

AU - Brand, Harrison

AU - Talkowski, Michael E.

AU - Ma, Alan

AU - Ghedia, Sondy

AU - Wilson, Meredith

AU - Sandaradura, Sarah A.

AU - Smith, Janine

AU - Kamien, Benjamin

AU - Turner, Anne

AU - Bakshi, Madhura

AU - Ades, Lesley C.

AU - Mowat, David

AU - Regan, Matthew

AU - McGillivray, George

AU - Savarirayan, Ravi

AU - White, Susan M.

AU - Tan, Tiong Yang

AU - Stark, Zornitza

AU - Brown, Natasha J.

AU - Pérez-Jurado, Luis A.

AU - Krzesinski, Emma I.

AU - Hunter, Matthew F.

AU - Akesson, Lauren

AU - Fennell, Andrew Paul

AU - Yeung, Alison

AU - Boughtwood, Tiffany

AU - Ewans, Lisa J.

AU - Kerkhof, Jennifer

AU - Lucas, Christopher

AU - Carey, Louise

AU - French, Hugh

AU - Rapadas, Melissa

AU - Stevanovski, Igor

AU - Deveson, Ira W.

AU - Cliffe, Corrina

AU - Elakis, George

AU - Kirk, Edwin P

AU - Dudding-Byth, Tracy

AU - Fletcher, Janice

AU - Walsh, Rebecca

AU - Corbett, Mark A.

AU - Kroes, Thessa

AU - Gecz, Jozef

AU - Meldrum, Cliff

AU - Cliffe, Simon

AU - Wall, Meg

AU - Lunke, Sebastian

AU - North, Kathryn

AU - Amor, David J.

AU - Field, Michael

AU - Sadikovic, Bekim

AU - Buckley, Michael F.

AU - O’Donnell-Luria, Anne

AU - Roscioli, Tony

PY - 2024/5

Y1 - 2024/5

N2 - 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.

AB - 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.

KW - episignature

KW - exome negative

KW - genome sequencing

KW - health economics

KW - intellectual disability

UR - http://www.scopus.com/inward/record.url?scp=85187212699&partnerID=8YFLogxK

U2 - 10.1016/j.gim.2024.101076

DO - 10.1016/j.gim.2024.101076

M3 - Article

C2 - 38258669

SN - 1098-3600

VL - 26

SP - 1

EP - 13

JO - Genetics in Medicine

JF - Genetics in Medicine

IS - 5

M1 - 101076

ER -

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

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