Identification of clinically actionable variants from genome sequencing of families with congenital heart disease

Dimuthu Alankarage; Eddie Ip; Justin O. Szot; Jacob Munro; Gillian M. Blue; Katrina Harrison; Hartmut Cuny; Annabelle Enriquez; Michael Troup; David T. Humphreys; Meredith Wilson; Richard P. Harvey; Gary F. Sholler; Robert M. Graham; Joshua W.K. Ho; Edwin P. Kirk; Nicholas Pachter; Gavin Chapman; David S. Winlaw; Eleni Giannoulatou; Sally L. Dunwoodie

doi:10.1038/s41436-018-0296-x

Identification of clinically actionable variants from genome sequencing of families with congenital heart disease

Dimuthu Alankarage, Eddie Ip, Justin O. Szot, Jacob Munro, Gillian M. Blue, Katrina Harrison, Hartmut Cuny, Annabelle Enriquez, Michael Troup, David T. Humphreys, Meredith Wilson, Richard P. Harvey, Gary F. Sholler, Robert M. Graham, Joshua W.K. Ho, Edwin P. Kirk, Nicholas Pachter, Gavin Chapman, David S. Winlaw, Eleni GiannoulatouSally L. Dunwoodie^*

^*Corresponding author for this work

Surgery

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

65 Scopus citations

Abstract

Purpose: Congenital heart disease (CHD) affects up to 1% of live births. However, a genetic diagnosis is not made in most cases. The purpose of this study was to assess the outcomes of genome sequencing (GS) of a heterogeneous cohort of CHD patients. Methods: Ninety-seven families with probands born with CHD requiring surgical correction were recruited for genome sequencing. At minimum, a proband–parents trio was sequenced per family. GS data were analyzed via a two-tiered method: application of a high-confidence gene screen (hcCHD), and comprehensive analysis. Identified variants were assessed for pathogenicity using the American College of Medical Genetics and Genomics–Association for Molecular Pathology (ACMG-AMP) guidelines. Results: Clinically relevant genetic variants in known and emerging CHD genes were identified. The hcCHD screen identified a clinically actionable variant in 22% of families. Subsequent comprehensive analysis identified a clinically actionable variant in an additional 9% of families in genes with recent disease associations. Overall, this two-tiered approach provided a clinically relevant variant for 31% of families. Conclusions: Interrogating GS data using our two-tiered method allowed identification of variants with high clinical utility in a third of our heterogeneous cohort. However, association of emerging genes with CHD etiology, and development of novel technologies for variant assessment and interpretation, will increase diagnostic yield during future reassessment of our GS data.

Original language	English (US)
Pages (from-to)	1111-1120
Number of pages	10
Journal	Genetics in Medicine
Volume	21
Issue number	5
DOIs	https://doi.org/10.1038/s41436-018-0296-x
State	Published - May 1 2019

Funding

This work was supported by the National Health and Medical Research Council (NHMRC) (fellowships ID1135886, ID1042002 to S.L.D., ID573732 to R.P.H, and ID1105271 to J.W.K.H. and program grant ID1074386 to R.P.H., R.M.G., S.L.D.); Australian National Heart Foundation (fellowship ID100848 to J.W.K.H. and ID101204 to E.G.); Australian Postgraduate Award (UNSW) (J.O. S., E.I.); Office of Health and Medical Research NSW Government to S.L.D., R.P.H, R.M.G; Chain Reaction (The Ultimate Corporate Bike Challenge) to S.L.D.; Channel 7 Telethon to S.L.D., R.M.G.; and The Key Foundation to S.L.D. The authors would like to thank all families who took part in the study. The authors also thank Elizabeth Anderson for assistance with analysis.

Keywords

ACMG
clinical utility
congenital heart disease
genetic diagnosis
genome sequencing

ASJC Scopus subject areas

Genetics(clinical)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41436-018-0296-x

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Alankarage, D., Ip, E., Szot, J. O., Munro, J., Blue, G. M., Harrison, K., Cuny, H., Enriquez, A., Troup, M., Humphreys, D. T., Wilson, M., Harvey, R. P., Sholler, G. F., Graham, R. M., Ho, J. W. K., Kirk, E. P., Pachter, N., Chapman, G., Winlaw, D. S., ... Dunwoodie, S. L. (2019). Identification of clinically actionable variants from genome sequencing of families with congenital heart disease. Genetics in Medicine, 21(5), 1111-1120. https://doi.org/10.1038/s41436-018-0296-x

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title = "Identification of clinically actionable variants from genome sequencing of families with congenital heart disease",

abstract = "Purpose: Congenital heart disease (CHD) affects up to 1% of live births. However, a genetic diagnosis is not made in most cases. The purpose of this study was to assess the outcomes of genome sequencing (GS) of a heterogeneous cohort of CHD patients. Methods: Ninety-seven families with probands born with CHD requiring surgical correction were recruited for genome sequencing. At minimum, a proband–parents trio was sequenced per family. GS data were analyzed via a two-tiered method: application of a high-confidence gene screen (hcCHD), and comprehensive analysis. Identified variants were assessed for pathogenicity using the American College of Medical Genetics and Genomics–Association for Molecular Pathology (ACMG-AMP) guidelines. Results: Clinically relevant genetic variants in known and emerging CHD genes were identified. The hcCHD screen identified a clinically actionable variant in 22% of families. Subsequent comprehensive analysis identified a clinically actionable variant in an additional 9% of families in genes with recent disease associations. Overall, this two-tiered approach provided a clinically relevant variant for 31% of families. Conclusions: Interrogating GS data using our two-tiered method allowed identification of variants with high clinical utility in a third of our heterogeneous cohort. However, association of emerging genes with CHD etiology, and development of novel technologies for variant assessment and interpretation, will increase diagnostic yield during future reassessment of our GS data.",

keywords = "ACMG, clinical utility, congenital heart disease, genetic diagnosis, genome sequencing",

author = "Dimuthu Alankarage and Eddie Ip and Szot, {Justin O.} and Jacob Munro and Blue, {Gillian M.} and Katrina Harrison and Hartmut Cuny and Annabelle Enriquez and Michael Troup and Humphreys, {David T.} and Meredith Wilson and Harvey, {Richard P.} and Sholler, {Gary F.} and Graham, {Robert M.} and Ho, {Joshua W.K.} and Kirk, {Edwin P.} and Nicholas Pachter and Gavin Chapman and Winlaw, {David S.} and Eleni Giannoulatou and Dunwoodie, {Sally L.}",

note = "Publisher Copyright: {\textcopyright} 2018, American College of Medical Genetics and Genomics.",

year = "2019",

month = may,

day = "1",

doi = "10.1038/s41436-018-0296-x",

language = "English (US)",

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Alankarage, D, Ip, E, Szot, JO, Munro, J, Blue, GM, Harrison, K, Cuny, H, Enriquez, A, Troup, M, Humphreys, DT, Wilson, M, Harvey, RP, Sholler, GF, Graham, RM, Ho, JWK, Kirk, EP, Pachter, N, Chapman, G, Winlaw, DS, Giannoulatou, E & Dunwoodie, SL 2019, 'Identification of clinically actionable variants from genome sequencing of families with congenital heart disease', Genetics in Medicine, vol. 21, no. 5, pp. 1111-1120. https://doi.org/10.1038/s41436-018-0296-x

TY - JOUR

T1 - Identification of clinically actionable variants from genome sequencing of families with congenital heart disease

AU - Alankarage, Dimuthu

AU - Ip, Eddie

AU - Szot, Justin O.

AU - Munro, Jacob

AU - Blue, Gillian M.

AU - Harrison, Katrina

AU - Cuny, Hartmut

AU - Enriquez, Annabelle

AU - Troup, Michael

AU - Humphreys, David T.

AU - Wilson, Meredith

AU - Harvey, Richard P.

AU - Sholler, Gary F.

AU - Graham, Robert M.

AU - Ho, Joshua W.K.

AU - Kirk, Edwin P.

AU - Pachter, Nicholas

AU - Chapman, Gavin

AU - Winlaw, David S.

AU - Giannoulatou, Eleni

AU - Dunwoodie, Sally L.

PY - 2019/5/1

Y1 - 2019/5/1

N2 - Purpose: Congenital heart disease (CHD) affects up to 1% of live births. However, a genetic diagnosis is not made in most cases. The purpose of this study was to assess the outcomes of genome sequencing (GS) of a heterogeneous cohort of CHD patients. Methods: Ninety-seven families with probands born with CHD requiring surgical correction were recruited for genome sequencing. At minimum, a proband–parents trio was sequenced per family. GS data were analyzed via a two-tiered method: application of a high-confidence gene screen (hcCHD), and comprehensive analysis. Identified variants were assessed for pathogenicity using the American College of Medical Genetics and Genomics–Association for Molecular Pathology (ACMG-AMP) guidelines. Results: Clinically relevant genetic variants in known and emerging CHD genes were identified. The hcCHD screen identified a clinically actionable variant in 22% of families. Subsequent comprehensive analysis identified a clinically actionable variant in an additional 9% of families in genes with recent disease associations. Overall, this two-tiered approach provided a clinically relevant variant for 31% of families. Conclusions: Interrogating GS data using our two-tiered method allowed identification of variants with high clinical utility in a third of our heterogeneous cohort. However, association of emerging genes with CHD etiology, and development of novel technologies for variant assessment and interpretation, will increase diagnostic yield during future reassessment of our GS data.

AB - Purpose: Congenital heart disease (CHD) affects up to 1% of live births. However, a genetic diagnosis is not made in most cases. The purpose of this study was to assess the outcomes of genome sequencing (GS) of a heterogeneous cohort of CHD patients. Methods: Ninety-seven families with probands born with CHD requiring surgical correction were recruited for genome sequencing. At minimum, a proband–parents trio was sequenced per family. GS data were analyzed via a two-tiered method: application of a high-confidence gene screen (hcCHD), and comprehensive analysis. Identified variants were assessed for pathogenicity using the American College of Medical Genetics and Genomics–Association for Molecular Pathology (ACMG-AMP) guidelines. Results: Clinically relevant genetic variants in known and emerging CHD genes were identified. The hcCHD screen identified a clinically actionable variant in 22% of families. Subsequent comprehensive analysis identified a clinically actionable variant in an additional 9% of families in genes with recent disease associations. Overall, this two-tiered approach provided a clinically relevant variant for 31% of families. Conclusions: Interrogating GS data using our two-tiered method allowed identification of variants with high clinical utility in a third of our heterogeneous cohort. However, association of emerging genes with CHD etiology, and development of novel technologies for variant assessment and interpretation, will increase diagnostic yield during future reassessment of our GS data.

KW - ACMG

KW - clinical utility

KW - congenital heart disease

KW - genetic diagnosis

KW - genome sequencing

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ER -

Identification of clinically actionable variants from genome sequencing of families with congenital heart disease

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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