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 & 1 others Sally L. Dunwoodie

Research output: Contribution to journalArticle

2 Citations (Scopus)

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 languageEnglish
Pages (from-to)1111-1120
Number of pages10
JournalGenetics in Medicine
Volume21
Issue number5
DOIs
Publication statusPublished - 1 May 2019

Fingerprint

Heart Diseases
Genome
Genes
Biomedical Technology Assessment
Molecular Pathology
Live Birth
Virulence
Guidelines

Cite this

Alankarage, D., Ip, E., Szot, J. O., Munro, J., Blue, G. M., Harrison, K., ... 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
Alankarage, Dimuthu ; Ip, Eddie ; Szot, Justin O. ; Munro, Jacob ; Blue, Gillian M. ; Harrison, Katrina ; Cuny, Hartmut ; Enriquez, Annabelle ; Troup, Michael ; Humphreys, David T. ; Wilson, Meredith ; Harvey, Richard P. ; Sholler, Gary F. ; Graham, Robert M. ; Ho, Joshua W.K. ; Kirk, Edwin P. ; Pachter, Nicholas ; Chapman, Gavin ; Winlaw, David S. ; Giannoulatou, Eleni ; Dunwoodie, Sally L. / Identification of clinically actionable variants from genome sequencing of families with congenital heart disease. In: Genetics in Medicine. 2019 ; Vol. 21, No. 5. pp. 1111-1120.
@article{b305f0c6238547fe944a37ada382a240,
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.}",
year = "2019",
month = "5",
day = "1",
doi = "10.1038/s41436-018-0296-x",
language = "English",
volume = "21",
pages = "1111--1120",
journal = "Genetics in Medicine",
issn = "1098-3600",
publisher = "Nature Publishing Group - Macmillan Publishers",
number = "5",

}

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

Identification of clinically actionable variants from genome sequencing of families with congenital heart disease. / Alankarage, Dimuthu; Ip, Eddie; Szot, Justin O.; Munro, Jacob; Blue, Gillian M.; Harrison, Katrina; Cuny, Hartmut; Enriquez, Annabelle; Troup, Michael; Humphreys, David T.; Wilson, Meredith; Harvey, Richard P.; Sholler, Gary F.; Graham, Robert M.; Ho, Joshua W.K.; Kirk, Edwin P.; Pachter, Nicholas; Chapman, Gavin; Winlaw, David S.; Giannoulatou, Eleni; Dunwoodie, Sally L.

In: Genetics in Medicine, Vol. 21, No. 5, 01.05.2019, p. 1111-1120.

Research output: Contribution to journalArticle

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

UR - http://www.scopus.com/inward/record.url?scp=85054513241&partnerID=8YFLogxK

U2 - 10.1038/s41436-018-0296-x

DO - 10.1038/s41436-018-0296-x

M3 - Article

VL - 21

SP - 1111

EP - 1120

JO - Genetics in Medicine

JF - Genetics in Medicine

SN - 1098-3600

IS - 5

ER -