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

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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.


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.


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.


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.

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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.

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Correspondence to Sally L. Dunwoodie BSc, PhD.

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Alankarage, D., Ip, E., Szot, J.O. et al. Identification of clinically actionable variants from genome sequencing of families with congenital heart disease. Genet Med 21, 1111–1120 (2019) doi:10.1038/s41436-018-0296-x

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  • congenital heart disease
  • genetic diagnosis
  • genome sequencing
  • clinical utility
  • ACMG

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