Whole genome sequencing identifies clinically actionable variants in families with CHD

Alakarage D1, Ip E1, Szot JO1, Munro J1, Blue GM1,2,3, Pachter N4,6, Chapman G1, Winlaw DS1,2,3, Giannoulatou E1,5 and Dunwoodie SL1,5

  1. Victor Chang Cardiac Research Institute.
  2. Heart Centre for Children, The Children’s Hospital at Westmead.
  3. University of Sydney.
  4. Genetic Services of Western Australia, King Edward Memorial Hospital.
  5. University of New South Wales.
  6. University of Western Australia.

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 whole-genome sequencing (WGS) of a heterogeneous cohort of CHD patients. 97 families, with probands born with CHD requiring surgical correction, were recruited for genome sequencing. At minimum, a proband-parents trio was sequenced per family. WGS 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 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 WGS 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 WGS data.