Genetic burden and associations with adverse neurodevelopment in neonates with congenital heart disease

Gillian M Blue; Eddie Ip; Karen Walker; Edwin P Kirk; Alison Loughran-Fowlds; Gary F Sholler; Sally L Dunwoodie; Richard P Harvey; Eleni Giannoulatou; Nadia Badawi; David S Winlaw

doi:10.1016/j.ahj.2018.03.021

Genetic burden and associations with adverse neurodevelopment in neonates with congenital heart disease

Am Heart J. 2018 Jul:201:33-39. doi: 10.1016/j.ahj.2018.03.021. Epub 2018 Apr 5.

Authors

Affiliations

¹ Kids Heart Research, The Children's Hospital at Westmead, Sydney, Australia; Heart Centre for Children, The Children's Hospital at Westmead, Sydney, Australia; Sydney Medical School, University of Sydney, Sydney, Australia.
² Victor Chang Cardiac Research Institute, Darlinghurst, Sydney, Australia.
³ Sydney Medical School, University of Sydney, Sydney, Australia; Grace Centre for Newborn Care, The Children's Hospital at Westmead, Sydney, Australia; Cerebral Palsy Alliance Research Institute, Discipline of Child and Adolescent Health, University of Sydney, Sydney, Australia.
⁴ Centre for Clinical Genetics, Sydney Children's Hospital, Sydney, Australia; School of Women's and Children's Health, Faculty of Medicine, University of New South Wales, Sydney, Australia.
⁵ Sydney Medical School, University of Sydney, Sydney, Australia; Grace Centre for Newborn Care, The Children's Hospital at Westmead, Sydney, Australia.
⁶ Victor Chang Cardiac Research Institute, Darlinghurst, Sydney, Australia; St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia.
⁷ Victor Chang Cardiac Research Institute, Darlinghurst, Sydney, Australia; St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia; School of Biotechnology and Biomolecular Sciences, University of New South Wales, Kensington, Sydney, Australia.
⁸ Kids Heart Research, The Children's Hospital at Westmead, Sydney, Australia; Heart Centre for Children, The Children's Hospital at Westmead, Sydney, Australia; Sydney Medical School, University of Sydney, Sydney, Australia. Electronic address: david.winlaw@health.nsw.gov.au.

PMID: 29910053
DOI: 10.1016/j.ahj.2018.03.021

Abstract

Background: Up to 20% of children with congenital heart disease (CHD) undergoing cardiac surgery develop neurodevelopmental disabilities (NDD), with some studies reporting persistent impairment. Recent large-scale studies have demonstrated shared genetic mechanisms contributing to CHD and NDD. In this study, a targeted approach was applied to assess direct clinical applicability of this information.

Methods: A gene panel comprising 148 known CHD and/or NDD genes was used to sequence 15 patients with CHD + NDD, 15 patients with CHD, and 15 healthy controls. The number and types of variants between the 3 groups were compared using Poisson log-linear regression, and the SNP-set (Sequence) Kernel Association Test-Optimized was used to conduct single-gene and gene-pathway burden analyses.

Results: A significant increase in rare (minor allele frequency < 0.01) and novel variants was identified between the CHD + NDD cohort and controls, P < .001 and P = .001, respectively. There was also a significant increase in rare variants in the CHD cohort compared with controls (P = .04). Rare variant burden analyses implicated pathways associated with "neurotransmitters," "axon guidance," and those incorporating "RASopathy" genes in the development of NDD in CHD patients.

Conclusions: These findings suggest that an increase in novel and rare variants in known CHD and/or NDD genes is associated with the development of NDD in patients with CHD. Furthermore, burden analyses point toward rare variant burden specifically in pathways related to brain development and function as contributors to NDD. Although promising variants and pathways were identified, further research, utilizing whole-genome approaches, is required prior to demonstrating clinical utility in this patient group.

MeSH terms

Cardiac Surgical Procedures
DNA / genetics*
Female
Follow-Up Studies
Gene Frequency
Heart Defects, Congenital / genetics*
Heart Defects, Congenital / surgery
Humans
Infant, Newborn
Male
Neurodevelopmental Disorders / genetics*
Polymorphism, Single Nucleotide*
Retrospective Studies

Substances

DNA