The Cardiac Genome Clinic: implementing genome sequencing in pediatric heart disease

Abstract

Purpose This study investigated the diagnostic utility of nontargeted genomic testing in patients with pediatric heart disease. Methods We analyzed genome sequencing data of 111 families with cardiac lesions for rare, disease-associated variation. Results In 14 families (12.6%), we identified causative variants: seven were de novo (ANKRD11, KMT2D, NR2F2, POGZ, PTPN11, PURA, SALL1) and six were inherited from parents with no or subclinical heart phenotypes (FLT4, DNAH9, MYH11, NEXMIF, NIPBL, PTPN11). Outcome of the testing was associated with the presence of extracardiac features (p = 0.02), but not a positive family history for cardiac lesions (p = 0.67). We also report novel plausible gene–disease associations for tetralogy of Fallot/pulmonary stenosis (CDC42BPA, FGD5), hypoplastic left or right heart (SMARCC1, TLN2, TRPM4, VASP), congenitally corrected transposition of the great arteries (UBXN10), and early-onset cardiomyopathy (TPCN1). The identified candidate genes have critical functions in heart development, such as angiogenesis, mechanotransduction, regulation of heart size, chromatin remodeling, or ciliogenesis. Conclusion This data set demonstrates the diagnostic and scientific value of genome sequencing in pediatric heart disease, anticipating its role as a first-tier diagnostic test. The genetic heterogeneity will necessitate large-scale genomic initiatives for delineating novel gene–disease associations.

Clinical genetic risk variants inform a functional protein interaction network for tetralogy of Fallot

“…The identified genetic results add evidence for a major contribution of VEGF/Notch dysregulation and provide novel findings for functionally interacting protein networks relevant to the pathomechanism of TOF. We anticipate that clinical genomic sequencing, especially where capability of detecting structural variants is included, will become an essential component for assessing risks and outcomes in patients with CHD 22 . Re-analysis of existing datasets is warranted, as our knowledge to identify and interpret disease-related variants continuously evolves.…”

“…The cumulative genetic evidence indicates a pattern of molecular etiology for TOF that is characterized by genetic heterogeneity and some distinction from congenital heart disease (CHD) as a whole 14, 16-21 . However, there has been relatively limited consideration of the clinical pathogenicity of genetic variants for TOF and translation of findings into the clinic 22, 23 .…”

GeneTerpret: a customizable multilayer approach to genomic variant prioritization and interpretation

“…To assess the performance of GeneTerpret, we did a performance assessment in two ways. First, we used two well-established external resources (ClinGen database 17,18 for testing clinical validity modules and DECIPHER database 19 for testing the variant pathogenicity module independently), and secondly, our expert-interpreted internal datasets composed on a Tetralogy of Fallot (TOF) cohort 20 and Cardiac Genome Clinic (CGC) families 21 .…”

“…We tested 10 parent-child trios (VCF files) from a previous whole-genome sequencing (WGS) study of pediatric patients with cardiac phenotypes. 21 Supplementary Table S6.…”

“…(A)The top hundred of ranked variants from the family-based analysis of ten families are represented. The red colour is highlighting the variant of interest (VOI) selected by a human analyst as published before21 . The boxes around the variants cluster the same ranked variants by GeneTerpret (the same pathogenicity and validity terms).…”