A Reassessment of Copy Number Variations in Congenital Heart Defects: Picturing the Whole Genome.

Ilse Meerschaut,Bert Callewaert,Annelies Dheedene,Laura Muiño Mosquera,Sarah Vergult,Daniël De Wolf,Kristof Vandekerckhove,Hans De Wilde,Joseph Panzer,Katya De Groote,Paul J Coucke,Björn Menten

doi:10.3390/genes12071048

Ilse Meerschaut, Bert Callewaert + Show 10 more

Open Access

https://doi.org/10.3390/genes12071048

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Journal: Genes	Publication Date: Jul 8, 2021
Citations: 7	License type: CC BY 4.0

Affiliation: Ghent University Hospital, Antwerp University Hospital

Abstract

Copy number variations (CNVs) can modulate phenotypes by affecting protein-coding sequences directly or through interference of gene expression. Recent studies in cancer and limb defects pinpointed the relevance of non-coding gene regulatory elements such as long non-coding RNAs (lncRNAs) and topologically associated domain (TAD)-related gene-enhancer interactions. The contribution of such non-coding elements is largely unexplored in congenital heart defects (CHD). We performed a retrospective analysis of CNVs reported in a cohort of 270 CHD patients. We reviewed the diagnostic yield of pathogenic CNVs, and performed a comprehensive reassessment of 138 CNVs of unknown significance (CNV-US), evaluating protein-coding genes, lncRNA genes, and potential interferences with TAD-related gene-enhancer interactions. Fifty-two of the 138 CNV-US may relate to CHD, revealing three candidate CHD regions, 19 candidate CHD genes, 80 lncRNA genes of interest, and six potentially CHD-related TAD interferences. Our study thus indicates a potential relevance of non-coding gene regulatory elements in CNV-related CHD pathogenesis. Shortcomings in our current knowledge on genomic variation call for continuous reporting of CNV-US in international databases, careful patient counseling, and additional functional studies to confirm these preliminary findings.

Highlights

Copy number variations (CNVs) are DNA segments of one kilobase or larger, which are present at a variable copy number in comparison with the reference genome [1,2]
Many CNVs are classified as a CNV of unknown significance (CNV-US), with some of these CNVUS possibly being causative for the phenotype
Patients with a congenital heart defects (CHD) born between January 2012 and July 2018 were recruited from the departments of pediatric cardiology and medical genetics of the Ghent University Hospital

Summary

Introduction

Copy number variations (CNVs) are DNA segments of one kilobase (kb) or larger, which are present at a variable copy number in comparison with the reference genome [1,2]. Current clinical practice classifies CNV pathogenicity mainly based on size, parental inheritance, population frequency, known genotype–phenotype correlations, and proteincoding gene content of the CNV [9,10,11,12]. Despite these classification tools, many CNVs are classified as a CNV of unknown significance (CNV-US), with some of these CNVUS possibly being causative for the phenotype. In particular, common and often inherited variants might render a small effect to the phenotype, complicating the interpretation of CNV pathogenicity using the current criteria

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